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Introduction: This study aimed to prepare cholesterol and stearic acid-based solid lipid nanoparticles of gabapentin (GAB-SLNs) for protection against streptozotocin (STZ)-induced retinal injury in rats. Methods: We prepared four preparations of GAB-SLNs using a hot high-shear homogenization ultrasonication process, and the best formulation was selected and tested for biological activity. The retinal injury was brought in male adult albino rats while gabapentin doses continued for 6 weeks. Six groups of rats were assigned as the vehicle, diabetic, diabetic + gabapentin (10–20 mg/kg), and diabetic + GAB-SLNs (10–20 mg/kg). GAB-SLN#2 was selected as the optimized formulation with high entrapment efficacy (EE%, 98.64% ± 1.97%), small particle size (185.65 ± 2.41 nm), high negative Zeta potential (−32.18 ± 0.98 mV), low polydispersity index (0.28 ± 0.02), and elevated drug release (99.27% ± 3.48%). The TEM image of GAB-SLN#2 revealed a smooth surface with a spherical shape. Results: GAB-SLNs provided greater protection against retinal injury than free gabapentin as indicated by the histopathology data which demonstrated more organization of retinal layers and less degeneration in ganglion cell layer in rats treated with GAB-SLN#2. Further, GAB-SLN#2 reduced the inflammatory proteins (IL-6/JAK2/STAT3) and vascular endothelial growth factor (VEGF). Conclusion: The preparation of GAB-SLNs enhanced the physical properties of gabapentin and improved its biological activity as a neuroprotectant. Further studies are warranted to validate this technique for the use of oral gabapentin in other neurological disorders. [ABSTRACT FROM AUTHOR]

Background/Objectives: One of the most abundant and growing neurodevelopmental disorders in recent decades is attention deficit hyperactivity disorder (ADHD). Many trials have been performed on using drugs for the improvement of ADHD signs. This study aimed to detect the possible interaction of naringin with Wnt/β-catenin signaling and its putative anti-inflammatory and protective effects in the mouse ADHD model based on bioinformatic, behavioral, and molecular investigations. Furthermore, molecular docking was applied to investigate possible interactions with the GSK-3β and HSP90 proteins. Methods: Male Swiss albino mice were divided into four groups, a normal control group, monosodium glutamate (SGL) control, SGL + naringin 50 mg/kg, and SGL + naringin 100 mg/kg. The psychomotor activity of the mice was assessed using the self-grooming test, rope crawling test, and attentional set-shifting task (ASST). In addition, biochemical analyses were performed using brain samples. Results: The results of the SGL group showed prolonged grooming time (2.47-folds), a lower percentage of mice with successful crawling on the rope (only 16.6%), and a higher number of trials for compound discrimination testing in the ASST (12.83 ± 2.04 trials versus 5.5 ± 1.88 trials in the normal group). Treatment with naringin (50 or 100 mg per kg) produced significant shortening in the grooming time (31% and 27% reductions), as well as a higher percentage of mice succeeding in crawling with the rope (50% and 83%, respectively). Moreover, the ELISA assays indicated decreased dopamine levels (0.36-fold) and increased TNF-α (2.85-fold) in the SGL control group compared to the normal mice, but an improvement in dopamine level was observed in the naringin (50 or 100 mg per kg)-treated groups (1.58-fold and 1.97-fold). Similarly, the PCR test showed significant declines in the expression of the Wnt (0.36), and β-catenin (0.33) genes, but increased caspase-3 (3.54-fold) and BAX (5.36-fold) genes in the SGL group; all these parameters were improved in the naringin 50 or 100 mg/kg groups. Furthermore, molecular docking indicated possible inhibition for HSP90 and GSK-3β. Conclusions: Overall, we can conclude that naringin is a promising agent for alleviating ADHD symptoms, and further investigations are required to elucidate its mechanism of action. [ABSTRACT FROM AUTHOR]

Attention deficit hyperactivity disorder (ADHD) manifests as poor attention, hyperactivity, as well as impulsive behaviors. Hesperetin (HSP) is a citrus flavanone with strong antioxidant and anti-inflammatory activities. The present study aimed to test hesperetin efficacy in alleviating experimental ADHD in mice and its influence on hippocampal neuron integrity and sirtuin 1 (SIRT1) signaling. An in silico study was performed to test the related proteins. Groups of mice were assigned as control, ADHD model, ADHD/HSP (25 mg/kg), and ADHD/HSP (50 mg/kg). ADHD was induced by feeding with monosodium glutamate (0.4 g/kg, for 8 weeks) and assessed by measuring the motor and attentive behaviors (open filed test, Y-maze test, and marble burying test), histopathological examination of the whole brain tissues, and estimation of inflammatory markers. The in-silico results indicated the putative effects of hesperetin on ADHD by allowing the integration and analysis of large-scale genomic, transcriptomic, and proteomic data. The in vivo results showed that ADHD model mice displayed motor hyperactivity and poor attention in the behavioral tasks and shrank neurons at various hippocampal regions. Further, there was a decline in the mRNA expression and protein levels for SIRT1, the erythroid 2-related factor-2 (Nrf2), kelch like ECH associated protein 1 (Keap1) and hemeoxygenase-1 (OH-1) proteins. Treatment with HSP normalized the motor and attentive behaviors, prevented hippocampal neuron shrinkage, and upregulated SIRT1/Nrf2/Keap1/OH-1 proteins. Taken together, HSP mainly acts by its antioxidant potential. However, therapeutic interventions with hesperetin or a hesperetin-rich diet can be suggested as a complementary treatment in ADHD patients but cannot be suggested as an ADHD treatment per se as it is a heterogeneous and complex disease. [ABSTRACT FROM AUTHOR]

Polymeric poly (lactic-co-glycolic acid) (PLGA)-lipid hybrid nanoparticles (PNPs)-based therapy are powerful carriers for various therapeutic agents. This study was conducted to evaluate the chemotherapeutic potential of free 5-flurouracil (5FU) and synthetized 5FU-PNPs and impact on p53-dependent apoptosis in mammary carcinomas (MCs) grown in mice. Breast cancer cells were injected in Swiss albino female mice and 2 bilateral masses of MC were confirmed after one week. Mice were distributed to five experimental groups; Group 1: MC control group. Groups 2 and 3: MC + free 5FU [5 or 10 mg per kg] groups. Groups 4 and 5: synthetized MC+ 5FU-PNPs [5 or 10 mg per kg] groups. Medications were administered orally, twice weekly for 3 weeks. Then, tumors were dissected, and sections were stained with hematoxylin-eosin (HE) while the other MC was used for measuring of cell death and inflammatory markers. Treatment with 5FU-PNPs suppressed the MC masses and pathologic scores based on HE-staining. Similarly, greater proapoptotic activity was recorded in 5FU-PNPs groups compared to free 5FU groups as shown by significant upregulation in tumoral p53 immunostaining. The current results encourage the utility of PNPs for improving the antitumor effect of 5FU. The chemotherapeutic potential was mediated through enhancement of tumoral p53-mediated p53 up-regulated modulator of apoptosis (PUMA) genes. Additional studies are warranted for testing the antitumor activity of this preparation in other mouse models of breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: Betanin (C24H26N2O13) is safe to use as food additives approved by the FDA with anti-inflammatory and anticancer effects in many types of cancer cell lines. The current experiment was designed to test the chemotherapeutic effect of the combination of betanin with the standard chemotherapeutic agent, capecitabine, against chemically induced colon cancer in mice. Methods: Bioinformatic approachwas designed to get information about the possible mechanisms through which the drugs may control cancer development. Five groups of mice were assigned as, (i) saline, (ii) colon cancer, (iii) betanin, (iv) capecitabine and (v) betanin/capecitabine. Drugs were given orally for a period of six weeks. Colon tissues were separated and used for biological assays and histopathology. Results: In addition, the mRNA expression of TNF-a (4.58-fold), NFκB (5.33-fold), IL-1β (4.99-fold), cyclin D1 (4.07-fold), and IL-6 (3.55-fold) and protein levels showed several folds increases versus the saline group. Tumor histopathology scores in the colon cancer group (including cryptic distortion and hyperplasia) staining demonstrated poor mucin content (33% of the saline group). These pathologic manifestations were reduced remarkably in betanin/capecitabine group. Conclusion: Collectively, our findings demonstrated the usefulness of betanin/capecitabine combination in targeting colon cancer and highlighted that betanin is a promising adjuvant therapy to capecitabine in treating colon cancer patients. [ABSTRACT FROM AUTHOR]

In this study, three-dimensional desirability spaces were introduced as a graphical representation method of design space. This was illustrated in the context of application of quality-by-design concepts on development of a stability indicating gradient reversed-phase highperformance liquid chromatography method for the determination of vinpocetine and -αtocopheryl acetate in a capsule dosage form. A mechanistic retention model to optimize gradient time, initial organic solvent concentration and ternary solvent ratio was constructed for each compound from six experimental runs. Then, desirability function of each optimized criterion and subsequently the global desirability function were calculated throughout the knowledge space. The three-dimensional desirability spaces were plotted as zones exceeding a threshold value of desirability index in space defined by the three optimized method parameters. Probabilistic mapping of desirability index aided selection of design space within the potential desirability subspaces. Three-dimensional desirability spaces offered better visualization and potential design spaces for the method as a function of three method parameters with ability to assign priorities to this critical quality as compared with the corresponding resolution spaces. [ABSTRACT FROM AUTHOR]