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Öğe Assessing the In Vitro and In Vivo Performance of L-Carnitine-Loaded Nanoparticles in Combating Obesity(Mdpi, 2023) Uner, Burcu; Ergin, Ahmet Dogan; Ansari, Irfan Aamer; Macit-Celebi, Melahat Sedanur; Ansari, Siddique Akber; Kahtani, Hamad M. AlAddressing obesity is a critical health concern of the century, necessitating urgent attention. L-carnitine (LC), an essential water-soluble compound, plays a pivotal role in lipid breakdown via beta-oxidation and facilitates the transport of long-chain fatty acids across mitochondrial membranes. However, LC's high hydrophilicity poses challenges to its diffusion through bilayers, resulting in limited bioavailability, a short half-life, and a lack of storage within the body, mandating frequent dosing. In our research, we developed LC-loaded nanoparticle lipid carriers (LC-NLCs) using economically viable and tissue-localized nanostructured lipid carriers (NLCs) to address these limitations. Employing the central composite design model, we optimized the formulation, employing the high-pressure homogenization (HPH) method and incorporating Poloxamer (R) 407 (surfactant), Compritol (R) 888 ATO (solid lipid), and oleic acid (liquid oil). A comprehensive assessment of nanoparticle physical attributes was performed, and an open-field test (OFT) was conducted on rats. We employed immunofluorescence assays targeting CRP and PPAR-gamma, along with an in vivo rat study utilizing an isolated fat cell line to assess adipogenesis. The optimal formulation, with an average size of 76.4 +/- 3.4 nm, was selected due to its significant efficacy in activating the PPAR-gamma pathway. Our findings from the OFT revealed noteworthy impacts of LC-NLC formulations (0.1 mg/mL and 0.2 mg/mL) on adipocyte cells, surpassing regular L-carnitine formulations' effects (0.1 mg/mL and 0.2 mg/mL) by 169.26% and 156.63%, respectively (p < 0.05).Öğe Characterization, optimization, and in vitro evaluation of cholesterol-free liposomes(Elsevier, 2023) Ergin, Ahmet Dogan; Uner, BurcuObjectives: Alzheimer's disease (AD) is a neurological disorder that causes dementia and a progressive loss of thinking, social, and memory abilities. Afterwards, this worsening induces the person incapable of doing even the most fundamental duties. Recent research have proven that Coenzyme-q10 (CoQ10), one of the endogenous fatty acids, suppresses phosphorylated Tau protein which is GM1-ganglioside-bound amyloid beta-protein (GM1-A beta), and inhibiting the formation of amyloid plaques in Alzheimer's disease. Unfortunately, CoQ10 is poorly absorbed due to its high molecular weight (863.34 g/mol) and high lipophilicity, and its bioavailability is quite low. Therefore, we developed the CoQ10-loaded, cholesterol-free liposomes to get across the limitations.Material and methods: Liposomes were developed by ether injection method, and physicochemical characterization of the liposomes were evaluated in terms of particle size, size distribution (PDI), zeta potential, encapsulation efficiency (% EE), and process recovery as well. Release study, DSC analysis, morphological analysis, and cytotoxicity assay were performed with optimized formulations.Results: The particle size, PDI, zeta potential, EE%, and process recovery of the formulations ranged from 343.8 to 167.9 nm; 0.269 to 0.431; (-56) to (-31.7); 18.15-93.48%; 74.63 to 99.62, respectively. According to cytotoxicity tests, liposomes have no significant toxic effect on cells while having decreased p-tau 181 and p-tau 231 proteins (p > 0.05). Conclusions: As a result, the novel cholesterol-free liposome formulation were proved that it might be candidate of including the therapeutical guideline for the future alzheimer's disease treatment with these substantial results.Öğe Effects of arginine on coenzyme-Q10 micelle uptake for mitochondria-targeted nanotherapy in phenylketonuria(Springer Heidelberg, 2024) Uner, Burcu; Dwivedi, Pankaj; Ergin, Ahmet DoganPhenylketonuria (PKU) is a rare inherited metabolic disease characterized by phenylalanine hydroxylase enzyme deficiency. In PKU patients, coenzyme Q10 (CoQ10) levels were found low. Therefore, we focused on the modification of CoQ10 to load the micelles and increase entry of micelles into the cell and mitochondria, and it is taking a part in ATP turnover. Micelles had produced by comparing two different production methods (thin-film layer and direct-dissolution), and characterization studies were performed (zeta potential, size, and encapsulation efficiency). Then, l-arginine (LARG) and poly-arginine (PARG) were incorporated with the micelles for subsequential release and PKU cell studies. The effects of these components on intracellular uptake and their use in the cellular cycle were analyzed by ELISA, Western blot, membrane potential measurement, and flow cytometry methods. In addition, both effects of LARG and PARG micelles on pharmacokinetics at the cellular level and their cell binding rate were determined. The thin- film method was found superior in micelle preparation. PARG/LARG-modified micelles showed sustained release. In the cellular and mitochondrial uptake of CoQ10, CoQ10micelle + PARG > CoQ10-micelle + LARG > CoQ10-micelle > CoQ10 was found. This increased localization caused lowering of oxygen consumption rates, but maintaining mitochondrial membrane potential. The study results had showed that besides micelle formulation, PARG and LARG are effective in cellular and mitochondrial targeting.Öğe Enhanced mitochondrial co-localization of 8-escin micelle and pancreatic tumor accumulation relation(Elsevier, 2023) Uner, Burcu; Ergin, Ahmet Dogan8-escin, a triterpenoid saponin derived from plants, is a valuable natural product that possesses strong antiinflammatory, as well as the potential for anticancer effects. However, its limited water solubility restricts its application. The 8-escin was efficiently loaded into Pluronic F127 micelles using the thin film method to improve its solubility and effectiveness. The formulations underwent various tests, including particle size, encapsulation efficiency, and product yield. Human pluripotent fibroblast and AsPC-1 pancreatic cancer cell lines were subjected to MTT studies. Fluorescence-labeled micelles were used to analyze cellular and mitochondrial uptake, and the results were analyzed using flow cytometry. The micelle formulation was found to be optimal with a particle size of 94.8 +/- 6.35 nm, zeta potential of 43.2 +/- 2.62 mV, PDI of 0.13 +/- 0.01, and encapsulation efficiency of 93.20 +/- 0.09. It demonstrated sustained release in all mediums. The micelle formulation had a stronger impact on cancer cells than healthy cells, but when compared to a marketed anticancer drug, it showed less ROS activity on healthy cells. Overall, the fluorescence-labeled micelle had greater uptake by cellular and mitochondrial systems. Micelles show great potential as a drug delivery system for 8-escin and other similar anticancer candidates that operate through a mitochondria-mediated anticancer mechanism.Öğe Improving the Bioavailability and Efficacy of Coenzyme Q10 on Alzheimer's Disease Through the Arginine Based Proniosomes(Elsevier Science Inc, 2023) Ergin, Ahmet Dogan; Uner, Burcu; Balcib, Sencan; Demirbag, Caglar; Benetti, Camillo; Oltulu, CagatayCoenzyme Q10 (CoQ10) is a fat-soluble vitamin-with a benzoquinone-like structure. CoQ10 plays a role in membrane stability, energy conversion, and ATP production. It is also one of the important antioxidants in the body. The bioavailability of exogenous CoQ10 is extremely low due to its poor aqueous solubility and large molecular mass.In this study, mixed proniosomal drug delivery systems have been used to increase solubility and bioavailability of CoQ10. Arginine (semi-essential amino acid) was incorporated in the formulation composition to achieve higher efficacy by boosting nitric oxide presence, endothelial dysfunction, and cellular uptake.Proniosomes were investigated in terms of particle size, polydispersity index, zeta potential, encapsulation efficiency, and process yield, and optimization studies were carried on by utilizing STATISTICA 8.0 software considering dependent factors (carrier amount, drug amount, and surfactant ratio). Optimum proniosome formulation (particle size 187.5 +/- 16.35 nm, zeta potential: -44.7 +/- 12.8 mV, encapsulation efficiency 99.05 +/- 0.30%, and product yield: 90.55%) was evaluated for thermal analysis, in-vitro drug release using microcentrifuge method. In-vitro cytotoxicity studies of proniosomes were performed on intestinal Epithelial Cells (Cellartis (R), ChiPSC18) and no cytotoxic effects was seen during the 72 h. Besides, anti Alzheimer effect was investigated on APPSL-GFP lentivirus-infected human neural cells (APPSL-GFP-l-HNC) and Alzheimer biomarkers (p-tau181 and p-tau217).While CoQ10's relative bioavailability was statistically increased by proniosome compared to CoQ10 suspension (p<0.01, Grubb test). PK parameters of proniosome formulation, obtained with non-compartmental modeling, were fitting to the data (R-2=0.956 +/- 0.026).The study results proved that proniosomal formulation has a high potential drug delivery system for both increasing bioavailability and anti-Alzheimer effect of CoQ10.(c) 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.Öğe JOURNEY OF THE SAPONIN FROM THE PLANT TO THE FORMULATION FOR BLOCKING TUMOR ACTIVITIES(Marmara Univ, 2023) Uner, Burcu; Dogan Ergin, Ahmet; Altay Benetti, Ayca; Baranuskaite Ortasoz, Juste[Abstract Not Available]
