Browsing by Author "Oner, Sena"

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Anticancer Potential of Novel Cinnamoyl Derivatives Against U87mg and SHSY-5Y Cell Lines
(Bentham Science Publishing Ltd, 2024) Gouleni, Niki; Di Rienzo, Annalisa; Oner, Sena; Karagoz, Ceren; Arslan, Mehmet Enes; Mardinoglu, Adil; Cacciatore, Ivana
Background Glioblastoma multiforme (GBM) is probably the most malignant and aggressive brain tumor belonging to the class of astrocytomas. The considerable aggressiveness and high malignancy of GBM make it a tumor that is difficult to treat. Here, we report the synthesis and biological evaluation of eighteen novel cinnamoyl derivatives (3a-i and 4a-i) to obtain more effective antitumor agents against GBM.Methods The chemical structures of novel cinnamoyl derivatives (3a-i and 4a-i) were confirmed by NMR and MS analyses. The physicochemical properties and evaluation of the ADME profile of 3a-i and 4a-i were performed by the preADMETlab2.0 web program. Cinnamoyl derivatives 3a-i and 4a-i were tested in vitro for their cytotoxicity against the human healthy fibroblast (HDFa) cells using an MTT cell viability assay. Derivatives with no toxicity on HDFa cells were tested both on human glioblastoma (U87MG) and neuroblastoma (SHSY-5Y) cells, chosen as an experimental model of brain tumors. Cell death mechanisms were analyzed by performing flow cytometry analyses.Results Cinnamoyl derivatives 3a-i and 4a-i showed good physicochemical and ADME properties suggesting that these compounds could be developed as oral drugs endowed with a high capability to cross the blood-brain barrier. Compounds (E)-1-methoxy-4-(2-(phenylsulfonyl)vinyl)benzene (2c) and (E)-N-benzyl-N-(2-(cyclohexylamino)-2-oxoethyl)-3-(3,4,5-trimethoxyphenyl)acrylamide (3e) did not show cytotoxicity on healthy human fibroblast cells up to 100 mu g/mL. The most anticarcinogenic molecule, compound 3e, emerged as the most potent anticancer candidate in this study. Flow cytometry results showed that compound 3e (25 mu g/mL) application resulted in nearly 86% and 84% cytotoxicity in the U87MG and the SHSY-5Y cell lines, respectively. Compound 2c (25 mu g/mL) resulted in 81% and 82% cytotoxicity in the U87MG and the SHSY-5Y cell lines, respectively.Conclusion Cinnamoyl derivative 3e inhibits the proliferation of cultured U87MG and SHSY-5Y cells by inducing apoptosis. Further detailed research will be conducted to confirm these data in in vivo experimental animal models.
Boron Nitride Nanoparticles Loaded with a Boron-Based Hybrid as a Promising Drug Carrier System for Alzheimer's Disease Treatment
(MDPI, 2022) Yildirim, Ozge Caglar; Arslan, Mehmet Enes; Oner, Sena; Cacciatore, Ivana; Di Stefano, Antonio; Mardinoglu, Adil; Turkez, Hasan
The search for an innovative and effective drug delivery system that can carry and release targeted drugs with enhanced activity to treat Alzheimer's disease has received much attention in the last decade. In this study, we first designed a boron-based drug delivery system for effective treatment of AD by integrating the folic acid (FA) functional group into hexagonal boron nitride (hBN) nanoparticles (NPs) through an esterification reaction. The hBN-FA drug carrier system was assembled with a new drug candidate and a novel boron-based hybrid containing an antioxidant as BLA, to constitute a self-assembled AD nano transport system. We performed molecular characterization analyses by using UV-vis spectroscopy, Fourier transform infrared spectrophotometer (FTIR), scanning electron microscope (SEM), Energy-dispersive X-ray spectroscopy (EDS) and Zeta potential investigations. Second, we tested the anti-Alzheimer properties of the carrier system on a differentiated neuroblastoma (SHSY5-Y) cell line, which was exposed to beta-amyloid (1-42) peptides to stimulate an experimental in vitro AD model. Next, we performed cytotoxicity analyses of synthesized molecules on the human dermal fibroblast cell line (HDFa) and the experimental AD model. Cytotoxicity analyses showed that even higher concentrations of the carrier system did not enhance the toxicological outcome in HDFa cells. Drug loading analyses reported that uncoated hBN nano conjugate could not load the BLA, whereas the memantine loading capacity of hBN was 84.3%. On the other hand, memantine and the BLA loading capacity of the hBN-FA construct was found to be 95% and 97.5%, respectively. Finally, we investigated the neuroprotective properties of the nano carrier systems in the experimental AD model. According to the results, 25 mu g/mL concentrations of hBN-FA+memantine (94% cell viability) and hBN-FA+BLA (99% cell viability) showed ameliorative properties against beta-amyloid (1-42) peptide toxicity (50% cell viability). These results were generated through the use of flow cytometry, acetylcholinesterase (AChE) and antioxidant assays. In conclusion, the developed drug carrier system for AD treatment showed promising potential for further investigations and enlightened neuroprotective capabilities of boron molecules to treat AD and other neurodegenerative diseases. On the other hand, enzyme activity, systematic toxicity analyses, and animal studies should be performed to understand neuroprotective properties of the designed carrier system comprehensively.
Combined in Vitro and in Silico Evidence for Neuroprotection by Selected Sodium and Potassium Salts in an H2O2-Induced SH-SY5Y Neurodegeneration Model
(Wiley, 2026) Sevim, Yasemin; Arslan, Mehmet Enes; Duzgun, Zekeriya; Tozlu, Ozlem Ozdemir; Oner, Sena; Kadi, Abdurrahim; Turkez, Hasan
Neurodegenerative disorders are characterized by progressive neuronal dysfunction, cholinergic impairment, and disruption of cellular homeostasis. Ionic balance and metabolic stability are increasingly recognized as critical contributors to neuronal resilience under injurious conditions. The present study aimed to evaluate the potential protective effects of selected sodium (Na+) and potassium (K+) salts in differentiated SH-SY5Y neuronal cells subjected to hydrogen peroxide (H2O2; 100 mu M), a widely used model of neuronal injury. Following H2O2 exposure, cells were treated with non-toxic concentrations of the following salts: Sodium citrate tribasic dihydrate (Na3C6H5O72H(2)O), Sodium hydrogen carbonate (NaHCO3), Disodium hydrogen phosphate (Na2HPO4), Potassium sodium tartrate tetrahydrate (KNaC4H4O64H(2)O). Salt treatments ameliorated the decline in cell viability and partially reversed changes in total antioxidant status (TAS), total oxidant status (TOS), and acetylcholinesterase (AChE) activity induced by H2O2. To further explore potential mechanistic interactions, molecular docking and molecular dynamics (MD) simulations were conducted on human AChE. The salts were found to interact primarily with peripheral residues surrounding the active-site gorge, suggesting a possible allosteric influence rather than direct engagement with the catalytic triad. Among the tested compounds, disodium hydrogen phosphate (Na2HPO4) exhibited the most stable binding profile over 100 ns MD simulations. Overall, these findings provide preliminary evidence that selected Na+- and K+-based salts may attenuate neuronal injury and support cellular function under stress conditions. Given their established safety profiles and accessibility, these compounds warrant further investigation as potential adjunctive agents for mitigating processes relevant to neurodegeneration.
Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases
(MDPI, 2024) Altay, Ozlem; Yang, Hong; Yildirim, Serkan; Bayram, Cemil; Bolat, Ismail; Oner, Sena; Mardinoglu, Adil
Background: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate. Methods: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations. Findings: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals. Interpretation: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients.
Costunolide and Parthenolide Ameliorate MPP Plus Induced Apoptosis in the Cellular Parkinson's Disease Model
(MDPI, 2023) Arslan, Mehmet Enes; Turkez, Hasan; Sevim, Yasemin; Selvitopi, Harun; Kadi, Abdurrahim; Oner, Sena; Mardinoglu, Adil
Monoamine oxidase B (MAO-B) is an enzyme that metabolizes several chemicals, including dopamine. MAO-B inhibitors are used in the treatment of Parkinson's Disease (PD), and the inhibition of this enzyme reduces dopamine turnover and oxidative stress. The absence of dopamine results in PD pathogenesis originating from decreased Acetylcholinesterase (AChE) activity and elevated oxidative stress. Here, we performed a molecular docking analysis for the potential use of costunolide and parthenolide terpenoids as potential MAO-B inhibitors in the treatment of PD. Neuroprotective properties of plant-originated costunolide and parthenolide terpenoids were investigated in a cellular PD model that was developed by using MPP+ toxicity. We investigated neuroprotection mechanisms through the analysis of oxidative stress parameters, acetylcholinesterase activity and apoptotic cell death ratios. Our results showed that 100 mu g/mL and 50 mu g/mL of costunolide, and 50 mu g/mL of parthenolide applied to the cellular disease model ameliorated the cytotoxicity caused by MPP+ exposure. We found that acetylcholinesterase activity assays exhibited that terpenoids could ameliorate and restore the enzyme activity as in negative control levels. The oxidative stress parameter analyses revealed that terpenoid application could enhance antioxidant levels and decrease oxidative stress in the cultures. In conclusion, we reported that these two terpenoid molecules could be used in the development of efficient treatment strategies for PD patients.
Determination of the in Vitro Cytotoxic Activities of Several Coumarin Derivatives on Neuroblastoma Cell Lines with in Silico Inhibitory Effects on Cdk9, Vegfr2 and Egfr Proteins and ADME Studies
(Wiley, 2025) Celikezen, Fatih Caglar; Sarac, Kamuran; Seyhan, Ercan; Aslan, Mehmet Enes; Oner, Sena; Turkez, Hasan
Due to their stable nature and medical applicability properties, coumarin derivatives have fascinated medicinal chemists in the discovery of novel therapeutics. In this study, the cytotoxic/anticancer properties of some newly synthesized coumarin derivatives were aimed at designing, synthesizing, and examining cultured human neuroblastoma cells. Moreover, molecular docking studies were carried out to determine the potential mechanism. In addition, ADMET properties were evaluated to examine the drug-likeness of newly designed coumarin derivatives. To detect the cytotoxic action of compounds, 3-(4,5-dimethylthiazol-2-yl)-2,5 2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays were carried out. In addition, Hoechst 33258 staining was used to detect abnormal nuclear structures. In silico, the estimates for all compounds (3a-3c) used in the study revealed that they possessed desirable physicochemical properties for bioavailability. The results of our study showed that all tested compounds exhibited remarkable cytotoxic effects on human neuroblastoma cell lines (p < 0.05). Additionally, among the compounds tested, 3a and 3c showed selective effects on neuroblastoma cells effectively at all tested concentrations. However, it was found that the selective feature of 3b, unlike the others, was concentration-dependent. Our findings clearly showed that novel coumarin derivatives exerted potent and selective anticancer effects. Results of molecular docking studies were in parallel with in vitro studies. Unlike the majority of hybrid coumarin derivatives reported in anticancer research, the present study introduces minimalist, heteroatom-free coumarins bearing bulky aliphatic substituents. These compounds demonstrated selective cytotoxicity against SH-SY5Y neuroblastoma cells and a favorable multi-target binding profile, highlighting a distinct hydrophobic volume-based SAR. As a result, the obtained data exhibited that all used molecules may be good multitarget drug alternatives for the treatment of neuroblastoma.
Drug Synergism of Anticancer Action in Combination with Favipiravir and Paclitaxel on Neuroblastoma Cells
(MDPI, 2024) Turkez, Hasan; Arslan, Mehmet Enes; Selvitopi, Harun; Kadi, Abdurrahim; Oner, Sena; Mardinoglu, Adil
Background and Objectives: Favipiravir (FPV) is an antiviral medication and has an inhibitory effect on Cytochrome P450 (CYP2C8) protein, which is mainly involved in drug metabolism in the liver, and the expression of this gene is known to be enhanced in neuronal cells. The metabolization of Paclitaxel (PTX), a chemotherapeutic drug used in cancer patients, was analyzed for the first time in the human SH-SY5Y neuroblastoma cell line for monitoring possible synergistic effects when administered with FPV. Materials and Methods: Further, in vitro cytotoxic and genotoxic evaluations of FPV and PTX were also performed using wide concentration ranges in a human fibroblast cell culture (HDFa). Nuclear abnormalities were examined under a fluorescent microscope using the Hoechst 33258 fluorescent staining technique. In addition, the synergistic effects of these two drugs on cultured SH-SY5Y cells were determined by MTT cell viability assay. In addition, the death mechanisms that can occur in SHSY-5Y were revealed by using the flow cytometry technique. Results: Cell viability analyses on the HDFa healthy cell culture showed that both FPV and PTX have inhibitory effects at higher concentrations. On the other hand, there were no significant differences in nuclear abnormality numbers when both of the compounds were applied together. Cell viability analyses showed that FPV and PTX applications have higher cytotoxicity, which indicated synergistic toxicity against the SHSY-5Y cell line. Also, PTX exhibited higher anticancer properties against the neuroblastoma cell line when applied with FPV, as shown in both cytotoxicity and flow cytometry analyses. Conclusions: In light of our findings, the anticancer properties of PTX can be enhanced when the drug application is coupled with FPV exposure. Moreover, these results put forth that the anticancer drug dosage should be evaluated carefully in cancer patients who take COVID-19 treatment with FPV.
In Vitro Evaluation of Selective Cytotoxic Activity of Chaerophyllum Macropodum Boiss. on Cultured Human SH-SY5Y Neuroblastoma Cells
(Springer, 2022) Celikezen, Fatih Caglar; Turkez, Hasan; Firat, Mehmet; Arslan, Mehmet Enes; Oner, Sena
Neuroblastoma is the most common solid tumor in children. New treatment approaches are needed because of the harmful side effects and costs of the methods used in the treatment of neuroblastoma. Medicinal and aromatic plants are important for new treatment approaches due to their minimal side effects and economic advantages. Therefore, the present study was carried out to examine the cytotoxic effect of Chaerophyllum macropodum extract on human neuroblastoma (SH-SY5Y) and fibroblast (HDFa) cell lines. 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase release (LDH) assays were used to determine the cytotoxic effect of C. macropodum. The extracts were analyzed for their phenolic content by HPLC-PDA. Major components were determined as 63.600% o-coumaric acid, 15.606% catechine hydrate, 8.713% rosmarinic acid, 4.376% clorogenic acid, and 3.972% salicylic acid. The obtained results from cytotoxicity testing revealed that C. macropodum exerted a significant cytotoxic effect on human neuroblastoma cells at all tested concentrations (p < 0.05). But it did not lead to any cytotoxic potential on human fibroblasts. As a result, the obtained data clearly revealed C. macropodum exerted a selective cytotoxic action on neuroblastoma cells for the first time.
Integrative Study of Plantago Lanceolata L.: Phytochemical Properties and Therapeutic Effects on Cancer, Diabetes, and Alzheimer's Disease
(Taylor & Francis Ltd, 2025) Kadi, Abdulrahim; Oner, Sena; Yuca, Hafize; Arslan, Mehmet Enes; Atila, Alptug; Incekara, Umit; Karakaya, Songul
Alzheimer's disease is linked with diabetes and cancer, emphasising the need for effective treatments. Plantago lanceolata, recognised as safe by various pharmacopeias, was investigated in this study for therapeutic potential. We examined the effects of its leaf extracts and sub-extracts (methanol, hexane, dichloromethane, ethyl acetate, butanol, aqueous) on AChE, BChE, alpha-amylase, alpha-glucosidase enzymes, as well as their impact on HDF-a and U87-MG cancer cells. The phytochemical characterisation was performed using ICP-MS and LC-MS/MS. Cytotoxic effects were evaluated on HDF-a and U87-MG cell lines, along with assessments for nuclear abnormalities. Na and K were detected in extracts, with isoleucine and cyanidin-3-O-glucoside being the most concentrated compounds. Extracts at concentrations exceeding 25 mu g/mL significantly increased cytotoxicity in HDF-a cell lines compared to the control group, without inducing nuclear abnormalities. Methanol extract demonstrated moderate inhibition against AChE and BChE at concentrations of 100 mu g/mL and 500 mu g/mL, respectively. These findings suggest that extracts exhibit potential therapeutic effects.
Lipoic Acid Conjugated Boron Hybrids Enhance Wound Healing and Antimicrobial Processes
(MDPI, 2023) Turkez, Hasan; Yildirim, Ozge Caglar; Oner, Sena; Kadi, Abdurrahim; Mete, Abdulkadir; Arslan, Mehmet Enes; Mardinoglu, Adil
Complications of chronic non-healing wounds led to the emergence of nanotechnology-based therapies to enhance healing, facilitate tissue repair, and prevent wound-related complications like infections. Here, we design alpha lipoic acid (ALA) conjugated hexagonal boron nitride (hBN) and boron carbide (B4C) nanoparticles (NPs) to enhance wound healing in human dermal fibroblast (HDFa) cell culture and characterize its antimicrobial properties against Staphylococcus aureus (S. aureus, gram positive) and Escherichia coli (E. coli, gram negative) bacterial strains. ALA molecules are integrated onto hBN and C4B NPs through esterification procedure, and molecular characterizations are performed by using transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and UV-vis spectroscopy. Wound healing and antimicrobial properties are investigated via the use of cell viability assays, scratch test, oxidative stress, and antimicrobial activity assays. Based on our analysis, we observe that ALA-conjugated hBN NPs have the highest wound-healing feature and antimicrobial activity compared to ALA-B4C. On the other hand, hBN, ALA-B4C, and ALA compounds showed promising regenerative and antimicrobial properties. Also, we find that ALA conjugation enhances wound healing and antimicrobial potency of hBN and B4C NPs. We conclude that the ALA-hBN conjugate is a potential candidate to stimulate regeneration process for injuries.
Morphological, Anatomical, and Bioactive Properties of Hypericum Scabrum L.: Effects on Diabetes Mellitus, Alzheimer's Disease, and HDFa Fibroblasts and U87-Mg Cancer Cells
(Springer Wien, 2025) Oner, Sena; Kadi, Abdulrahim; Tekman, Enes; Kararenk, Ayse Cemre; Ozer, Elif Beyza; Ergin, Kuebra Nalkiran; Karakaya, Songul
Diabetes mellitus (DM) and cancer are multifactorial diseases with significant health consequences, and their relationship with aging makes them particularly challenging. Epidemiological data suggests that individuals with DM are more susceptible to certain cancers. This study examined the bioactive properties of Hypericum scabrum extracts, including methanol, hexane, and others, focusing on their inhibitory effects on key enzymes associated with DM and neurodegenerative diseases, such as acetylcholinesterase, butyrylcholinesterase, alpha-amylase, and alpha-glucosidase. Additionally, the impact of these extracts on human fibroblast (HDFa) and glioblastoma (U87MG) cancer cells was evaluated. The methanol extract was analyzed for elemental composition using ICP-MS, secondary metabolites, and amino acids via LC-MS/MS and underwent morphological and anatomical characterization. The methanol extract demonstrated notable inhibitory activity, with an IC50 value of g/mL against alpha-glucosidase, surpassing acarbose in efficacy. The flower essential oil exhibited the highest inhibition (79.95%) of butyrylcholinesterase and the strongest acetylcholinesterase inhibition (21.62%). Elemental analysis revealed high concentrations of Na and K, while quinic acid and proline were identified as major metabolites, with proline concentrations reaching 494.0482 nmol/mL in the aerial part extract. The anticancer assays revealed higher cytotoxicity in U87MG glioblastoma cells compared to HDFa fibroblasts, suggesting potential applications for cancer therapy. The plant grows 20-50 cm tall, with yellow flowers and ovoid-ribbed capsules containing brown, reniform seeds. Its leaves are amphistomatic and ornamented, while stems feature striate cuticles and paracytic stomata. The pollen grains are microreticulate with syncolporate apertures. These results underscore the promising therapeutic potential of H. scabrum in managing DM, cancer, and neurodegenerative diseases, with its ability to inhibit key enzymes and show selective cytotoxicity against cancer cells. [GRAPHICS] .
Structural, Biocompatibility, and Antibacterial Properties of Ge-DLC Nanocomposite for Biomedical Applications
(Wiley, 2022) Arslan, Mehmet Enes; Kurt, Mustafa Sukru; Aslan, Naim; Kadi, Abdurrahim; Oner, Sena; Cobanoglu, Seymanur; Yazici, Aysenur
Integrative production of new nanocomposites has been used to enhance favorable features of biomaterials for unlocking ultimate potential of different molecules. In the present study, advantageous properties of diamond like carbons (DLC) and germanium (Ge) like greater biocompatibility and antibacterial attributes were aimed to combined into a thin film. For this purpose, 400 nm DLC-Ge nanocomposite was coated on the borosilicate glasses via the magnetron sputtering and surface characteristics was analyzed by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and The Raman spectrum. Biocompatibility analysis were performed by 3-(4,5-Dimethylthiazol-2-yl) (MTT) cell viability assay and Hoechst 33258 fluorescent staining genotoxicity assessments on the human fibroblast cell line (HDFa). Finally, antibacterial properties of DLC-Ge nanocomposite coatings were investigated by Pseudomonas aeruginosa (ATCC 27853) and Staphylococcus aureus (ATCC 25923) bacterial attachment analysis. As a result of magnetron sputtering coating, nearly 400 nm thick DLC-Ge nanocomposite film showed a smooth, a non-porous, and a dense characteristic. Cell viability analysis showed that Ge-DLC coatings permits %95 cell surface growth of fibroblast cells. Also, there were no significant difference in aspect of nuclear abnormalities compared to the (-) control which showed nonmutagenic features of the thin film. Finally, antibacterial attachment analysis put forth that Ge-DLC coatings inhibits bacterial adhesion as %40 and %25 rates for P. aeruginosa and S. aureus bacterial strains, respectively. From these results, DLC-Ge nanocomposites could be proposed as a potential new biomaterial for various biomedical applications.
Synthesis and Characterization of Memantine-Loaded Niosomes for Enhanced Alzheimer's Disease Targeting
(MDPI, 2025) Turkez, Hasan; Oner, Sena; Yildirim, Ozge Caglar; Arslan, Mehmet Enes; Dimmito, Marilisa Pia; Kahraman, cigdem Yuce; Mardinoglu, Adil
Background/Objectives: Over the past 25 years, numerous biological molecules, like recombinant lysosomal enzymes, neurotrophins, receptors, and therapeutic antibodies, have been tested in clinical trials for neurological diseases. However, achieving significant success in clinical applications has remained elusive. A primary challenge has been the inability of these molecules to traverse the blood-brain barrier (BBB). Recognizing this hurdle, our study aimed to utilize niosomes as delivery vehicles, leveraging the "molecular Trojan horse" technology, to enhance the transport of molecules across the BBB. Methods: Previously synthesized memantine derivatives (MP1-4) were encapsulated into niosomes for improved BBB permeability, hypothesizing that this approach could minimize peripheral drug toxicity while ensuring targeted brain delivery. Using the human neuroblastoma (SH-SY5Y) cell line differentiated into neuron-like structures with retinoic acid and then exposed to amyloid beta 1-42 peptide, we established an in vitro Alzheimer's disease (AD) model. In this model, the potential usability of MP1-4 was assessed through viability tests (MTT) and toxicological response analysis. The niosomes' particle size and morphological structures were characterized using scanning electron microscopy (SEM), with their loading and release capacities determined via UV spectroscopy. Crucially, the ability of the niosomes to cross the BBB and their potential anti-Alzheimer efficacy were analyzed in an in vitro transwell system with endothelial cells. Results: The niosomal formulations demonstrated effective drug encapsulation (encapsulation efficiency: 85.3% +/- 2.7%), controlled release (72 h release: 38.5% +/- 1.2%), and stable morphology (PDI: 0.22 +/- 0.03, zeta potential: -31.4 +/- 1.5 mV). Among the derivatives, MP1, MP2, and MP4 exhibited significant neuroprotective effects, enhancing cell viability by approximately 40% (p g/mL. The niosomal delivery system improved BBB permeability by 2.5-fold compared to free drug derivatives, as confirmed using an in vitro bEnd.3 cell model. Conclusions: Memantine-loaded niosomes provide a promising platform for overcoming BBB limitations and enhancing the therapeutic efficacy of Alzheimer's disease treatments. This study highlights the potential of nanotechnology-based delivery systems in developing targeted therapies for neurodegenerative diseases. Further in vivo studies are warranted to validate these findings and explore clinical applications.
Targeting Alzheimer's Disease with Novel Dual-Function 3,5-Diaryl Derivatives
(Elsevier, 2024) Katsogiannou, Aikaterini; Karta, Danai; Di Stefano, Antonio; Oner, Sena; Arslan, Mehmet Enes; Mardinoglu, Adil; Cacciatore, Ivana
In the field of medicinal chemistry, the versatility of the thiosemicarbazone scaffold makes it a promising platform for the development of next-generation pharmaceuticals. In this paper the thiosemicarbazone scaffold was explored to obtain novel series of derivatives: a) thiosemicarbazones 15-31, and 33 containing a linear thiosemicarbazone scaffold, b) 34-38 and 44-64 containing pyrazoline ring, and c) 39-43 containing the dihydropyrimidine cycle. Among these, compounds 21 , 23 , 26 , 33-35, 37 , 38 , 44 , 57 , 61 , and 62 demonstrated no significant cytotoxic effects on HDFa cells at concentrations up to 500 mu g/mL. Importantly, compounds 21 , 23 , 26 , 33 , 34 , 35 , and 37 exhibited significant protective effects against neurotoxicity induced by beta-amyloid peptide (1-42) in differentiated SHSY-5Y cell cultures. Enzymatic assays targeting BACE1 and AChE revealed modest inhibitory activity in compounds 21 , 23 , and 34 , 37 , respectively. The identification of compounds with inhibitory effects and neuroprotective activity against beta-amyloid peptide (1-42) offers a platform for further optimization and refinement of these compounds to enhance their potency and selectivity.