Browsing by Author "Bayram, Cemil"

Now showing 1 - 9 of 9

Assessment of the Neuroprotective Potential of D-Cycloserine and L-Serine in Aluminum Chloride-Induced Experimental Models of Alzheimer's Disease: In Vivo and In Vitro Studies
(Frontiers Media SA, 2022) Tozlu, OEzlem OEzdemir; Tuerkez, Hasan; Okkay, Ufuk; Ceylan, Onur; Bayram, Cemil; Hacimueftueoglu, Ahmet; Mardinoglu, Adil
Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid-beta (A beta) plaques and neurofibrillary tangles in the brain accompanied by synaptic dysfunction and neurodegeneration. No effective treatment has been found to slow the progression of the disease. Therapeutic studies using experimental animal models have therefore become very important. Therefore, this study aimed to investigate the possible neuroprotective effect of D-cycloserine and L-serine against aluminum chloride (AlCl3)-induced AD in rats. Administration of AlCl3 for 28 days caused oxidative stress and neurodegeneration compared to the control group. In addition, we found that aluminum decreases alpha -secretase activity while increasing beta -secretase and gamma -secretase activities by molecular genetic analysis. D-cycloserine and L-serine application resulted in an improvement in neurodegeneration and oxidative damage caused by aluminum toxicity. It is believed that the results of this study will contribute to the synthesis of new compounds with improved potential against AlCl3-induced neurodegeneration, cognitive impairment, and drug development research.
Astaxanthin-Loaded Silver Nanoparticles Mitigate 6-Ohda Parkinson's Via Er Stress and Pi3k/Akt Signaling
(Springer, 2025) Kara, Hulya; Tekiner, Deniz; Ustundag, Hilal; Bayram, Cemil; Sebin, Saime Ozbek; Ozkanlar, Seckin; Kara, Adem
Parkinson's disease (PD) is characterized by progressive dopaminergic neuronal loss, with oxidative stress and neuroinflammation as critical pathological mechanisms. The blood-brain barrier presents a significant challenge for therapeutic delivery, while current treatments provide only symptomatic relief without halting disease progression. This study investigated the neuroprotective effects of astaxanthin-loaded citrate-coated silver nanoparticles (AST-AgNPs), leveraging their potent antioxidant properties, anti-inflammatory capacity, and enhanced blood-brain barrier penetration. In vitro cytotoxicity analyses were performed using 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y neuroblastoma cells, while in vivo experiments utilized a unilateral 6-OHDA-induced rat model. Following 14 days of treatment, comprehensive evaluations included behavioral assessments, biochemical analyses (MDA, GSH, SOD, TNF-alpha, IL-1 beta, IFN-gamma), histopathology, immunohistochemistry (BrdU, tyrosine hydroxylase), and molecular analyses. Western blot measured CHOP, IRE1, ATF6, p-AKT, total AKT, caspase-3, and cleaved caspase-3, while RT-PCR quantified caspase-3, Bcl-2, Bax, PI3K, mTOR, Akt, CREB, and NF-kappa B-p65 expression. AST-AgNP treatment significantly ameliorated motor dysfunction, reduced neuroinflammation (TNF-alpha, IL-1 beta), improved oxidative stress parameters (MDA, GSH, SOD), and preserved dopaminergic neurons (all p < 0.05). Western blot revealed significant downregulation of ER stress markers (CHOP, IRE1, ATF6) and cleaved caspase-3, while restoring p-AKT and total AKT levels (p < 0.05). RT-PCR demonstrated decreased pro-apoptotic gene expression (caspase-3, NF-kappa B-p65) and increased anti-apoptotic Bcl-2 expression (p < 0.05). These findings demonstrate that AST-AgNPs provide neuroprotection through simultaneous modulation of ER stress and PI3K/Akt/mTOR pathways, representing a novel dual-pathway therapeutic strategy for PD addressing multiple pathological mechanisms through enhanced nanoparticle-mediated delivery.
Boric Acid Impedes Glioblastoma Growth in a Rat Model: Insights from Multi-Approach Analysis
(Humana Press Inc, 2025) Turkez, Hasan; Alper, Fatih; Bayram, Cemil; Baba, Cem; Yildiz, Edanur; Saracoglu, Melik; Hacimuftuoglu, Ahmet
Limited advancements in managing malignant brain tumors have resulted in poor prognoses for glioblastoma (GBM) patients. Standard treatment involves surgery, radiotherapy, and chemotherapy, which lack specificity and damage healthy brain tissue. Boron-containing compounds, such as boric acid (BA), exhibit diverse biological effects, including anticancer properties. This study aimed to examine whether boron supplementation, as BA, can inhibit glioblastoma growth in a xenograft animal model. Using MRI-based tumor size measurement, survival rates, hematological, clinical biochemistry analyses, and genotoxicity parameters, we assessed the impact of BA. Histopathological, immunohistochemical, and immunofluorescence examinations were also conducted. All BA doses (3.25, 6.5, and 13 mg kg-1 b.w.) extended survival compared to GBM controls after 14 days, with a dose-dependent anti-GBM effect observed in MRI analyses. BA treatment improved hematological (WBC and PLT counts) and biochemical parameters (LDL-C, CREA, and ALP). Histopathological examination revealed a significant reduction in tumor diameter with 6.5 and 13 mg kg-1 BA. Immunohistochemical and immunofluorescence staining showed modulation of intracytoplasmic Ki67, cytoplasmic CMPK2, and GFAP expressions in tumor cells post-BA treatment. Additionally, BA did not increase micronuclei formations, indicating its non-genotoxic nature. In conclusion, targeting tumor suppressor networks with boron demonstrates significant therapeutic potential for GBM treatment.
Colemanite and Biological Disruptions: Behavioral, Neurological, and Physiological Findings
(Academic Press Inc Elsevier Science, 2025) Turkez, Hasan; Tozlu, Ozlem Ozdemir; Saracoglu, Melik; Yildiz, Edanur; Baba, Cem; Bayram, Cemil; Cadirci, Kenan
Colemanite (COL), a boron-containing mineral, has shown potential therapeutic applications, particularly in the fields of drug delivery and bone health. However, despite its promising bioactive properties, there is a lack of comprehensive toxicological data on its safety, especially regarding its potential medical use. Previous studies have primarily focused on its industrial applications, with limited investigation into its biological effects. This gap in knowledge prompted the current study, which aimed to investigate the subacute toxicity of colemanite in rats using behavioral, hematological, biochemical, genotoxic, and histopathological analyses. Over a 7-day period, rats were treated with doses of 10, 30, and 300 mg/kg. Behavioral assessments, including locomotor activity and elevated plus maze tests, indicated enhanced exploratory behaviors, indicating heightened curiosity or activity and no alterations in motor coordination or anxiety-like behaviors. Hematological findings revealed dose-dependent reductions in hematocrit, hemoglobin, and red blood cell counts, while biochemical analyses showed elevated aspartate aminotransferase, lactate dehydrogenase, and cholesterol levels at higher doses, suggesting hepatotoxicity and lipid metabolism disruption. Genotoxicity analysis demonstrated increased micronucleus formation at 30 and 300 mg/kg, indicative of chromosomal instability possibly linked to oxidative stress. Histopathological evaluations revealed mild hepatocyte degeneration and hyperemia in the liver and brain tissues at the highest dose. Importantly, no significant toxic effects were observed at the 10 mg/kg dose. These findings highlight the dose-dependent toxicity of colemanite, with low doses exhibiting a favorable safety profile. This study underscores the need for dose optimization and further research to elucidate the molecular mechanisms underlying colemanite's toxicological effects, including its impact on various organs over both short-term and long-term exposures. Additionally, future studies should focus on assessing the human relevance of these effects to ensure its safe and effective therapeutic application.
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.
Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase
(MDPI, 2023) Battisti, Umberto Maria; Gao, Chunixa; Akladios, Fady; Kim, Woonghee; Yang, Hong; Bayram, Cemil; Grotli, Morten
Liver pyruvate kinase (PKL) has recently emerged as a new target for non-alcoholic fatty liver disease (NAFLD), and inhibitors of this enzyme could represent a new therapeutic option. However, this breakthrough is complicated by selectivity issues since pyruvate kinase exists in four different isoforms. In this work, we report that ellagic acid (EA) and its derivatives, present in numerous fruits and vegetables, can inhibit PKL potently and selectively. Several polyphenolic analogues of EA were synthesized and tested to identify the chemical features responsible for the desired activity. Molecular modelling studies suggested that this inhibition is related to the stabilization of the PKL inactive state. This unique inhibition mechanism could potentially herald the development of new therapeutics for NAFLD.
Multi-Tissue Network Analysis Reveals the Effect of Jnk Inhibition on Dietary Sucrose-Induced Metabolic Dysfunction in Rats
(eLife Sciences Publishing Ltd, 2025) Yang, Hong; Zhang, Cheng; Kim, Woonghee; Shi, Mengnan; Kiliclioglu, Metin; Bayram, Cemil; Mardinoglu, Adil
Excessive consumption of sucrose, in the form of sugar-sweetened beverages, has been implicated in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD) and other related metabolic syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role in response to dietary stressors, and it was demonstrated that the inhibition of the JNK pathway could potentially be used in the treatment of MAFLD. However, the intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water and investigated the potential effects of JNK inhibition by employing network analysis based on the transcriptome profiling obtained from hepatic and extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, and brain. Our data demonstrate that JNK inhibition by JNK-IN-5A effectively reduces the circulating triglyceride accumulation and inflammation in rats subjected to sucrose consumption. Coexpression analysis and genome-scale metabolic modeling reveal that sucrose overconsumption primarily induces transcriptional dysfunction related to fatty acid and oxidative metabolism in the liver and adipose tissues, which are largely rectified after JNK inhibition at a clinically relevant dose. Skeletal muscle exhibited minimal transcriptional changes to sucrose overconsumption but underwent substantial metabolic adaptation following the JNK inhibition. Overall, our data provides novel insights into the molecular basis by which JNK inhibition exerts its metabolic effect in the metabolically active tissues. Furthermore, our findings underpin the critical role of extrahepatic metabolism in the development of diet-induced steatosis, offering valuable guidance for future studies focused on JNK-targeting for effective treatment of MAFLD.
Retracted: Combined Metabolic Activators Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases
(Pergamon-Elsevier Science Ltd, 2023) Turkez, Hasan; Altay, Ozlem; Yildirim, Serkan; Li, Xiangyu; Yang, Hong; Bayram, Cemil; Mardinoglu, Adil
Background: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by acti-vating mitochondrial metabolism. Methods: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation. Findings: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats.Interpretation: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.
Retraction: Combined Metabolic Activators Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases (Retraction of Vol 314, Art No 121325, 2023)
(Pergamon-Elsevier Science Ltd, 2024) Turkez, Hasan; Altay, Ozlem; Yildirim, Serkan; Li, Xiangyu; Yang, Hong; Bayram, Cemil; Mardinoglu, Adil