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Öğe EGb 761 reduces Ca2+ influx and apoptosis after pentylenetetrazole treatment in a neuroblastoma cell line(Frontiers Media Sa, 2023) Ovey, Ishak Suat; Ozsimsek, Ahmet; Velioglu, Halil Aziz; Altay, Ozlem; Mardinoglu, Adil; Yulug, BurakBackground: Transient receptor potential (TRP) channels have been found to have significant implications in neuronal outgrowth, survival, inflammatory neurogenic pain, and various epileptogenic processes. Moreover, there is a growing body of evidence indicating that transient receptor potential (TRP) channels have a significant impact on epilepsy and its drug-resistant subtypes.Objective: We postulated that EGb 761 would modulate TRPA1 channels, thereby exhibiting anti-inflammatory and neuroprotective effects in a neuroblastoma cell line. Our rationale was to investigate the impact of EGb 761 in a controlled model of pentylenetetrazole-induced generalized epilepsy.Methodology: We evaluated the neuroprotective, antioxidant and anti-apoptotic effects of EGb 761 both before and after the pentylenetetrazole application in a neuroblastoma cell line. Specifically, we focused on the effects of EGB 761 on the activity of Transient receptor potential (TRP) channels.Results: EGb 761 applications both before and after the pentylenetetrazole incubation period reduced Ca release and restored apoptosis, ROS changes, mitochondrial depolarization and caspase levels, suggesting a prominent prophylactic and therapeutic effect of EGb 761 in the pentylenetetrazole-induced epileptogenesis process.Conclusion: Our basic mechanistic framework for elucidating the pathophysiological significance of fundamental ion mechanisms in a pentylenetetrazole treated neuroblastoma cell line provided compelling evidence for the favorable efficacy and safety profile of Egb 761 in human-relevant in vitro model of epilepsy. To the best of our knowledge, this is the first study to investigate the combined effects of EGb 761 and pentylenetetrazole on TRP channels and measure their activation level in a relevant model of human epileptic diseases.Öğe Multi-omics analysis reveals the key factors involved in the severity of the Alzheimer's disease(Bmc, 2024) Meng, Lingqi; Jin, Han; Yulug, Burak; Altay, Ozlem; Li, Xiangyu; Hanoglu, Lutfu; Cankaya, SeydaAlzheimer's disease (AD) is a debilitating neurodegenerative disorder with a global impact, yet its pathogenesis remains poorly understood. While age, metabolic abnormalities, and accumulation of neurotoxic substances are potential risk factors for AD, their effects are confounded by other factors. To address this challenge, we first utilized multi-omics data from 87 well phenotyped AD patients and generated plasma proteomics and metabolomics data, as well as gut and saliva metagenomics data to investigate the molecular-level alterations accounting the host-microbiome interactions. Second, we analyzed individual omics data and identified the key parameters involved in the severity of the dementia in AD patients. Next, we employed Artificial Intelligence (AI) based models to predict AD severity based on the significantly altered features identified in each omics analysis. Based on our integrative analysis, we found the clinical relevance of plasma proteins, including SKAP1 and NEFL, plasma metabolites including homovanillate and glutamate, and Paraprevotella clara in gut microbiome in predicting the AD severity. Finally, we validated the predictive power of our AI based models by generating additional multi-omics data from the same group of AD patients by following up for 3 months. Hence, we observed that these results may have important implications for the development of potential diagnostic and therapeutic approaches for AD patients.Öğe Multi-omics characterization of improved cognitive functions in Parkinson's disease patients after the combined metabolic activator treatment: a randomized, double-blinded, placebo-controlled phase II trial(Oxford Univ Press, 2025) Yulug, Burak; Altay, Ozlem; Li, Xiangyu; Hanoglu, Lutfu; Cankaya, Seyda; Velioglu, Halil A.; Lam, SimonParkinson's disease is primarily marked by mitochondrial dysfunction and metabolic abnormalities. We recently reported that the combined metabolic activators improved the immunohistochemical parameters and behavioural functions in Parkinson's disease and Alzheimer's disease animal models and the cognitive functions in Alzheimer's disease patients. These metabolic activators serve as the precursors of nicotinamide adenine dinucleotide and glutathione, and they can be used to activate mitochondrial metabolism and eventually treat mitochondrial dysfunction. Here, we designed a randomized, double-blinded, placebo-controlled phase II study in Parkinson's disease patients with 84 days combined metabolic activator administration. A single dose of combined metabolic activator contains L-serine (12.35 g), N-acetyl-L-cysteine (2.55 g), nicotinamide riboside (1 g) and L-carnitine tartrate (3.73 g). Patients were administered either one dose of combined metabolic activator or a placebo daily for the initial 28 days, followed by twice-daily dosing for the next 56 days. The main goal of the study was to evaluate the clinical impact on motor functions using the Unified Parkinson's Disease Rating Scale and to determine the safety and tolerability of combined metabolic activator. A secondary objective was to assess cognitive functions utilizing the Montreal Cognitive Assessment and to analyse brain activity through functional MRI. We also performed comprehensive plasma metabolomics and proteomics analysis for detailed characterization of Parkinson's disease patients who participated in the study. Although no improvement in motor functions was observed, cognitive function was shown to be significantly improved (P < 0.0000) in Parkinson's disease patients treated with the combined metabolic activator group over 84 days, whereas no such improvement was noted in the placebo group (P > 0.05). Moreover, a significant reduction (P = 0.001) in Montreal Cognitive Assessment scores was observed in the combined metabolic activator group, with no decline (P > 0.05) in the placebo group among severe Parkinson's disease patients with lower baseline Montreal Cognitive Assessment scores. We showed that improvement in cognition was associated with critical brain network alterations based on functional MRI analysis, especially relevant to areas with cognitive functions in the brain. Finally, through a comprehensive multi-omics analysis, we elucidated the molecular mechanisms underlying cognitive improvements observed in Parkinson's disease patients. Our results show that combined metabolic activator administration leads to enhanced cognitive function and improved metabolic health in Parkinson's disease patients as recently shown in Alzheimer's disease patients. The trial was registered in ClinicalTrials.gov NCT04044131 (17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131).Öğe Retraction notice to “Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases” [Life Sci. 314 (2023) 121325] (Life Sciences (2023) 314, (S0024320522010256), (10.1016/j.lfs.2022.121325))(Elsevier Inc., 2024) Türkez, Hasan; Altay, Ozlem; Yildirim, Serkan; Li, Xiangyu; Yang, Hong; Bayram, Cemil; Bolat, İsmailThis article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of Editor-in-Chief. The journal was alerted to concerns about the validity of the images shown in Figs. 3, 6 and 7 as also detailed in the following Pubpeer post: https://pubpeer.com/publications/BDEA6585A4941F7F97EB34426937FF. As per the journal policy, the authors were contacted on this matter, and they informed the journal that wrong images were included in the above-mentioned figures by accident. The authors claimed that the unintentional inclusion of the wrong images worsened the results and asked for a corrigendum in April 2023. The authors also offered to submit the raw data and physical pathology slides to be analysed by independent experts. The Editor has declined the authors' offer and decided to retract the article due to these concerns. The authors do not agree with the retraction and have maintained that the retraction of their article is not in line with Elsevier policy. They have included their explanation of the issues in the comments section of the Pubpeer post. © 2024 The Author(s)
