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Öğe Combined metabolic activators accelerates recovery in mild-to-moderate COVID-19(Wiley, 2021) Altay, Özlem; Arif, Muhammad; Li, Xiangyu; Yang, Hong; Aydın, Mehtap; Alkurt, Gizem; Kim, Woonghee; Akyol, Doğukan; Zhang, Cheng; Dinler Doğanay, Gizem; Türkez, Hasan; Shoaie, Saeed; Nielsen, Jens; Boren, Jan; Olmuşçelik, Oktay; Doğanay, Levent; Uhlen, Mathias; Mardinoğlu, AdilCOVID-19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD(+)) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID-19 patients. CMAs include l-serine, N-acetyl-l-cysteine, nicotinamide riboside, and l-carnitine tartrate, salt form of l-carnitine. Placebo-controlled, open-label phase 2 study and double-blinded phase 3 clinical trials are conducted to investigate the time of symptom-free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems.Öğe Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: A randomised, double-blinded, placebo-controlled phase-II trial(BioMed Central Ltd, 2023) Yuluğ, Burak; Altay, Özlem; Li, Xiangyu; Hanoğlu, Lütfü; Çankaya, Şeyda; Lam, Simon; Velioğlu, Halil Aziz; Yang, Hong; Coşkun, Ebru; İdil, Ezgi; Nogaylar, Rahim; Özşimşek, Ahmet; Bayram, Cemil; Bolat, İsmail; Öner, Sena; Özdemir Tozlu, Özlem; Arslan, Mehmet Enes; Hacimuftüoğlu, Ahmet; Yıldırım, Serkan; Arif, Muhammad; Shoaie, Saeed; Zhang, Cheng; Nielsen, Jens; Türkez, Hasan; Borén, Jan; Uhlén, Mathias; Mardinoglu, AdilBackground: Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress. Methods: Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients. Results: We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. Conclusion: Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis. Trial registration ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131.Öğe Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases(Elsevier Inc., 2023) Türkez, Hasan; Altay, Özlem; Yıldırım, Serkan; Li, Xiangyu; Yang, Hong; Bayram, Cemil; Bolat, İsmail; Öner, Sena; Özdemir Tozlu, Özlem; Arslan, Mehmet Enes; Arif, Muhammad; Yuluğ, Burak; Hanoğlu, Lütfü; Çankaya, Şeyda; Lam, Simon; Velioğlu, Halil Aziz; Coşkun, Ebru; İdil, Ezgi; Nogaylar, Rahim; Özşimşek, Ahmet; Hacımüftüoğlu, Ahmet; Shoaie, Saeed; Zhang, Cheng; Nielsen, Jens; Borén, Jan; Uhlén, Mathias; Mardinoğlu, AdilBackground: 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 activating 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.Öğe Longitudinal metabolomics analysis reveals the acute effect of cysteine and NAC included in the combined metabolic activators(Elsevier Inc., 2023) Yang, Hong; Li, Xiangyu; Jin, Han; Türkez, Hasan; Öztürk, Gürkan; Doğanay, Hamdi LeventGrowing evidence suggests that the depletion of plasma NAD+ and glutathione (GSH) may play an important role in the development of metabolic disorders. The administration of Combined Metabolic Activators (CMA), consisting of GSH and NAD+ precursors, has been explored as a promising therapeutic strategy to target multiple altered pathways associated with the pathogenesis of the diseases. Although studies have examined the therapeutic effect of CMA that contains N-acetyl-L-cysteine (NAC) as a metabolic activator, a system-wide comparison of the metabolic response to the administration of CMA with NAC and cysteine remains lacking. In this placebo-controlled study, we studied the acute effect of the CMA administration with different metabolic activators, including NAC or cysteine with/without nicotinamide or flush free niacin, and performed longitudinal untargeted-metabolomics profiling of plasma obtained from 70 well-characterized healthy volunteers. The time-series metabolomics data revealed the metabolic pathways affected after the administration of CMAs showed high similarity between CMA containing nicotinamide and NAC or cysteine as metabolic activators. Our analysis also showed that CMA with cysteine is well-tolerated and safe in healthy individuals throughout the study. Last, our study systematically provided insights into a complex and dynamics landscape involved in amino acid, lipid and nicotinamide metabolism, reflecting the metabolic responses to CMA administration containing different metabolic activators.Öğe Retraction notice to "Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases" [Life Sci. 314 (2023) 121325](2024) Türkez, Hasan; Altay, Özlem; Yıldırım, Serkan; Li, Xiangyu; Yang, Hong; Bayram, Cemil; Bolat, İsmail; Öner, Sena; Özdemir Tozlu, Özlem; Arslan, Mehmet Enes; Arif, Muhammad; Yuluğ, Burak; Hanoğlu, Lütfü; Çankaya, Şeyda; Lam, Simon; Velioğlu, Halil Aziz; Coşkun, Ebru; İdil, Ezgi; Nogaylar, Rahim; Özşimşek, Ahmet; Hacımüftüoğlu, Ahmet; Shoaie, Saeed; Zhang, Cheng; Nielsen, Jens; Borén, Jan; Uhlén, Mathias; Mardinoğlu, AdilThis 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.Öğe The acute effect of different NAD plus precursors included in the combined metabolic activators(Elsevier Science Inc, 2023) Li, Xiangyu; Yang, Hong; Jin, Han; Türkez, Hasan; Öztürk, Gürkan; Doğanay, Hamdi Levent; Zhang, Cheng; Nielsen, Jens; Uhlen, Mathias; Boren, Jan; Mardinoğlu, AdilNAD+ and glutathione precursors are currently used as metabolic modulators for improving the metabolic conditions associated with various human diseases, including non-alcoholic fatty liver disease, neurodegenerative diseases, mitochondrial myopathy, and age-induced diabetes. Here, we performed a one-day double blinded, placebo-controlled human clinical study to assess the safety and acute effects of six different Combined Metabolic Activators (CMAs) with 1 g of different NAD+ precursors based on global metabolomics analysis. Our integrative analysis showed that the NAD+ salvage pathway is the main source for boosting the NAD+ levels with the administration of CMAs without NAD+ precursors. We observed that incorporation of nicotinamide (Nam) in the CMAs can boost the NAD+ products, followed by niacin (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), but not flush free niacin (FFN). In addition, the NA administration led to a flushing reaction, accompanied by decreased phospholipids and increased bilirubin and bilirubin derivatives, which could be potentially risky. In conclusion, this study provided a plasma metabolomic landscape of different CMA formulations, and proposed that CMAs with Nam, NMN as well as NR can be administered for boosting NAD+ levels to improve altered metabolic conditions.
