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| 2. |
- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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| 3. |
- Altay, Özlem, et al.
(författare)
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Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases
- 2024
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Marazioti, Antonia, et al.
(författare)
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KRAS signaling in malignant pleural mesothelioma
- 2022
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.
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| 5. |
- Peker, Yuksel, et al.
(författare)
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Effect of High-Risk Obstructive Sleep Apnea on Clinical Outcomes in Adults with Coronavirus Disease 2019
- 2021
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Ingår i: Annals of the American Thoracic Society. - 2329-6933. ; 18:9, s. 1548-1559
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Coronavirus disease (COVID-19) is an ongoing pandemic, in which obesity, hypertension, and diabetes have been linked to poor outcomes. Obstructive sleep apnea (OSA) is associated with these conditions and may influence the prognosis of adults with COVID-19. Objectives: To determine the effect of OSA on clinical outcomes in patients with COVID-19. Methods: The current prospective observational study was conducted in three hospitals in Istanbul, Turkey from March 10 to June 22, 2020. The participants were categorized as high-risk or low-risk OSA according to the Berlin questionnaire that was administered in the out-patient clinic, in hospital, or shortly after discharge from hospital blinded to the clinical outcomes. A modified high-risk (mHR)–OSA score based on the snoring patterns (intensity and/or frequency), breathing pauses, and morning/daytime sleepiness, without taking obesity and hypertension into account, were used in the regression models. Results: The primary outcome was the clinical improvement defined as a decline of two categories from admission on a 7-category ordinal scale that ranges from 1 (discharged with normal activity) to 7 (death) on Days 7, 14, 21, and 28, respectively. Secondary outcomes included clinical worsening (an increase of 1 category), need for hospitalization, supplemental oxygen, and intensive care. In total, 320 eligible patients (median [interquartile range] age, 53.2 [41.3–63.0] yr; 45.9% female) were enrolled. In all, 121 (37.8%) were categorized as known (n = 3) or high-risk OSA (n = 118). According to the modified scoring, 70 (21.9%) had mHR-OSA. Among 242 patients requiring hospitalization, clinical improvement within 2 weeks occurred in 75.4% of the mHR-OSA group compared with 88.4% of the modified low-risk–OSA group (P = 0.014). In multivariate regression analyses, mHR-OSA (adjusted odds ratio [OR], 0.42; 95% confidence interval [CI], 0.19–0.92) and male sex (OR, 0.39; 95% CI, 0.17–0.86) predicted the delayed clinical improvement. In the entire study population (n = 320), including the nonhospitalized patients, mHR-OSA was associated with clinical worsening (adjusted hazard ratio, 1.55; 95% CI, 1.00–2.39) and with the need for supplemental oxygen (OR, 1.95; 95% CI, 1.06–3.59). Snoring patterns, especially louder snoring, significantly predicted delayed clinical improvement, worsening, need for hospitalization, supplemental oxygen, and intensive care. Conclusions: Adults with mHR-OSA in our COVID-19 cohort had poorer clinical outcomes than those with modified low-risk OSA independent of age, sex, and comorbidities. Clinical trial registered with www.clinicaltrials.gov (NCT04363333).
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| 6. |
- Tozlu, OEzlem OEzdemir, et al.
(författare)
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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
- 2022
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Ingår i: Frontiers in Nutrition. - : Frontiers Media SA. - 2296-861X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Yang, Hong, et al.
(författare)
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Integrative proteo-transcriptomic characterization of advanced fibrosis in chronic liver disease across etiologies
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Various causes of chronic hepatic injury and inflammation can lead to fibrosis and cirrhosis, potentially predisposing individuals to hepatocellular carcinoma. Despite extensive research, the molecular mechanisms underlying liver fibrosis and its associated progression to cancer remain incompletely understood. In this study, we employed an integrated proteotranscriptomics approach to characterize the molecular pathophysiology of liver fibrosis in both liver and plasma samples from 330 individuals. This cohort included 40 healthy subjects and 290 patients with histologically characterized fibrosis due to chronic viral infection, alcohol consumption, or metabolic-dysfunction associated steatotic liver disease. We demonstrated that pathways related to extracellular matrix alterations, immune response, inflammation, and metabolism are dysregulated in advanced hepatic fibrosis, regardless of the underlying cause. Additionally, our analysis of peritumoral hepatic tissues revealed transcription signatures linked to cell proliferation, survival, and inflammation in hepatocellular carcinoma. Furthermore, we observed extensive remodeling of the plasma proteome linked with severe fibrosis and identified 132 circulating proteomic signatures associated with advanced fibrosis by integrative analysis of plasma proteomics with hepatic transcriptomics. We finally developed predictive models using machine learning to facilitate the non-invasive detection of advanced fibrosis and cirrhosis.
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| 8. |
- Yang, Hong, et al.
(författare)
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Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- 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 modelling 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.
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