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Nuffield Department of Women's & Reproductive Health sits within the Medical Sciences Division of the University of Oxford. The department encompasses multi-disciplinary research across four overarching themes; Cancer, Global Health, Maternal & Fetal Health and Reproductive Medicine & Genetics
Cognitive Function Changes in Older People. Results of Second Wave of Cognition of Older People, Education, Recreational Activities, NutritIon, Comorbidities, fUnctional Capacity Studies (COPERNICUS).
BACKGROUND: Cognitive reserve explains why subjects with more years of education, professional achievement, or participation in recreational activities show less cognitive decline with aging. We hypothesize that levels of recreational travel, education, occupation, systemic health, physical performance, and current cognitive activity levels affect the trajectory of cognitive function in older, healthy people in Poland. MATERIALS AND METHODS: Healthy, older people (N = 205) were examined and followed-up at 2 years. Participants completed physical and cognitive function assessments: including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and its two subtests Delayed Recall (DR) and Verbal Fluency (VF), and Trail Making Test Part B (TMT B). Factors associated with cognitive functioning were also examined. RESULTS: The MMSE result significantly decreased over 2 years. No significant decrease in other cognitive tests was noted. However, the trajectory of cognitive tests results varied between individual participants. Percentage of variance of change was explained by the following predictors: 21 in MMSE, 24 in MoCA, 8 in DR, 25 in VF, and 24 in TMT B. Age and the presence of varicose veins were significantly linked to negative changes in MMSE and MoCA scores, while working in a professional occupational status associated with a higher score. The subgroup with varicose veins did worse on the Delayed Recall subtest of MoCA. CONCLUSION: Cognitive reserve could be extended by proxies of reserve that are related to systemic health and travel activity. The latter is a combination of social, physical, and cognitive activity and potentially might serve as an intervention to improve cognitive function in older people. However, due to the limitations of this study, results should be interpreted with caution and needs to be replicated in the further studies.
Growth Differentiation Factor-11 Causes Neurotoxicity During Ischemia in vitro.
Age-related neuronal dysfunction can be overcome by circulating factors present in young blood. Growth differentiation factor-11 (GDF-11), a systemic factor that declines with age, can reverse age-related dysfunction in brain, heart and skeletal muscle. Given that age increases susceptibility to stroke, we hypothesized that GDF-11 may be directly protective to neurons following ischemia. Primary cortical neurons were isolated from E18 Wistar rat embryos and cultured for 7-10 days. Neurons were deprived of oxygen and glucose (OGD) to simulate ischemia. Neuronal death was assessed by lactate dehydrogenase, propidium iodide or CellTox™ green cytotoxicity assays. 40 ng/mL GDF-11 administration during 2 h OGD significantly increased neuronal death following 24 h recovery. However, GDF-11 pre-treatment did not affect neuronal death during 2 h OGD. GDF-11 treatment during the 24 h recovery period after 2 h OGD also did not alter death. Real-time monitoring for 24 h revealed that by 2 h OGD, GDF-11 treatment had increased neuronal death which remained raised at 24 h. Co-treatment of 1 μM SB431542 (ALK4/5/7 receptor inhibitor) with GDF-11 prevented GDF-11 neurotoxicity after 2 h OGD and 24 h OGD. Transforming growth factor beta (TGFβ) did not increase neuronal death to the same extent as GDF-11 following OGD. GDF-11 neurotoxicity was also exhibited following neuronal exposure to hydrogen peroxide. These results reveal for the first time that GDF-11 is neurotoxic to primary neurons in the acute phase of simulated stroke through primarily ALK4 receptor signaling.
Acetyl-leucine slows disease progression in lysosomal storage disorders
AbstractAcetyl-dl-leucine is a derivative of the branched chain amino acid leucine. In observational clinical studies, acetyl-dl-leucine improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder, Niemann-Pick disease type C1. Here, we investigated acetyl-dl-leucine and its enantiomers acetyl-l-leucine and acetyl-d-leucine in symptomatic Npc1−/− mice and observed improvement in ataxia with both individual enantiomers and acetyl-dl-leucine. When acetyl-dl-leucine and acetyl-l-leucine were administered pre-symptomatically to Npc1−/− mice, both treatments delayed disease progression and extended life span, whereas acetyl-d-leucine did not. These data are consistent with acetyl-l-leucine being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the l-enantiomer in Npc1−/− mice. When the standard of care drug miglustat and acetyl-dl-leucine were used in combination significant synergy resulted. In agreement with these pre-clinical data, when Niemann-Pick disease type C1 patients were evaluated after 12 months of acetyl-dl-leucine treatment, rates of disease progression were slowed, with stabilization or improvement in multiple neurological domains. A beneficial effect of acetyl-dl-leucine on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual-cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-l-leucine and underlying mechanisms of action in lysosomal storage diseases, supporting its further evaluation in clinical trials in lysosomal disorders.
Whole-body cryostimulation application with age: A review.
In this review we examine studies exploring the effects of whole-body cryostimulation (WBC) from the perspective of applications with age with subjects over the age of 55 years old. Blood based factors such as Erythropoietin and Il-3 increased in exercised trained and normal subjects after WBC while other parameters did not change. WBC treatment of patients with Rheumatoid Arthritis decreased levels of the inflammatory markers IL-6 and TNF-α with a in the elasticity of erythrocytes. In older subjects with Mild Cognitive Impairment (MCI) a significant improvement of short-term memory was noted with reduced levels of IL-6 with an increase in BDNF release when whole blood was challenged with Aβ42. WBC appears to be an exciting non-pharmacological treatments with pleiotropic action. It has potential in enhancing performance and alleviating chronic conditions in older subjects as part of an active rest programme in combination with regular physical exercise. In conditions associated with cognitive dysfunction including Alzheimer's and other forms of dementia the many properties of WBC as an affordable treatment has exciting therapeutic potential.
Developing a Blood Cell‐Based Diagnostic Test for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Peripheral Blood Mononuclear Cells
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by debilitating fatigue that profoundly impacts patients' lives. Diagnosis of ME/CFS remains challenging, with most patients relying on self‐report, questionnaires, and subjective measures to receive a diagnosis, and many never receiving a clear diagnosis at all. In this study, a single‐cell Raman platform and artificial intelligence are utilized to analyze blood cells from 98 human subjects, including 61 ME/CFS patients of varying disease severity and 37 healthy and disease controls. These results demonstrate that Raman profiles of blood cells can distinguish between healthy individuals, disease controls, and ME/CFS patients with high accuracy (91%), and can further differentiate between mild, moderate, and severe ME/CFS patients (84%). Additionally, specific Raman peaks that correlate with ME/CFS phenotypes and have the potential to provide insights into biological changes and support the development of new therapeutics are identified. This study presents a promising approach for aiding in the diagnosis and management of ME/CFS and can be extended to other unexplained chronic diseases such as long COVID and post‐treatment Lyme disease syndrome, which share many of the same symptoms as ME/CFS.
The Warburg effect: 80 years on
Influential research by Warburg and Cori in the 1920s ignited interest in how cancer cells' energy generation is different from that of normal cells. They observed high glucose consumption and large amounts of lactate excretion from cancer cells compared with normal cells, which oxidised glucose using mitochondria. It was therefore assumed that cancer cells were generating energy using glycolysis rather than mitochondrial oxidative phosphorylation, and that the mitochondria were dysfunctional. Advances in research techniques since then have shown the mitochondria in cancer cells to be functional across a range of tumour types. However, different tumour populations have different bioenergetic alterations in order to meet their high energy requirement; the Warburg effect is not consistent across all cancer types. This review will discuss the metabolic reprogramming of cancer, possible explanations for the high glucose consumption in cancer cells observed by Warburg, and suggest key experimental practices we should consider when studying the metabolism of cancer.
Abstract 2903: Differential regulation of LC3 A and B, GABARAPL 1 and 2 autophagy genes by micro-environmental stress and role in breast cancer survival
Abstract The microtubule-associated protein light chain 3 MAP1LC3 (LC3) and GABARAPL1 and 2 are the major proteins to monitor autophagy. Here, we analyzed the role of both MAP1LC3, GABARAPL1 and 2 in breast cancer cells and primary human breast cancer. HER2 amplified (BT474, SKBR3, MDA-MB-453), ER positive (MCF7, T47D) and triple negative (MDAMB231) breast cancer cell lines were studied in response to hypoxia, in high [25mM] and low glucose [5mM] treatment. Low glucose increased the basal levels for LC3A-II, LC3B-II and GABARAPL2-II in BT474, MCF7 and MDAMB231 cell lines. SKBR3 cell line had the lowest autophagic protein levels for LC3B-II, and Gabarapl2-II and was the most resistance to the autophagy inhibition mediated using siRNAs to all theseIn hypoxia both LC3B (up to 8 fold) and GABARAPL1 (up to 12 fold) mRNA expression were induced in all cell lines (p<0.001). MAP1LC3A knockdown significantly decrease cell proliferation in BT474, MCF7 and MDAMB231 while GABARAPL2 knockdown additionally decreased baseline cell proliferation in T47D and SKBR3 breast cancer cells (p<0.05, n = 3). Moreover, using the Seahorse, decreased MAP1LC3A and GABARAPL2 expression by siRNA led to cellular bioenergetic changes including increased basal oxygen consumption of the MCF7. Co-expression analysis of autophagic genes define distinctive clusters of MAP1LC3, GABARAPL 1 and 2 with the hypoxic signature in breast cancer subtypes using the METABRIC series. The expression levels of the MAP1LC3 and GABARAPL1 and 2 among the breast cancer subtypes and normal tissue showed significant suppession of all of them in cancer compared to normal breast tissue. In conclusion, all the pathways were suppressed at RNA level in cancer compared to normal, baseline levels were not associated with core classification of breast cancer types. These latter data were confirmed in a breast cancer cell line panel, which showed a marked variation in inducibility by environemntal stress and role in survival under low glucose and hypoxia. Thus analysis of induced gene expression in response to stress may be important, or heterogeneity in selection of tumors for anti-autophagy therapy. Citation Format: Christos E. Zois, Syed Haider, Simon Wigfield, Alexandra Giatromanolaki, Efthimios Sivridis, Karl Morten, Ioannis Roxanis, Russell Leek, Francesca Buffa, Michael Koukourakis, Adrian L. Harris. Differential regulation of LC3 A and B, GABARAPL 1 and 2 autophagy genes by micro-environmental stress and role in breast cancer survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2903. doi:10.1158/1538-7445.AM2015-2903
Modulating mitochondrial quality in disease transmission: towards enabling mitochondrial DNA disease carriers to have healthy children
One in 400 people has a maternally inherited mutation in mtDNA potentially causing incurable disease. In so-called heteroplasmic disease, mutant and normal mtDNA co-exist in the cells of carrier women. Disease severity depends on the proportion of inherited abnormal mtDNA molecules. Families who have had a child die of severe, maternally inherited mtDNA disease need reliable information on the risk of recurrence in future pregnancies. However, prenatal diagnosis and even estimates of risk are fraught with uncertainty because of the complex and stochastic dynamics of heteroplasmy. These complications include an mtDNA bottleneck, whereby hard-to-predict fluctuations in the proportions of mutant and normal mtDNA may arise between generations. In ‘mitochondrial replacement therapy’ (MRT), damaged mitochondria are replaced with healthy ones in early human development, using nuclear transfer. We are developing non-invasive alternatives, notably activating autophagy, a cellular quality control mechanism, in which damaged cellular components are engulfed by autophagosomes. This approach could be used in combination with MRT or with the regular management, pre-implantation genetic diagnosis (PGD). Mathematical theory, supported by recent experiments, suggests that this strategy may be fruitful in controlling heteroplasmy. Using mice that are transgenic for fluorescent LC3 (the hallmark of autophagy) we quantified autophagosomes in cleavage stage embryos. We confirmed that the autophagosome count peaks in four-cell embryos and this correlates with a drop in the mtDNA content of the whole embryo. This suggests removal by mitophagy (mitochondria-specific autophagy). We suggest that modulating heteroplasmy by activating mitophagy may be a useful complement to mitochondrial replacement therapy.