Showing papers by "Garth J. S. Cooper published in 2016"

Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer's disease: metabolic basis for dementia

Abstract: Impairment of brain-glucose uptake and brain-copper regulation occurs in Alzheimer’s disease (AD). Here we sought to further elucidate the processes that cause neurodegeneration in AD by measuring levels of metabolites and metals in brain regions that undergo different degrees of damage. We employed mass spectrometry (MS) to measure metabolites and metals in seven post-mortem brain regions of nine AD patients and nine controls, and plasma-glucose and plasma-copper levels in an ante-mortem case-control study. Glucose, sorbitol and fructose were markedly elevated in all AD brain regions, whereas copper was correspondingly deficient throughout (all P < 0.0001). In the ante-mortem case-control study, by contrast, plasma-glucose and plasma-copper levels did not differ between patients and controls. There were pervasive defects in regulation of glucose and copper in AD brain but no evidence for corresponding systemic abnormalities in plasma. Elevation of brain glucose and deficient brain copper potentially contribute to the pathogenesis of neurodegeneration in AD.

Integrity of the Human Faecal Microbiota following Long-Term Sample Storage.

Abstract: In studies of the human microbiome, faecal samples are frequently used as a non-invasive proxy for the study of the intestinal microbiota. To obtain reliable insights, the need for bacterial DNA of high quality and integrity following appropriate faecal sample collection and preservation steps is paramount. In a study of dietary mineral balance in the context of type 2 diabetes (T2D), faecal samples were collected from healthy and T2D individuals throughout a 13-day residential trial. These samples were freeze-dried, then stored mostly at -20°C from the trial date in 2000/2001 until the current research in 2014. Given the relative antiquity of these samples (~14 years), we sought to evaluate DNA quality and comparability to freshly collected human faecal samples. Following the extraction of bacterial DNA, gel electrophoresis indicated that our DNA extracts were more sheared than extracts made from freshly collected faecal samples, but still of sufficiently high molecular weight to support amplicon-based studies. Likewise, spectrophotometric assessment of extracts revealed that they were of high quality and quantity. A subset of bacterial 16S rRNA gene amplicons were sequenced using Illumina MiSeq and compared against publicly available sequence data representing a similar cohort analysed by the American Gut Project (AGP). Notably, our bacterial community profiles were highly consistent with those from the AGP data. Our results suggest that when faecal specimens are stored appropriately, the microbial profiles are preserved and robust to extended storage periods.

Harmine Induces Adipocyte Thermogenesis through RAC1-MEK-ERK-CHD4 Axis.

Abstract: Harmine is a natural compound possessing insulin-sensitizing effect in db/db diabetic mice. However its effect on adipose tissue browning is unknown. Here we reveal that harmine antagonizes high fat diet-induced adiposity. Harmine-treated mice gained less weight on a high fat diet and displayed increased energy expenditure and adipose tissue thermogenesis. In vitro, harmine potently induced the expression of thermogenic genes in both brown and white adipocytes, which was largely abolished by inhibition of RAC1/MEK/ERK pathway. Post-transcriptional modification analysis revealed that chromodomain helicase DNA binding protein 4 (CHD4) is a potential downstream target of harmine-mediated ERK activation. CHD4 directly binds the proximal promoter region of Ucp1, which is displaced upon treatment of harmine, thereby serving as a negative modulator of Ucp1. Thus, here we reveal a new application of harmine in combating obesity via this off-target effect in adipocytes.

Thalamic amplification of sensory input in experimental diabetes.

Abstract: Diabetic neuropathy is a common, and often debilitating, secondary complication of diabetes mellitus. As pain, hypersensitivity and paraesthesias present in a distal–proximal distribution, symptoms are generally believed to originate from damaged afferents within the peripheral nervous system. Increasing evidence suggests altered processing within the central nervous system in diabetic neuropathy contributes towards somatosensory dysfunction, but whether the accurate coding and relay of peripherally encoded information through the central nervous system is altered in diabetes is not understood. Here, we applied the strengths of the rodent whisker–barrel system to study primary afferent‐thalamic processing in diabetic neuropathy. We found that neurons in the thalamic ventral posteromedial nucleus from rats with experimental diabetic neuropathy showed increased firing to precisely graded, multidirectional whisker deflection compared to non‐diabetic rats. This thalamic hyperactivity occurred without any overt primary afferent dysfunction, as recordings from the trigeminal ganglion showed these primary afferents to be unaffected by diabetes. These findings suggest that central amplification can substantially transform ascending sensory input in diabetes, even in the absence of a barrage of ectopic primary afferent activity.

Misrepresentation of the National Women's Hospital in Auckland, New Zealand.

Abstract: A letter to the editor in response to the article "The rationalization of unethical research: revisionist accounts of the Tuskegee Syphilis Study and the New Zealand 'Unfortunate Experiment'" by C. Paul and B. Brookes which was published in the 2015 issue, 105 (10), is presented.