Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
84
result(s) for
"Braidy, Nady"
Sort by:
Plasma lipidome is dysregulated in Alzheimer’s disease and is associated with disease risk genes
Lipidomics research could provide insights of pathobiological mechanisms in Alzheimer’s disease. This study explores a battery of plasma lipids that can differentiate Alzheimer’s disease (AD) patients from healthy controls and determines whether lipid profiles correlate with genetic risk for AD. AD plasma samples were collected from the Sydney Memory and Ageing Study (MAS) Sydney, Australia (aged range 75–97 years; 51.2% male). Untargeted lipidomics analysis was performed by liquid chromatography coupled–mass spectrometry (LC–MS/MS). We found that several lipid species from nine lipid classes, particularly sphingomyelins (SMs), cholesterol esters (ChEs), phosphatidylcholines (PCs), phosphatidylethanolamines (PIs), phosphatidylinositols (PIs), and triglycerides (TGs) are dysregulated in AD patients and may help discriminate them from healthy controls. However, when the lipid species were grouped together into lipid subgroups, only the DG group was significantly higher in AD. ChEs, SMs, and TGs resulted in good classification accuracy using the Glmnet algorithm (elastic net penalization for the generalized linear model [glm]) with more than 80% AUC. In general, group lipids and the lipid subclasses LPC and PE had less classification accuracy compared to the other subclasses. We also found significant increases in SMs, PIs, and the LPE/PE ratio in human U251 astroglioma cell lines exposed to pathophysiological concentrations of oligomeric Aβ42. This suggests that oligomeric Aβ42 plays a contributory, if not causal role, in mediating changes in lipid profiles in AD that can be detected in the periphery. In addition, we evaluated the association of plasma lipid profiles with AD-related single nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS) of AD. We found that FERMT2 and MS4A6A showed a significantly differential association with lipids in all lipid classes across disease and control groups. ABCA7 had a differential association with more than half of the DG lipids (52.63%) and PI lipids (57.14%), respectively. Additionally, 43.4% of lipids in the SM class were differentially associated with CLU. More than 30% of lipids in ChE, PE, and TG classes had differential associations with separate genes (ChE-PICALM, SLC24A4, and SORL1; PE-CLU and CR1; TG-BINI) between AD and control group. These data may provide renewed insights into the pathobiology of AD and the feasibility of identifying individuals with greater AD risk.
Journal Article
Kynurenine pathway metabolism and neuroinflammatory disease
Immune-mediated activation of tryptophan（TRYP） catabolism via the kynurenine pathway（KP） is a consistent finding in all inflammatory disorders.Several studies by our group and others have examined the neurotoxic potential of neuroreactive TRYP metabolites,including quinolinic acid（QUIN） in neuroinflammatory neurological disorders,including Alzheimer＇s disease（AD）,multiple sclerosis,amylotropic lateral sclerosis（ALS）,and AIDS related dementia complex（ADC）.Our current work aims to determine whether there is any benefit to the affected individuals in enhancing the catabolism of TRYP via the KP during an immune response.Under physiological conditions,QUIN is metabolized to the essential pyridine nucleotide,nicotinamide adenine dinucleotide（NAD＋）,which represents an important metabolic cofactor and electron transporter.NAD＋ also serves as a substrate for the DNA ‘nick sensor＇ and putative nuclear repair enzyme,poly（ADP-ribose） polymerase（PARP）.Free radical initiated DNA damage,PARP activation and NAD＋ depletion may contribute to brain dysfunction and cell death in neuroinflammatory disease.
Journal Article
Age-Associated Changes In Oxidative Stress and NAD+ Metabolism In Human Tissue
Nicotinamide adenine dinucleotide (NAD(+)) is an essential electron transporter in mitochondrial respiration and oxidative phosphorylation. In genomic DNA, NAD(+) also represents the sole substrate for the nuclear repair enzyme, poly(ADP-ribose) polymerase (PARP) and the sirtuin family of NAD-dependent histone deacetylases. Age associated increases in oxidative nuclear damage have been associated with PARP-mediated NAD(+) depletion and loss of SIRT1 activity in rodents. In this study, we further investigated whether these same associations were present in aging human tissue. Human pelvic skin samples were obtained from consenting patients aged between 15-77 and newborn babies (0-1 year old) (n = 49) previously scheduled for an unrelated surgical procedure. DNA damage correlated strongly with age in both males (p = 0.029; r = 0.490) and females (p = 0.003; r = 0.600) whereas lipid oxidation (MDA) levels increased with age in males (p = 0.004; r = 0.623) but not females (p = 0.3734; r = 0.200). PARP activity significantly increased with age in males (p<0.0001; r = 0.768) and inversely correlated with tissue NAD(+) levels (p = 0.0003; r = -0.639). These associations were less evident in females. A strong negative correlation was observed between NAD(+) levels and age in both males (p = 0.001; r = -0.706) and females (p = 0.01; r = -0.537). SIRT1 activity also negatively correlated with age in males (p = 0.007; r = -0.612) but not in females. Strong positive correlations were also observed between lipid peroxidation and DNA damage (p<0.0001; r = 0.4962), and PARP activity and NAD(+) levels (p = 0.0213; r = 0.5241) in post pubescent males. This study provides quantitative evidence in support of the hypothesis that hyperactivation of PARP due to an accumulation of oxidative damage to DNA during aging may be responsible for increased NAD(+) catabolism in human tissue. The resulting NAD(+) depletion may play a major role in the aging process, by limiting energy production, DNA repair and genomic signalling.
Journal Article
Age Related Changes in NAD+ Metabolism Oxidative Stress and Sirt1 Activity in Wistar Rats
The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of metabolism, stress resistance and longevity. Apart from its role as an important redox carrier, NAD+ also serves as the sole substrate for NAD-dependent enzymes, including poly(ADP-ribose) polymerase (PARP), an important DNA nick sensor, and NAD-dependent histone deacetylases, Sirtuins which play an important role in a wide variety of processes, including senescence, apoptosis, differentiation, and aging. We examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female wistar rats. Our results are the first to show a significant decline in intracellular NAD+ levels and NAD:NADH ratio in all organs by middle age (i.e.12 months) compared to young (i.e. 3 month old) rats. These changes in [NAD(H)] occurred in parallel with an increase in lipid peroxidation and protein carbonyls (o- and m- tyrosine) formation and decline in total antioxidant capacity in these organs. An age dependent increase in DNA damage (phosphorylated H2AX) was also observed in these same organs. Decreased Sirt1 activity and increased acetylated p53 were observed in organ tissues in parallel with the drop in NAD+ and moderate over-expression of Sirt1 protein. Reduced mitochondrial activity of complex I-IV was also observed in aging animals, impacting both redox status and ATP production. The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.
Journal Article
Editorial: From Oxidative Stress to Cognitive Decline - Towards Novel Therapeutic Approaches
Oxidative stress is caused by multiple factors, including aging, greater vulnerability of easily oxidizable unsaturated fatty acids in the brain, higher metabolic activity by the brain, increased production of mitochondrial-derived free radicals, calcium dyshomeostasis, and glutamate-induced excitotoxicity. [...]environmental chemicals/toxins, heavy metals, and an imbalanced diet can contribute significantly to the accumulation of oxidative stress, potentially leading to reduced cellular viability, cognitive decline, and eventually death. Dong et al. demonstrated that nicotine could protect against exposure hydrogen peroxide toxicity in vitro through the activation of the α7-nAChR/Erk1/2 signaling pathway, which suggests that nicotine usage may be a novel strategy for the treatment of neurodegenerative disorders associated with increased oxidative stress. The original research article by Dare et al. used a neurotoxicity model induced by Aβ in rats to demonstrate that physical and cognitive exercise could reverse recognition memory deficits, lower hippocampal lipid peroxidation, and maintain optimal acetylcholinesterase activity following exposure to pathophysiological concentrations of Aβ.
Journal Article
Protective Effects of Fibroblast Growth Factor 21 Against Amyloid-Beta1–42-Induced Toxicity in SH-SY5Y Cells
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of cholinergic neurons. Amyloid beta is a misfolded protein that represents one of the key pathological hallmarks of AD. Numerous studies have shown that Aβ
1–42
induces oxidative damage, neuroinflammation, and apoptosis, leading to cognitive decline in AD. Recently, fibroblast growth factor 21 (FGF21) has been suggested to be a potential regulator of oxidative stress in mammalian cells. FGF21 has been shown to improve insulin sensitivity, reduce hyperglycemia, increase adipose tissue glucose uptake and lipolysis, and decrease body fat and weight loss by enhancing energy expenditure. In this study, we investigated the effect of FGF21 Aβ
1–42
toxicity in SH-SY5Y neuroblastoma cells. Our data shows that FGF21 significantly decreased Aβ
1−
42-induced toxic effects and repressed oxidative stress and apoptosis in cells exposed to Aβ
1–42
peptide. Our investigation also confirmed that FGF21 pretreatment favorably affects HSP90/TLR4/NF-κB signaling pathway. Therefore, FGF21 represents a viable therapeutic strategy to abrogate Aβ
1–42
-induced cellular inflammation and apoptotic death in the SH-SY5Y neuroblastoma cells.
Journal Article
Blood-Based Biomarkers for Predictive Diagnosis of Cognitive Impairment in a Pakistani Population
Numerous studies have identified association between age-related cognitive impairment (CI) and oxidative damage, accumulation of metals, amyloid levels, tau and deranged lipid profile. There is a concerted effort to establish reliability of these blood based biomarkers for predictive diagnosis of CI and its progression. We assessed the serum levels of high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, total cholesterol, selected metals (Cu, Al, Zn, Pb, Mn, Cad), and total-tau and amyloid beta-42 protein in mild (n=71), moderate (n=86) and severe (n=25) cognitively impaired patients and compared them with age-matched healthy controls (n=90)from Pakistan. We found that a decrease in HDL cholesterol (correlation coefficient r=0.467) and amyloid beta-42 (r=0.451) were associated with increase severity of CI. On the other hand, an increase in cholesterol ratio (r= -0.562), LDL cholesterol (r= -0.428), triglycerides and total-tau (r= -0.443) were associated with increased severity of CI. Increases in cholesterol ratio showed the strongest association and correlated with increases in tau concentration (r=0.368), and increased triglycerides were associated with decreased amyloid beta-42 (r= -0.345). Increased Cu levels showed the strongest association with tau increase and increased Zn and Pb levels showed the strongest association with reduced amyloid beta-42 levels. Receiver Operating Characteristic (ROC) showed the cutoff values of blood metals (Al, Pb, Cu, Cad, Zn and Mn), total-tau and amyloid beta-42 with sensitivity and specificity. Our data shows for the first time that blood lipids, metals (particularly Cu, Zn, Pb and Al), serum amyloid beta-42/tau proteins modulate each other’s levels and can be collectively used as a predictive marker for CI.
Journal Article
Antioxidant, antimicrobial and neuroprotective effects of Octaviania asterosperma in vitro
Octaviania asterosperma: (hypogeous Basidiomycota) We investigated the phenolic composition, and antioxidant, antimicrobial and antigenotoxic effects of methanol extracts of fruiting bodies from Octaviania asterosperma. The total phenolic content (ppm) of O. asterosperma was found to be catechin (54.73 ± 4.68), epicatechin (123.90 ± 8.52), caffeic acid (4.23 ± 0.97), p-hydroxybenzoic acid (37.72 ± 3.84), cinnamic acid (58.07 ± 5.40), gallic acid (56.64 ± 6.39), clorogenic acid (80.76 ± 4.92) and coumaric acid (2.45 ± 0.15). The total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) were 3.410 ± 0.099 mmol/L, 7.548 ± 0.147 μmol/L and 0.221 ± 0.005 respectively. O. asterosperma showed some promising antimicrobial activity. The extract showed no genotoxic potential and attenuated hydrogen peroxide (H2O2)-induced oxidative DNA damage in neurons. Pre-treatment with O. asterosperma maintained mitochondrial function, reduced expression levels of cleaved-caspase-3 and apoptosis-inducing factor (AIF) when HT22 cells were exposed to pathophysiological concentrations of GLU (25 mM) and modulated protein kinase B (Akt), the mammalian target of rapamycin (mTOR), and the phosphotase and tensin homolog on chromosome ten (PTEN). O. asterosperma is an important food for the treatment or management of neurodegenerative disorders due to its phenolic content and potent antioxidant and anti-excitotoxic effects.
Journal Article
Plasma lipidome variation during the second half of the human lifespan is associated with age and sex but minimally with BMI
Recent advances in mass spectrometry-based techniques have inspired research into lipidomics, a subfield of '-omics', which aims to identify and quantify large numbers of lipids in biological extracts. Although lipidomics is becoming increasingly popular as a screening tool for understanding disease mechanisms, it is largely unknown how the lipidome naturally varies by age and sex in healthy individuals. We aimed to identify cross-sectional associations of the human lipidome with 'physiological' ageing, using plasma from 100 subjects with an apolipoprotein E (APOE) E3/E3 genotype, and aged between 56 to 100 years. Untargeted analysis was performed by liquid chromatography coupled-mass spectrometry (LC-MS/MS) and data processing using LipidSearch software. Regression analyses confirmed a strong negative association of age with the levels of various lipid, which was stronger in males than females. Sex-related differences include higher LDL-C, HDL-C, total cholesterol, particular sphingomyelins (SM), and docosahexaenoic acid (DHA)-containing phospholipid levels in females. Surprisingly, we found a minimal relationship between lipid levels and body mass index (BMI). In conclusion, our results suggest substantial age and sex-related variation in the plasma lipidome of healthy individuals during the second half of the human lifespan. In particular, globally low levels of blood lipids in the 'oldest old' subjects over 95 years could signify a unique lipidome associated with extreme longevity.
Journal Article