Key TCA cycle metabolites, especially fumarate, may be involved in the pathophysiologic pathway independent of traditional cardio-renal risk factors, leading to CKD progression in patients with T2DM.

Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on the deeper metabolic changes associated with this Aβ-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aβ expression. In particular, GRU102 showed reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects were associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurred before any significant increase in global protein aggregate was detectable. Treatment with an anti-diabetes drug, Metformin, reversed Aβ-induced metabolic defects, reduced protein aggregation and normalized lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in Aβ-induced pathology and a promising target for intervention.

26Alzheimer's disease (AD) is the most common neurodegenerative disease affecting 27 the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in 28 the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced 29 mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by 30 expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on a 31 deeper analysis of these metabolic changes associated with A-induced mitochondrial 32 dysfunction. Integrating metabolomics, transcriptomics, biochemical studies and 33 computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle 34 metabolism following even low-level Aβ expression. In particular, GRU102 show 35 reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate 36 dehydrogenase. These defects are associated with elevation of protein carbonyl 37 content specifically in mitochondria. Importantly, metabolic failure occurs before any 38 significant increase in global protein aggregate is detectable. Treatment with an anti-39 diabetes drug, Metformin, reverses A-induced metabolic defects, reduces protein 40 aggregation and normalizes the lifespan of GRU102. Our results point to metabolic 41 dysfunction as an early and causative event in AD pathology and a promising target 42 for intervention. 43 44 45 46 47 48 49 50 51 Introduction 52Alzheimer's disease (AD) is a debilitating neurodegenerative disease, that is clinically 53 characterized by the formation of amyloid-beta (A) plaques and aggregates of 54 hyperphosphorylated tau protein in the brain 1 . Even though AD is primarily a 55 neuronal disorder, perturbations in mitochondrial functions including energy 56 metabolism have consistently been observed not only in the brain 2-4 but also in non-57 neuronal cells derived from AD subjects, including in fibroblasts and platelets [5][6][7][8][9][10] . 58These findings form part of an emerging story that there is an important metabolic 59 component to the etiology of AD 11 , and that these metabolic defects may precede A 60 aggregate formation 12,13 . The metabolism-related hypothesis of AD therefore posits 61 that AD is, in part, mediated by impairments to the brain's insulin response, which 62 promotes oxidative stress and inflammation, similar to that seen in diabetes 11,14 . 63Intranasal insulin treatment has been shown to ameliorate AD pathology in a 64 transgenic rat model and to improve mild cognitive impairment (MCI) in patients [15][16][17][18] . 65 66Several animal studies have confirmed that oxidative stress, mitochondrial 67 dysfunction and metabolic alterations are early events in the pathophysiological 68 progression of AD. Energy deficits, reduction in mitochondrial membrane potential, 69 abnormal mitochondrial gene expression and increased oxidative stress have been 70 observed early in transgenic AD mice (2-3 months of age) well before the appearance 71 of A plaques 19,20 . The A-induced oxidative stress hypothesis further posits that A, 72 predomi...

Objective: To demonstrate differences in cardiovascular structure and function between diabetic and nondiabetic older adults. To investigate associations between acyl-carnitines and cardiovascular function as indexed by imaging measurements. Methods: A community-based cohort of older adults without cardiovascular disease underwent current cardiovascular imaging and metabolomics acyl-carnitines profiling based on current and archived sera obtained fifteen years prior to examination. Results: A total of 933 participants (women 56%, n=521) with a mean age 63±13 years were studied. Old diabetics compared to old non-diabetics had lower myocardial relaxation (0.8±0.2 vs 0.9±0.3, p=0.0039); lower left atrial conduit strain (12±4.3 vs 14±4.1, p=0.045), lower left atrial conduit strain rate (-1.2±0.4 vs -1.3±0.5, p=0.042) and lower ratio of left atrial conduit strain to left atrial booster strain (0.5±0.2 vs 0.7±0.3, p=0.0029). Higher levels of archived short chain acyl-carnitine were associated with present-day impairments in myocardial relaxation (C5:1; OR 1.03, p=0.011), worse left atrial conduit strain function (C5:1; OR 1.03, p=0.037). Increases in hydroxylated acylcarnitines were associated with worse left atrial conduit strain [(C4-OH; OR 1.05, p=0.0017), (C16:2-OH; OR 1.18, p=0.037)]. Current, archived and changes in long chain acyl-carnitines were associated with cardiovascular functions [(C16; OR 1.02, p=0.002), (C20:3; OR 1.01, p=0.014), (C14:3; OR 1.12, p=0.033), (C18:1; OR 1.01, p=0.018), (C18:2; OR 1.01, p=0.028), (C20:4; OR 1.10, p=0.038)] (all p<0.05). Conclusion: Older diabetic adults had significant impairments in left ventricular myocardial relaxation and left atrial strain, compared to older non-diabetic adults. Short chain and long chain, di-carboxyl and hydroxylated acyl-carnitines were associated with these cardiovascular functional differences.1Medium and long-chain carnitines C8,

Transdermal skin delivery is the placement of active ingredients on the skin to improve healthcare or for aesthetic purposes. Active ingredients are absorbed through the skin by percutaneous permeation, so that they can achieve the desired effects. Transdermal skin delivery systems are increasingly being used by cosmetics manufacturers. So, the issue of whether the cosmetic ingredients may be absorbed through the skin or the bloodstream is becoming a challenge in balancing safety and effectiveness. 1 The trend of drugs and cosmetics safety evaluation has shifted away from animal testing due to ethical concerns and the European Union's ban on animal testing since 2009. 2 This is particularly significant in the cosmetics sector, where there has been strong consumer opposition arising from animal ethics and consumers awareness. In terms of biological relevance, it would be preferable to test cosmetics ingredients on human skin rather than animals. However, human skin is extremely difficult to obtain. Since then, much effort has been expended on developing in vitro and ex vivo alternatives and reproducible substitutes for human skin, even though these methods do