Additional file 2: of Aldehyde dehydrogenase 2 activation and coevolution of its εPKC-mediated phosphorylation sites

The table shows the 10 species with εPKC (left panel), the 10 species without εPKC (right panel) and their amino acid residues at the three human ALDH2 phosphorylation sites, T185, S279 and T412. (PDF 313 kb

Development of Selective Inhibitors for Aldehyde Dehydrogenases Based on Substituted Indole-2,3-diones

Aldehyde dehydrogenases (ALDH) participate in multiple metabolic pathways and have been indicated to play a role in several cancerous disease states. Our laboratory is interested in developing novel and selective ALDH inhibitors. We looked to further work recently published by developing a class of isoenzyme-selective inhibitors using similar indole-2,3-diones that exhibit differential inhibition of ALDH1A1, ALDH2, and ALDH3A1. Kinetic and X-ray crystallography data suggest that these inhibitors are competitive against aldehyde binding, forming direct interactions with active-site cysteine residues. The selectivity is precise in that these compounds appear to interact directly with the catalytic nucleophile, Cys243, in ALDH3A1 but not in ALDH2. In ALDH2, the 3-keto group is surrounded by the adjacent Cys301/303. Surprisingly, the orientation of the interaction changes depending on the nature of the substitutions on the basic indole ring structure and correlates well with the observed structure–activity relationships for each ALDH isoenzyme

Additional file 1: of Aldehyde dehydrogenase 2 activation and coevolution of its εPKC-mediated phosphorylation sites

Phylogenetic Tree of the 20 species for ALDH2 and εPKC coevolution comparison. Species in green letters are those with a homology of εPKC. Species in red letters are those without a homology of εPKC. (PDF 73 kb

Sensitivity analyses: Effect of different research characteristics on POCD or POD with ApoE4 carriers.

Sensitivity analyses: Effect of different research characteristics on POCD or POD with ApoE4 carriers.</p

Characteristics of included studies.

The aim of systematic review and meta-analysis was to investigate whether APOE4 was associated with postoperative neurologic dysfunction occurrence in short- or medium-term among surgical patients and to study the potential genetic association among these two entities. We searched electronic databases for reserch studies to evaluate the association of APOE4 with postoperative delirium (POD) or short- and medium term postoperative cognitive dysfunction (POCD). Twenty-two trials (16 prospective and six retrospective) with 6734 patients were included. APOE4 alleles was shown significantly associated with POCD within 1 week (odds ratio, OR, 1.89, 95% confidence interval, CI, 1.36 to 2.6278, p </div

Activation of ALDH2 promotes adipocyte differentiation.

<p><i>A</i>, Effect of various dose of Alda-1 on adipogenesis. The results shown are representative of an individual experiment. 3T3-L1 preadipocytes were maintained in induction medium with or without Alda-1 for 2 days. After 8 day of adipogenic stimulation, cells on the plates were stained with Oil-Red O. <i>B</i>, Quantification of Oil-Red O dye in ethanol-treated and Alda-1-treated cells after 8 day induction. Data are shown as mean ± SE from 3 independent experiments. <i>C</i>, Expression of adipogenic gene (FABP4, ADIPONECTIN, LPL and ACC) expression in ethanol-treated and Alda-1-treated cells after 8 day induction. Data are shown as mean ± SE from 3 independent experiments. * P < 0.05 versus ethanol. <i>D</i>, shRNA control (shLuc) and ALDH2-knockdown preadipocytes were maintained in induction medium with or without 10 μM Alda-1 treatment for 2 days. After 8 day of adipogenic stimulation, cells on the plates were stained with Oil-Red O. <i>E</i>, Quantification of Oil-Red O dye in shRNA control (shLuc) and ALDH2-knockdown preadipocytes with or without 10 μM Alda-1 treatment after 8 day induction. <i>F</i>, Determination of adipogenic gene (FABP4 and ADIPONECTIN) expression in shRNA control (shLuc) and ALDH2-knockdown preadipocytes with or without 10 μM Alda-1 treatment after 8 day induction. Data are shown as mean ± SE from 4 independent experiments. * P < 0.05 versus shLuc. <i>G</i>, Functional classification of representative microarray data for the most significant upregulated genes in Alda-1-treated versus ethanol-treated 3T3-L1 adipocytes. Percentage of genes sharing common biological processes is presented. Data are shown from 3 independent experiments. <i>H</i>, Verification of microarray data by quantitative reverse transcription-PCR. PPAR target genes (AQP7, ACOX2, PCK1, NR1H3 and OLR1) identified from microarray data were selected for verification. Data are shown as mean ± SE from 3 independent experiments. * P < 0.05 versus ethanol.</p

Sensitivity analyses: Effect of different research characteristics on POCD or POD with ApoE4 carriers.

Sensitivity analyses: Effect of different research characteristics on POCD or POD with ApoE4 carriers.</p

Details of thirty-three full-text studies excluded.

Details of thirty-three full-text studies excluded.</p

PKC-ALDH2 Pathway Plays a Novel Role in Adipocyte Differentiation

<div><p>The <i>ALDH2</i> gene encodes the mitochondrial aldehyde dehydrogenase 2 (ALDH2), a critical enzyme involved in ethanol clearance through acetaldehyde metabolism. ALDH2 also catalyzes the metabolism of other bioreactive aldehydes, including propionaldehyde, butyraldehyde, and 4-hydroxykenals (4-HNE). Increased levels of 4-HNE in adipose tissue positively correlate with obesity and insulin resistance. However, it remains unclear whether ALDH2 is involved in regulation of adipocyte differentiation. Here, we found that ALDH2 protein levels were lower in white adipose tissue of high-fat diet-fed mice and <i>ob/ob</i> mice relative to lean mice. Knockdown of ALDH2 expression in 3T3-L1 preadipocytes caused an increase in intracellular 4-HNE, thereby attenuated adipocyte differentiation. By contrast, an ALDH2 activator, Alda-1, significantly accelerated adipogenesis, which was accompanied by an increase in adipogenic gene expression. Consistently, adipogenesis was reduced when protein kinase C ε (PKCε), an ALDH2 phosphorylating activator, was silenced in 3T3-L1 preadipocytes, whereas treatment with a PKCε agonist in 3T3-L1 preadipocytes enhanced adipogenesis. Whole-genome microarray profiling of Alda-1-treated cells demonstrated several upregulated transcripts encoding proteins involved in metabolism and the majority of these transcripts are for proteins involved in PPAR signaling pathways. Furthermore, PKCε-ALDH2 interaction alleviates 4-HNE induced aberrant PPARγ regulation on adipogenesis. Taken together, these results demonstrate that ALDH2 activation enhances adipogenesis and signaling pathways involving PPARγ. Thus, activation of PKCε-ALDH2 regulatory axis may be a therapeutic target for treating obesity and type 2 diabetes.</p></div

MOESM3 of Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology

Additional file 3: Figure S3. ALDH2 plays a critical role in regulating cell health in Alzheimer’s disease patient fibroblast. a) Measurement of mitochondrial ROS using MitoSOX™ in 4 control and 4 AD patient-derived fibroblasts in the presence or absence of Alda-1 (20 μM/48 h; 50 mM Ethanol). b) 4-HNE levels were measured using 4-HNE Assay Kit in control and AD patient-derived fibroblasts in the presence or absence of Alda-1 (20 μM/48 h; 50 mM Ethanol). c) Cellular ATP levels were analyzed using CellTiter-Glo Luminescent Cell Viability kit in control and AD patient-derived fibroblasts in the presence or absence of Alda-1 (20 μM/36 h; 50 mM Ethanol). d) Cellular ROS production was measured using 2,7 dichloro- fluorescein diacetate (DCFDA) in control and AD patient-derived fibroblasts in the presence or absence of Alda-1 (20 μM/48 h; 50 mM Ethanol). Data information: Mean, standard deviation, and p-values are shown. Results are presented as fold change. n = 3–7 independent biological replicates; probability by one-way ANOVA (with Holm-Sidak post hoc test)