Unlocking the potential: A novel prognostic index signature for acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive malignancy characterized by challenges in treatment, including drug resistance and frequent relapse. Recent research highlights the crucial roles of tumor microenvironment (TME) in assisting tumor cell immune escape and promoting tumor aggressiveness. This study delves into the interplay between AML and TME. Through the exploration of potential driver genes, we constructed an AML prognostic index (AMLPI). Cross-platform data and multi-dimensional internal and external validations confirmed that the AMLPI outperforms existing models in terms of areas under the receiver operating characteristic curves, concordance index values, and net benefits. High AMLPIs in AML patients were indicative of unfavorable prognostic outcomes. Immune analyses revealed that the high-AMLPI samples exhibit higher expression of HLA-family genes and immune checkpoint genes (including PD1 and CTLA4), along with lower T cell infiltration and higher macrophage infiltration. Genetic variation analyses revealed that the high-AMLPI samples associate with adverse variation events, including TP53 mutations, secondary NPM1 co-mutations, and copy number deletions. Biological interpretation indicated that ALDH2 and SPATS2L contribute significantly to AML patient survival, and their abnormal expression correlates with DNA methylation at cg12142865 and cg11912272. Drug response analyses revealed that different AMLPI samples tend to have different clinical selections, with low-AMLPI samples being more likely to benefit from immunotherapy. Finally, to facilitate broader access to our findings, a user-friendly and publicly accessible webserver was established and available at http://bioinfor.imu.edu.cn/amlpi. This server provides tools including TME-related AML driver genes mining, AMLPI construction, multi-dimensional validations, AML patients risk assessment, and figures drawing.

Aldehyde Dehydrogenase 2 (ALDH2) Deficiency, Obesity, and Atrial Fibrillation Susceptibility: Unraveling the Connection.

Atrial fibrillation (AF), characterized by structural remodeling involving atrial myocardial degradation and fibrosis, is linked with obesity and transforming growth factor beta 1 (TGF-ß1). Aldehyde dehydrogenase 2 (ALDH2) deficiency, highly prevalent in East Asian people, is paradoxically associated with a lower AF risk. This study investigated the impact of ALDH2 deficiency on diet-induced obesity and AF vulnerability in mice, exploring potential compensatory upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme-oxygenase 1 (HO-1). Wild-type (WT) and ALDH2*2 knock-in (KI) mice were administered a high-fat diet (HFD) for 16 weeks. Despite heightened levels of reactive oxygen species (ROS) post HFD, the ALDH2*2 KI mice did not exhibit a greater propensity for AF compared to the WT controls. The ALDH2*2 KI mice showed equivalent myofibril degradation in cardiomyocytes compared to WT after chronic HFD consumption, indicating suppressed ALDH2 production in the WT mice. Atrial fibrosis did not proportionally increase with TGF-ß1 expression in ALDH2*2 KI mice, suggesting compensatory upregulation of the Nrf2 and HO-1 pathway, attenuating fibrosis. In summary, ALDH2 deficiency did not heighten AF susceptibility in obesity, highlighting Nrf2/HO-1 pathway activation as an adaptive mechanism. Despite limitations, these findings reveal a complex molecular interplay, providing insights into the paradoxical AF-ALDH2 relationship in the setting of obesity.

LncRNA CHKB-DT Downregulation Enhances Dilated Cardiomyopathy Through ALDH2.

BACKGROUND: Human cardiac long noncoding RNA (lncRNA) profiles in patients with dilated cardiomyopathy (DCM) were previously analyzed, and the long noncoding RNA CHKB (choline kinase beta) divergent transcript (CHKB-DT) levels were found to be mostly downregulated in the heart. In this study, the function of CHKB-DT in DCM was determined. METHODS: Long noncoding RNA expression levels in the human heart tissues were measured via quantitative reverse transcription-polymerase chain reaction and in situ hybridization assays. A CHKB-DT heterozygous or homozygous knockout mouse model was generated using the clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 system, and the adeno-associated virus with a cardiac-specific promoter was used to deliver the RNA in vivo. Sarcomere shortening was performed to assess the primary cardiomyocyte contractility. The Seahorse XF cell mitochondrial stress test was performed to determine the energy metabolism and ATP production. Furthermore, the underlying mechanisms were explored using quantitative proteomics, ribosome profiling, RNA antisense purification assays, mass spectrometry, RNA pull-down, luciferase assay, RNA-fluorescence in situ hybridization, and Western blotting. RESULTS: CHKB-DT levels were remarkably decreased in patients with DCM and mice with transverse aortic constriction-induced heart failure. Heterozygous knockout of CHKB-DT in cardiomyocytes caused cardiac dilation and dysfunction and reduced the contractility of primary cardiomyocytes. Moreover, CHKB-DT heterozygous knockout impaired mitochondrial function and decreased ATP production as well as cardiac energy metabolism. Mechanistically, ALDH2 (aldehyde dehydrogenase 2) was a direct target of CHKB-DT. CHKB-DT physically interacted with the mRNA of ALDH2 and fused in sarcoma (FUS) through the GGUG motif. CHKB-DT knockdown aggravated ALDH2 mRNA degradation and 4-HNE (4-hydroxy-2-nonenal) production, whereas overexpression of CHKB-DT reversed these molecular changes. Furthermore, restoring ALDH2 expression in CHKB-DT+/- mice alleviated cardiac dilation and dysfunction. CONCLUSIONS: CHKB-DT is significantly downregulated in DCM. CHKB-DT acts as an energy metabolism-associated long noncoding RNA and represents a promising therapeutic target against DCM.

Determination of pharmacological inhibition of ALDH2 by ethanol clearance in mice.

OBJECTIVES: Retinoic acid plays diverse physiological and pathophysiological roles in reproduction, immune function, energy metabolism and carcinogenesis. Because of the potential benefits of inhibiting retinoic acid biosynthesis in certain disease states, efforts are underway to develop inhibitors of retinoic acid biosynthesis via inhibition of the aldehyde dehydrogenase-1 A (ALDH1A) family of enzymes. However, many potential ALDH1A inhibitors also inhibit the related ALDH2 enzyme that plays a role in the metabolism of ethanol. Accurate in vitro assessment of ALDH2 inhibition is problematic, and to date, there are no published in vivo assays to determine inhibition of ALDH2 by candidate ALDH1A inhibitors. STUDY DESIGN: To address this, we developed a novel gas-chromatography-mass-spectrometry ethanol clearance assay in mice using orally administered ethanol and serial measurement of ethanol over time. We then used this assay to determine pharmacological inhibition of ALDH2 by candidate ALDH1A inhibitors. RESULTS: Ethanol clearance in untreated male mice occurs within sixty minutes. Male mice treated with WIN 18,446, a known ALDH1A inhibitor that also inhibits ALDH2, demonstrated significant inhibition of ethanol clearance compared to untreated controls. Novel pyrazole and piperazine ALDH1A inhibitors were then tested with the piperazine inhibitor demonstrating ALDH2 inhibition via impaired ethanol clearance while the pyrazole inhibitor did not interfere with ethanol metabolism, suggesting a lack of ALDH2 inhibition. CONCLUSIONS: Inhibition of ethanol clearance is a useful in vivo method of inferring pharmacologic inhibition of hepatic ALDH2. This assay may be useful in the development of novel ALDH1A specific inhibitors for a variety of therapeutic indications.

Aldehyde dehydrogenase 2 serves as a key cardiometabolic adaptation regulator in response to plateau hypoxia in mice.

High-altitude heart disease (HAHD) is a complex pathophysiological condition related to systemic hypobaric hypoxia in response to transitioning to high altitude. Hypoxia can cause myocardial metabolic dysregulation, leading to an increased risk of heart failure and sudden cardiac death. Aldehyde dehydrogenase 2 (ALDH2) could regulate myocardial energy metabolism and plays a protective role in various cardiovascular diseases. This study aims to determine the effects of plateau hypoxia (PH) on cardiac metabolism and function, investigate the associated role of ALDH2, and explore potential therapeutic targets. We discovered that PH significantly reduced survival rate and cardiac function. These effects were exacerbated by ALDH2 deficiency. PH also caused a shift in the myocardial fuel source from fatty acids to glucose; ALDH2 deficiency impaired this adaptive metabolic shift. Untargeted/targeted metabolomics and transmission electron microscopy revealed that ALDH2 deficiency promoted myocardial fatty-acid deposition, leading to enhanced fatty-acid transport, lipotoxicity and mitochondrial dysfunction. Furthermore, results showed that ALDH2 attenuated PH-induced impairment of adaptive metabolic programs through 4-HNE/CPT1 signaling, and the CPT1 inhibitor etomoxir significantly ameliorated ALDH2 deficiency-induced cardiac impairment and improved survival in PH mice. Together, our data reveal ALDH2 acts as a key cardiometabolic adaptation regulator in response to PH. CPT1 inhibitor, etomoxir, may attenuate ALDH2 deficiency-induced effects and improved cardiac function in response to PH.

Remote Ischemic Conditioning Mediates Cardio-protection After Myocardial Ischemia/Reperfusion Injury by Reducing 4-HNE Levels and Regulating Autophagy via the ALDH2/SIRT3/HIF1α Signaling Pathway.

Remote ischemic conditioning (RIC) can be effectively applied for cardio-protection. Here, to clarify whether RIC exerts myocardial protection via aldehyde dehydrogenase 2 (ALDH2), we established a myocardial ischemia/reperfusion (I/R) model in C57BL/6 and ALDH2 knockout (ALDH2-KO) mice and treated them with RIC. Echocardiography and single-cell contraction experiments showed that RIC significantly improved myocardial function and alleviated I/R injury in C57BL/6 mice but did not exhibit its cardioprotective effects in ALDH2-KO mice. TUNEL, Evan's blue/triphenyl tetrazolium chloride, and reactive oxygen species (ROS) assays showed that RIC's effect on reducing myocardial cell apoptosis, myocardial infarction area, and ROS levels was insignificant in ALDH2-KO mice. Our results showed that RIC could increase ALDH2 protein levels, activate sirtuin 3 (SIRT3)/hypoxia-inducible factor 1-alpha (HIF1α), inhibit autophagy, and exert myocardial protection. This study revealed that RIC could exert myocardial protection via the ALDH2/SIRT3/HIF1α signaling pathway by reducing 4-HNE secretion.

Aldehyde Dehydrogenase 2 Preserves Mitochondrial Function in the Ischemic Heart: A Redox-dependent Mechanism for AMPK Activation by Thioredoxin-1.

ABSTRACT: Aldehyde dehydrogenase 2 (ALDH2) protects the ischemic heart by activating adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling. However, the molecular mechanisms linking ALDH2 and AMPK signaling are not fully understood. This study aimed to explore the potential mechanisms linking ALDH2 and AMPK in myocardial ischemic injury. An ischemic model was established by ligating the left anterior descending coronary artery in rats. The overexpression or knockdown of ALDH2 in H9c2 cells treated with oxygen-glucose deprivation was obtained through lentivirus infection. Transferase-mediated dUTP nick-end labeling was used to evaluate apoptosis in an ischemic rat model and oxygen-glucose deprivation cells. ALDH2 activity, mitochondrial oxidative stress markers, adenosine triphosphate, respiratory control ratio, and cell viability in H9c2 cells were evaluated using a biological kit and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide. Protein expression of ALDH2 , 4-hydroxynonenal, thioredoxin-1 (Trx-1), and AMPK-proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling pathway was detected through Western blotting. ALDH2 activation reduced ischemic-induced myocardial infarct size and apoptosis. ALDH2 protected mitochondrial function by enhancing mitochondrial respiratory control ratio and adenosine triphosphate production, alleviated mitochondrial oxidative stress, and suppressed myocardial apoptosis. Moreover, ALDH2 attenuated ischemia-induced oxidative stress and maintained Trx-1 levels by reducing 4-hydroxynonenal, thereby promoting AMPK-PGC-1α signaling activation. Inhibiting Trx-1 or AMPK abolished the cardioprotective effect of ALDH2 on ischemia. ALDH2 alleviates myocardial injury through increased mitochondrial biogenesis and reduced oxidative stress, and these effects were achieved through Trx1-mediating AMPK-PGC1-α signaling activation.

Mitochondrial aldehyde dehydrogenase-2 coordinates the hydrogen sulfide - AMPK axis to attenuate high glucose-induced pancreatic ß-cell dysfunction by glutathione antioxidant system.

Progression of ß-cell loss in diabetes mellitus is significantly influenced by persistent hyperglycemia. At the cellular level, a number of signaling cascades affect the expression of apoptotic genes, ultimately resulting in ß-cell failure; these cascades have not been elucidated. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) plays a central role in the detoxification of reactive aldehydes generated from endogenous and exogenous sources and protects against mitochondrial deterioration in cells. Here we report that under diabetogenic conditions, ALDH2 is strongly inactivated in ß-cells through CDK5-dependent glutathione antioxidant imbalance by glucose-6-phosphate dehydrogenase (G6PD) degradation. Intriguingly, CDK5 inhibition strengthens mitochondrial antioxidant defense through ALDH2 activation. Mitochondrial ALDH2 activation selectively preserves ß-cells against high-glucose-induced dysfunction by activating AMPK and Hydrogen Sulfide (H2S) signaling. This is associated with the stabilization and enhancement of the activity of G6PD by SIRT2, a cytoplasmic NAD+-dependent deacetylase, and is thereby linked to an elevation in the GSH/GSSG ratio, which leads to the inhibition of mitochondrial dysfunction under high-glucose conditions. Furthermore, treatment with NaHS, an H2S donor, selectively preserves ß-cell function by promoting ALDH2 activity, leading to the inhibition of lipid peroxidation by high-glucose concentrations. Collectively, our results provide the first direct evidence that ALDH2 activation enhances H2S-AMPK-G6PD signaling, leading to improved ß-cell function and survival under high-glucose conditions via the glutathione redox balance.

Alda-1 ameliorates air embolism-induced acute lung injury.

OBJECTIVE: Evidence suggests that aldehyde dehydrogenase 2 (ALDH2) offers protection against damage caused by oxidative stress in diverse rodent models. Nonetheless, the effect of Alda-1, a compound that activates ALDH2, on acute lung injury (ALI) induced by air embolism (AE) remains unclear. The objective of this study was to explore the protective effects of Alda-1 in ALI induced by AE. METHODS: A rat model of in situ isolated perfused lung was established to investigate AE-induced ALI. Air was infused into the pulmonary artery at 0.25 mL/min for 1 minute. Before inducing AE, different doses (10, 20, or 30 mg/kg) of Alda-1 were given through intraperitoneal injection. Pathological changes in lung tissue were assessed using hematoxylin-eosin staining. We performed Western blot analysis to assess the protein levels of ALDH2,4-hydroxy-trans-2-nonenal (4-HNE), Bcl-2, caspase-3, phosphatidylinositol 3-kinase (PI3K), Akt, IκB-α, and nuclear NF-κB. RESULTS: Notably, AE results were demonstrated as harmful to the lungs, which is evidenced by intensified lung edema and disruption of lung tissue structure. Furthermore, AE caused a decrease in ALDH2 expression, increased accumulation of 4-HNE and MDA, infiltration of neutrophils, increased production of inflammatory cytokines, apoptosis, and upregulation of the PI3K/Akt and NF-κB signaling pathways within the lungs. Administration of a 20 mg/kg dose of Alda-1 alleviated the detrimental effects induced by AE. CONCLUSION: Alda-1 shows promise in mitigating AE-induced ALI, possibly through the upregulation of ALDH2 expression and suppression of the PI3K/Akt and NF-κB signaling pathways. Further research is warranted to validate these findings and to explore their translational potential in human subjects.

ALDH2 activation attenuates oxygen–glucose deprivation/reoxygenation-induced cell apoptosis, pyroptosis, ferroptosis and autophagy

Purpose It is previously reported that aldehyde dehydrogenase 2 family member (ALDH2) shows neuroprotective effects in cerebral ischemia/reperfusion injury. However, whether the protective effects are through mediating the programmed cell death is yet to be fully elucidated. Methods In vitro oxygen–glucose deprivation/reoxygenation (OGD/R) model was established in HT22 cells and mouse cortical neurons. Subsequently, ALDH2 expression were assessed by qRT-PCR and western blot. The methylation status was examined by methylation-specific PCR (MS-PCR). Then, ALDH2 expression was promoted and suppressed to explore the role of ALDH2 in OGD/R-treated cells. CCK-8 assay was applied to detect cell viability, and flow cytometry was applied to evaluate cell apoptosis. Western blot was applied to detect the apoptosis-related proteins (Caspase 3, Bcl-2 and Bax), necroptosis-related proteins (RIP3 and MLKL), pyroptosis-related proteins (NLRP3 and GSDMD), ferroptosis-related protein (ACSL4 and GPX4), and autophagy-related proteins (LC3B, and p62). IL-1β and IL-18 production was evaluated by ELISA assay. Reactive oxygen species production and Fe2+ content were evaluated by the corresponding detection kit. Results In OGD/R-treated cells, ALDH2 expression was decreased, which was due to the hypermethylation of ALDH2 in the promoter region. ALDH2 overexpression improved cell viability and ALDH2 knockdown suppressed cell viability in OGD/R-treated cells. We also found that ALDH2 overexpression attenuated OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy, while ALDH2 knockdown facilitated the OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy. Conclusions Collectively, our results implied that ALDH2 attenuated OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy to promote cell viability in HT22 cells and mouse cortical neurons (AU)

Early Progression of Abdominal Aortic Aneurysm is Decelerated by Improved Endothelial Barrier Function via ALDH2-LIN28B-ELK3 Signaling.

The involvement of endothelial barrier function in abdominal aortic aneurysm (AAA) and its upstream regulators remains unknown. Single-cell RNA sequencing shows that disrupted endothelial focal junction is an early (3 days) and persistent (28 days) event during Angiotensin II (Ang II)-induced AAA progression. Consistently, mRNA sequencing on human aortic dissection tissues confirmed downregulated expression of endothelial barrier-related genes. Aldehyde dehydrogenase 2 (ALDH2), a negative regulator of AAA, is found to be upregulated in the intimal media of AAA samples, leading to testing its role in early-stage AAA. ALDH2 knockdown/knockout specifically in endothelial cells (ECs) significantly increases expression of EC barrier markers related to focal adhesion and tight junction, restores endothelial barrier integrity, and suppresses early aortic dilation of AAA (7 and 14 days post-Ang II). Mechanically, ELK3 acts as an ALDH2 downstream regulator for endothelial barrier function preservation. At the molecular level, ALDH2 directly binds to LIN28B, a regulator of ELK3 mRNA stability, hindering LIN28B binding to ELK3 mRNA, thereby depressing ELK3 expression and impairing endothelial barrier function. Therefore, preserving vascular endothelial barrier integrity via ALDH2-specific knockdown in ECs holds therapeutic potential in the early management of AAAs.

A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators.

Obesity and type 2 diabetes have reached pandemic proportion. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal. A missense Glu504Lys mutation of the ALDH2 gene is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We find that male Aldh2 knock-in mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver due to reduced adaptive thermogenesis and energy expenditure. We find reduced activity of ALDH2 of the brown adipose tissue from the male Aldh2 homozygous knock-in mice. Proteomic analyses of the brown adipose tissue from the male Aldh2 knock-in mice identifies increased 4-hydroxynonenal-adducted proteins involved in mitochondrial fatty acid oxidation and electron transport chain, leading to markedly decreased fatty acid oxidation rate and mitochondrial respiration of brown adipose tissue, which is essential for adaptive thermogenesis and energy expenditure. AD-9308 is a water-soluble, potent, and highly selective ALDH2 activator. AD-9308 treatment ameliorates diet-induced obesity and fatty liver, and improves glucose homeostasis in both male Aldh2 wild-type and knock-in mice. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for metabolic diseases.

Alpha-lipoic Acid Protects Against Chronic Alcohol Consumption-induced Cardiac Damage by the Aldehyde Dehydrogenase 2-associated PINK/Parkin Pathway.

ABSTRACT: Chronic alcohol intake contributes to high mortality rates due to ethanol-induced cardiac hypertrophy and contractile dysfunction, which are accompanied by increased oxidative stress and disrupted mitophagy. Alpha-lipoic acid (α-LA), a well-known antioxidant, has been shown to protect against cardiac hypertrophy and inflammation. However, little is known about its role and mechanism in the treatment of alcoholic cardiomyopathy. Here, we evaluated the role of α-LA in alcohol-induced cardiac damage by feeding mice a 4.8% (v/v) alcohol diet with or without α-LA for 6 w. Our results suggested that chronic alcohol consumption increased mortality, blood alcohol concentrations, and serum aldehyde levels, but a-LA attenuated the elevations in mortality and aldehydes. Chronic alcohol intake also induced cardiac dysfunction, including enlarged left ventricles, reduced left ventricular ejection fraction, enhanced cardiomyocyte size, and increased serum levels of brain natriuretic peptide, lactate dehydrogenase, and creatine kinase myocardial isoenzyme. Moreover, alcohol intake led to the accumulation of collagen fiber and mitochondrial dysfunction, the effects of which were alleviated by α-LA. In addition, α-LA intake also prevented the increase in reactive oxygen species production and the decrease in mitochondrial number that were observed after alcohol consumption. Chronic alcohol exposure activated PINK1/Parkin-mediated mitophagy. These effects were diminished by α-LA intake by the activation of aldehyde dehydrogenase 2. Our data indicated that α-LA helps protect cardiac cells against the effects of chronic alcohol intake, likely by inhibiting PINK1/Parkin-related mitophagy through the activation of aldehyde dehydrogenase 2.

Fanconi anemia and Aldehyde Degradation Deficiency Syndrome: Metabolism and DNA repair protect the genome and hematopoiesis from endogenous DNA damage.

We have identified a set of Japanese children with hypoplastic anemia caused by combined defects in aldehyde degrading enzymes ADH5 and ALDH2. Their clinical characteristics overlap with a hereditary DNA repair disorder, Fanconi anemia. Our discovery of this disorder, termed Aldehyde Degradation Deficiency Syndrome (ADDS), reinforces the notion that endogenously generated aldehydes exert genotoxic effects; thus, the coupled actions of metabolism and DNA repair are required to maintain proper hematopoiesis and health.

SNHG3/miR-330-5p/HSD11B1 Alleviates Myocardial Ischemia-reperfusion Injury by Regulating the ERK/p38 Signaling Pathway.

BACKGROUND: Studies have found that microRNAs (miRNAs) participate in the pathogenesis of myocardial ischemia-reperfusion injury (MIRI). miR-330-5p alleviated cerebral IR injury and regulated myocardial damage. However, the mechanism of the effect of miR-330-5p on MIRI needs to be further studied. OBJECTIVE: The study aimed to explore the role and mechanism of miR-330-5p in MIRI. METHODS: The oxygen-glucose deprivation reperfusion (OGD/R) model was constructed in cardiomyocytes to simulate MIRI in vitro. QRT-PCR was used for the detection of gene expression. ELISA was used for evaluation of the levels of aldehyde dehydrogenase 2 family member (ALDH2), 4-hydroxynonenal (4-HNE), and malondialdehyde (MDA). Flow cytometry was used to evaluate apoptosis. Western blot was employed for protein determination. Bioinformatic analysis was performed for predicting the targets of miR-330-5p. RESULTS: miR-330-5p was found to be down-regulated in MIRI-induced cardiomyocytes (Model group). miR-330-5p mimic enhanced ALDH2 activity, inhibited apoptosis, and suppressed 4-HNE and MDA of MIRI-induced cardiomyocytes. miR-330-5p inhibited ERK expression while increasing the p38 expression. Bioinformatic analysis showed hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1) to be a target of miR-330-5p. HSD11B1 expression was inhibited by miR-330-5p mimic while increased by miR-330-5p inhibitor in MIRI-induced cardiomyocytes. HSD11B1 overexpression reversed the effect of miR-330-5p on ALDH2, 4-HNE, MDA, apoptosis, and ERK/p38 signaling pathway. Furthermore, lncRNA small nucleolar RNA host gene 3 (SNHG3) was the upstream lncRNA of miR-330-5p. SNHG3 decreased miR-330-5p expression and increased HSD11B1 expression. CONCLUSION: SNHG3/miR-330-5p alleviated MIRI in vitro by targeting HSD11B1 to regulate the ERK/p38 signaling pathway.

Astragaloside IV Blunts Epithelial-Mesenchymal Transition and G2/M Arrest to Alleviate Renal Fibrosis via Regulating ALDH2-Mediated Autophagy.

Previous studies show that astragaloside IV (ASIV) has anti-renal fibrosis effects. However, its mechanism remains elusive. In this study, we investigated the anti-fibrosis mechanisms of ASIV on chronic kidney disease (CKD) in vivo and in vitro. A CKD model was induced in rats with adenine (200 mg/kg/d, i.g.), and an in vitro renal fibrosis model was induced in human kidney-2 (HK-2) cells treated with TGF-ß1. We revealed that ASIV significantly alleviated renal fibrosis by suppressing the expressions of epithelial-mesenchymal transition (EMT)-related proteins, including fibronectin, vimentin, and alpha-smooth muscle actin (α-SMA), and G2/M arrest-related proteins, including phosphorylated p53 (p-p53), p21, phosphorylated histone H3 (p-H3), and Ki67 in both of the in vivo and in vitro models. Transcriptomic analysis and subsequent validation showed that ASIV rescued ALDH2 expression and inhibited AKT/mTOR-mediated autophagy. Furthermore, in ALDH2-knockdown HK-2 cells, ASIV failed to inhibit AKT/mTOR-mediated autophagy and could not blunt EMT and G2/M arrest. In addition, we further demonstrated that rapamycin, an autophagy inducer, reversed the treatment of ASIV by promoting autophagy in TGF-ß1-treated HK-2 cells. A dual-luciferase report assay indicated that ASIV enhanced the transcriptional activity of the ALDH2 promoter. In addition, a further molecular docking analysis showed the potential interaction of ALDH2 and ASIV. Collectively, our data indicate that ALDH2-mediated autophagy may be a novel target in treating renal fibrosis in CKD models, and ASIV may be an effective targeted drug for ALDH2, which illuminate a new insight into the treatment of renal fibrosis and provide new evidence of pharmacology to elucidate the anti-fibrosis mechanism of ASIV in treating renal fibrosis.

SLC3A2, as an indirect target gene of ALDH2, exacerbates alcohol-associated liver cancer via the sphingolipid biosynthesis pathway.

Excessive drinking is one of the main causes of liver cancer. In the process of alcohol metabolism, aldehyde dehydrogenase 2 (ALDH2) is the key enzyme of acetaldehyde metabolism. ALDH2 gene deficiency is positively associated with the risk of hepatocellular carcinoma (HCC). However, no studies have shown a connection between ALDH2 and another metabolic regulatory gene, SLC3A2. In this study, we analyzed the expression levels of ALDH2 and SLC3A2 in liver cancer tissues based on the TCGA database. Subsequently, we constructed ALDH2 knockout and SLC3A2 knock-in transgenic mice to check the roles of ALDH2 and SLC3A2 in tumorigenesis in vivo. In addition, we examined the mechanisms of ALDH2 and SLC3A2 in HCC cells using small RNA interference technology. Consistent with previous studies, we also confirmed the functions of ALDH2 in inhibiting hepatocarcinogenesis, while SLC3A2 had the opposite effect. The main finding of this study is that ALDH2 inhibited BSG expression through the TGF-ß1 pathway, which indirectly inhibited SLC3A2 expression; subsequently, the sphingolipid metabolism pathway was also inhibited in HCC cells. Therefore, SLC3A2 is a novel target for HCC treatment.

Commentary: Aldehyde dehydrogenase, redox balance and exercise physiology: What is missing?

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in reactive aldehyde detoxification. Approximately 560 million people (about 8% of the world's population) carry a point mutation in the aldehyde dehydrogenase 2 gene (ALDH2), identified as ALDH2*2, which leads to decreased ALDH2 catalytic activity. ALDH2*2 variant is associated with an accumulation of toxic reactive aldehydes and consequent disruption of cellular metabolism, which contributes to the establishment and progression of several degenerative diseases. Consequences of aldehyde accumulation include impaired mitochondrial functional, hindered anabolic signaling in the skeletal muscle, impaired cardiovascular and pulmonary function, and reduced osteoblastogenesis. Considering that aldehydes are endogenously produced through redox processes, it is expected that conditions that have a high energy demand, such as exercise, might be affected by impaired aldehyde clearance in ALDH2*2 individuals. Despite the large body of evidence supporting the importance of ALDH2 to ethanol metabolism, redox homeostasis and overall health, specific research investigating the impact of ALDH2*2 on phenotypes relevant to exercise performance are notoriously scarce. In this commentary, we highlight the consolidated knowledge on the impact of ALDH2*2 on physiological processes that are relevant to exercise.

ALDH2 inhibition by lead and ethanol elicits redox imbalance and mitochondrial dysfunction in SH-SY5Y human neuroblastoma cell line: Reversion by Alda-1.

Lead (Pb), a common environmental contaminant, and ethanol (EtOH), a widely available drug of abuse, are well-known neurotoxicants. In vivo, experimental evidence indicates that Pb exposure affects oxidative EtOH metabolism with a high impact on living organisms. On these bases, we evaluated the consequences of combined Pb and EtOH exposure on aldehyde dehydrogenase 2 (ALDH2) functionality. In vitro exposure to 10 µM Pb, 200 mM EtOH, or their combination for 24 h reduced ALDH2 activity and content in SH-SY5Y human neuroblastoma cells. In this scenario, we observed mitochondrial dysfunction characterized by reduced mass and membrane potential, decreased maximal respiration, and spare capacity. We also evaluated the oxidative balance in these cells finding a significant increase in reactive oxygen species (ROS) production and lipid peroxidation products under all treatments accompanied by an increase in catalase (CAT) activity and content. These data suggest that ALDH2 inhibition induces the activation of converging cytotoxic mechanisms resulting in an interplay between mitochondrial dysfunction and oxidative stress. Notably, NAD+ (1 mM for 24 h) restored ALDH2 activity in all groups, while an ALDH2 enhancer (Alda-1, 20 µM for 24 h) also reversed some of the deleterious effects resulting from impaired ALDH2 function. Overall, these results reveal the crucial role of this enzyme on the Pb and EtOH interaction and the potential of activators such as Alda-1 as therapeutic approaches against several conditions involving aldehydes accumulation.

ALDH2 promotes cancer stemness and metastasis in colorectal cancer through activating ß-catenin signaling.

Colorectal cancer (CRC) is the primary cause of death from gastrointestinal cancers. Aldehyde dehydrogenase 2 (ALDH2), a crucial mitochondrial enzyme for the oxidative pathway of alcohol metabolism, plays a dual role in cancer progression. In some cancers, it is tumor suppressive; in others, it drives cancer progression. However, whether targeting ALDH2 has any therapeutic implications or prognostic value in CRC is still unclear. Here, we investigated the role of ALDH2 in CRC progression by targeting its enzymatic activity rather than gene expression. We found that inhibiting ALDH2 by CVT-10216 and daidzein significantly decrease migration and stemness properties of both DLD-1 and HCT 116 cells, whereas activating ALDH2 by Alda-1 enhances migration rate. Concomitantly, ALDH2 inhibition by both CVT-10216 and daidzein downregulates the mRNA levels of fibronectin, snail, twist, MMP7, CD44, c-Myc, SOX2, and OCT-4, which are oncogenic in the advanced stage of CRC. Furthermore, Gene Set Enrichment Analysis (GSEA) on ALDH2 co-expressed genes from The Cancer Genome Atlas (TCGA) revealed that MYC target gene sets are upregulated. We found that ALDH2 inhibition decreased the nuclear protein levels of pGSK3ß serine 9 and c-Myc. This suggests that ALDH2 probably targets ß-catenin signaling in CRC cells. Together, our results demonstrate the prognostic value of ALDH2 in CRC as it regulates both CRC stemness and migration. Our findings also propose that the plant-derived isoflavone daidzein could be a potential chemotherapeutic drug targeting ALDH2 in CRC.