scholarly journals Targeting Reactive Aldehyde Detoxification by Aldehyde Dehydrogenase 2 (ALDH2) as a Treatment Strategy for Endometriosis

2020 ◽  
Author(s):  
Stacy L. McAllister ◽  
Pritam Sinharoy ◽  
Megana Vasu
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Treatment Strategies ◽  
Stage Iv ◽  
Adduct Formation ◽  
Aldehyde Dehydrogenase 2 ◽  
Proliferative Phase ◽  
Severe Stage ◽  
Reactive Aldehydes ◽  
Key Enzyme ◽  
Reactive Aldehyde

AbstractEndometriosis affects ∼176 million women worldwide, yet on average, women experience pain ∼10 years from symptom onset before being properly diagnosed. Standard treatments (drugs or surgery) often fail to provide long-term pain relief. Elevated levels of reactive aldehydes such as 4-hydroxynonenal (4-HNE) have been implicated in the peritoneal fluid of women with endometriosis and upon accumulation, reactive aldehydes can form protein-adducts and/or generate pain. A key enzyme in detoxifying reactive aldehydes to less reactive forms, is the mitochondrial enzyme aldehyde dehydrogenase-2 (ALDH2). Here, we tested the hypothesis that aberrant reactive aldehyde detoxification by ALDH2, underlies endometriosis and its associated pain. We determined, in the eutopic and ectopic endometrium of women with severe (stage IV) peritoneal endometriosis, that ALDH2 enzyme activity was decreased, which was associated with decreased ALDH2 expression and increased 4-HNE adduct formation compared to the eutopic endometrium of controls in the proliferative phase. Using a rodent model of endometriosis and an ALDH2*2 knock-in mouse with decreased ALDH2 activity, we determined that increasing ALDH2 activity with the enzyme activator Alda-1 could prevent endometriosis lesion development as well as alleviate pain-associated behaviors in proestrus. Overall, our findings suggest that targeting the ALDH2 enzyme in endometriosis may lead to better treatment strategies and in the proliferative phase, that increased 4-HNE adduct formation within the endometrium may serve as a less invasive diagnostic biomarker to reduce years of suffering in women.One Sentence SummaryALDH2 activity influences endometriosis and its associated pain.

Abstract 491: E-cigarette Aerosol Elevates Cardiovascular Oxidative Stress in Mice With Aldehyde Dehydrogenase 2 Deficiency

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Xuan Yu ◽  
Xiaocong Zeng ◽  
Ri Chen ◽  
Pritam Sinharoy ◽  
Eric R Gross
Keyword(s):  
Oxidative Stress ◽  
Heart Rate ◽  
Aldehyde Dehydrogenase ◽  
Whole Body ◽  
Protein Carbonyls ◽  
Wild Type ◽  
Aldehyde Dehydrogenase 2 ◽  
Maximal Increase ◽  
Reactive Aldehydes ◽  
Reactive Aldehyde

Introduction: E-cigarette aerosol contains reactive aldehydes including acetaldehyde, formaldehyde, and acrolein when e-cigarette is heated. Approximately 560 million people worldwide cannot efficiently metabolize aldehydes present in e-cigarette aerosol, due to a genetic deficiency in aldehyde dehydrogenase 2 enzyme (ALDH2), known as ALDH2*2. Little is known how aldehyde exposure from e-cigarettes, coupled with genetic differences in aldehyde metabolism, affects cardiovascular oxidative stress both at a physiological and cellular level. Hypothesis: E-cigarette aerosol exposure will elevate heart rate and cellular oxidative stress more substantially in ALDH2*2 knock-in mice versus wild type ALDH2 mice. Methods: To measure aldehyde levels, e-cigarette Juul aerosols were collected and quantified by selective ion flow gas mass spectrometry. Further, age-matched male wild type and homozygous ALDH2*2 mice (8-10 weeks old, ~25g) were implanted with EKG telemeters. After surgical recovery, mice were paired by genotype (one wild type ALDH2 and one ALDH2*2 mice) and exposed to either Juul aerosol or room air 4 sessions per day for 10 days. For each session, 7 puffs/min were drawn for the first two minutes (a total of 14 puffs), and the whole body exposure to Juul aerosol lasted 7 minutes, continued with 23 minutes smoking-free intervals in each session. Mice EKG waveforms were recorded daily. After 10 days of exposure, heart homogenates were subjected to biochemical assays including lipid peroxidation, 4-HNE protein adduct formation, and protein carbonylation. Results: Quantification of reactive aldehyde levels in e-cigarettes revealed that Juul aerosol contained acetaldehyde (5.3±0.32 ppm), formaldehyde (0.20±0.02 ppm), and acrolein (0.09±0.01 ppm). When exposed to Juul aerosol, ALDH2*2 mice showed a maximal increase in heart rate unlike ALDH2 wild type mice (774.6±29.5 bpm versus 678.9±32.8 bpm respectively, * p <0.01, n=8) at day 6. Furthermore, heart homogenates from ALDH2*2 mice demonstrated exacerbated oxidative stress, including higher level of 4-HNE adducts (1.5-fold), protein carbonyls (1.5-fold) and lipid peroxides (2-fold) relative to hearts from wild type ALDH2 mice, when both genotype mice were exposed to Juul e-cigarette aerosol (n=4/group). Conclusions: These findings indicate e-cigarette aerosols contain reactive aldehydes, primarily acetaldehyde. A deficiency in reactive aldehyde metabolism by having an ALDH2*2 deficiency may contribute to increases in heart rate and oxidative stress within the cardiovascular system while smoking e-cigarettes.

scholarly journals Alda-1 Ameliorates Liver Ischemia-Reperfusion Injury by Activating Aldehyde Dehydrogenase 2 and Enhancing Autophagy in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Meng Li ◽  
Min Xu ◽  
Jichang Li ◽  
Lili Chen ◽  
Dongwei Xu ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Aldehyde Dehydrogenase ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Liver Ischemia ◽  
Aldehyde Dehydrogenase 2 ◽  
Serum Samples ◽  
Reactive Aldehydes ◽  
Key Enzyme

Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme for metabolism of reactive aldehydes, but its role during liver ischemia-reperfusion injury (IRI) remains unclear. In the present study, we investigated the effects of the ALDH2 activator, Alda-1, in liver IRI and elucidated the underlying mechanisms. Mice were pretreated with Alda-1 and subjected to a 90 min hepatic 70% ischemia model, and liver tissues or serum samples were collected at indicated time points after reperfusion. We demonstrated that Alda-1 pretreatment had a hepatoprotective role in liver IRI as evidenced by decreased liver necrotic areas, serum ALT/AST levels, and liver inflammatory responses. Mechanistically, Alda-1 treatment enhanced ALDH2 activity and subsequently reduced the accumulation of reactive aldehydes and toxic protein adducts, which result in decreased hepatocyte apoptosis and mitochondrial dysfunction. We further demonstrated that Alda-1 treatment could activate AMPK and autophagy and that AMPK activation was required for Alda-1-mediated autophagy enhancement. These findings collectively indicate that Alda-1-mediated ALDH2 activation could be a promising strategy to improve liver IRI by clearance of reactive aldehydes and enhancement of autophagy.

scholarly journals Targeting liver aldehyde dehydrogenase-2 prevents heavy but not moderate alcohol drinking

2019 ◽  
Vol 116 (51) ◽  
pp. 25974-25981 ◽  
Author(s):  
Adrien Guillot ◽  
Tianyi Ren ◽  
Tony Jourdan ◽  
Robert J. Pawlosky ◽  
Elaine Han ◽  
...  
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Heavy Drinking ◽  
Cumulative Effect ◽  
Alcohol Preference ◽  
Aldehyde Dehydrogenase 2 ◽  
Moderate Drinking ◽  
Relative Contribution ◽  
Seeking Behavior ◽  
Key Enzyme ◽  
Acute Ethanol

Aldehyde dehydrogenase 2 (ALDH2), a key enzyme for detoxification the ethanol metabolite acetaldehyde, is recognized as a promising therapeutic target to treat alcohol use disorders (AUDs). Disulfiram, a potent ALDH2 inhibitor, is an approved drug for the treatment of AUD but has clinical limitations due to its side effects. This study aims to elucidate the relative contribution of different organs in acetaldehyde clearance through ALDH2 by using global- (Aldh2−/−) and tissue-specificAldh2-deficient mice, and to examine whether liver-specific ALDH2 inhibition can prevent alcohol-seeking behavior.Aldh2−/−mice showed markedly higher acetaldehyde concentrations than wild-type (WT) mice after acute ethanol gavage. Acetaldehyde levels in hepatocyte-specificAldh2knockout (Aldh2Hep−/−) mice were significantly higher than those in WT mice post gavage, but did not reach the levels observed inAldh2−/−mice. Energy expenditure and motility were dramatically dampened inAldh2−/−mice, but moderately decreased inAldh2Hep−/−mice compared to controls. In the 2-bottle paradigm and the drinking-in-the-dark model,Aldh2−/−mice drank negligible volumes from ethanol-containing bottles, whereasAldh2Hep−/−mice showed reduced alcohol preference at high but not low alcohol concentrations. Glial cell- or neuron-specificAldh2deficiency did not affect voluntary alcohol consumption. Finally, specific liverAldh2knockdown via injection ofshAldh2markedly decreased alcohol preference. In conclusion, although the liver is the major organ responsible for acetaldehyde metabolism, a cumulative effect of ALDH2 from other organs likely also contributes to systemic acetaldehyde clearance. Liver-targeted ALDH2 inhibition can decrease heavy drinking without affecting moderate drinking, providing molecular basis for hepaticALDH2targeting/editing for the treatment of AUD.

Abstract 432: Elamipretide (BendaviaTM) Restores Aldehyde Dehydrogenase-2 Protein Levels and 4-Hydroxy-2-Nonenal Protein Adducts in Left Ventricular Myocardium of Dogs with Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Ramesh C Gupta ◽  
Vinita Singh-Gupta ◽  
Hani N Sabbah
Keyword(s):  
Heart Failure ◽  
Aldehyde Dehydrogenase ◽  
Left Ventricular ◽  
Protein Adducts ◽  
Term Therapy ◽  
Aldehyde Dehydrogenase 2 ◽  
Protein Levels ◽  
Reactive Aldehydes ◽  
Long Term Therapy

Background: Reactive aldehydes such as 4-hydroxy-2-nonenal (4-HNE) are generated in the failing heart and contribute to cardiomyocyte injury and death and progressive left ventricular (LV) dysfunction. Aldehyde dehydrogenase-2 (ALDH2) plays a pivotal role in detoxifying mitochondrial (MITO) reactive aldehydes. We previously showed that long-term therapy with Elamipretide (ELA, Bendavia TM ), a novel MITO targeting peptide, improves LV systolic function and normalizes MITO function and rate of ATP synthesis in dogs with heart failure (HF). In this study, we examined the effects of long-term treatment with ELA on protein levels of 4-HNE adducts and ALDH2 in LV myocardium of dogs with coronary microembolization-induced HF (LV ejection fraction ~30%). Methods: LV tissue from 14 HF dogs randomized to 3 months monotherapy with subcutaneous injections of ELA (0.5 mg/kg once daily, n=7) or saline (control, CTR, n=7) and tissue from 6 normal (NL) dogs was used in the study. Using LV tissue extracts, 4-HNE protein adducts levels were quantified using a commercially available Elisa kit and expressed as ng/mg. In isolated MITO fractions prepared from LV tissue, protein levels of ALDH2 and porin, the latter used as an internal loading control, were determined by Western blotting coupled with Chemiluminescence. Band intensity was expressed in densitometric units (DU). Results: No changes in protein level of porin was observed among the 3 study groups (NL: 0.26±0.02; CTR: 0.24±0.01; BEN: 0.26±0.01 DU). 4-HNE protein adducts levels were increased in CTR dogs compared to NL dogs and treatment with ELA partially restored 4-HNE to near normal levels (NL: 185±21; CTR: 399±35*; ELA: 252 ± 18† ng/mg, *=p<0.05 vs. NL; †=p<0.05 vs. CTR). Compared to NL, dogs, ALDH2 protein levels were significantly reduced in HF CTR dogs (0.49±0.02 vs. 1.16±0.10; p<0.05). Treatment with ELA significantly increased ALDH2 protein compared to untreated CTR (0.74±0.02 DU, p<0.05). Conclusions: Long-term therapy with ELA normalizes ALDH2 and 4-HNE levels in LV myocardium of dogs with HF. Improved protein levels of ALDH2 in HF after therapy with ELA can account, in part, for the observed improvement of global LV function elicited by long-term therapy with ELA.

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