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Yang P, Su W, Wang L, Xu F, Kong Y, Long J. From aldehyde metabolism to delay aging: targeting ALDH2 as a novel strategy. Free Radic Biol Med 2025; 236:70-86. [PMID: 40349798 DOI: 10.1016/j.freeradbiomed.2025.05.389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 04/19/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025]
Abstract
Aldehydes are molecules that are commonly found in both human physiology and the environment. The accumulation of these substances can lead to the cross-linking of intracellular DNA and proteins, thereby disrupting cellular function and contributing to the processes of premature aging and age-related diseases. Aldehyde dehydrogenase 2 (ALDH2), the key member of ALDH family, is an enzyme responsible for aldehyde metabolism, composed of four identical subunits located within the mitochondrial matrix. Its primary role is to catalyze the oxidation of aldehydes, resulting in the formation of their corresponding acid metabolites. This paper presents a succinct overview of the sources and metabolic pathways of key aldehydes within the human body, compares the various primary enzymes involved in aldehyde metabolism, and explores the structural and functional characteristics of ALDH2. Furthermore, ALDH2 is proposed as a potential therapeutic target for addressing aging and associated diseases. The discussion also includes prospective research avenues, particularly focusing on ALDH2 agonists and aldehyde scavengers designed to enhance the clearance of reactive aldehydes and safeguard cellular functions, thereby mitigating aldehyde-induced cellular damage and potentially delaying the aging process.
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Affiliation(s)
- Peng Yang
- Xi'an Key Laboratory of Aging Biology, Institude of Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710116, China
| | - Wu Su
- Xi'an Key Laboratory of Aging Biology, Institude of Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710116, China
| | - Lizhuo Wang
- Xi'an Key Laboratory of Aging Biology, Institude of Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710116, China
| | - Fanding Xu
- Xi'an Key Laboratory of Aging Biology, Institude of Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710116, China
| | - Yu Kong
- Xi'an Key Laboratory of Aging Biology, Institude of Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710116, China
| | - Jiangang Long
- Xi'an Key Laboratory of Aging Biology, Institude of Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710116, China.
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Tahiliani H, Dhayalan A, Li MC, Hsieh HP, Coumar MS. Aldehyde dehydrogenases as drug targets for cancer: SAR and structural biology aspects for inhibitor design. Bioorg Chem 2025; 154:108019. [PMID: 39689509 DOI: 10.1016/j.bioorg.2024.108019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/20/2024] [Accepted: 11/28/2024] [Indexed: 12/19/2024]
Abstract
Aldehydes are organic compounds containing a carbonyl group found exogenously or produced by normal metabolic processes and their accumulation can lead to toxicity if not cleared. Aldehyde dehydrogenases (ALDHs) are NAD(P)+-dependent enzymes that catalyze the oxidation of such aldehydes and prevent their accumulation. Along with this primary detoxification function, the known 19 human isoforms of ALDHs, which act on different substrates, are also involved in various physiological and developmental processes. Functional alterations of ALDHs via mutations or expression levels cause various disease conditions, including many different cancer types like lung, ovarian, etc. These properties make this family of enzymes an ideal therapeutic and prognostic target for drug development. However, sequence similarities between the ALDH isoforms force the need to design inhibitors for a specific isoform using the differences in the substrate-binding sites of each protein. This has resulted in developing isoform-specific inhibitors, especially for ALDH1A1, ALDH2, and ALDH3A1, which are implicated in various cancers. In this review, we briefly outline the functional roles of the different isoforms of the ALDH family members, their role in cancer and discuss the various selective inhibitors that have been developed for the ALDH1A1 and ALDH3A1 enzymes, along with a detailed examination of the respective structure-activity relationship (SAR) studies available. From the available SAR and structural biology data, insights into the functional groups and interactions necessary to develop selective inhibitors for ALDH1A1 and ALDH3A1 are highlighted, which can act as a guide for developing more potent and selective inhibitors of ALDH isoforms.
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Affiliation(s)
- Himanshu Tahiliani
- Department of Bioinformatics, School of Life Scicnces, Pondicherry University, Pondicherry 605014, India
| | - Arunkumar Dhayalan
- Department of Biotechnology, School of Life Sciences, Pondicherry University, Pondicherry 605014, India
| | - Mu-Chun Li
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC; Biomedical Translation Research Center, Academia Sinica, Taipei City 115202, Taiwan, ROC
| | - Hsing-Pang Hsieh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC; Biomedical Translation Research Center, Academia Sinica, Taipei City 115202, Taiwan, ROC; Department of Chemistry, National Tsing Hua University, Hsinchu City 300044, Taiwan, ROC
| | - Mohane Selvaraj Coumar
- Department of Bioinformatics, School of Life Scicnces, Pondicherry University, Pondicherry 605014, India.
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Chen J, Chen W, Zhang J, Zhao H, Cui J, Wu J, Shi A. Dual effects of endogenous formaldehyde on the organism and drugs for its removal. J Appl Toxicol 2024; 44:798-817. [PMID: 37766419 DOI: 10.1002/jat.4546] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/25/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023]
Abstract
Endogenous formaldehyde (FA) is produced in the human body via various mechanisms to preserve healthy energy metabolism and safeguard the organism. However, endogenous FA can have several negative effects on the body through epigenetic alterations, including cancer growth promotion; neuronal, hippocampal and endothelial damages; atherosclerosis acceleration; haemopoietic stem cell destruction and haemopoietic cell production reduction. Certain medications with antioxidant effects, such as glutathione, vitamin E, resveratrol, alpha lipoic acid and polyphenols, lessen the detrimental effects of endogenous FA by reducing oxidative stress, directly scavenging endogenous FA or promoting its degradation. This study offers fresh perspectives for managing illnesses associated with endogenous FA exposure.
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Affiliation(s)
- Jiaxin Chen
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, China
| | - Wenhui Chen
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, China
| | - Jinjia Zhang
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, China
| | - Huanhuan Zhao
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, China
| | - Ji Cui
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, China
| | - Junzi Wu
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, China
- Department of Basic Medical, Yunnan University of Chinese Medicine, Kunming, China
| | - Anhua Shi
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, China
- Department of Basic Medical, Yunnan University of Chinese Medicine, Kunming, China
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Zhu R, Chen H, Liu M, Xu Y, Jiang W, Si X, Yi L, Gu Y, Ren D, Wang J. Nontargeted screening of aldehydes and ketones by chemical isotope labeling combined with ultra-high performance liquid chromatography-high resolution mass spectrometry followed by hybrid filtering of features. J Chromatogr A 2023; 1708:464332. [PMID: 37703764 DOI: 10.1016/j.chroma.2023.464332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/19/2023] [Accepted: 08/24/2023] [Indexed: 09/15/2023]
Abstract
Aldehydes and ketones are important carbonyl compounds that are widely present in foodstuffs, biological organisms and human living environment. However, it is still challenging to comprehensively detect and capture them using liquid chromatography - mass spectrometry. In this work, a chemical isotope labeling (CIL) coupled with ultra-high performance liquid chromatography - high resolution mass spectrometry (UHPLC-HRMS) strategy was developed for the capture and detection of this class of compounds. 2,4-Dinitrophenylhydrazine (DNPH) and isotope-labeled DNPH (DNPH-d3) were utilized to selectively label the target analytes. To address the difficulties in processing UHPLC-HRMS data, a post-acquisition data processing method called MSFilter was proposed to facilitate the screening and identification aldehydes and ketones in complex matrices. The MSFilter consists of four independent filters, namely statistical characteristic-based filtering, mass defect filtering, CIL paired peaks filtering, and diagnostic fragmentation ion filtering. These filters can be used individually or in combination to eliminate unrelated interfering MS features and efficiently detect DNPH-labeled aldehydes and ketones. The results of a mixture containing 48 model compounds showed that although all individual filtering methods could significantly reduce more than 95% of the raw MS features with acceptable recall rates above 85%, but they had relatively high false positive ratios of over 90%. In comparison, the hybrid filtering method combining four filters is able to eliminate massive interfering features (> 99.5%) with a high recall rate of 81.25% and a much lower false positive ratio of 15.22%. By implementing the hybrid filtering method in MSFilter, a total of 154 features were identified as potential signals of CCs from the original 45,961 features of real tobacco samples, of which 70 were annotated. We believe that the proposed strategy is promising to analyze the potential CCs in complex samples by UHPLC-HRMS.
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Affiliation(s)
- Ruizhi Zhu
- Yunnan Key Laboratory of Tobacco Chemistry, R&D Center of China Tobacco Yunnan Industrial Co., Ltd., Kunming 650231, China
| | - Han Chen
- Yunnan Key Laboratory of Tobacco Chemistry, R&D Center of China Tobacco Yunnan Industrial Co., Ltd., Kunming 650231, China; Faculty of Agriculture and Food, Kunming University of Science and Technology, Kunming, 650500, China
| | - Meiyan Liu
- Yunnan Key Laboratory of Tobacco Chemistry, R&D Center of China Tobacco Yunnan Industrial Co., Ltd., Kunming 650231, China; Faculty of Agriculture and Food, Kunming University of Science and Technology, Kunming, 650500, China
| | - Yanqun Xu
- Yunnan Key Laboratory of Tobacco Chemistry, R&D Center of China Tobacco Yunnan Industrial Co., Ltd., Kunming 650231, China
| | - Wei Jiang
- Yunnan Key Laboratory of Tobacco Chemistry, R&D Center of China Tobacco Yunnan Industrial Co., Ltd., Kunming 650231, China
| | - Xiaoxi Si
- Yunnan Key Laboratory of Tobacco Chemistry, R&D Center of China Tobacco Yunnan Industrial Co., Ltd., Kunming 650231, China
| | - Lunzhao Yi
- Faculty of Agriculture and Food, Kunming University of Science and Technology, Kunming, 650500, China
| | - Ying Gu
- Faculty of Agriculture and Food, Kunming University of Science and Technology, Kunming, 650500, China
| | - Dabing Ren
- Faculty of Agriculture and Food, Kunming University of Science and Technology, Kunming, 650500, China.
| | - Juan Wang
- College of Arts and Sciences·Kunming, Kunming, 650221, China.
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Xanthis V, Mantso T, Dimtsi A, Pappa A, Fadouloglou VE. Human Aldehyde Dehydrogenases: A Superfamily of Similar Yet Different Proteins Highly Related to Cancer. Cancers (Basel) 2023; 15:4419. [PMID: 37686694 PMCID: PMC10650815 DOI: 10.3390/cancers15174419] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/30/2023] [Accepted: 09/01/2023] [Indexed: 09/10/2023] Open
Abstract
The superfamily of human aldehyde dehydrogenases (hALDHs) consists of 19 isoenzymes which are critical for several physiological and biosynthetic processes and play a major role in the organism's detoxification via the NAD(P) dependent oxidation of numerous endogenous and exogenous aldehyde substrates to their corresponding carboxylic acids. Over the last decades, ALDHs have been the subject of several studies as it was revealed that their differential expression patterns in various cancer types are associated either with carcinogenesis or promotion of cell survival. Here, we attempt to provide a thorough review of hALDHs' diverse functions and 3D structures with particular emphasis on their role in cancer pathology and resistance to chemotherapy. We are especially interested in findings regarding the association of structural features and their changes with effects on enzymes' functionalities. Moreover, we provide an updated outline of the hALDHs inhibitors utilized in experimental or clinical settings for cancer therapy. Overall, this review aims to provide a better understanding of the impact of ALDHs in cancer pathology and therapy from a structural perspective.
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Affiliation(s)
| | | | | | | | - Vasiliki E. Fadouloglou
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
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Harkin C, Cobice D, Watt J, Kurth MJ, Brockbank S, Bolton S, Johnston F, Strzelecka A, Lamont JV, Moore T, Fitzgerald P, Ruddock MW. Analysis of reactive aldehydes in urine and plasma of type-2 diabetes mellitus patients through liquid chromatography-mass spectrometry: Reactive aldehydes as potential markers of diabetic nephropathy. Front Nutr 2023; 9:997015. [PMID: 36726822 PMCID: PMC9885194 DOI: 10.3389/fnut.2022.997015] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 12/22/2022] [Indexed: 01/17/2023] Open
Abstract
Introduction Diabetes is a major public health issue that is approaching epidemic proportions globally. Diabetes mortality is increasing in all ethnic groups, irrespective of socio-economic class. Obesity is often seen as the main contributor to an increasing prevalence of diabetes. Oxidative stress has been shown to trigger obesity by stimulating the deposition of white adipose tissue. In this study, we measured reactive aldehydes by liquid chromatography-mass spectrometry (LC-MS), in the urine and plasma of type-2 diabetic mellitus (T2DM) patients, as potential surrogates of oxidative stress. Our hypothesis was that reactive aldehydes play a significant role in the pathophysiology of diabetes, and these reactive species, may present potential drug targets for patient treatment. Materials and methods Study participants [N = 86; control n = 26; T2DM n = 32, and diabetic nephropathy (DN) n = 28] were recruited between 2019 and 2020. Urine and blood samples were collected from all participants, including a detailed clinical history, to include patient behaviours, medications, and co-morbidities. Reactive aldehyde concentrations in urine and plasma were measured using pre-column derivatisation and LC-MS, for control, T2DM and DN patients. Results Reactive aldehydes were measured in the urine and plasma of control subjects and patients with T2DM and DN. In all cases, the reactive aldehydes under investigation; 4-HNE, 4-ONE, 4-HHE, pentanal, methylglyoxal, and glyoxal, were significantly elevated in the urine and serum of the patients with T2DM and DN, compared to controls (p < 0.001) (Kruskal-Wallis). Urine and serum reactive aldehydes were significantly correlated (≥0.7) (p < 0.001) (Spearman rho). The concentrations of the reactive aldehydes were significantly higher in plasma samples, when compared to urine, suggesting that plasma is the optimal matrix for screening T2DM and DN patients for oxidative stress. Conclusion Reactive aldehydes are elevated in the urine and plasma of T2DM and DN patients. Reactive aldehydes have been implicated in the pathobiology of T2DM. Therefore, if reactive aldehydes are surrogates of oxidative stress, these reactive aldehyde species could be therapeutic targets for potential drug development.
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Affiliation(s)
- Carla Harkin
- Biomedical Sciences Research Institute, Ulster University, Coleraine, United Kingdom
| | - Diego Cobice
- Biomedical Sciences Research Institute, Ulster University, Coleraine, United Kingdom
| | - Joanne Watt
- Clinical Studies Group, Randox Laboratories Ltd., Randox Science Park, Antrim, United Kingdom
| | - Mary Jo Kurth
- Clinical Studies Group, Randox Laboratories Ltd., Randox Science Park, Antrim, United Kingdom
| | - Simon Brockbank
- Clinical Studies Group, Randox Laboratories Ltd., Randox Science Park, Antrim, United Kingdom
| | - Stephanie Bolton
- Renal Unit, Antrim Area Hospital, Northern Health and Social Care Trust, Antrim, United Kingdom
| | - Frances Johnston
- Renal Unit, Antrim Area Hospital, Northern Health and Social Care Trust, Antrim, United Kingdom
| | - Anna Strzelecka
- Diabetic Services, Whiteabbey Hospital, Northern Health and Social Care Trust, Newtownabbey, United Kingdom
| | - John V. Lamont
- Clinical Studies Group, Randox Laboratories Ltd., Randox Science Park, Antrim, United Kingdom
| | - Tara Moore
- Biomedical Sciences Research Institute, Ulster University, Coleraine, United Kingdom
| | - Peter Fitzgerald
- Clinical Studies Group, Randox Laboratories Ltd., Randox Science Park, Antrim, United Kingdom
| | - Mark W. Ruddock
- Clinical Studies Group, Randox Laboratories Ltd., Randox Science Park, Antrim, United Kingdom,*Correspondence: Mark W. Ruddock,
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Sana SRGL, Chen GM, Lv Y, Guo L, Li EY. Metabonomics fingerprint of volatile organic compounds in serum and urine of pregnant women with gestational diabetes mellitus. World J Diabetes 2022; 13:888-899. [PMID: 36312001 PMCID: PMC9606790 DOI: 10.4239/wjd.v13.i10.888] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 07/23/2022] [Accepted: 09/12/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is a metabolic disease with an increasing annual incidence rate. Our previous observational study found that pregnant women with GDM had mild cognitive decline.
AIM To analyze the changes in metabonomics in pregnant women with GDM and explore the mechanism of cognitive function decline.
METHODS Thirty GDM patients and 30 healthy pregnant women were analyzed. Solid-phase microextraction gas chromatography/mass spectrometry was used to detect organic matter in plasma and urine samples. Statistical analyses were conducted using principal component analysis and partial least squares discriminant analysis.
RESULTS Differential volatile metabolites in the serum of pregnant women with GDM included hexanal, 2-octen-1-ol, and 2-propanol. Differential volatile metabolites in the urine of these women included benzene, cyclohexanone, 1-hexanol, and phenol. Among the differential metabolites, the conversion of 2-propanol to acetone may further produce methylglyoxal. Therefore, 2-propanol may be a potential marker for serum methylglyoxal.
CONCLUSION 2-propanol may be a potential volatile marker to evaluate cognitive impairment in pregnant women with GDM.
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Affiliation(s)
- Si-Ri-Gu-Leng Sana
- Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Guang-Min Chen
- Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yang Lv
- Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Lei Guo
- Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - En-You Li
- Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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A novel approach for the bioanalysis of short-lived aldehydes. Bioanalysis 2022; 14:1317-1326. [PMID: 36541259 DOI: 10.4155/bio-2022-0187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: The instability of aldehydes in biological matrices is associated with their reactions with thiol and amino moieties in proteins. This chemical reaction is reversible by nature and highly pH dependent. Method: A novel approach that includes protein precipitation with an acidic solution of acetonitrile/water/formic acid (85/14/1; v/v/v) was developed to efficiently recover Aldehyde-1 from plasma by shifting the equilibrium toward the formation of the free form. Results: This enabled the support of two GLP studies where Aldehyde-1 was administered to mice. The recovery of Aldehyde-1 from plasma exceeded 88% at three concentration levels. Plasma stability was confirmed at ambient conditions for 24 h and in the freezer for at least 43 (-20°C) and 64 (-70°C) days.
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Jin J, Chen J, Wang Y. Aldehyde dehydrogenase 2 and arrhythmogenesis. Heart Rhythm 2022; 19:1541-1547. [PMID: 35568135 DOI: 10.1016/j.hrthm.2022.05.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 05/03/2022] [Accepted: 05/06/2022] [Indexed: 12/25/2022]
Abstract
Cardiac arrhythmia is a common cardiovascular disease that leads to considerable economic burdens and significant global public health challenges. Despite the remarkable progress made in recent decades, antiarrhythmic therapy remains suboptimal. Aldehyde dehydrogenase 2 (ALDH2), a critical detoxifying enzyme, catalyzes toxic aldehydes and protects individuals from damages caused by oxidative stress. Accumulating evidence has demonstrated that ALDH2 activation has potential antiarrhythmic benefits. The correlation between ALDH2 deficiency and arrhythmogenesis has been widely recognized. In this review, we summarize recent researches on the potential roles of ALDH2 activation and antiarrhythmic protection, as well as the role played by the ALDH2*2 polymorphism (rs671) in promoting arrhythmic risk. Additionally, we discuss important new findings illustrating the use of ALDH2 activators, which may prove to be promising antiarrhythmic therapy agents.
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Affiliation(s)
- Junyan Jin
- Department of Cardiology, Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Jieying Chen
- Department of Cardiology, Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Yaping Wang
- Department of Cardiology, Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.
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Zhu Y, Liu M, Fu W, Bo Y. Association Between Serum Aldehydes and Hypertension in Adults: A Cross-Sectional Analysis of the National Health and Nutrition Examination Survey. Front Cardiovasc Med 2022; 9:813244. [PMID: 35321099 PMCID: PMC8934859 DOI: 10.3389/fcvm.2022.813244] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 02/01/2022] [Indexed: 11/13/2022] Open
Abstract
Background Exposure to ambient pollutants and chemicals were found to be associated with increased risk of hypertension. However, the relationship between the increased aldehyde exposure and hypertension are still unclear. This study aimed to investigate the potential associations of serum aldehydes levels with prevalent hypertension. Methods A total of 1,733 U.S. adults with data on hypertension outcome and serum aldehydes measurement from the National Health and Nutrition Examination Survey 2013–2014 were included. The serum levels of aldehydes were measured via an automated analytical method using solid phase microextraction gas chromatography and high-resolution mass spectrometry. Multivariate logistic regression models were adopted to assess the associations between six selected aldehydes exposure (benzaldehyde, butyraldehyde, heptanaldehyde, hexanaldehyde, isopentanaldehyde, and propanaldehyde) and prevalence of hypertension. Results The mean age was 48.0 ± 16.7 years and an approximately equivalent of sex distribution was observed (female 49.9%). There seems to be a numerically higher level of hexanaldehyde in participants with hypertension when compared to participants without hypertension (2.6 ± 3.9 ng/mL vs. 2.3 ± 1.1 ng/mL). After adjusting for potential confounders, the odds ratio (OR) for hypertension was 2.15 [95% confidence interval (CI): 1.33–3.51] in participants from the highest quartile of serum hexanaldehyde concentration in comparison to those from the lowest quartile. Subgroup analyses and sensitivity analyses showed generally similar results. Conclusion In summary, current evidence suggested that increased serum hexanaldehyde level was positively associated with prevalent hypertension in U.S. adults.
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Affiliation(s)
- Yongjian Zhu
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Yongjian Zhu
| | - Mingjing Liu
- Department of Clinical Medicine, Sanquan College of Xinxiang Medical University, Xinxiang, China
| | - Wanrong Fu
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yacong Bo
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Peng Z, Luo Y, Song C, Zhang Y, Sun S, Yu A, Zhang W, Zhao W, Zhang S, Xie J. A novel methodology and strategy to detect low molecular aldehydes in beer based on charged microdroplet driving online derivatization and high resolution mass spectrometry. Food Chem 2022; 383:132380. [PMID: 35180599 DOI: 10.1016/j.foodchem.2022.132380] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 01/11/2022] [Accepted: 02/05/2022] [Indexed: 11/25/2022]
Abstract
The concentration of aldehydes is one of the important indicators in the food quality and safety. To efficiently analyze the four aldehydes (methanal, ethanal, propanal and n-butanal) in beer, charged microdroplet driving online derivatization apparatus coupled with high resolution mass spectrometry was firstly developed. Utilizing the high-speed reaction accelerated by microdroplets, the offline derivative of aldehydes with 2,4-dinitrophenylhydrazine in bulk was transferred into online derivatization. The developed method featured acceptable linearities (R2 ≥ 0.95), high sensitivities (LODs at ng mL-1 level) and qualified precisions (RSDs ≤ 8.4 %) for target compounds. Four aldehydes with trace amount were successfully determined in beer. The results indicated that the novel online analytical strategy did not require complex sample preparation and could conduct simple, rapid, sensitive detection of small molecule aldehydes with high throughput in beer or even other food samples.
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Affiliation(s)
- Zifang Peng
- College of Chemistry, Zhengzhou University, Zhengzhou 450001, PR China
| | - Yake Luo
- College of Chemistry, Zhengzhou University, Zhengzhou 450001, PR China
| | - Chenchen Song
- College of Chemistry, Zhengzhou University, Zhengzhou 450001, PR China
| | - Yanhao Zhang
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, PR China.
| | - Shihao Sun
- Center of Advanced Analysis and Gene Sequencing, Zhengzhou University, Zhengzhou 450001, PR China
| | - Ajuan Yu
- College of Chemistry, Zhengzhou University, Zhengzhou 450001, PR China
| | - Wenfen Zhang
- College of Chemistry, Zhengzhou University, Zhengzhou 450001, PR China
| | - Wuduo Zhao
- College of Chemistry, Zhengzhou University, Zhengzhou 450001, PR China.
| | - Shusheng Zhang
- College of Chemistry, Zhengzhou University, Zhengzhou 450001, PR China
| | - Jianping Xie
- Center of Advanced Analysis and Gene Sequencing, Zhengzhou University, Zhengzhou 450001, PR China
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Crawford RA, Gilardoni E, Monroe TB, Regazzoni L, Anderson EJ, Doorn JA. Characterization of Catecholaldehyde Adducts with Carnosine and l-Cysteine Reveals Their Potential as Biomarkers of Catecholaminergic Stress. Chem Res Toxicol 2021; 34:2184-2193. [PMID: 34506109 PMCID: PMC8527522 DOI: 10.1021/acs.chemrestox.1c00153] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
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Monoamine oxidase
(MAO) catalyzes the oxidative deamination of
dopamine and norepinephrine to produce 3,4-dihydroxyphenylacetaldehyde
(DOPAL) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), respectively.
Both of these aldehydes are potently cytotoxic and have been implicated
in pathogenesis of neurodegenerative and cardiometabolic disorders.
Previous work has demonstrated that both the catechol and aldehyde
moieties of DOPAL are reactive and cytotoxic via their propensity
to cause macromolecular cross-linking. With certain amines, DOPAL
likely reacts via a Schiff base before oxidative activation of the
catechol and rearrangement to a stable indole product. Our current
work expands on this reactivity and includes the less-studied DOPEGAL.
Although we confirmed that antioxidants mediated DOPAL’s reactivity
with carnosine and N-acetyl-l-lysine, antioxidants
had no effect on reactivity with l-cysteine. Therefore, we
propose a non-oxidative mechanism where, following Schiff base formation,
the thiol of l-cysteine reacts to form a thiazolidine. Similarly,
we demonstrate that DOPEGAL forms a putative thiazolidine conjugate
with l-cysteine. We identified and characterized both l-cysteine conjugates via HPLC-MS and additionally identified
a DOPEGAL adduct with carnosine, which is likely an Amadori product.
Furthermore, we were able to demonstrate that these conjugates are
produced in biological systems via MAO after treatment of the cell
lysate with norepinephrine or dopamine along with the corresponding
nucleophiles (i.e., l-cysteine and carnosine). As it has
been established that metabolic and oxidative stress leads to increased
MAO activity and accumulation of DOPAL and DOPEGAL, it is conceivable
that conjugation of these aldehydes to carnosine or l-cysteine
is a newly identified detoxification pathway. Furthermore, the ability
to characterize these adducts via analytical techniques reveals their
potential for use as biomarkers of dopamine or norepinephrine metabolic
disruption.
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Affiliation(s)
- Rachel A Crawford
- Department of Pharmaceutical Sciences & Experimental Therapeutics, College of Pharmacy, University of Iowa, 180 South Grand Avenue, Iowa City, Iowa 52242, United States
| | - Ettore Gilardoni
- Department of Pharmaceutical Sciences & Experimental Therapeutics, College of Pharmacy, University of Iowa, 180 South Grand Avenue, Iowa City, Iowa 52242, United States.,Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, Milan 20133, Italy
| | - T Blake Monroe
- Department of Pharmaceutical Sciences & Experimental Therapeutics, College of Pharmacy, University of Iowa, 180 South Grand Avenue, Iowa City, Iowa 52242, United States
| | - Luca Regazzoni
- Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, Milan 20133, Italy
| | - Ethan J Anderson
- Department of Pharmaceutical Sciences & Experimental Therapeutics, College of Pharmacy, University of Iowa, 180 South Grand Avenue, Iowa City, Iowa 52242, United States.,Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, United States
| | - Jonathan A Doorn
- Department of Pharmaceutical Sciences & Experimental Therapeutics, College of Pharmacy, University of Iowa, 180 South Grand Avenue, Iowa City, Iowa 52242, United States
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Ostadkarampour M, Putnins EE. Monoamine Oxidase Inhibitors: A Review of Their Anti-Inflammatory Therapeutic Potential and Mechanisms of Action. Front Pharmacol 2021; 12:676239. [PMID: 33995107 PMCID: PMC8120032 DOI: 10.3389/fphar.2021.676239] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 04/06/2021] [Indexed: 12/18/2022] Open
Abstract
Chronic inflammatory diseases are debilitating, affect patients' quality of life, and are a significant financial burden on health care. Inflammation is regulated by pro-inflammatory cytokines and chemokines that are expressed by immune and non-immune cells, and their expression is highly controlled, both spatially and temporally. Their dysregulation is a hallmark of chronic inflammatory and autoimmune diseases. Significant evidence supports that monoamine oxidase (MAO) inhibitor drugs have anti-inflammatory effects. MAO inhibitors are principally prescribed for the management of a variety of central nervous system (CNS)-associated diseases such as depression, Alzheimer's, and Parkinson's; however, they also have anti-inflammatory effects in the CNS and a variety of non-CNS tissues. To bolster support for their development as anti-inflammatories, it is critical to elucidate their mechanism(s) of action. MAO inhibitors decrease the generation of end products such as hydrogen peroxide, aldehyde, and ammonium. They also inhibit biogenic amine degradation, and this increases cellular and pericellular catecholamines in a variety of immune and some non-immune cells. This decrease in end product metabolites and increase in catecholamines can play a significant role in the anti-inflammatory effects of MAO inhibitors. This review examines MAO inhibitor effects on inflammation in a variety of in vitro and in vivo CNS and non-CNS disease models, as well as their anti-inflammatory mechanism(s) of action.
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Affiliation(s)
- Mahyar Ostadkarampour
- Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, BC, Canada
| | - Edward E Putnins
- Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, BC, Canada
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14
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Babanejad N, Kandalam U, Ahmad R, Omidi Y, Omidian H. Abuse-deterrent properties and cytotoxicity of poly(ethylene oxide) after thermal tampering. Int J Pharm 2021; 600:120481. [PMID: 33766634 DOI: 10.1016/j.ijpharm.2021.120481] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/28/2021] [Accepted: 03/06/2021] [Indexed: 12/18/2022]
Abstract
Poly(ethylene oxide) (PEO) is the most common deterring agent used in the abuse-deterrent formulations (ADFs). In this study, we investigated the PEO's abuse-deterrent properties and its potential cytotoxicity after being heated at high temperatures (80 °C and 180 °C). The results indicated a significant loss in both crush and extraction resistance features of the polymer, which is primarily associated with the polymer degradation at the higher temperatures. The heat-treated PEO at the high temperature was also found to lose its controlled-release feature, upon which over 80% of the drug was released after one hour in the simulated gastric fluid. The cytotoxicity of the PEO was further assessed to evaluate the safety of the polymer following the thermal treatment. Our findings revealed a substantial loss in the viability of the cells exposed to the PEO treated at higher temperatures. Taken all, heating PEO at high temperatures can lead to a significant loss in both the crush/extraction resistance characteristics and the safety of the polymer. These findings reemphasize the fact that more appropriate and stricter test and regulations will be needed to assure that the abuse deterrent formulations are safe and effective under severe conditions of abuse.
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Affiliation(s)
- Niloofar Babanejad
- College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Umadevi Kandalam
- College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Rand Ahmad
- College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Yadollah Omidi
- College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Hamid Omidian
- College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA.
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15
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Gianazza E, Brioschi M, Martinez Fernandez A, Casalnuovo F, Altomare A, Aldini G, Banfi C. Lipid Peroxidation in Atherosclerotic Cardiovascular Diseases. Antioxid Redox Signal 2021; 34:49-98. [PMID: 32640910 DOI: 10.1089/ars.2019.7955] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Significance: Atherosclerotic cardiovascular diseases (ACVDs) continue to be a primary cause of mortality worldwide in adults aged 35-70 years, occurring more often in countries with lower economic development, and they constitute an ever-growing global burden that has a considerable socioeconomic impact on society. The ACVDs encompass diverse pathologies such as coronary artery disease and heart failure (HF), among others. Recent Advances: It is known that oxidative stress plays a relevant role in ACVDs and some of its effects are mediated by lipid oxidation. In particular, lipid peroxidation (LPO) is a process under which oxidants such as reactive oxygen species attack unsaturated lipids, generating a wide array of oxidation products. These molecules can interact with circulating lipoproteins, to diffuse inside the cell and even to cross biological membranes, modifying target nucleophilic sites within biomolecules such as DNA, lipids, and proteins, and resulting in a plethora of biological effects. Critical Issues: This review summarizes the evidence of the effect of LPO in the development and progression of atherosclerosis-based diseases, HF, and other cardiovascular diseases, highlighting the role of protein adduct formation. Moreover, potential therapeutic strategies targeted at lipoxidation in ACVDs are also discussed. Future Directions: The identification of valid biomarkers for the detection of lipoxidation products and adducts may provide insights into the improvement of the cardiovascular risk stratification of patients and the development of therapeutic strategies against the oxidative effects that can then be applied within a clinical setting.
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Affiliation(s)
- Erica Gianazza
- Proteomics Unit, Monzino Cardiology Center IRCCS, Milan, Italy
| | - Maura Brioschi
- Proteomics Unit, Monzino Cardiology Center IRCCS, Milan, Italy
| | | | | | | | - Giancarlo Aldini
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Cristina Banfi
- Proteomics Unit, Monzino Cardiology Center IRCCS, Milan, Italy
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16
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Plescia J, De Cesco S, Patrascu MB, Kurian J, Di Trani J, Dufresne C, Wahba AS, Janmamode N, Mittermaier AK, Moitessier N. Integrated Synthetic, Biophysical, and Computational Investigations of Covalent Inhibitors of Prolyl Oligopeptidase and Fibroblast Activation Protein α. J Med Chem 2019; 62:7874-7884. [PMID: 31393718 DOI: 10.1021/acs.jmedchem.9b00642] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Jessica Plescia
- Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada
| | - Stéphane De Cesco
- Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada
| | - Mihai Burai Patrascu
- Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada
| | - Jerry Kurian
- Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada
| | - Justin Di Trani
- Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada
| | - Caroline Dufresne
- Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada
| | - Alexander S. Wahba
- Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada
| | - Naëla Janmamode
- Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada
| | - Anthony K. Mittermaier
- Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada
| | - Nicolas Moitessier
- Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada
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17
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Contente ML, Paradisi F. Transaminase‐Catalyzed Continuous Synthesis of Biogenic Aldehydes. Chembiochem 2019; 20:2830-2833. [DOI: 10.1002/cbic.201900356] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Martina L. Contente
- School of ChemistryUniversity of Nottingham University Park Nottingham NG7 2RD UK
| | - Francesca Paradisi
- School of ChemistryUniversity of Nottingham University Park Nottingham NG7 2RD UK
- Department of Chemistry and BiochemistryUniversity of Bern Freiestrasse 3 3012 Bern Switzerland
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18
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Ahmed Laskar A, Younus H. Aldehyde toxicity and metabolism: the role of aldehyde dehydrogenases in detoxification, drug resistance and carcinogenesis. Drug Metab Rev 2019; 51:42-64. [DOI: 10.1080/03602532.2018.1555587] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Amaj Ahmed Laskar
- Enzymology Laboratory, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India
| | - Hina Younus
- Enzymology Laboratory, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India
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19
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Burcham PC. Carbonyl scavengers as pharmacotherapies in degenerative disease: Hydralazine repurposing and challenges in clinical translation. Biochem Pharmacol 2018; 154:397-406. [PMID: 29883705 DOI: 10.1016/j.bcp.2018.06.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 06/04/2018] [Indexed: 12/26/2022]
Abstract
During cellular metabolism, spontaneous oxidative damage to unsaturated lipids generates many electrophilic carbonyl compounds that readily attack cell macromolecules, forming adducts that are potential drivers of tissue dysfunction. Since such damage is heightened in many degenerative conditions, researchers have assessed the efficacy of nucleophilic carbonyl-trapping drugs in animal models of such disorders, anticipating that they will protect tissues by intercepting toxic lipid-derived electrophiles (LDEs) within cells. This Commentary explores recent animal evidence for carbonyl scavenger efficacy in two disparate yet significant conditions known to involve LDE production, namely spinal cord injury (SCI) and alcoholic liver disease (ALD). Primary emphasis is placed on studies that utilised hydralazine, a clinically-approved "broad-spectrum" scavenger known to trap multiple LDEs. In addition to reviewing recent studies of hydralazine efficacy in animal SCI and ALD models, the Commentary reviews new insights concerning novel lifespan- and healthspan-extending properties of hydralazine obtained during studies in model invertebrate organisms, since the mechanisms involved seem of likely benefit during the treatment of degenerative disease. Finally, noting that human translation of the histoprotective properties of hydralazine have been limited, the final section of the Commentary will address two obstacles that hamper clinical translation of LDE-trapping therapies while also suggesting potential strategies for overcoming these problems.
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Affiliation(s)
- Philip C Burcham
- Discipline of Pharmacology, School of Biomedical Science, The University of Western Australia, Crawley, WA 6007, Australia.
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