Acrolein: A Potential Mediator of Oxidative Damage in Diabetic Retinopathy

Alfarhan, Moaddey; Jafari, Eissa; Narayanan, S. Priya

doi:10.3390/biom10111579

Cited by 27 publications

(23 citation statements)

References 142 publications

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“…RCS are spontaneously formed in the metabolism and are considered as dangerous molecules because they can modify and impair the function of DNA, proteins and lipids [ 24 , [35] , [36] , [37] , [38] , [39] ] In recent years, it was shown that the loss of a specific RCS detoxifying enzyme led to an increase of a preferred RCS, which subsequently altered the glucose metabolism and mediated the development of diabetic organ complications. Specifically, loss of glo1 in zebrafish increased MG concentrations and was accompanied by an impaired glucose tolerance [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

Accumulation of acetaldehyde in aldh2.1 zebrafish causes increased retinal angiogenesis and impaired glucose metabolism

Wohlfart

Lou²,

Middel³

et al. 2022

Redox Biology

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Reactive carbonyl species (RCS) are spontaneously formed in the metabolism and modify and impair the function of DNA, proteins and lipids leading to several organ complications. In zebrafish, knockout of the RCS detoxifying enzymes glyoxalase 1 (Glo 1), aldehyde dehydrogenase 3a1 (Aldh3a1) and aldo-ketoreductase 1a1a (Akr1a1a) showed a signature of elevated RCS which specifically regulated glucose metabolism, hyperglycemia and diabetic organ damage. aldh2.1 was compensatory upregulated in glo1 −/− animals and therefore this study aimed to investigate the detoxification ability for RCS by Aldh2.1 in zebrafish independent of ethanol exposure. aldh2.1 knockout zebrafish were generated using CRISPR/Cas9 and subsequently analyzed on a histological, metabolomic and transcriptomic level. aldh2.1 −/− zebrafish displayed increased endogenous acetaldehyde (AA) inducing an increased angiogenesis in retinal vasculature. Expression and pharmacological interventional studies identified an imbalance of c -Jun N-terminal kinase (JNK) and p38 MAPK induced by AA, which mediate an activation of angiogenesis. Moreover, increased AA in aldh2.1 −/− zebrafish did not induce hyperglycemia, instead AA inhibited the expression of glucokinase ( gck) and glucose-6-phosphatase ( g6pc) , which led to an impaired glucose metabolism. In conclusion, the data have identified AA as the preferred substrate for Aldh2.1's detoxification ability, which subsequently causes microvascular organ damage and impaired glucose metabolism.

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Section: Discussionmentioning

confidence: 99%

Accumulation of acetaldehyde in aldh2.1 zebrafish causes increased retinal angiogenesis and impaired glucose metabolism

Wohlfart

Lou²,

Middel³

et al. 2022

Redox Biology

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“…Cyclophosphamide is converted into two bioactive metabolites, 4-hydoxycyclophasphamide and acrolein by hepatic microsomal cytochrome 450 enzyme, 4-hydoxycyclophasphamide that has chemotherapeutic effect whereas acrolein shows toxic effect ( Ludeman, 1999 ; Kern and Kehrer, 2002 ; Arumugam et al., 1997 ). According to Alfarhan et al., 2020 ) the acrolein can directly stimulate mitochondrial oxidative stress via increasing the ROS level and therefore decline the defense mechanism of the cell by lowering the expression of catalase or glutathione. Other statements of this study include that ANT (adenine nucleotide translocase) is facilitated by the ATP/ADP exchange across the inner mitochondrial membrane.…”

Section: Chemotherapy Associated Cognitive Impairment Via Mitochondrial Dysfunction and Oxidative Stress In The Brainmentioning

confidence: 99%

“…The accessibility of electrons in mitochondria was found to be more, which increases the production of superoxide from oxygen. The deficiency of ANT inhibits the mitochondrial respiratory chain function, which further causes oxidative stress via promoting the production of ROS and reducing the expression of mitochondrial antioxidant defense mechanisms ( Luo and Shi, 2005 ; Alfarhan et al., 2020 ). Some studies state that the increased malonaldehyde (MDA) level is an important indicator of lipid peroxidation, acrolein shows a toxic effect by increasing MDA level in the cerebral cortex and reducing the first line protector, most abundant antioxidant glutathione level ( Rashedinia et al., 2015 ) GSH shows a protective effect against various oxidative stress in several diseases like lungs, brain cancer ( Bains and Shaw, 1997 ; Subramaniam et al., 1997 ).…”

Section: Chemotherapy Associated Cognitive Impairment Via Mitochondrial Dysfunction and Oxidative Stress In The Brainmentioning

confidence: 99%

Crosstalk between anticancer drugs and mitochondrial functions

Sahu

Langeh

Singh

et al. 2021

Current Research in Pharmacology and Drug Discovery

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Chemotherapy is an important component of cancer treatment, which has side effects like vomiting, peripheral neuropathy, and numerous organ toxicity but the most significant outcomes of chemotherapy are cognitive impairment, which is mainly referred to as chemobrain or CICI (chemotherapy-induced cognitive impairment). It is characterized by difficulty with language, concentrating, processing speed, learning, and memory, as it affects the hippocampus areas of the brain. Mitochondrial dysfunction and oxidative stress are one of the major mechanisms causing chemobrain. The generation of reactive oxygen species (byproducts of oxidative phosphorylation) mainly occurs in mitochondria that play a prominent role in the induction of oxidative stress. The homeostasis of ROS in the mitochondria is maintained by mitochondrial antioxidant mechanism via enzymes like catalase, glutathione, and superoxide dismutase. Lungs and breast cancer are the two most common types of cancer, which are the most leading cancers in the world with about 4.18 million cases. In this review we exposed the current knowledge regarding chemotherapy-induced oxidative stress and mitochondrial dysfunction to cause cognitive impairment.We especially focused on the antineoplastic agent (ADRIAMYCIN, CYCLOPHOSPHAMIDE), platinum group agent CISPLATIN, antimetabolite agents (METHOTREXATE), and nitrogen mustard agent (CARMUSTINE) which increase oxidative stress and inflammatory markers in the PNS (peripheral nervous system) as well as the central nervous system. We also highlight the behavioural and functional changes in the brain.

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“…The reason might be that acrolein induced mild cognitive impairment, which mimic the early stage of AD (Chen, Lu, et al, 2021 ) and acrolein is a pollutant that can adducted to a wide range of proteins and then affects multiple pathways beyond of ROCK to induce early AD (Moghe et al, 2015 ). The omics data demonstrated that acrolein is related to mitochondrial function, endoplasmic reticulum stress, and immune dysfunction (Alfarhan et al, 2020 ; Chen, Chen, et al, 2021 ; Moghe et al, 2015 ). The exact mechanisms of acrolein toxicity are needed to be further explored.…”

Section: Discussionmentioning

confidence: 99%

Acrolein, an endogenous aldehyde induces synaptic dysfunction in vitro and in vivo: Involvement of RhoA/ROCK2 pathway

Zhu

Wang

et al. 2022

Aging Cell

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Acrolein, an unsaturated aldehyde, is increased in the brain of Alzheimer's disease (AD) patients and identified as a potential inducer of sporadic AD. Synaptic dysfunction, as a typical pathological change occurring in the early stage of AD, is most closely associated with the severity of dementia. However, there remains a lack of clarity on the mechanisms of acrolein inducing AD‐like pathology and synaptic impairment. In this study, acrolein‐treated primary cultured neurons and mice were applied to investigate the effects of acrolein on cognitive impairment and synaptic dysfunction and their signaling mechanisms. In vitro, ROCK inhibitors, Fasudil, and Y27632, could attenuate the axon ruptures and synaptic impairment caused by acrolein. Meanwhile, RNA‐seq distinct differentially expressed genes in acrolein models and initially linked activated RhoA/Rho‐kinase2 (ROCK2) to acrolein‐induced synaptic dysfunction, which could regulate neuronal cytoskeleton and neurite. The Morris water maze test and in vivo field excitatory postsynaptic potential (fEPSP) were performed to evaluate spatial memory and long‐term potential (LTP), respectively. Acrolein induced cognitive impairment and attenuated LTP. Furthermore, the protein level of Synapsin 1 and postsynaptic density 95 (PSD95) and dendritic spines density were also decreased in acrolein‐exposed mice. These changes were improved by ROCK2 inhibitor Fasudil or in ROCK2 +/− mice. Together, our findings suggest that RhoA/ROCK2 signaling pathway plays a critical role in acrolein‐induced synaptic damage and cognitive dysfunction, suggesting inhibition of ROCK2 should benefit to the early AD.

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Acrolein: A Potential Mediator of Oxidative Damage in Diabetic Retinopathy

Cited by 27 publications

References 142 publications

Accumulation of acetaldehyde in aldh2.1 zebrafish causes increased retinal angiogenesis and impaired glucose metabolism

Accumulation of acetaldehyde in aldh2.1 zebrafish causes increased retinal angiogenesis and impaired glucose metabolism

Crosstalk between anticancer drugs and mitochondrial functions

Acrolein, an endogenous aldehyde induces synaptic dysfunction in vitro and in vivo: Involvement of RhoA/ROCK2 pathway

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