Environmental Aldehyde Sources and the Health Implications of Exposure

Sinharoy, Pritam; McAllister, Stacy L.; Vasu, M. A.; Gross, Eric R.

doi:10.1007/978-981-13-6260-6_2

Cited by 48 publications

(33 citation statements)

References 74 publications

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“…Intracellular ROS accumulation leads to lipid membrane peroxidation, oxidative modifications of proteins and DNA damage, ultimately leading to loss of structural function and cell death. 4-Hydroxynonenal (4-HNE), a cytotoxic reactive aldehyde is produced endogenously as a byproduct of the lipid membrane peroxidation and forms protein adducts with amino acid residues that disrupt protein structure and functions 12 – 14 . Studies have shown that 30% of 4-HNE adducted proteins are located in the mitochondria and a majority of them are the members of mitochondrial electron transport chain 15 .…”

Section: Resultsmentioning

confidence: 99%

Perfusion reduces bispecific antibody aggregation via mitigating mitochondrial dysfunction-induced glutathione oxidation and ER stress in CHO cells

Sinharoy

Aziz

Majewska

et al. 2020

Sci Rep

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One major challenge observed for the expression of therapeutic bispecific antibodies (BisAbs) is high product aggregates. Aggregates increase the risk of immune responses in patients and therefore must be removed at the expense of purification yields. BisAbs contain engineered disulfide bonds, which have been demonstrated to form product aggregates, if mispaired. However, the underlying intracellular mechanisms leading to product aggregate formation remain unknown. We demonstrate that impaired glutathione regulation underlies BisAb aggregation formation in a CHO cell process. Aggregate formation was evaluated for the same clonal CHO cell line producing a BisAb using fed-batch and perfusion processes. The perfusion process produced significantly lower BisAb aggregates compared to the fed-batch process. Perfusion bioreactors attenuated mitochondrial dysfunction and ER stress resulting in a favorable intracellular redox environment as indicated by improved reduced to oxidized glutathione ratio. Conversely, mitochondrial dysfunction-induced glutathione oxidation and ER stress disrupted the intracellular redox homeostasis, leading to product aggregation in the fed-batch process. Combined, our results demonstrate that mitochondrial dysfunction and ER stress impaired glutathione regulation leading to higher product aggregates in the fed-batch process. This is the first study to utilize perfusion bioreactors as a tool to demonstrate the intracellular mechanisms underlying product aggregation formation.

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Section: Resultsmentioning

confidence: 99%

Perfusion reduces bispecific antibody aggregation via mitigating mitochondrial dysfunction-induced glutathione oxidation and ER stress in CHO cells

Sinharoy

Aziz

Majewska

et al. 2020

Sci Rep

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Section: Introductionmentioning

confidence: 99%

“…Exposure to endogenous and exogenous aldehydes has emerged as a key contributor to disease pathology in recent years [1,2]. The body is exposed to exogenous reactive aldehydes through such things as tobacco products or alcoholic beverages [2][3][4]. Importantly, aldehydes are also an endogenous product derived from the peroxidation of polyunsaturated fatty acids during oxidative stress and are elevated in acute disease states, such as myocardial reperfusion injury or sepsis, and chronic disease states-for example, diabetes, cancer, or neurodegeneration [5,6].…”

Section: Introductionmentioning

confidence: 99%

TRP Channels as Sensors of Aldehyde and Oxidative Stress

et al. 2021

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The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade that can lead to disease pathophysiology. The body is not only exposed to exogenous aldehydes via tobacco products or alcoholic beverages, but also to endogenous aldehydes triggered by lipid peroxidation. In response to lipid peroxidation from inflammation or organ injury, polyunsaturated fatty acids undergo lipid peroxidation to aldehydes. such as 4-hydroxynonenal. Reactive aldehydes activate TRP channels via aldehyde-induced protein adducts, leading to the release of pro-inflammatory mediators driving the pathophysiology caused by cellular injury, including inflammatory pain and organ reperfusion injury. Recent studies have outlined how aldehyde dehydrogenase 2 protects against aldehyde toxicity through the clearance of toxic aldehydes, indicating that targeting the endogenous aldehyde metabolism may represent a novel treatment strategy. An addition approach can involve targeting specific TRP channel regions to limit the triggering of a cellular cascade induced by aldehydes. In this review, we provide a comprehensive summary of aldehydes, TRP channels, and their interactions, as well as their role in pathological conditions and the different therapeutical treatment options.

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“…Aldehydes are toxic compounds that can be inhaled, consumed, or endogenously produced [1][2][3][4] .…”

Section: Introductionmentioning

confidence: 99%

“…Aldehydes are toxic compounds that can be inhaled, consumed, or endogenously produced 1-4 . Exogenous exposures of aldehydes, such as acetaldehyde and formaldehyde, can occur from sources such as air pollution, cigarette smoke, and alcohol 2 . Endogenous sources of aldehydes, such as 4-hydroxynonenal and malondialdehyde, are produced from lipid peroxidation such as during surgery or organ injury 3, 4 .…”

Section: Introductionmentioning

confidence: 99%

Phenotyping genetic differences in aldehyde dehydrogenase 2 after an alcohol challenge in humans

Rwere

White

Zeng

et al. 2020

Preprint

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Inefficient aldehyde metabolism by an aldehyde dehydrogenase 2 (ALDH2) genetic variant, ALDH2*2 (rs671), increases the risk of esophageal cancer with alcohol consumption. Here we tested the hypothesis that additional genetic differences in ALDH2 besides ALDH2*2 exist resulting in inefficient acetaldehyde metabolism after alcohol consumption. Human volunteers were recruited who self-reported flushing after alcohol. The first stage recruited East Asians and the second stage non-East Asians. After phone screening and ALDH2 sequencing, volunteers were subjected to an alcohol challenge (0.25g/kg). Physiological parameters and breath acetaldehyde levels were assessed. Twenty-six participants were given an alcohol challenge. In the first stage, when comparing the ALDH2*1/*2 genotype to ALDH2*1/*1 genotype, tachycardia (104±3* versus 73±4 beats per minute), increases in facial skin temperature (99.6±0.4* versus 95.9±0.50F), and increases in breath acetaldehyde (peak: 2.1±0.4* versus 0.2±0.3ppm, n=8/group, *p<0.01) occurred after alcohol consumption. In the second stage, heterozygotes for an ALDH2 intron variant (rs4646777, G>A) caused increases in facial skin temperature (98±1* versus 94±1 OF, n=4, *p<0.01) without tachycardia or acetaldehyde accumulation after alcohol consumption. Subjects self-identifying as non-East Asian genotyped with an ALDH2*1/*2 variant also displayed a characteristic ALDH2*1/*2 phenotype after alcohol consumption. Further, ALDH2 point mutations rs747096195 (R101G) and rs190764869 (R114W) showed reduced acetaldehyde metabolism and increases in facial skin temperature after an alcohol challenge relative to wild type ALDH2 subjects. Taken together, we developed a method to non-invasively phenotype genetic differences for ALDH2 in humans including quantifying aldehyde metabolism in single subjects. We also discovered genetic differences besides ALDH2*2 that cause inefficient aldehyde metabolism.

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Environmental Aldehyde Sources and the Health Implications of Exposure

Cited by 48 publications

References 74 publications

Perfusion reduces bispecific antibody aggregation via mitigating mitochondrial dysfunction-induced glutathione oxidation and ER stress in CHO cells

Perfusion reduces bispecific antibody aggregation via mitigating mitochondrial dysfunction-induced glutathione oxidation and ER stress in CHO cells

TRP Channels as Sensors of Aldehyde and Oxidative Stress

Phenotyping genetic differences in aldehyde dehydrogenase 2 after an alcohol challenge in humans

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