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The concentration-dependent effects of a,b-unsaturated alkene derivatives on dopamine transport in striatal synaptosomes (A) and corresponding sulfhydryl content (B). Data are expressed as mean percent control ± SEM and calculated IC 50 's are provided in parentheses. Results show that exposure of synaptosomes to a relatively broad concentration range (1lM10mM) of type-2 alkenes produced parallel, concentration-dependent decreases in synaptosomal transport (A). The decreases in neurotransmitter transport induced by each structural congener were highly correlated (r 2 ! 0.91) to corresponding reductions in sulfhydryl content (B). Although differences in potency were evident, all conjugated analogs exhibited comparable neurotoxic efficacy; that is, each chemical was capable of producing maximal inhibitions of the measured neurochemical parameters and correspondingly depleted sulfhydryl contents. These structure-toxicity data are consistent with previous studies and suggest that nerve terminal toxicity mediated by sulfhydryl adduct formation is a class characteristic of the type-2 alkenes (see also Castegna et al., 2004; Keller et al., 1997a,b; Morel et al., 1999; Pocernich et al., 2001). These data also indicate that the synaptosomal toxicity of the type-2 alkenes is related to their common conjugated a,b-unsaturated structure (see LoPachin et al., 2007a,b; LoPachin et al., unpublished data, for more detailed discussions).
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Conjugated alpha,beta-unsaturated carbonyl derivatives such acrylamide, acrolein, and 4-hydroxy-2-nonenal (HNE) are members of a large class of chemicals known as the type-2 alkenes. Human exposure through diet, occupation, and pollution is pervasive and has been linked to toxicity in most major organs. Evidence suggests that these soft electrophil...
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Context 1
... define the structural requirements of the sulfhydryl- dependent nerve terminal toxicity induced by ACR, we deter- mined the structure-toxicity relationships for a series of conjugated type-2 alkenes and their nonconjugated analogs ( Fig. 2A) and vesicular storage in exposed striatal synaptosomes (LoPachin et al., 2007a,b). Parallel mass spectral analyses and measurements of free sulfhydryl loss (Fig. 2B) confirmed that the type-2 alkene neurotoxicity involved the formation of Michael-type monoadducts with sulfhydryl groups on presynaptic proteins ( Barber and LoPachin, 2004;Barber et al., in press;LoPachin et al., 2004LoPachin et al., , 2007aMorel et al., 1999). Nonconjugated structural analogs such as allyl alcohol and propanal (Fig. 1B) did not affect synaptosomal sulfhydryl content and were devoid of in vitro neurotoxicity. These findings are consistent with results from earlier in vitro studies, which were designed to test the hypothesis that liberation of conjugated a,b-unsaturated carbonyls in oxidatively stressed Results show that exposure of synaptosomes to a relatively broad concentration range (1lM- 10mM) of type-2 alkenes produced parallel, concentration-dependent decreases in synaptosomal transport (A). The decreases in neurotransmitter transport induced by each structural congener were highly correlated (r 2 ! 0.91) to corresponding reductions in sulfhydryl content (B). Although differences in potency were evident, all conjugated analogs exhibited comparable neurotoxic efficacy; that is, each chemical was capable of producing maximal inhibitions of the measured neurochemical parameters and correspondingly depleted sulfhydryl contents. These structure-toxicity data are consistent with previous studies and suggest that nerve terminal toxicity mediated by sulfhydryl adduct formation is a class characteristic of the type-2 alkenes (see also Castegna et al., 2004;Keller et al., 1997a,b;Morel et al., 1999;Pocernich et al., 2001). These data also indicate that the synaptosomal toxicity of the type-2 alkenes is related to their common conjugated a,b-unsaturated structure (see LoPachin et al., 2007a,b; LoPachin et al., unpublished data, for more detailed ...
Context 2
... define the structural requirements of the sulfhydryl- dependent nerve terminal toxicity induced by ACR, we deter- mined the structure-toxicity relationships for a series of conjugated type-2 alkenes and their nonconjugated analogs ( Fig. 2A) and vesicular storage in exposed striatal synaptosomes (LoPachin et al., 2007a,b). Parallel mass spectral analyses and measurements of free sulfhydryl loss (Fig. 2B) confirmed that the type-2 alkene neurotoxicity involved the formation of Michael-type monoadducts with sulfhydryl groups on presynaptic proteins ( Barber and LoPachin, 2004;Barber et al., in press;LoPachin et al., 2004LoPachin et al., , 2007aMorel et al., 1999). Nonconjugated structural analogs such as allyl alcohol and propanal (Fig. 1B) did not affect synaptosomal sulfhydryl content and were devoid of in vitro neurotoxicity. These findings are consistent with results from earlier in vitro studies, which were designed to test the hypothesis that liberation of conjugated a,b-unsaturated carbonyls in oxidatively stressed Results show that exposure of synaptosomes to a relatively broad concentration range (1lM- 10mM) of type-2 alkenes produced parallel, concentration-dependent decreases in synaptosomal transport (A). The decreases in neurotransmitter transport induced by each structural congener were highly correlated (r 2 ! 0.91) to corresponding reductions in sulfhydryl content (B). Although differences in potency were evident, all conjugated analogs exhibited comparable neurotoxic efficacy; that is, each chemical was capable of producing maximal inhibitions of the measured neurochemical parameters and correspondingly depleted sulfhydryl contents. These structure-toxicity data are consistent with previous studies and suggest that nerve terminal toxicity mediated by sulfhydryl adduct formation is a class characteristic of the type-2 alkenes (see also Castegna et al., 2004;Keller et al., 1997a,b;Morel et al., 1999;Pocernich et al., 2001). These data also indicate that the synaptosomal toxicity of the type-2 alkenes is related to their common conjugated a,b-unsaturated structure (see LoPachin et al., 2007a,b; LoPachin et al., unpublished data, for more detailed ...
Citations
... The most applied class of warheads for TCIs are Michael acceptors of the α,β-unsaturated amide type (19), especially as kinase inhibitors in cancer treatment (20)(21)(22). They interact particularly with the nucleophilic anionic thiolates present in cysteine because they are soft electrophiles (8,23). Depending upon the alkene substituent(s), acrylamides exhibit a high tunability of thiol reactivity. ...
Drug discovery involving covalent drugs has a rich history dating back to the 20th century. Despite their longevity, concerns about safety have relegated covalent drug development to the periphery of research focus. The emergence of the groundbreaking concept of Targeted Covalent Inhibition (TCI) has catalyzed a renewed emphasis on covalent medications, elevating their status within the field. This review delves into the landscape of covalent inhibitors, comprehensively examining those developed to date and those currently under investigation. Covalent inhibitors are categorized based on their target proteins, simplifying the understanding of their diverse applications. Notable targets include disease-related proteins such as EGFR, BTK, and SARS-COV-2, signifying the broad therapeutic potential of covalent drugs across various medical domains. One of the most significant aspects discussed is the potential of covalent drugs to overcome the drawbacks associated with conventional therapy, contingent upon the effective consideration of toxicity-related factors. These drugs present a range of advantages, including heightened selectivity, the ability to administer lower doses, and the degradation of previously deemed undruggable proteins. The trajectory of covalent drugs appears promising for drug discovery. By targeting different proteins, these compounds hold the potential to provide effective treatment options in the years to come. The comprehensive exploration of covalent drugs in this review not only contributes to our understanding of their historical evolution and contemporary applications but also underscores their importance as a focal point for advancing therapeutic options and addressing the limitations of current treatment modalities.
... Acrylamide (ACR, C 3 H 5 NO) in its monomeric reactive form is not only a carcinogen [1,2], but also a neurotoxin [3][4][5][6] that due to its high solubility in water and lipids [7] can cross all biological barriers, including the blood-brain barrier and placenta [8,9]. Incidentally, high amounts of ACR are produced in the Maillard reaction that occurs during frying and baking [10][11][12]; hence they are present in breakfast cereals, potato and tortilla chips, crisps, and all types of carbohydrate-rich snacks that are processed at temperatures above 120 • C. It is of great consequence then that these snacks are now being consumed in growing quantities [2,7]. ...
... C: The morning (MA; white bars) and evening (EA; black bars) anticipation in ACR and CON flies on consecutive days of LD. In the CON group, EA was significantly higher than MA (M-W Test: U=2906 (1) , 2311 (2) , 2572 (3) , 2821 (4) , 2361 (5) , 2627 (6) ; p marked on the graph), but neither MA nor EA changed significantly during LD (K-W Test, H MA =4.8, p > 0.5; H EA =6.2, p > 0.5). In ACR flies, significant differences between MA and EA were observed only on some days (M-W Test, ACR10: U=901.5 (1) , 786.5 (2) , 727 (3) , 759 (4) , 713 (5) , p marked on the graph; ACR60: U= 916.5 (1) , 702 (2) , 1026 (3) , 988.5 (4) , 1014 (6) , p marked on the graph; ACR80: U= 1318.5 (1) , 937 (2) , p marked on the graph; ACR110: U= 532 (4) , 414 (5) , p marked on the graph), but MA and/or EA were significantly altered in the course of LD (K-W Test, ACR10: H MA =3.5, p > 0. 5 6. ...
... In the CON group, EA was significantly higher than MA (M-W Test: U=2906 (1) , 2311 (2) , 2572 (3) , 2821 (4) , 2361 (5) , 2627 (6) ; p marked on the graph), but neither MA nor EA changed significantly during LD (K-W Test, H MA =4.8, p > 0.5; H EA =6.2, p > 0.5). In ACR flies, significant differences between MA and EA were observed only on some days (M-W Test, ACR10: U=901.5 (1) , 786.5 (2) , 727 (3) , 759 (4) , 713 (5) , p marked on the graph; ACR60: U= 916.5 (1) , 702 (2) , 1026 (3) , 988.5 (4) , 1014 (6) , p marked on the graph; ACR80: U= 1318.5 (1) , 937 (2) , p marked on the graph; ACR110: U= 532 (4) , 414 (5) , p marked on the graph), but MA and/or EA were significantly altered in the course of LD (K-W Test, ACR10: H MA =3.5, p > 0. 5 6. Box plots showing the mean free-running period (τ) of the locomotor activity rhythm of CON, ACR10, ACR60 and ACR80 flies, estimated by chisquare (χ 2 ) periodogram analysis using data from the first three days of DD (DD3) and 7 days of DD (DD7). ...
... These synaptic proteins activity is based on the functional molecular interaction of the catalytic triad of cysteine amino acids in their active site through the redox state of their sulfhydryl groups. The adduct formation of AA with synaptic proteins at these regulatory cysteines selectively affects their specific functions at the synapse [41,46,47]. Various studies have shown that AA targets multiple proteins and thus affects many processes at the synapse, such as disrupted neurotransmitter release, altered membrane re-uptake, and dysregulated synaptic vesicular movement and storage [18,39]. ...
Acrylamide (AA) is a potential neurotoxic chemical used widely in numerous large-scale industries and molecular research labs. It is a common toxic contaminant in potato and grain-based food products prepared at high temperatures. AA has received serious attention due to the cumulative toxic level exposure to the human population regularly through dietary, environmental, and cosmetics routes other than just occupational exposure. AA is a well-characterized neurotoxin in many rodents and human studies; however mechanistic pathway lacks detailed characterization. Putatively, AA exerts its neurotoxic effects primarily mediated by terminal nerve damage due to inhibition of neurotransmission upon formation of irreversible AA-neuronal protein adducts. Other potential contributors to the AA-induced neuropathological alterations involve an imbalance in redox potential in neuronal cells, inhibition of kinesin-based axonal transport, increased neuronal apoptosis, degenerative changes in cholinergic and dopaminergic neurons, and hyperphosphorylation of Tau. These neurological alterations substantiate the prognosis of the pathological development of severe neurodegenerative diseases. This review summarizes the possible advances in understanding the neuropathological mechanisms of AA-induced neurotoxicity and its clinical implications. Furthermore, we also discuss the potential therapeutic and mitigation strategies to counter the severe toxic health implications of AA.
... This axis likely describes a spectrum of leaf chemical defense strategies (12). Unsaturated aromatic metabolites, such as alkaloids, coumarins, and flavonoids ( Fig. 2), are reactive and serve as toxins or antioxidants in response to stress (54)(55)(56). For instance, conjugated bond structures can interfere with protein function by binding covalently to sidechains (54), generate or quench oxidative stress (55), or absorb damaging wavelengths of light (56). ...
The metabolome is the biochemical basis of plant form and function, but we know little about its macroecological variation across the plant kingdom. Here, we used the plant functional trait concept to interpret leaf metabolome variation among 457 tropical and 339 temperate plant species. Distilling metabolite chemistry into five metabolic functional traits reveals that plants vary on two major axes of leaf metabolic specialization-a leaf chemical defense spectrum and an expression of leaf longevity. Axes are similar for tropical and temperate species, with many trait combinations being viable. However, metabolic traits vary orthogonally to life-history strategies described by widely used functional traits. The metabolome thus expands the functional trait concept by providing additional axes of metabolic specialization for examining plant form and function.
... Conversely, unsaturated α,β-unsaturated aldehydes are less electrophilic and tend to target sulfhydryl thiolate sites that are often present on cysteine residues within proteins. 84 This becomes even more critical given that the catalytic centers of many key enzymes harbor cysteine residues, implying that adduct formation on such residues is highly detrimental to many key cellular processes. The following sections summarize specific types of DNA adducts associated with aldehyde exposure. ...
Aldehydes are widespread in the environment, with multiple sources such as food and beverages, industrial effluents, cigarette smoke, and additives. The toxic effects of exposure to several aldehydes have been observed in numerous studies. At the molecular level, aldehydes damage DNA, cross-link DNA and proteins, lead to lipid peroxidation, and are associated with increased disease risk including cancer. People genetically predisposed to aldehyde sensitivity exhibit severe health outcomes. In various diseases such as Fanconi's anemia and Cockayne syndrome, loss of aldehyde-metabolizing pathways in conjunction with defects in DNA repair leads to widespread DNA damage. Importantly, aldehyde-associated mutagenicity is being explored in a growing number of studies, which could offer key insights into how they potentially contribute to tumorigenesis. Here, we review the genotoxic effects of various aldehydes, focusing particularly on the DNA adducts underlying the mutagenicity of environmentally derived aldehydes. We summarize the chemical structures of the aldehydes and their predominant DNA adducts, discuss various methodologies, in vitro and in vivo, commonly used in measuring aldehyde-associated mutagenesis, and highlight some recent studies looking at aldehyde-associated mutation signatures and spectra. We conclude the Review with a discussion on the challenges and future perspectives of investigating aldehyde-associated mutagenesis.
... Numerous studies demonstrated that acrylamide induces oxidative stress and lipid peroxidation via reactive oxygen species (ROS) production (79,80). Free radicals, which are produced from the peroxidation of polyunsaturated fatty acids, damage cellular components notably cell membranes and induce protein oxidation (81). Based on quantified lipidomics and metabolic pathway analysis, we found that acrylamide-treated zebrafish display a higher level of lipid peroxidation in the brain than the nontreated control group. ...
Western dietary patterns have been unfavorably linked with mental health. However, the long-term effects of habitual fried food consumption on anxiety and depression and underlying mechanisms remain unclear. Our population-based study with 140,728 people revealed that frequent fried food consumption, especially fried potato consumption, is strongly associated with 12% and 7% higher risk of anxiety and depression, respectively. The associations were more pronounced among male and younger consumers. Consistently, long-term exposure to acrylamide, a representative food processing contaminant in fried products, exacerbates scototaxis and thigmotaxis, and further impairs exploration ability and sociality of adult zebrafish, showing anxiety- and depressive-like behaviors. Moreover, treatment with acrylamide significantly down-regulates the gene expression of tjp2a related to the permeability of blood-brain barrier. Multiomics analysis showed that chronic exposure to acrylamide induces cerebral lipid metabolism disturbance and neuroinflammation. PPAR signaling pathway mediates acrylamide-induced lipid metabolism disorder in the brain of zebrafish. Especially, chronic exposure to acrylamide dysregulates sphingolipid and phospholipid metabolism, which plays important roles in the development of anxiety and depression symptoms. In addition, acrylamide promotes lipid peroxidation and oxidation stress, which participate in cerebral neuroinflammation. Acrylamide dramatically increases the markers of lipid peroxidation, including (±)5-HETE, 11(S)-HETE, 5-oxoETE, and up-regulates the expression of proinflammatory lipid mediators such as (±)12-HETE and 14(S)-HDHA, indicating elevated cerebral inflammatory status after chronic exposure to acrylamide. Together, these results both epidemiologically and mechanistically provide strong evidence to unravel the mechanism of acrylamide-triggered anxiety and depression, and highlight the significance of reducing fried food consumption for mental health.
... [Q] and τ 0 represent the AA concentration and fluorophore average lifetime, respectively [24]. Previous studies indicated that the quenching mechanism was static when the K q value was greater than 2.0 × 10 10 L·mol −1 ·s −1 [24]. ...
... [Q] and τ 0 represent the AA concentration and fluorophore average lifetime, respectively [24]. Previous studies indicated that the quenching mechanism was static when the K q value was greater than 2.0 × 10 10 L·mol −1 ·s −1 [24]. The following equation (double logarithmic) was used to analyze the binding situation: ...
... The -SH groups in SPI participate in many interactions in food systems due to their higher chemical activity [49]. The correlation studies reported that the -SH group of thiols rapidly reacted with the carbon-carbon double bonds of AA and generated the corresponding adducts [24]. The -SH group of cysteine contributes to the scavenging reaction of AA by binding with AA [50]. ...
Acrylamide (AA), a common carcinogen, has been found in many dietary products.. This study aimed to explore the interaction of soybean protein isolate (SPI) with AA and further research the different effects of SPI on the AA release due to interactions in the in vitro digestion model. Analysis of variance was used to analyze the data. The results suggested that AA could bind with SPI in vitro, leading to the variation in SPI structure. The intrinsic fluorescence of SPI was quenched by AA via static quenching. The non-covalent (van der Waals forces and hydrogen bonding) and covalent bonds were the main interaction forces between SPI and AA. Furthermore, the release of AA significantly decreased due to its interaction with SPI under simulated gastrointestinal conditions. SPI had different effects on the AA release rate after different treatments. The thermal (80, 85, 90, and 95 °C for either 10 or 20 min) and ultrasound (200, 300, and 400 W for either 15, 30, or 60 min) treatments of SPI were useful in reducing the release of AA. However, the high pressure-homogenized (30, 60, 90, and 120 MPa once, twice, or thrice) treatments of SPI were unfavorable for reducing the release of AA.
... Animal and clinical studies suggest that acrylamide neurotoxicity could mimic the symptoms or even contribute to the etiology of neurodegenerative disorders like Parkinson's disease (LoPachin and Gavin, 2012;Erkekoglu and Baydar, 2014;Li et al., 2015;Murray et al., 2020), as well as result in depression and anxiety-like behavioral effects (Faria et al., 2018(Faria et al., , 2019Raldúa et al., 2020). Three possible mechanisms have been proposed for acrylamide neurotoxicity: (i) inhibition of fast axonal transport, (ii) alteration of neurotransmitter levels, and (iii) direct inhibition of neurotransmission (LoPachin et al., , 2008Pruser and Flynn, 2011;LoPachin and Gavin, 2012;Erkekoglu and Baydar, 2014;Semla et al., 2017). In addition, acrylamide has been shown to indirectly increase oxidative stress by depleting the levels of the antioxidant glutathione (Catalgol et al., 2009;Kopanska et al., 2015;Raldúa et al., 2020). ...
... Frontiers in Pharmacology frontiersin.org 11 Acrylamide (ACR) is a toxicant that has been shown to affect protein function by reacting with Cys residues of several protein targets (LoPachin and Barber, 2006;LoPachin et al., 2007LoPachin et al., , 2008LoPachin and Gavin, 2012). Such covalent adduct formation proceeds through a Michael addition mechanism and requires the Cys thiol group to be accessible to acrylamide, as well as deprotonated (i.e. ...
Acrylamide (ACR) is formed during food processing by Maillard reaction between sugars and proteins at high temperatures. It is also used in many industries, from water waste treatment to manufacture of paper, fabrics, dyes and cosmetics. Unfortunately, cumulative exposure to acrylamide, either from diet or at the workplace, may result in neurotoxicity. Such adverse effects arise from covalent adducts formed between acrylamide and cysteine residues of several neuronal proteins via a Michael addition reaction. The molecular determinants of acrylamide reactivity and its impact on protein function are not completely understood. Here we have compiled a list of acrylamide protein targets reported so far in the literature in connection with neurotoxicity and performed a systematic covalent docking study. Our results indicate that acrylamide binding to cysteine is favored in the presence of nearby positively charged amino acids, such as lysines and arginines. For proteins with more than one reactive Cys, docking scores were able to discriminate between the primary ACR modification site and secondary sites modified only at high ACR concentrations. Therefore, docking scores emerge as a potential filter to predict Cys reactivity against acrylamide. Inspection of the ACR-protein complex structures provides insights into the putative functional consequences of ACR modification, especially for non-enzyme proteins. Based on our study, covalent docking is a promising computational tool to predict other potential protein targets mediating acrylamide neurotoxicity.
... This result suggests that AA is dangerous not only for the liver but also for the whole body. Studies have shown that the negative effects of AA treatment on body weight gain may be due to pathological changes in central and peripheral nerves such as neurotransmitter metabolism and NO signaling pathway [33,34]. Besides, this is likely the result of the breakdown of tissue and blood cells in the liver by the AA in rats [35]. ...
Introduction
This study aims to investigate whether boric acid (BA) can protect rats from acrylamide (AA)-induced acute liver injury.
Materials and methods
AA was used to induce acute liver injury. Thirty rats were divided into five group including Group 1 (saline), Group 2 (AA), Group 3 (20 mg/kg BA), Group 4 (10 mg/kg BA+AA) and Group 5 (20 mg/kg BA+AA). Their blood and liver were harvested to be kept for analysis. Liver function enzyme activities were performed by spectrophotometric method. Catalase (CAT), superoxide dismutase (SOD) activity, and malondialdehyde levels were determined by colorimetric method. The in-silico studies were performed using the “blind docking” method.
Results
Administration AA to rats, biochemical parameters, liver histology, and expression levels of apoptotic markers were negatively affected. However, after the administration of BA, the altered biochemical parameters, liver histology, and expression levels of apoptotic markers were reversed. Moreover, the mechanisms of AA-induced deterioration in the levels of SOD, CAT, and Nrf2-Keap-1 and the mechanisms of the protective effect of BA against these deteriorations were explained by in silico studies.
Conclusion
Thus, the present study could explain the interactions between AA and thiol-containing amino acid residues of Keap-1, the effect of BA on these interactions, and the biochemical toxicity caused by the AA. In this sense, this work is the first of its kind in the literature. Based on the biochemical, histopathological, and in silico results, it can be suggested that BA has the potential to be used as a protective agent against AA-induced liver injury.
... Unsaturated carbonyl compounds are not only versatile synthetic building blocks, but also ubiquitous in natural products and biologically relevant molecules [24][25][26][27][28][29] . Although protocols for carbonyl desaturation at the adjacent sites (α-/β-) have been widely established, a mild and general strategy for remote site desaturation of ketone would be very appealing, but has not been reported. ...
In the biosynthesis sterols an enzyme-catalyzed demethylation is achieved via a stepwise oxidative transformation of alcohols to olefins. The overall demethylation proceeds through two sequential monooxygenation reactions and a subsequent dehydroformylative saturation. To mimic the desaturation processes observed in nature, we have successfully integrated photoredox proton-coupled electron transfer (PCET) and cobaloxime chemistry for the acceptorless dehydrogenation of alcohols. The state-of-the-art remote and precise desaturation of ketones proceeds efficiently through the activation of cyclic alcohols using bond-dissociation free energy (BDFE) as thermodynamic driving force. The resulting transient alkoxyl radical allows C-C bond scission to generate the carbon-centered radical remote to the carbonyl moiety. This key intermediate is subsequently combined with cobaloxime photochemistry to furnish the alkene. Moreover, the mild protocol can be extended to desaturation of linear alcohols as well as aromatic hydrocarbons. Application to bioactive molecules and natural product derivatives is also presented.
