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Iranian Journal of Basic Medical... 2024Ischemic disorders, including myocardial infarction, cerebral ischemia, and peripheral vascular impairment, are the main common reasons for debilitating diseases and... (Review)
Review
Ischemic disorders, including myocardial infarction, cerebral ischemia, and peripheral vascular impairment, are the main common reasons for debilitating diseases and death in Western cultures. Ischemia occurs when blood circulation is reduced in tissues. Reperfusion, although commanded to return oxygen to ischemic tissues, generates paradoxical tissue responses. The responses include generating reactive oxygen species (ROS), stimulating inflammatory responses in ischemic organs, endoplasmic reticulum stress, and the expansion of postischemic capillary no-reflow, which intensifies organ damage. Multiple pathologic processes contribute to ischemia/reperfusion; therefore, targeting different pathologic processes may yield an effective therapeutic approach. Transient Receptor Potential A1 (TRPA1) belongs to the TRP family of ion channels, detects a broad range of chemicals, and promotes the transduction of noxious stimuli, e.g., methylglyoxal, ROS, and acrolein effects are attributed to the channel's sensitivity to intracellular calcium elevation or phosphoinositol phosphate modulation. Hypoxia and ischemia are associated with oxidative stress, which activates the TRPA1 channel. This review describes the role of TRPA1 and its related mechanisms that contribute to ischemia/reperfusion. Relevant articles were searched from PubMed, Scopus, Web of Sciences, and Google Scholar electronic databases, up to the end of August 2023. Based on the evidence presented here, TRPA1 may have protective or deteriorative functions during the ischemia/reperfusion process. Its function depends on the activation level, the ischemic region, the extent of lesions, and the duration of ischemia.
PubMed: 38333756
DOI: 10.22038/IJBMS.2023.74590.16198 -
Lab on a Chip Jul 2023Trauma-induced Alzheimer's disease (AD) is rapidly emerging as a major consequence of traumatic brain injuries (TBI), with devastating social and economic impacts....
The contribution of initial concussive forces and resulting acrolein surge to β-amyloid accumulation and functional alterations in neuronal networks using a TBI-on-a-chip model.
Trauma-induced Alzheimer's disease (AD) is rapidly emerging as a major consequence of traumatic brain injuries (TBI), with devastating social and economic impacts. Unfortunately, few treatment options are currently available due to a limited understanding of the underlying mechanisms. A clinically-relevant, experimental model that emulates scenarios with high levels of spatial and temporal resolution is critical for demystifying the pathways of post-TBI AD. Using a unique, recently established "TBI-on-a-chip" system with murine cortical networks, we demonstrate the correlative elevation of oxidative stress (acrolein), inflammation (TNF-α), and Aβ42 aggregation, with concomitant reduction of neuronal network electrical activity post-concussive impact. These findings confirm that TBI-on-a-chip could provide a novel paradigm to supplement studies of trauma, while simultaneously validating the interaction of these alleged, key-pathological factors in post-TBI AD development. Specifically, we have shown that acrolein, acting as a diffusive factor of secondary injury, is both critical and sufficient in promoting inflammation (TNF-α) and Aβ42 aggregation, two known contributors of AD pathogenesis. Furthermore, using a cell-free preparation with TBI-on-a-chip, we have confirmed that both force and acrolein can independently and directly stimulate the aggregation of purified Aβ42, highlighting the key capabilities of primary and secondary injury mechanisms towards inducing Aβ42 aggregation, independently and synergistically. In addition to morphological and biochemical assessment, we also demonstrate parallel monitoring of neuronal network activity, further validating the chief pathological role of acrolein in not only inflicting biochemical abnormalities, but also functional deficits in neuronal networks. In conclusion, through this line of investigations, we have shown that by recapitulating clinically-relevant events, the TBI-on-a-chip device is capable of quantitatively characterizing parallel force-dependent increases in oxidative stress, inflammation, protein aggregation, and network activity, offering a unique platform for mechanistic investigations of post-TBI AD, and trauma-induced neuronal injury in general. It is expected that this model could provide crucial insights into pathological mechanisms which will be critical in developing novel, effective diagnostics and treatment strategies that significantly benefit TBI victims.
Topics: Mice; Animals; Amyloid beta-Peptides; Acrolein; Tumor Necrosis Factor-alpha; Brain Injuries, Traumatic; Alzheimer Disease; Lab-On-A-Chip Devices; Inflammation
PubMed: 37337817
DOI: 10.1039/d3lc00248a -
The Science of the Total Environment Jun 2024Volatile organic compounds (VOCs) are ubiquitous in both indoor and outdoor environments. Evidence on the associations of individual and joint VOC exposure with...
Volatile organic compounds (VOCs) are ubiquitous in both indoor and outdoor environments. Evidence on the associations of individual and joint VOC exposure with all-cause and cause-specific mortality is limited. Measurements of 15 urinary VOC metabolites were available to estimate exposure to 12 VOCs in the National Health and Nutritional Examination Survey (NHANES) 2005-2006 and 2011-2018. The environment risk score (ERS) was calculated using LASSO regression to reflect joint exposure to VOCs. Follow-up data on death were obtained from the NHANES Public-Use Linked Mortality File through December 31, 2019. Cox proportional hazard models and restricted cubic spline models were applied to evaluate the associations of individual and joint VOC exposures with all-cause and cause-specific mortality. Population attributable fractions were calculated to assess the death burden attributable to VOC exposure. During a median follow-up of 6.17 years, 734 (8.34 %) deaths occurred among 8799 adults. Urinary metabolites of acrolein, acrylonitrile, 1,3-butadiene, and ethylbenzene/styrene were significantly associated with all-cause, cardiovascular disease (CVD), respiratory disease (RD), and cancer mortality in a linear dose-response manner. Linear and robust dose-response relationships were also observed between ERS and all-cause and cause-specific mortality. Each 1-unit increase in ERS was associated with a 33.6 %, 39.1 %, 109.8 %, and 67.8 % increase for all-cause, CVD, RD, and cancer mortality risk, respectively. Moreover, joint exposure to VOCs contributed to 17.95 % of all-cause deaths, 13.49 % of CVD deaths, 35.65 % of RD deaths, and 33.85 % of cancer deaths. Individual and joint exposure to VOCs may enhance the risk of all-cause and cause-specific mortality. Reducing exposure to VOCs may alleviate the all-cause and cause-specific death burden.
Topics: Humans; Volatile Organic Compounds; Prospective Studies; Male; United States; Adult; Environmental Exposure; Female; Middle Aged; Air Pollutants; Nutrition Surveys; Cardiovascular Diseases; Butadienes; Neoplasms; Respiratory Tract Diseases; Mortality; Benzene Derivatives
PubMed: 38636853
DOI: 10.1016/j.scitotenv.2024.172512 -
Current Medical Science Aug 2023This study aims to investigate the effects of hydralazine on inflammation induced by spinal cord injury (SCI) in the central nervous system (CNS) and its mechanism in...
OBJECTIVE
This study aims to investigate the effects of hydralazine on inflammation induced by spinal cord injury (SCI) in the central nervous system (CNS) and its mechanism in promoting the structural and functional recovery of the injured CNS.
METHODS
A compressive SCI mouse model was utilized for this investigation. Immunofluorescence and quantitative real-time polymerase chain reaction were employed to examine the levels of acrolein, acrolein-induced inflammation-related factors, and macrophages at the injury site and within the CNS. Western blotting was used to evaluate the activity of the phosphoinositide 3-kinase (PI3K)/AKT pathway to study macrophage regulation. The neuropathic pain and motor function recovery were evaluated by glutamic acid decarboxylase 65/67 (GAD65/67), vesicular glutamate transporter 1 (VGLUT1), paw withdrawal response, and Basso Mouse Scale score. Nissl staining and Luxol Fast Blue (LFB) staining were performed to investigate the structural recovery of the injured CNS.
RESULTS
Hydralazine downregulated the levels of acrolein, IL-1β, and TNF-α in the spinal cord. The downregulation of acrolein induced by hydralazine promoted the activation of the PI3K/AKT pathway, leading to M2 macrophage polarization, which protected neurons against SCI-induced inflammation. Additionally, hydralazine promoted the structural recovery of the injured spinal cord area. Mitigating inflammation and oxidative stress by hydralazine in the animal model alleviated neuropathic pain and altered neurotransmitter expression. Furthermore, hydralazine facilitated motor function recovery following SCI. Nissl staining and LFB staining indicated that hydralazine promoted the structural recovery of the injured CNS.
CONCLUSION
Hydralazine, an acrolein scavenger, significantly mitigated SCI-induced inflammation and oxidative stress in vivo, modulated macrophage activation, and consequently promoted the structural and functional recovery of the injured CNS.
Topics: Rats; Mice; Animals; Phosphatidylinositol 3-Kinases; Acrolein; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Spinal Cord Injuries; Hydralazine; Neuralgia; Inflammation; Oxidative Stress; Macrophages
PubMed: 37558864
DOI: 10.1007/s11596-023-2767-9 -
Toxicology and Industrial Health Nov 2023Smoking or occupational exposure leads to low concentrations of acrolein on the surface of the airways. Acrolein is involved in the pathophysiological processes of...
Smoking or occupational exposure leads to low concentrations of acrolein on the surface of the airways. Acrolein is involved in the pathophysiological processes of various respiratory diseases. Reports showed that acrolein induced an increase in mitochondrial reactive oxygen species (mROS). Furthermore, exogenous H₂O₂ was found to increase intracellular Zn⁺ concentration ([Zn⁺]ᵢ). However, the specific impact of acrolein on changes in intracellular Zn⁺ levels has not been fully investigated. Therefore, this study aimed to investigate the effects of acrolein on mROS and [Zn⁺]ᵢ in A549 cells. We used Mito Tracker Red CM-HXros (MitoROS) and Fluozin-3 fluorescent probes to observe changes in mROS and intracellular Zn⁺. The results revealed that acrolein increased [Zn⁺]ᵢ in a time- and dose-dependent manner. Additionally, the production of mROS was observed in response to acrolein treatment. Subsequent experiments showed that the intracellular Zn⁺ chelator TPEN could inhibit the acrolein-induced elevation of [Zn⁺]ᵢ but did not affect the acrolein-induced mROS production. Conversely, the acrolein-induced elevation of mROS and [Zn⁺]ᵢ were significantly decreased by the inhibitors of ROS formation (NaHSO₃, NAC). Furthermore, external oxygen free radicals increased both [Zn⁺]ᵢ levels and mROS production. These results demonstrated that acrolein-induced elevation of [Zn⁺]ᵢ in A549 cells was mediated by mROS generation, rather than through a pathway where [Zn⁺]ᵢ elevation leads to mROS production.
Topics: Humans; Reactive Oxygen Species; Oxidative Stress; Acrolein; A549 Cells; Hydrogen Peroxide; Zinc
PubMed: 37644888
DOI: 10.1177/07482337231198350 -
Carcinogenesis May 2024The tobacco-specific nitrosamines N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered 'carcinogenic to humans' by the... (Review)
Review
The tobacco-specific nitrosamines N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered 'carcinogenic to humans' by the International Agency for Research on Cancer (IARC) and are believed to be important in the carcinogenic effects of both smokeless tobacco and combusted tobacco products. This short review focuses on the results of recent studies on the formation of NNN and NNK in tobacco, and their carcinogenicity and toxicity in laboratory animals. New mechanistic insights are presented regarding the role of dissimilatory nitrate reductases in certain microorganisms involved in the conversion of nitrate to nitrite that leads to the formation of NNN and NNK during curing and processing of tobacco. Carcinogenicity studies of the enantiomers of the major NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and the enantiomers of NNN are reviewed. Recent toxicity studies of inhaled NNK and co-administration studies of NNK with formaldehyde, acetaldehyde, acrolein and CO2, all of which occur in high concentrations in cigarette smoke, are discussed.
Topics: Nitrosamines; Humans; Animals; Carcinogens; Nicotiana
PubMed: 38437625
DOI: 10.1093/carcin/bgae018 -
Reviews on Environmental Health Sep 2023Despite the quantum of research findings on tobacco epidemic, a review on the formation characteristics of nicotine, aldehydes and phenols, and their associated... (Review)
Review
OBJECTIVES
Despite the quantum of research findings on tobacco epidemic, a review on the formation characteristics of nicotine, aldehydes and phenols, and their associated etiological risks is still limited in literature. Accordingly, knowledge on the chemical properties and free radical formation during tobacco burning is an important subject towards unravelling the relationship between smoking behaviour and disease. This review investigates how scientific efforts have been advanced towards understanding the release of molecular products from the thermal degradation of tobacco, and harm reduction strategies among cigarette smokers in general. The mechanistic characteristics of nicotine and selected aldehydes are critically examined in this review. For the purpose of this work, articles published during the period 2004-2021 and archived in PubMed, Google Scholar, Medley, Cochrane, and Web of Science were used. The articles were selected based on the health impacts of cigarette smoking, tobacco burning kinetics, tobacco cessation and tobacco as a precursor for emerging diseases such as Covid-19.
CONTENT
The toxicity of cigarette smoke is directly correlated with its chemical composition derived from the pyrolysis of tobacco stem and leaves. Most of the harmful toxic substances are generated by pyrolysis during smoking and depends on pyrolysis conditions. Detailed studies have been conducted on the kinetics of nicotine by use of robust theoretical models in order to determine the rate constants of reactions in nicotine and those of nicotine dissociation via C-C and C-N scission, yielding pyridinyl and methyl radicals, respectively. Research has suggested that acetaldehyde enhances the effect of nicotine, which in turn reinforces addiction characteristics whereas acrolein and crotonaldehyde are ciliatoxic, and can inhibit lung clearance. On the other hand, phenol affects liver enzymes, lungs, kidneys, and the cardiovascular system while -cresol attacks the nervous system.
SUMMARY AND OUTLOOK
The characteristics of chemical release during tobacco burning are very important in the tobacco industry and the cigarette smoking community. Understanding individual chemical formation from cigarette smoking will provide the necessary information needed to formulate sound tobacco reform policies from a chemical standpoint. Nonetheless, intense research is needed in this field in order to prescribe possible measures to deter cigarette smoking addiction and ameliorate the grave miseries bedevilling the tobacco smoking community.
Topics: Nicotiana; Nicotine; COVID-19; Aldehydes; Acrolein
PubMed: 35538694
DOI: 10.1515/reveh-2022-0013 -
Drug Testing and Analysis Oct 2023The use of electronic cigarettes (e-cigarettes) has increased rapidly in the United States, especially among high school students. e-Cigarettes contain some recognized... (Review)
Review
The use of electronic cigarettes (e-cigarettes) has increased rapidly in the United States, especially among high school students. e-Cigarettes contain some recognized carcinogens and may induce DNA damage in oral cells. The aim of this review is to summarize studies reporting DNA adducts or other types of DNA damage in oral cells in vitro or in vivo upon exposure to e-cigarette vapor and to evaluate the possible connections between e-cigarette exposure and oral cancer. Three databases including PubMed, Scopus, and EMBASE and gray literature were searched for articles published up to April 24, 2022. After screening 321 articles, we extracted 27 for further investigation. Based on the inclusion criteria, 22 articles were eligible for this review. The in vitro studies demonstrate that e-cigarette liquid or vapor can induce DNA damage, oxidative stress, DNA double-stranded breaks, apoptosis, cytotoxicity, and genotoxicity in different types of oral cells. The clinical studies showed that e-cigarette users have significantly higher levels of N'-nitrosonornicotine, acrolein DNA adducts, metanuclear anomalies, gene regulation, and lactate dehydrogenase enzyme expression and significantly lower levels of apurinic/apyrimidinic sites than non-users. Comparison of micronuclei levels between e-cigarette users and non-users gave inconsistent results. e-Cigarettes are implicated in DNA damage to oral cells, but publications to date present limited evidence. Future studies with larger sample sizes are required to investigate the long-term consequences of e-cigarette use.
Topics: Humans; United States; Electronic Nicotine Delivery Systems; DNA Adducts; Tobacco Products; DNA Damage
PubMed: 36169810
DOI: 10.1002/dta.3375 -
Frontiers in Toxicology 2023Acrolein is a significant component of anthropogenic and wildfire emissions, as well as cigarette smoke. Although acrolein primarily deposits in the upper respiratory...
Acrolein is a significant component of anthropogenic and wildfire emissions, as well as cigarette smoke. Although acrolein primarily deposits in the upper respiratory tract upon inhalation, patterns of site-specific injury in nasal pulmonary tissues are not well characterized. This assessment is critical in the design of and studies performed for assessing health risk of irritant air pollutants. In this study, male and female Wistar-Kyoto rats were exposed nose-only to air or acrolein. Rats in the acrolein exposure group were exposed to incremental concentrations of acrolein (0, 0.1, 0.316, 1 ppm) for the first 30 min, followed by a 3.5 h exposure at 3.16 ppm. In the first cohort of male and female rats, nasal and bronchoalveolar lavage fluids were analyzed for markers of inflammation, and in a second cohort of males, nasal airway and left lung tissues were used for mRNA sequencing. Protein leakage in nasal airways of acrolein-exposed rats was similar in both sexes; however, inflammatory cells and cytokine increases were more pronounced in males when compared to females. No consistent changes were noted in bronchoalveolar lavage fluid of males or females except for increases in total cells and IL-6. Acrolein-exposed male rats had 452 differentially expressed genes (DEGs) in nasal tissue only 95 in the lung. Pathway analysis of DEGs in the nose indicated acute phase response signaling, Nrf2-mediated oxidative stress, unfolded protein response, and other inflammatory pathways, whereas in the lung, xenobiotic metabolism pathways were changed. Genes associated with glucocorticoid and GPCR signaling were also changed in the nose but not in the lung. These data provide insights into inhaled acrolein-mediated sex-specific injury/inflammation in the nasal and pulmonary airways. The transcriptional response in the nose reflects acrolein-induced acute oxidative and cytokine signaling changes, which might have implications for upper airway inflammatory disease susceptibility.
PubMed: 38090360
DOI: 10.3389/ftox.2023.1280230 -
Pigment Cell & Melanoma Research Sep 2023Vitiligo is a common depigmentation disorder characterized by the selective loss of melanocytes. In our daily clinic experience, we noticed that the skin tightness of...
Vitiligo is a common depigmentation disorder characterized by the selective loss of melanocytes. In our daily clinic experience, we noticed that the skin tightness of hypopigmented lesions would be more evident in comparison to that of uninvolved perilesional skin in vitiligo patients. Therefore, we hypothesized that collagen homeostasis might be maintained in vitiligo lesions, irrespective of the substantial excessive oxidative stress that occurs in association with the disease. We found that the expression levels of collagen-related genes and anti-oxidative enzymes were upregulated in vitiligo-derived fibroblasts. Abundant collagenous fibers were observed in the papillary dermis of vitiligo lesions in comparison to uninvolved perilesional skin by electron microscopy. The production of matrix metalloproteinases that degraded collagen fibers was suppressed. The deposition of acrolein adduct protein, which is a product of oxidative stress, was significantly reduced in vitiligo dermis and fibroblasts. As part of the mechanism, we found upregulation of the NRF2 signaling pathway activity, which is an important defense system against oxidative stress. Taken together, we demonstrated that the anti-oxidative action and collagen production were upregulated and that the collagen degeneration was attenuated in vitiligo dermis. These new findings may provide important clues for the maintenance of antioxidant ability in vitiligo lesions.
Topics: Humans; Vitiligo; Hypopigmentation; Skin; Melanocytes; Oxidative Stress; Dermis; Collagen
PubMed: 37230937
DOI: 10.1111/pcmr.13094