Last data update: Sep 16, 2024. (Total: 47680 publications since 2009)
Records 1-30 (of 50 Records) |
Query Trace: Kagan J [original query] |
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Transformational narrative changes as a community-level approach to the prevention of adverse childhood experiences and substance use
Harper CR , Treves-Kagan S . Am J Community Psychol 2024 There is increasing scientific evidence linking substance use, childhood adversity, and social determinants of health. However, little research has considered the evaluation of community-level strategies to reduce substance use by increasing awareness and implementation of evidence-based strategies for preventing adverse childhood experiences (ACEs). This article lays out the conceptual framework for a $2.9 million demonstration project designed to raise awareness of the impact of ACEs on substance use, including primary prevention strategies. Communities used transformational narrative change-with an emphasis on the voices of those most impacted by ACEs and substance use-to highlight the importance of addressing social determinants of health along with primary prevention strategies. The conceptual background highlighted in this article informed media, public health, and local efforts in the three accompanying articles and invited commentary. These findings may help inform future efforts to promote community-level strategies and strengthen the evidence-base for transformational narrative change efforts. |
Increasing support for the prevention of adverse childhood experiences and substance use: Implementation of narrative change strategies in local health departments
Harper CR , Tan-Schriner C , Royster J , Morgan KL , Burnett V , Treves-Kagan S , Bradford J , Ettman L , Espinosa O , Marziale E . Am J Community Psychol 2024 Adverse childhood experiences (ACEs) are potentially traumatic but preventable experiences that occur before the ages of 18, including child abuse, witnessing violence, and parental substance use. ACEs have been linked with increased risk for substance use, along with a variety of other negative health outcomes. However, there is limited evidence of community-level strategies that link ACEs and substance to increase awareness of prevention efforts. This article reports on a $2.9 million program to promote health equity and inform narratives for the prevention of ACEs and substance use within three Midwestern communities. Program partners sought to create new transformational narratives that linked ACEs and substance use, while underscoring the importance of addressing social determinants of health (SDOH) that lead to disparities in ACEs and substance use. A mixed-methods evaluation design included document review, in-depth interviews with program staff (N = 8) and community liaisons (N = 2), and site reports from program staff (N = 8) and their community partners (N = 17). Analyses showed that successful implementation efforts had early leadership buy-in and support, set clear and manageable expectations at the outset of implementation, and developed strong relationships with organizations that engage in health equity work. Training and technical assistance were critical to helping community partners build trust, recognize each other's perspectives, broaden and reframe their world view, and better understand narrative efforts for the primary prevention of ACEs and substance use. |
Examining narratives around adverse childhood experiences and social determinants of health in media coverage of substance use in two mid-western cities
Treves-Kagan S , Kennedy K , Carrington M . Am J Community Psychol 2023 Local media narratives play an important role in how people interpret and propose solutions for health issues in their community. This research characterized narratives about adverse childhood experiences (ACEs), and/or social determinants of health (SDOH) in media coverage of substance use. Scans covered articles published in the Detroit Free Press and the Cincinnati Enquirer from March 1, 2019 to June 1, 2019 and March 1, 2021 to June 1, 2021. Scans used search terms for opioids and substance use. Included articles were coded and analyzed for narratives about why people use substances, how to prevent substance use, and how ACEs or SDOH relate to substance use. While half of the included articles reported on the overdose epidemic, the most common type of media coverage reported on criminal justice milestones. Other common narratives identified addiction as an illness that should be treated; and over-prescription of painkillers or the strength of the drugs as causes of substance use disorders. Narratives about SDOH and the primary prevention of ACEs and substance use were limited. Transformational narrative change work can increase support for addressing the root causes of ACEs and substance use. Results suggest this strategy remains largely untapped in the formal media. |
Formation of protein adducts with Hydroperoxy-PE electrophilic cleavage products during ferroptosis
Amoscato AA , Anthonymuthu T , Kapralov O , Sparvero LJ , Shrivastava IH , Mikulska-Ruminska K , Tyurin VA , Shvedova AA , Tyurina YY , Bahar I , Wenzel S , Bayir H , Kagan VE . Redox Biol 2023 63 102758 Ferroptosis is an iron dependent form of cell death, that is triggered by the discoordination of iron, lipids, and thiols. Its unique signature that distinguishes it from other forms of cell death is the formation and accumulation of lipid hydroperoxides, particularly oxidized forms of polyunsaturated phosphatidylethanolamines (PEs), which drives cell death. These readily undergo iron-catalyzed secondary free radical reactions leading to truncated products which retain the signature PE headgroup and which can readily react with nucleophilic moieties in proteins via their truncated electrophilic acyl chains. Using a redox lipidomics approach, we have identified oxidatively-truncated PE species (trPEox) in enzymatic and non-enzymatic model systems. Further, using a model peptide we demonstrate adduct formation with Cys as the preferred nucleophilic residue and PE(26:2) +2 oxygens, as one of the most reactive truncated PE-electrophiles produced. In cells stimulated to undergo ferroptosis we identified PE-truncated species with sn-2 truncations ranging from 5 to 9 carbons. Taking advantage of the free PE headgroup, we have developed a new technology using the lantibiotic duramycin, to enrich and identify the PE-lipoxidated proteins. Our results indicate that several dozens of proteins for each cell type, are PE-lipoxidated in HT-22, MLE, and H9c2 cells and M2 macrophages after they were induced to undergo ferroptosis. Pretreatment of cells with the strong nucleophile, 2-mercaptoethanol, prevented the formation of PE-lipoxidated proteins and blocked ferroptotic death. Finally, our docking simulations showed that the truncated PE species bound at least as good to several of the lantibiotic-identified proteins, as compared to the non-truncated parent molecule, stearoyl-arachidonoyl PE (SAPE), indicating that these oxidatively-truncated species favor/promote the formation of PEox-protein adducts. The identification of PEox-protein adducts during ferroptosis suggests that they are participants in the ferroptotic process preventable by 2-mercaptoethanol and may contribute to a point of no return in the ferroptotic death process. |
Identification of Human Monkeypox Virus Genome Deletions That Impact Diagnostic Assays.
Garrigues JM , Hemarajata P , Lucero B , Alarcón J , Ransohoff H , Marutani AN , Kim M , Marlowe EM , Realegeno SE , Kagan RM , Montero CI , Chen NFG , Grubaugh ND , Vogels CBF , Green NM . J Clin Microbiol 2022 60 (12) e0165522 In August 2022, the Los Angeles County Department of Public Health initiated an investigation into human monkeypox virus (MPXV) cases with unusual results from a multiplex laboratory-developed test used by Quest Diagnostics, which is based on the CDC nonvariola Orthopoxvirus (NVO) (1) and MPXV clade II (MPXV-WA) (2) real-time PCR assays. These specimens returned NVO–positive and either MPXV-WA–negative or positive results with high Ct values, which differ from the strong dual-positive results typically associated with the current outbreak. Since these patients met the case definition for probable human MPXV infection, (3) these discordant results were presumed to be due to a mutation affecting the performance of the MPXV-WA assay. |
Does binge drinking mediate the relationship between four adverse childhood experiences and adult traumatic brain injury Results from the National Longitudinal Survey of Youth 1979 Cohort
Daugherty J , Treves-Kagan S , Gottfredson NC , Miedema S , Haarbauer-Krupa J . Inj Prev 2022 29 (2) 111-115 OBJECTIVE: Adverse childhood experiences (ACEs) are associated with increased risk of sustaining a traumatic brain injury (TBI). Alcohol use may play an important role in this relationship. This study examines whether binge drinking mediates the relationship between four ACEs and TBIs sustained in adulthood. METHODS: Using the National Longitudinal Survey of Youth, 1979 cohort, we conducted longitudinal mediation analyses (n=6317). Interviews occurred annually from 1979 to 1994 and biennially until 2016. We evaluated the direct and indirect effects of individual ACEs (ie, experiencing physical violence, low parental warmth, familial alcoholism and familial mental illness; reported retrospectively) and a cumulative ACEs score on mean level of binge drinking (calculated across waves) and having a TBI in adulthood. To establish temporality, we included binge drinking that was measured at age 18 or older and before any reported TBI. RESULTS: Cumulative ACEs, familial alcoholism and physical abuse exposure were significantly associated with having a TBI through binge drinking, although this only explained a small part of the association between ACEs and TBI. Other ACEs were not significantly associated with binge drinking or TBI. CONCLUSION: The results indicate that while ACEs and adult TBI risk were significantly associated, lifetime binge drinking explains only a small part of the association. Future research could examine alternative social, biological and behavioural mechanisms along the pathway between ACEs and TBI. Determining this mechanism will allow public health practitioners to design and implement effective TBI prevention programmes for those at higher risk of injury due to ACE exposure. |
The role of gender and romantic jealousy in intimate partner violence against women, a mixed-methods study in Northern Ecuador
Buller AM , Pichon M , Chevalier C , Treves-Kagan S . Cult Health Sex 2022 25 (2) 1-18 Male romantic jealousy is a commonly cited driver of intimate partner violence (IPV) against women. An in-depth, contextualised understanding of the pathways and mechanisms from jealousy to intimate partner violence is however needed to inform programmes and interventions. We triangulated data from 48 interviews, eight focus groups and 1216 survey findings from low-income married women and men in northern Ecuador. Male jealousy was associated with controlling behaviours (aOR: 14.47, 95% CI: 9.47, 22.12) and sexual intimate partner violence (aOR: 2.4, 95% CI: 1.12, 5.12). Controlling behaviours were associated with physical and sexual intimate partner violence (aOR: 2.16, 95% CI: 1.21, 3.84). Qualitatively we found that most respondents framed jealousy within a discourse of love, and three triggers of male jealousy leading to intimate partner violence were identified: (1) community gossip, which acted as a mechanism of community control over women's movements and sexuality; (2) women joining the labour force, which was quantitatively associated with intimate partner violence and partially mediated by jealousy; and (3) women's refusal to have sex, which could lead husbands to coerce sex through accusations of infidelity. Gender-transformative interventions at the individual, couple and community level providing models of alternative masculinities and femininities may offer promise in reducing intimate partner violence in Ecuador. Importantly, future economic empowerment interventions should address jealousy to mitigate potential intimate partner violence backlash. |
Strengthening Communities: A Qualitative Assessment of Opportunities for the Prevention of Adverse Childhood Experiences in the Wake of the Opioid Crisis
Matjasko JL , Chovnick G , Bradford J , Treves-Kagan S , Usher K , Vaughn E , Ingoldsby E . J Child Fam Stud 2022 31 (4) 1-13 The opioid crisis is a significant challenge for health and human service systems that serve children, youth, and families across the United States. Between 2000 and 2017, the number of foster care entries, a type of adverse childhood experience (ACE), attributable to parental drug use increased by 147%. Nevertheless, there is variation in the burden of opioid overdose and foster care rates across the U.S., suggesting community supports and systems to support families affected by substance use also vary. This qualitative study sampled communities experiencing high and low rates of overdose mortality and foster care entries (i.e., a qualitative comparison group) to better understand what might protect some counties from high overdose mortality and foster care entries. The sample included six counties from three states that were selected based on their rates of opioid overdose mortality and foster care entries. Using purposive sampling within counties, interview and discussion group participants included multi-sector community partners, parents whose children had been removed due to parental substance use, and caregivers caring for children who had been removed from their homes. Across all counties, prevention was not front-of-mind. Yet, participants from communities experiencing high rates of overdose mortality and foster care entries identified several factors that might help lessen exposure to substance use and ACEs including more community-based prevention services for children and youth. Both parents and caregivers across all communities also described the need for additional supports and services. Participants also described the impact of COVID-19 on services, including greater utilization of mental health and substance use treatment services and the challenges with engaging children and youth on virtual platforms. The implications for prevention are discussed, including the need to encourage primary prevention programs in communities. |
Association of public explanations of why children struggle and support for policy solutions using a national sample
Klevens J , Treves-Kagan S , Metzler M , Merrick M , Reidy MC , Herbst JH , Ports K . Anal Soc Issues Public Policy 2021 22 (1) 268-285 Purpose: Despite evidence showing the importance of structural determinants for child well-being and the existence of policies that can promote child well-being, many communities are not adopting these policies. Limited awareness of structural determinants may explain this gap. This study establishes the public's recognition of structural determinants and their associations with support for policies that promote child well-being. Methods: Secondary analyses of survey data collected in 2019 from a random sample of 2496 adults in the United States. This survey asked why some children “struggle” (e.g., do poorly in school, use drugs, or get involved in crime). Respondents could select individual (e.g., lack of effort) and structural (e.g., low wages) explanations. Respondents were also asked about their support for policies that are supportive of children and families. Results: Stronger beliefs of structural explanations were associated with greater support for policies that strengthen family economics, family-friendly work, and afford access to high-quality early childcare and education. Beliefs in individual explanations were inversely associated with support for these policies. Conclusions: These findings suggest increasing recognition of the structural determinants that hinder child development may help increase support for policies that are effective in improving children's outcomes. © 2021 Society for the Psychological Study of Social Issues. This article has been contributed to by US Government employees and their work is in the public domain in the USA. |
Breaking the cycle of Adverse Childhood Experiences (ACEs): Economic position moderates the relationship between mother and child ACE scores among Black and Hispanic families
Ports KA , Tang S , Treves-Kagan S , Rostad W . Child Youth Serv Rev 2021 127 Importance: Adverse Childhood Experiences (ACEs) are prevalent, preventable, and a public health issue that cycles from one generation to the next with serious implications for health and wellbeing, particularly. Research is needed to identify factors, including those related to economic position (i.e., wage, net family wealth, home ownership), that break the cycle of ACEs and inform decisions about policies, practices, and programs. Objective: To determine whether economic position moderates the association between mother's ACE score and child's ACE score and whether these pathways differ by race and ethnicity. Design: Conducted regression and moderation analysis using mother-child dyadic data from panel surveys, stratified by race. The simple slopes for the interactions were probed to determine the magnitude and significance of the interaction. Setting: Secondary data analysis utilizing data from two cohorts of the National Longitudinal Surveys: 1) National Longitudinal Survey of Youth 1979; and 2) National Longitudinal Survey of Youth 1979 Children and Young Adults. Participants: The sample included 6,261 children and 2,967 matched mothers. Main Outcomes (s) and Measure(s): The outcome variable was the child's ACE score. Mother's ACE score was the independent variable. Three economic position moderators were examined: mother's and her spouse's average wage and salary, average net family wealth, and percent of time owning a home during her child's first five years of life. Results: Mother's ACE score was positively associated with her child's ACE score. Economic position was a significant moderator for Black families. Higher wages and net family wealth during children's first five years were associated with weakened associations between mother and child ACEs for Black families. For Hispanic families, higher wages and salary were significantly associated with weakened associations. Among White families, higher net family wealth was associated with stronger ACEs transmission. Conclusions and Relevance: Taken together, these findings highlight the important role that economic position may play on breaking the cycle of ACEs. This information can inform decisions about what public assistance policies, practices, and programs may be used to improve economic stability among families as an effective ACEs prevention strategy, and for whom these strategies might be most effective at reducing the cycle of ACEs. © 2021 |
Redox epiphospholipidome in programmed cell death signaling: Catalytic mechanisms and regulation
Kagan VE , Tyurina YY , Vlasova II , Kapralov AA , Amoscato AA , Anthonymuthu TS , Tyurin VA , Shrivastava IH , Cinemre FB , Lamade A , Epperly MW , Greenberger JS , Beezhold DH , Mallampalli RK , Srivastava AK , Bayir H , Shvedova AA . Front Endocrinol (Lausanne) 2020 11 628079 A huge diversification of phospholipids, forming the aqueous interfaces of all biomembranes, cannot be accommodated within a simple concept of their role as membrane building blocks. Indeed, a number of signaling functions of (phospho)lipid molecules has been discovered. Among these signaling lipids, a particular group of oxygenated polyunsaturated fatty acids (PUFA), so called lipid mediators, has been thoroughly investigated over several decades. This group includes oxygenated octadecanoids, eicosanoids, and docosanoids and includes several hundreds of individual species. Oxygenation of PUFA can occur when they are esterified into major classes of phospholipids. Initially, these events have been associated with non-specific oxidative injury of biomembranes. An alternative concept is that these post-synthetically oxidatively modified phospholipids and their adducts with proteins are a part of a redox epiphospholipidome that represents a rich and versatile language for intra- and inter-cellular communications. The redox epiphospholipidome may include hundreds of thousands of individual molecular species acting as meaningful biological signals. This review describes the signaling role of oxygenated phospholipids in programs of regulated cell death. Although phospholipid peroxidation has been associated with almost all known cell death programs, we chose to discuss enzymatic pathways activated during apoptosis and ferroptosis and leading to peroxidation of two phospholipid classes, cardiolipins (CLs) and phosphatidylethanolamines (PEs). This is based on the available LC-MS identification and quantitative information on the respective peroxidation products of CLs and PEs. We focused on molecular mechanisms through which two proteins, a mitochondrial hemoprotein cytochrome c (cyt c), and non-heme Fe lipoxygenase (LOX), change their catalytic properties to fulfill new functions of generating oxygenated CL and PE species. Given the high selectivity and specificity of CL and PE peroxidation we argue that enzymatic reactions catalyzed by cyt c/CL complexes and 15-lipoxygenase/phosphatidylethanolamine binding protein 1 (15LOX/PEBP1) complexes dominate, at least during the initiation stage of peroxidation, in apoptosis and ferroptosis. We contrast cell-autonomous nature of CLox signaling in apoptosis correlating with its anti-inflammatory functions vs. non-cell-autonomous ferroptotic signaling facilitating pro-inflammatory (necro-inflammatory) responses. Finally, we propose that small molecule mechanism-based regulators of enzymatic phospholipid peroxidation may lead to highly specific anti-apoptotic and anti-ferroptotic therapeutic modalities. |
Enhanced morphological transformation of human lung epithelial cells by continuous exposure to cellulose nanocrystals
Kisin ER , Yanamala N , Rodin D , Menas A , Farcas M , Russo M , Guppi S , Khaliullin TO , Iavicoli I , Harper M , Star A , Kagan VE , Shvedova AA . Chemosphere 2020 250 126170 Cellulose nanocrystals (CNC), also known as nanowhiskers, have recently gained much attention due to their biodegradable nature, advantageous chemical and mechanical properties, economic value and renewability thus making them attractive for a wide range of applications. However, before these materials can be considered for potential uses, investigation of their toxicity is prudent. Although CNC exposures are associated with pulmonary inflammation and damage as well as oxidative stress responses and genotoxicity in vivo, studies evaluating cell transformation or tumorigenic potential of CNC's were not previously conducted. In this study, we aimed to assess the neoplastic-like transformation potential of two forms of CNC derived from wood (powder and gel) in human pulmonary epithelial cells (BEAS-2B) in comparison to fibrous tremolite (TF), known to induce lung cancer. Short-term exposure to CNC or TF induced intracellular ROS increase and DNA damage while long-term exposure resulted in neoplastic-like transformation demonstrated by increased cell proliferation, anchorage-independent growth, migration and invasion. The increased proliferative responses were also in-agreement with observed levels of pro-inflammatory cytokines. Based on the hierarchical clustering analysis (HCA) of the inflammatory cytokine responses, CNC powder was segregated from the control and CNC-gel samples. This suggests that CNC may have the ability to influence neoplastic-like transformation events in pulmonary epithelial cells and that such effects are dependent on the type/form of CNC. Further studies focusing on determining and understanding molecular mechanisms underlying potential CNC cell transformation events and their likelihood to induce tumorigenic effects in vivo are highly warranted. |
Redox phospholipidomics of enzymatically generated oxygenated phospholipids as specific signals of programmed cell death
Kagan VE , Tyurina YY , Sun WY , Vlasova II , Dar H , Tyurin VA , Amoscato AA , Mallampalli R , van der Wel PCA , He RR , Shvedova AA , Gabrilovich DI , Bayir H . Free Radic Biol Med 2019 147 231-241 High fidelity and effective adaptive changes of the cell and tissue metabolism to changing environments require strict coordination of numerous biological processes. Multicellular organisms developed sophisticated signaling systems of monitoring and responding to these different contexts. Among these systems, oxygenated lipids play a significant role realized via a variety of re-programming mechanisms. Some of them are enacted as a part of pro-survival pathways that eliminate harmful or unnecessary molecules or organelles by a variety of degradation/hydrolytic reactions or specialized autophageal processes. When these "partial" intracellular measures are insufficient, the programs of cells death are triggered with the aim to remove irreparably damaged members of the multicellular community. These regulated cell death mechanisms are believed to heavily rely on signaling by a highly diversified group of molecules, oxygenated phospholipids (PLox). Out of thousands of detectable individual PLox species, redox phospholipidomics deciphered several specific molecules that seem to be diagnostic of specialized death programs. Oxygenated cardiolipins (CLs) and phosphatidylethanolamines (PEs) have been identified as predictive biomarkers of apoptosis and ferroptosis, respectively. This has led to decoding of the enzymatic mechanisms of their formation involving mitochondrial oxidation of CLs by cytochrome c and endoplasmic reticulum-associated oxidation of PE by lipoxygenases. Understanding of the specific biochemical radical-mediated mechanisms of these oxidative reactions opens new avenues for the design and search of highly specific regulators of cell death programs. This review emphasizes the usefulness of such selective lipid peroxidation mechanisms in contrast to the concept of random poorly controlled free radical reactions as instruments of non-specific damage of cells and their membranes. Detailed analysis of two specific examples of phospholipid oxidative signaling in apoptosis and ferroptosis along with their molecular mechanisms and roles in reprogramming has been presented. |
Redox (phospho)lipidomics of signaling in inflammation and programmed cell death
Tyurina YY , St Croix CM , Watkins SC , Watson AM , Epperly MW , Anthonymuthu TS , Kisin ER , Vlasova II , Krysko O , Krysko DV , Kapralov AA , Dar HH , Tyurin VA , Amoscato AA , Popova EN , Bolevich SB , Timashev PS , Kellum JA , Wenzel SE , Mallampalli RK , Greenberger JS , Bayir H , Shvedova AA , Kagan VE . J Leukoc Biol 2019 106 (1) 57-81 In addition to the known prominent role of polyunsaturated (phospho)lipids as structural blocks of biomembranes, there is an emerging understanding of another important function of these molecules as a highly diversified signaling language utilized for intra- and extracellular communications. Technological developments in high-resolution mass spectrometry facilitated the development of a new branch of metabolomics, redox lipidomics. Analysis of lipid peroxidation reactions has already identified specific enzymatic mechanisms responsible for the biosynthesis of several unique signals in response to inflammation and regulated cell death programs. Obtaining comprehensive information about millions of signals encoded by oxidized phospholipids, represented by thousands of interactive reactions and pleiotropic (patho)physiological effects, is a daunting task. However, there is still reasonable hope that significant discoveries, of at least some of the important contributors to the overall overwhelmingly complex network of interactions triggered by inflammation, will lead to the discovery of new small molecule regulators and therapeutic modalities. For example, suppression of the production of AA-derived pro-inflammatory mediators, HXA3 and LTB4, by an iPLA2 gamma inhibitor, R-BEL, mitigated injury associated with the activation of pro-inflammatory processes in animals exposed to whole-body irradiation. Further, technological developments promise to make redox lipidomics a powerful approach in the arsenal of diagnostic and therapeutic instruments for personalized medicine of inflammatory diseases and conditions. |
"Only a life lived for others is worth living": Redox signaling by oxygenated phospholipids in cell fate decisions
Tyurina YY , Shrivastava I , Tyurin VA , Mao G , Dar HH , Watkins S , Epperly M , Bahar I , Shvedova AA , Pitt B , Wenzel SE , Mallampalli RK , Sadovsky Y , Gabrilovich D , Greenberger JS , Bayir H , Kagan VE . Antioxid Redox Signal 2018 29 (13) 1333-1358 SIGNIFICANCE: Oxygenated polyunsaturated lipids are known to play multi-functional roles as essential signals coordinating metabolism and physiology. Among them are well-studied eicosanoids and docosanoids that are generated via phospholipase A2 hydrolysis of membrane phospholipids and subsequent oxygenation of free polyunsaturated fatty acids (PUFA) by cyclooxygenases and lipoxygenases. Recent Advances: There is an emerging understanding that oxygenated PUFA-phospholipids also represent a rich signaling language with yet-to-be-deciphered details of the execution machinery-oxygenating enzymes, regulators, and receptors. Both free and esterified oxygenated PUFA signals are generated in cells, and their cross-talk and inter-conversion through the de-acylation/re-acylation reactions is not sufficiently explored. CRITICAL ISSUES: Here, we review recent data related to oxygenated phospholipids as important damage signals that trigger programmed cell death pathways to eliminate irreparably injured cells and preserve the health of multicellular environments. We discuss the mechanisms underlying the trans-membrane redistribution and generation of oxygenated cardiolipins in mitochondria by cytochrome c as pro-apoptotic signals. We also consider the role of oxygenated phosphatidylethanolamines as proximate pro-ferroptotic signals. FUTURE DIRECTIONS: We highlight the importance of sequential processes of phospholipid oxygenation and signaling in disease contexts as opportunities to use their regulatory mechanisms for the identification of new therapeutic targets. |
Iron catalysis of lipid peroxidation in ferroptosis: Regulated enzymatic or random free radical reaction
Stoyanovsky DA , Tyurina YY , Shrivastava I , Bahar I , Tyurin VA , Protchenko O , Jadhav S , Bolevich SB , Kozlov AV , Vladimirov YA , Shvedova AA , Philpott CC , Bayir H , Kagan VE . Free Radic Biol Med 2018 133 153-161 Duality of iron as an essential cofactor of many enzymatic metabolic processes and as a catalyst of poorly controlled redox-cycling reactions defines its possible biological beneficial and hazardous role in the body. In this review, we discuss these two "faces" of iron in a newly conceptualized program of regulated cell death, ferroptosis. Ferroptosis is a genetically programmed iron-dependent form of regulated cell death driven by enhanced lipid peroxidation and insufficient capacity of thiol-dependent mechanisms (glutathione peroxidase 4, GPX4) to eliminate hydroperoxy-lipids. We present arguments favoring the enzymatic mechanisms of ferroptotically engaged non-heme iron of 15-lipoxygenases (15-LOX) in complexes with phosphatidylethanolamine binding protein 1 (PEBP1) as a catalyst of highly selective and specific oxidation reactions of arachidonoyl- (AA) and adrenoyl-phosphatidylethanolamines (PE). We discuss possible role of iron chaperons as control mechanisms for guided iron delivery directly to their "protein clients" thus limiting non-enzymatic redox-cycling reactions. We also consider opportunities of loosely-bound iron to contribute to the production of pro-ferroptotic lipid oxidation products. Finally, we propose a two-stage iron-dependent mechanism for iron in ferroptosis by combining its catalytic role in the 15-LOX-driven production of 15-hydroperoxy-AA-PE (HOO-AA-PE) as well as possible involvement of loosely-bound iron in oxidative cleavage of HOO-AA-PE to oxidatively truncated electrophiles capable of attacking nucleophilic targets in yet to be identified proteins leading to cell demise. |
Structural characterization of cardiolipin-driven activation of cytochrome C into a peroxidase and membrane perturbation.
Mohammadyani D , Yanamala N , Samhan Arias AK , Kapralov AA , Stepanov G , Nuar N , Planas-Iglesias J , Sanghera N , Kagan VE , Klein-Seetharaman J . Biochim Biophys Acta 2018 1860 (5) 1057-1068 The interaction between CL and cytochrome c (cyt-c), results in a gain of function of peroxidase activity by cyt-c. Despite intensive research, disagreements on nature and molecular details of this interaction remain. In particular, it is still not known how the interaction triggers the onset of apoptosis. Enzymatic characterization of peroxidase activity has highlighted the need for a critical threshold concentration of CL, a finding of profound physiological relevance in vivo. Using solution NMR, fluorescence spectroscopy, and in silico modeling approaches we here confirm that full binding of cyt-c to the membrane requires a CL:cyt-c threshold ratio of 5:1. Among three binding sites, the simultaneous binding of two sites, at two opposing sides of the heme, provides a mechanism to open the heme crevice to substrates, resulting in "productive binding" in which cyt-c then sequesters CL, inducing curvature in the membrane. Membrane perturbation along with lipid peroxidation, due to interactions of heme/CL acyl chains, initiates the next step in the apoptotic pathway of making the membrane leaky. The third CL binding site while allowing interaction with the membrane, does not cluster CL or induce subsequent events, making this interaction "unproductive". |
Mediation of the single-walled carbon nanotubes induced pulmonary fibrogenic response by osteopontin and TGF-beta1
Khaliullin TO , Kisin ER , Murray AR , Yanamala N , Shurin MR , Gutkin DW , Fatkhutdinova LM , Kagan VE , Shvedova AA . Exp Lung Res 2017 43 (8) 311-326 PURPOSE OF THE STUDY: A number of in vivo studies have shown that pulmonary exposure to carbon nanotubes (CNTs) may lead to an acute local inflammatory response, pulmonary fibrosis, and granulomatous lesions. Among the factors that play direct roles in initiation and progression of fibrotic processes are epithelial-mesenchymal transition and myofibroblasts recruitment/differentiation, both mediated by transforming growth factor-beta1 (TGF-beta1). Yet, other contributors to TGF-beta1 associated signaling, such as osteopontin (OPN) has not been fully investigated. MATERIALS AND METHODS: OPN-knockout female mice (OPN-KO) along with their wild-type (WT) counterparts were exposed to single-walled carbon nanotubes (SWCNT) (40 microg/mouse) via pharyngeal aspiration and fibrotic response was assessed 1, 7, and 28 days post-exposure. Simultaneously, RAW 264.7 and MLE-15 cells were treated with SWCNT (24 hours, 6 microg/cm(2) to 48 microg/cm(2)) or bleomycin (0.1 microg/ml) in the presence of OPN-blocking antibody or isotype control, and TGF-beta1 was measured in supernatants. RESULTS AND CONCLUSIONS: Diminished lactate dehydrogenase activity at all time points, along with less pronounced neutrophil influx 24 h post-exposure, were measured in broncho-alveolar lavage (BAL) of OPN-KO mice compared to WT. Pro-inflammatory cytokine release (IL-6, TNF-alpha, MCP-1) was reduced. A significant two-fold increase of TGF-beta1 was found in BAL of WT mice at 7 days, while TGF-beta1 levels in OPN-KO animals remained unaltered. Histological examination revealed marked decrease in granuloma formation and less collagen deposition in the lungs of OPN-KO mice compared to WT. RAW 264.7 but not MLE-15 cells exposed to SWCNT and bleomycin had significantly less TGF-beta1 released in the presence of OPN-blocking antibody. We believe that OPN is important in initiating the cellular mechanisms that produce an overall pathological response to SWCNT and it may act upstream of TGF-beta1. Further investigation to understand the mechanistic details of such interactions is critical to predict outcomes of pulmonary exposure to CNT. |
Detailed Transmission Network Analysis of a Large Opiate-Driven Outbreak of HIV Infection in the United States.
Campbell EM , Jia H , Shankar A , Hanson D , Luo W , Masciotra S , Owen SM , Oster AM , Galang RR , Spiller MW , Blosser SJ , Chapman E , Roseberry JC , Gentry J , Pontones P , Duwve J , Peyrani P , Kagan RM , Whitcomb JM , Peters PJ , Heneine W , Brooks JT , Switzer WM . J Infect Dis 2017 216 (9) 1053-1062 In January 2015, an outbreak of undiagnosed human immunodeficiency virus (HIV) infections among persons who inject drugs (PWID) was recognized in rural Indiana. By September 2016, 205 persons in this community of approximately 4400 had received a diagnosis of HIV infection. We report results of new approaches to analyzing epidemiologic and laboratory data to understand transmission during this outbreak. HIV genetic distances were calculated using the polymerase region. Networks were generated using data about reported high-risk contacts, viral genetic similarity, and their most parsimonious combinations. Sample collection dates and recency assay results were used to infer dates of infection. Epidemiologic and laboratory data each generated large and dense networks. Integration of these data revealed subgroups with epidemiologic and genetic commonalities, one of which appeared to contain the earliest infections. Predicted infection dates suggest that transmission began in 2011, underwent explosive growth in mid-2014, and slowed after the declaration of a public health emergency. Results from this phylodynamic analysis suggest that the majority of infections had likely already occurred when the investigation began and that early transmission may have been associated with sexual activity and injection drug use. Early and sustained efforts are needed to detect infections and prevent or interrupt rapid transmission within networks of uninfected PWID. |
Ins and outs in environmental and occupational safety studies of asthma and engineered nanomaterials
Dobrovolskaia MA , Shurin MR , Kagan VE , Shvedova AA . ACS Nano 2017 11 (8) 7565-7571 According to the Centers for Disease Control and Prevention, approximately 25 million Americans suffer from asthma. The disease total annual cost is about $56 billion and includes both the direct and indirect costs of medications, hospital stays, missed work, and decreased productivity. Air pollution with xenobiotics, bacterial agents, and industrial nanomaterials, such as carbon nanotubes, contribute to the exacerbation of this condition and are a point of particular attention in environmental toxicology as well as in occupational health and safety research. Mast cell degranulation and activation of Th2 cells triggered either by allergen-specific immunoglobulin E (IgE) or by alternative mechanisms, such as locally produced neurotransmitters, underlie the pathophysiological process of airway constriction during an asthma attack. Other immune and non-immune cell types, including basophils, eosinophils, Th1, Th17, Th9, macrophages, dendritic cells, and smooth muscle cells, are involved in the inflammatory and allergic responses during asthma, which, under chronic conditions, may progress without mast cells, the key trigger of the acute asthma attack. To decipher complex molecular, cellular, and genetic mechanisms, many researchers have attempted to develop in vitro and in vivo models to study asthma. Herein, we summarize the advantages and disadvantages of various models and their applicability to nanoparticle evaluation in asthma research. We further suggest that a framework for both in vitro and in vivo methods should be used to study the impact of engineered nanomaterials on asthma etiology, pathophysiology, and treatment. |
Gender differences in murine pulmonary responses elicited by cellulose nanocrystals
Shvedova AA , Kisin ER , Yanamala N , Farcas MT , Menas AL , Williams A , Fournier PM , Reynolds JS , Gutkin DW , Star A , Reiner RS , Halappanavar S , Kagan VE . Part Fibre Toxicol 2016 13 (1) 28 BACKGROUND: Cellulose-based materials have been used for centuries to manufacture different goods derived from forestry and agricultural sources. In the growing field of nanocellulose applications, its uniquely engineered properties are instrumental for inventive products coming to competitive markets. Due to their high aspect ratio and stiffness, it is speculated that cellulose nanocrystals (CNC) may cause similar pulmonary toxicity as carbon nanotubes and asbestos, thus posing a potential negative impact on public health and the environment. METHODS: The present study was undertaken to investigate the pulmonary outcomes induced by repeated exposure to respirable CNC. C57BL/6 female and male mice were exposed by pharyngeal aspiration to CNC (40 mug/mouse) 2 times a week for 3 weeks. Several biochemical endpoints and pathophysiological outcomes along with gene expression changes were evaluated and compared in the lungs of male and female mice. RESULTS: Exposure to respirable CNC caused pulmonary inflammation and damage, induced oxidative stress, elevated TGF-beta and collagen levels in lung, and impaired pulmonary functions. Notably, these effects were markedly more pronounced in females compared to male mice. Moreover, sex differences in responses to pulmonary exposure to CNC were also detected at the level of global mRNA expression as well as in inflammatory cytokine/chemokine activity. CONCLUSIONS: Overall, our results indicate that there are considerable differences in responses to respirable CNC based on gender with a higher pulmonary toxicity observed in female mice. |
Assessing clinical research capacity in Vietnam: a framework for strengthening capability for clinical trials in developing countries
Kagan J , Giang DD , Iademarco MF , Phung VTT , Lau CY , Quang NN . Public Health Rep 2016 131 (3) 396-403 Although improving health systems promises important benefits, most developing nations lack the resources to support nationally driven clinical research. Strengthened clinical research capacity can advance national health goals by supporting greater autonomy in aligning research with national priorities. From March through June 2010, we assessed six elements of clinical research capacity in Vietnam: research agenda; clinical investigators and biostatisticians; donors and sponsors; community involvement; scientific, ethical, safety, and quality oversight; and clinical research institutions. Assessments were drawn from interviews with investigators, Ministry of Health staff members, nongovernment organizations, and U.S. Mission staff members, and document review. Observations and recommendations were shared with collaborators. Reassessment in 2015 found growth in the number of clinical trials, improved regulation in human subjects protection and community engagement, and modest advances in research agenda setting. Training and investment in institutions remain challenging. A framework for assessing clinical research capacity can affirm strengths and weaknesses and guide the coordination of capacity-building efforts. © 2016, Association of Schools of Public Health. All rights reserved. |
Nanotoxicology ten years later: Lights and shadows
Shvedova A , Pietroiusti A , Kagan V . Toxicol Appl Pharmacol 2016 299 1-2 The mounting societal concerns about possible and maybe even likely adverse effects of nanomaterials are reflected in a large and growing number of publications in the field of nanotoxicology. Indeed, today's search in PubMed reveals >3700 publications on the subject denoted by (toxic+nanomaterials) - quite a growth over the last decade that began with only two dozens of them up-to 2005. |
Enzymatic oxidative biodegradation of nanoparticles: Mechanisms, significance and applications
Vlasova II , Kapralov AA , Michael ZP , Burkert SC , Shurin MR , Star A , Shvedova AA , Kagan VE . Toxicol Appl Pharmacol 2016 299 58-69 Biopersistence of carbon nanotubes, graphene oxide (GO) and several other types of carbonaceous nanomaterials is an essential determinant of their health effects. Successful biodegradation is one of the major factors defining the life span and biological responses to nanoparticles. Here, we review the role and contribution of different oxidative enzymes of inflammatory cells - myeloperoxidase, eosinophil peroxidase, lactoperoxidase, hemoglobin, and xanthine oxidase - to the reactions of nanoparticle biodegradation. We further focus on interactions of nanomaterials with hemoproteins dependent on the specific features of their physico-chemical and structural characteristics. Mechanistically, we highlight the significance of immobilized peroxidase reactive intermediates vs diffusible small molecule oxidants (hypochlorous and hypobromous acids) for the overall oxidative biodegradation process in neutrophils and eosinophils. We also accentuate the importance of peroxynitrite-driven pathways realized in macrophages via the engagement of NADPH oxidase- and NO synthase-triggered oxidative mechanisms. We consider possible involvement of oxidative machinery of other professional phagocytes such as microglial cells, myeloid-derived suppressor cells, in the context of biodegradation relevant to targeted drug delivery. We evaluate the importance of genetic factors and their manipulations for the enzymatic biodegradation in vivo. Finally, we emphasize a novel type of biodegradation realized via the activation of the "dormant" peroxidase activity of hemoproteins by the nano-surface. This is exemplified by the binding of GO to cyt c causing the unfolding and 'unmasking' of the peroxidase activity of the latter. We conclude with the strategies leading to safe by design carbonaceous nanoparticles with optimized characteristics for mechanism-based targeted delivery and regulatable life-span of drugs in circulation. |
MDSC and TGF-beta are required for facilitation of tumor growth in the lungs of mice exposed to carbon nanotubes
Shvedova AA , Kisin ER , Yanamala N , Tkach AV , Gutkin DW , Star A , Shurin GV , Kagan VE , Shurin MR . Cancer Res 2015 75 (8) 1615-23 During last decades, changes have been observed in the frequency of different histological subtypes of lung cancer - one of the most common causes of morbidity and mortality - with a declining proportion of squamous cell carcinomas and an increasing proportion of adenocarcinomas, particularly in developed countries. This suggests the emergence of new etiological factors and mechanisms including those defining the lung microenvironment promoting tumor growth. Assuming that the lung is the main portal of entry for broadly used nanomaterials and their established pro-inflammatory propensities, we hypothesized that nanomaterials may contribute to changes facilitating tumor growth. Here we report that an acute exposure to single-walled carbon nanotubes (SWCNT) induces recruitment and accumulation of lung-associated myeloid-derived suppressor cells (MDSC) and MDSC-derived production of TGF-beta resulting in up-regulated tumor burden in the lung. The production of TGF-beta by MDSC requires their interaction with both SWCNT and tumor cells. We conclude that pulmonary exposure to SWCNT favors the formation of a niche that supports ingrowth of lung carcinoma in vivo via activation of TGF-beta production by SWCNT-attracted and pre-sensitized MDSC. |
Abnormalities in the male reproductive system after exposure to diesel and biodiesel blend
Kisin ER , Yanamala N , Farcas MT , Gutkin DW , Shurin MR , Kagan VE , Bugarski AD , Shvedova AA . Environ Mol Mutagen 2014 56 (2) 265-76 Altering the fuel source from petroleum-based ultralow sulfur diesel to biodiesel and its blends is considered by many to be a sustainable choice for controlling exposures to particulate material. As the exhaust of biodiesel/diesel blends is composed of a combination of combustion products of polycyclic aromatic hydrocarbons and fatty acid methyl esters, we hypothesize that 50% biodiesel/diesel blend (BD50) exposure could induce harmful outcomes because of its ability to trigger oxidative damage. Here, adverse effects were compared in murine male reproductive organs after pharyngeal aspiration with particles generated by engine fueled with BD50 or neat petroleum diesel (D100). When compared with D100, exposure to BD50 significantly altered sperm integrity, including concentration, motility, and morphological abnormalities, as well as increasing testosterone levels in testes during the time course postexposure. Serum level of luteinizing hormone was significantly depleted only after BD50 exposure. Moreover, we observed that exposure to BD50 significantly increased sperm DNA fragmentation and the upregulation of inflammatory cytokines in the serum and testes on Day 7 postexposure when compared with D100. Histological evaluation of testes sections from BD50 exposure indicated more noticeable interstitial edema, degenerating spermatocytes, and dystrophic seminiferous tubules with arrested spermatogenesis. Significant differences in the level of oxidative stress assessed by accumulation of lipid peroxidation products and depletion of glutathione were detected on exposure to respirable BD50 and D100. Taken together, these results indicate that exposure of mice to inhalable BD50 caused more pronounced adverse effects on male reproductive function than diesel. |
In vivo evaluation of the pulmonary toxicity of cellulose nanocrystals: a renewable and sustainable nanomaterial of the future
Yanamala N , Farcas MT , Hatfield MK , Kisin ER , Kagan VE , Geraci CL , Shvedova AA . ACS Sustain Chem Eng 2014 2 (7) 1691-1698 The use of cellulose as building blocks for the development of novel functional materials is rapidly growing. Cellulose nanocrystals (CNC), with advantageous chemical and mechanical properties, have gained prominence in a number of applications, such as in nanofillers in polymer composites, building materials, cosmetics, food, and the drug industry. Therefore, it becomes critical to evaluate the potential health effects associated with CNC exposures. The objective of this study was to compare pulmonary outcomes caused by exposure of C57BL/6 mice to two different processed forms of CNC derived from wood, i.e., CNCS (10 wt %; gel/suspension) and CNCP (powder), and compare to asbestos induced responses. Pharyngeal aspiration with CNCS and CNCP was found to facilitate innate inflammatory response assessed by an increase in leukocytes and eosinophils recovered by bronchoalveolar lavage (BAL). Biomarkers of tissue damage were elevated to a higher extent in mice exposed to CNCP. Compared to CNCP, CNCS caused a significant increase in the accumulation of oxidatively modified proteins. The up-regulation of inflammatory cytokines was higher in the lungs after CNCS treatments. Most importantly, CNCP materials were significantly longer than CNCS. Taken together, our data suggests that particle morphology and nanosize dimensions of CNCs, regardless of the same source, may be critical factors affecting the type of innate immune inflammatory responses. Because various processes have been developed for producing highly sophisticated nanocellulose materials, detailed assessment of specific health outcomes with respect to their physical-structural-chemical properties is highly warranted. |
Lung macrophages "digest" carbon nanotubes using a superoxide/peroxynitrite oxidative pathway
Kagan VE , Kapralov AA , St Croix CM , Watkins SC , Kisin ER , Kotchey GP , Balasubramanian K , Vlasova II , Yu J , Kim K , Seo W , Mallampalli RK , Star A , Shvedova AA . ACS Nano 2014 8 (6) 5610-21 In contrast to short-lived neutrophils, macrophages display persistent presence in the lung of animals after pulmonary exposure to carbon nanotubes. While effective in the clearance of bacterial pathogens and injured host cells, the ability of macrophages to "digest" carbonaceous nanoparticles has not been documented. Here, we used chemical, biochemical, and cell and animal models and demonstrated oxidative biodegradation of oxidatively functionalized single-walled carbon nanotubes via superoxide/NO* --> peroxynitrite-driven oxidative pathways of activated macrophages facilitating clearance of nanoparticles from the lung. |
Graphene oxide attenuates Th2-type immune responses, but augments airway remodeling and hyperresponsiveness in a murine model of asthma
Shurin MR , Yanamala N , Kisin ER , Tkach AV , Shurin GV , Murray AR , Leonard HD , Reynolds JS , Gutkin DW , Star A , Fadeel B , Savolainen K , Kagan VE , Shvedova AA . ACS Nano 2014 8 (6) 5585-99 Several lines of evidence indicate that exposure to nanoparticles (NPs) is able to modify airway immune responses, thus facilitating the development of respiratory diseases. Graphene oxide (GO) is a promising carbonaceous nanomaterial with unique physicochemical properties, envisioned for a multitude of medical and industrial applications. In this paper, we determined how exposure to GO modulates the allergic pulmonary response. Using a murine model of ovalbumin (OVA)-induced asthma, we revealed that GO, given at the sensitization stage, augmented airway hyperresponsiveness and airway remodeling in the form of goblet cell hyperplasia and smooth muscle hypertrophy. At the same time, the levels of the cytokines IL-4, IL-5, and IL-13 were reduced in broncho-alveolar lavage (BAL) fluid in GO-exposed mice. Exposure to GO during sensitization with OVA decreased eosinophil accumulation and increased recruitment of macrophages in BAL fluid. In line with the cytokine profiles, sensitization with OVA in the presence of GO stimulated the production of OVA-specific IgG2a and down-regulated the levels of IgE and IgG1. Moreover, exposure to GO increased the macrophage production of the mammalian chitinases, CHI3L1 and AMCase, whose expression is associated with asthma. Finally, molecular modeling has suggested that GO may directly interact with chitinase, affecting AMCase activity, which has been directly proven in our studies. Thus, these data show that GO exposure attenuates Th2 immune response in a model of OVA-induced asthma, but leads to potentiation of airway remodeling and hyperresponsiveness, with the induction of mammalian chitinases. |
Biodegradation of single-walled carbon nanotubes by eosinophil peroxidase
Andon FT , Kapralov AA , Yanamala N , Feng W , Baygan A , Chambers BJ , Hultenby K , Ye F , Toprak MS , Brandner BD , Fornara A , Klein-Seetharaman J , Kotchey GP , Star A , Shvedova AA , Fadeel B , Kagan VE . Small 2013 9 (16) 2721-9 Eosinophil peroxidase (EPO) is one of the major oxidant-producing enzymes during inflammatory states in the human lung. The degradation of single-walled carbon nanotubes (SWCNTs) upon incubation with human EPO and H2 O2 is reported. Biodegradation of SWCNTs is higher in the presence of NaBr, but neither EPO alone nor H2 O2 alone caused the degradation of nanotubes. Molecular modeling reveals two binding sites for SWCNTs on EPO, one located at the proximal side (same side as the catalytic site) and the other on the distal side of EPO. The oxidized groups on SWCNTs in both cases are stabilized by electrostatic interactions with positively charged residues. Biodegradation of SWCNTs can also be executed in an ex vivo culture system using primary murine eosinophils stimulated to undergo degranulation. Biodegradation is proven by a range of methods including transmission electron microscopy, UV-visible-NIR spectroscopy, Raman spectroscopy, and confocal Raman imaging. Thus, human EPO (in vitro) and ex vivo activated eosinophils mediate biodegradation of SWCNTs: an observation that is relevant to pulmonary responses to these materials. |
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