Toxic Stress Response Research Articles

The energy nanosensor AMPfret, expressed stably in HEK cells, provides insights into toxic stress responses and heterogeneity within clonal cell populations

The energy nanosensor AMPfret, expressed stably in HEK cells, provides insights into toxic stress responses and heterogeneity within clonal cell populations

Cuproptosis and physical training: A review.

Copper is an essential element in the human body, involved in many physiological and metabolic functions, including coagulation, oxidative metabolism, and hormone production. The maintenance of copper homeostasis within cells is a complex procedure that is intrinsically controlled by a multitude of intricate mechanisms. Disorders of copper homeostasis encompass a wide range of pathological conditions, including degenerative neurological diseases, metabolic disorders, cardio-cerebrovascular diseases, and tumors. Cuproptosis, a recently identified non-apoptotic mode of cell death mode, is characterized by copper dependence and the regulation of mitochondrial respiration. Cuproptosis represents a novel form of cell death distinct from the previously described modes, including apoptosis, necrosis, pyroptosis, and ferroptosis. Excess copper has been shown to induce cuproptosis by stimulating protein toxic stress responses via copper-dependent abnormal oligomerization of lipoylation proteins within the tricarboxylic acid cycle and the subsequent reduction of iron-sulfur cluster protein levels. Ferredoxin1 facilitates the lipoacylation of dihydrolipoyl transacetylase, which in turn degrades iron-sulfur cluster proteins by reducing Cu2+ to Cu+, thereby inducing cell death. Furthermore, copper homeostasis is regulated by the copper transporter, and disturbances in this homeostasis result in cuproptosis. Current evidence suggests that cuproptosis plays an important role in the onset and development of several cardiovascular diseases. Copper-chelating agents, including ammonium tetrathiomolybdate (VI) and DL-penicillamine, have been shown to facilitate the alleviation of cardiovascular disease by inhibiting cuproptosis. It is hypothesized that oxidative phosphorylation inhibitors such as physical training may inhibit cuproptosis by inhibiting the protein stress response. In conclusion, the implementation of physical training may be a viable strategy to reducte the incidence of cuproptosis.

Potential impact of cuproptosis-related genes on tumor immunity in esophageal carcinoma.

Cuproptosis involves a direct interaction with the tricarboxylic acid (TCA) lipid acylation components. This process intricately intersects with post-transcriptional lipid acylation (LA) and is linked to mitochondrial respiration and LA metabolism. Copper ions form direct bonds with acylated DLAT, promoting DLAT oligomerization, reducing Fe-S cluster proteins, and inducing a protein-triggered toxic stress response that culminates in cell demise. Simultaneously, the importance of immune contexture in cancer progression and treatment has significantly increased. We assessed the expression of cuproptosis-related genes (CRGs) across TCGA and validated our findings using the GEO data. Consensus clustering divided esophageal cancer (ESCA) patients into two clusters based on the expression of 7 CRGs. We evaluated the expression of immune checkpoint inhibitor (ICI) targets and calculated the elevated tumor mutational burden (TMB). Weighted gene co-expression network analysis (WGCNA) identified genes associated with the expression of CRGs and immunity. Cluster 1 exhibited increased immune infiltration, higher expression of ICI targets, higher TMB, and a higher incidence of deficiency in mismatch repair-microsatellite instability-high status. WGCNA analysis identified 14 genes associated with the expression of CRGs and immune scores. ROC analysis revealed specific hub genes with strong predictive capabilities. The expression levels of SLC6A3, MITD1, and PDHA1 varied across different pathological stages; CCS, LIPT2, PDHB, and PDHA1 showed variation in response to radiation therapy; MITD1 and PDHA1 exhibited differences related to the pathological M stages of ESCA. CRGs influence the immune contexture and can potentially transform cold tumors into hot tumors in ESCA patients.

Toxicological and histopathological alterations in the heart of young and adult albino rats exposed to mosquito coil smoke

Mosquito coil repellents are well-known indoor air pollutant with significant health concerns. The present study investigated the toxic effects of mosquito coil smoke on the heart of young and adult male rats. The animals were subjected to the smoke for 6 h/day, 6 days/week, for 4 weeks. Within the first hour after lighting the coil, significant amounts of formaldehyde, total volatile organic compounds, and particulate matter (PM2.5 and PM10) were detected. Both exposed ages, particularly the young group, showed a significant increase in the activities of serum aspartate aminotransferase, lactate dehydrogenase, creatine kinase-MB, and the levels of troponin I, myoglobin, Na+ levels, lipid profile, and inflammatory markers (interleukin-6 and C-reactive protein) as well as a significant decrease in K+ levels and cardiac Na–K ATPase activity, indicating development of cardiac inflammation and dysfunction. Furthermore, the toxic stress response was validated by significant downregulation at expression of the detoxifying enzyme cytochrome p450. Histopathological studies in both age groups, especially the young group, revealed cardiomyocyte degeneration and necrotic areas. Moreover, upregulation at the pro-apoptotic markers, caspase3, P53, and cytochrome C expressions, was detected by immunohistochemical approach in heart sections of the exposed groups. Finally, the myocardial dysfunctional effects of the coil active ingredient, meperfluthrin, were confirmed by the docking results which indicated a high binding affinity of meperfluthrin, with Na–K ATPase and caspase 3. In conclusion, both the young and adult exposed groups experienced significant cardiac toxicity changes evidenced by cell apoptosis and histopathological alterations as well as disruption of biochemical indicators.Graphical

Providing patient-centred care as Medical Radiation Practitioners to children and young persons in out of home care.

Modern healthcare focuses on patient-centred care where patients' needs, beliefs, choices and preferences are valued and lead to better health outcomes. Children and young persons in out of home care (OOHC) require more health care services compared with children from similar social and economic backgrounds. Each state and territory government are responsible for statutory child protection in Australia. If a child is unsafe in their current environment, they may be removed and placed into OOHC where they have ongoing case management with either a government or non-government agency. Complex trauma is the prolonged and uncontrolled exposure to traumatic events, like those experienced by maltreated children. Complex trauma can create a toxic stress response that produces biological alteration to the developing brain and affects the lives of the child, other family members and their descendants. Children with complex trauma often do not have the ability to regulate their responses to stimuli, reacting to minor triggers with disproportionate reactions. Many of these children will present with challenging behaviours. Trauma-informed care is a method of service delivery that seeks to actively minimise re-traumatisation. Creating a safe space is an essential element of trauma-informed care. Children with a history of complex trauma have life experiences that may be re-lived in a healthcare setting. There are ethical and legal considerations like privacy, consent and mandatory reporting when dealing with children in OOHC. By practising trauma-informed care Medical Radiation Practitioners can minimise further trauma to one of the most vulnerable population groups in Australia.

Impact of progressively cumulative exposure of AgNPs on earthworms (Eisenia fetida) and implication for eco-toxicological risk assessment

Hazardous pollutants released into the real environment mostly own long-lasting cumulative characteristics and have progressively negative impacts on organisms, which are always neglected in laboratory toxicological tests. Here in this study, the different ecotoxicity of Ag nanoparticles (AgNPs) on earthworm Eisenia fetida was compared via various endpoints and transcriptional sequencing between the 28-day progressively repeated (from 60 to 80, final 100 mg/kg) and one-step (directly to 100 mg/kg) exposure. The results showed that earthworms under progressively repeated exposure showed significantly less biomass loss and reproductive inhibition, as well as lower Ag bioaccumulation (15.6 mg/kg) compared with one-step exposure (17.9 mg/kg). The increases in enzyme activities (superoxide enzyme and catalase) and gene expression (metallothionein) also implied higher antioxidant and genetic toxicity in one-step exposed earthworms compared with those from progressively repeated exposure. Furthermore, the transcriptomic analysis identified 582 and 854 differentially expressed genes in the treatments of one-step and repeated exposure respectively compared with the control group. The results of pathway annotation and classification suggested similar enrichments of damage induction but different in toxic stress responses, whereas earthworms from repeated exposure possessed more detoxification-related pathways like translation and multicellular organismal processes. This study innovatively took into account the impacts of processive exposure occurring in the real environment and elucidated distinctions of toxicity and adaptation caused by different exposure patterns, which provided the theoretical basis for real risk identification under the framework and guidance of traditional toxicology, also the implication for the improvement of eco-toxicological risk assessment.

Opportunities to Treat Toxic Stress.

Opportunities to Treat Toxic Stress.

Mitigating Toxic Stress in At-Risk Youth through an Agriculture-Based After School Program

Adverse childhood experiences and accompanying toxic stress have negative impacts on children. Of particular interest, then, is identifying strategies that could help at-risk youth mitigate the impacts of toxic stress. Using a phenomenology based, qualitatively dominant research approach, this study explores dynamics of toxic stress in at-risk youth and how the On The Rise program, an agricultural-based after school program for at-risk youth, addresses toxic stress. The findings elucidate that the youth endured several social and environmental conditions that could contribute to toxic stress. Youth also described several toxic stress responses (signs) in their day to day lives. Youth comments exemplify three areas that they perceive to have experienced positive outcomes (such as school performance, family, dynamics, and peer relationships) and five program attributes collectively contributing to positive outcomes. Implications for program development targeting at-risk youth are presented and discussed.

Screening for Toxic Stress Response and Buffering Factors: A Case-Based, Trauma-Informed Approach to Health Equity.

IntroductionExposure to adverse childhood experiences (ACEs) can lead to a toxic stress response with impacts on health that affect health equity. As part of our Health Equity, Social Justice, and Anti-racism curriculum, our aim was to introduce second-year medical students to a case-based method using a template-based screening and application of toxic stress, buffering factors, and resiliency-fostering tools to address health disparities and inequities with a trauma-informed care approach.MethodsWe developed an asynchronous e-learning module that demonstrated the impact of ACEs by introducing students to screening for toxic stress response and buffering factors on health, their role as health equity determinants, and the use of brief in-clinic resilience-fostering tools in patient care. This was followed by a synchronous, facilitated, small-group, virtual discussion of a clinical case. Pre- and postworkshop surveys assessed changes in knowledge, skills, and attitudes. A 3-month follow-up survey assessed students’ behavioral changes.ResultsSixty-four students completed the learning module. Paired t-test analysis showed a statistically significant increase in students’ knowledge, skills, and attitudes regarding the Educational Objectives, with a survey response rate of 98%. Three months after the workshop, a third of students were applying these concepts, with a survey response rate of 87%.DiscussionImplementing this case-based curriculum in trauma-informed patient care helped increase opportunities for equitable health in patient encounters by providing students with the skills to screen for toxic stress, buffering, and brief in-clinic resiliency-fostering tools. Such skills will become even more impactful as we emerge from the COVID-19 pandemic.

Let's Not Settle for Getting Back to "Normal" - Addressing ACEs and Health Behaviors in the Wake of the COVID-19 Pandemic.

Adverse childhood experiences (ACEs) are potentially traumatic events (eg, experiencing violence, abuse, or neglect; witnessing violence; living in a household with substance misuse, mental health problems, or instability) that occur before 18 years of age.1 Over the last 20 years, there has been a growing evidence base demonstrating that these traumatic childhood events, and the toxic stress response they elicit, lead to worse physical, behavioral, and mental health across the life course as well as negatively affect education, employment, and earnings potential.

Trauma-Informed Care in Child Health Systems.

Trauma-Informed Care in Child Health Systems.

Preventing Childhood Toxic Stress: Partnering With Families and Communities to Promote Relational Health.

By focusing on the safe, stable, and nurturing relationships (SSNRs) that buffer adversity and build resilience, pediatric care is on the cusp of a paradigm shift that could reprioritize clinical activities, rewrite research agendas, and realign our collective advocacy. Driving this transformation are advances in developmental sciences as they inform a deeper understanding of how early life experiences, both nurturing and adverse, are biologically embedded and influence outcomes in health, education, and economic stability across the life span. This revised policy statement on childhood toxic stress acknowledges a spectrum of potential adversities and reaffirms the benefits of an ecobiodevelopmental model for understanding the childhood origins of adult-manifested disease and wellness. It also endorses a paradigm shift toward relational health because SSNRs not only buffer childhood adversity when it occurs but also promote the capacities needed to be resilient in the future. To translate this relational health framework into clinical practice, generative research, and public policy, the entire pediatric community needs to adopt a public health approach that builds relational health by partnering with families and communities. This public health approach to relational health needs to be integrated both vertically (by including primary, secondary, and tertiary preventions) and horizontally (by including public service sectors beyond health care). The American Academy of Pediatrics asserts that SSNRs are biological necessities for all children because they mitigate childhood toxic stress responses and proactively build resilience by fostering the adaptive skills needed to cope with future adversity in a healthy manner.

Review of Tools for Measuring Exposure to Adversity in Children and Adolescents

Background: Exposure to childhood adversity can result in negative behavioral and physical health outcomes due to potential long-term embedding into regulatory biological processes. Screening for exposure to adversity is a critical first step in identifying children at risk for developing a toxic stress response. Primary care pediatric practitioners are uniquely positioned to screen for exposure to adversity in their child and adolescent patients, but screening requires tools that can effectively identify patients at risk within the logistical constraints of a clinic visit. A literature review was conducted to (a) …

Review of Tools for Measuring Exposure to Adversity in Children and Adolescents

Exposure to childhood adversity can result in negative behavioral and physical health outcomes due to potential long-term embedding into regulatory biological processes. Screening for exposure to adversity is a critical first step in identifying children at risk for developing a toxic stress response. We searched PubMed, PsycArticles, and CINAHL for studies published between January 1, 2012, and December 31, 2016, as well as other sources, to identify potential tools for measuring cumulative adversity in children and adolescents. We identified 32 tools and examined them for adversity categories, target population, administration time, administration qualifications and method, and reliability and validity. We also created a list of recommended tools that would be feasible for use by pediatric practitioners in most types of practice. This review provides a starting point for mobilizing screening in pediatric settings, highlighting the challenges with existing tools, and potential issues in the development and evaluation of future tools.

Toxic stress and protective factors in multi-ethnic school age children: A research protocol.

Exposure to stressful environments in early childhood can cause a toxic stress response and lead to poor health outcomes, including obesity, cardiac disease, diabetes, and mental illness. In animals and maltreated children, the presence of a nurturing caregiver can buffer against the physiological disruptions associated with a toxic stress response; however, the specific caregiver and parenting characteristics that best promote a protective relationship in humans remain largely unexplored, particularly in families living in high-risk environments. In this study, framed in an ecobiodevelopmental (EBD) model, a cross-sectional design is being used to study 54 multi-ethnic, urban maternal-child dyads with children at early school age (4-9 years). Mothers' past experiences, mental health, and caregiving patterns and children's hair cortisol, C-reactive protein, pro-inflammatory cytokines, blood pressure, BMI, behavior, and school performance are being analyzed to identify maternal characteristics that may protect against children's toxic stress response in families at high risk for exposure to stressors such as poverty, trauma, or exposure to violence.

Statistical Approaches for Gene Selection, Hub Gene Identification and Module Interaction in Gene Co-Expression Network Analysis: An Application to Aluminum Stress in Soybean (Glycine max L.).

Selection of informative genes is an important problem in gene expression studies. The small sample size and the large number of genes in gene expression data make the selection process complex. Further, the selected informative genes may act as a vital input for gene co-expression network analysis. Moreover, the identification of hub genes and module interactions in gene co-expression networks is yet to be fully explored. This paper presents a statistically sound gene selection technique based on support vector machine algorithm for selecting informative genes from high dimensional gene expression data. Also, an attempt has been made to develop a statistical approach for identification of hub genes in the gene co-expression network. Besides, a differential hub gene analysis approach has also been developed to group the identified hub genes into various groups based on their gene connectivity in a case vs. control study. Based on this proposed approach, an R package, i.e., dhga (https://cran.r-project.org/web/packages/dhga) has been developed. The comparative performance of the proposed gene selection technique as well as hub gene identification approach was evaluated on three different crop microarray datasets. The proposed gene selection technique outperformed most of the existing techniques for selecting robust set of informative genes. Based on the proposed hub gene identification approach, a few number of hub genes were identified as compared to the existing approach, which is in accordance with the principle of scale free property of real networks. In this study, some key genes along with their Arabidopsis orthologs has been reported, which can be used for Aluminum toxic stress response engineering in soybean. The functional analysis of various selected key genes revealed the underlying molecular mechanisms of Aluminum toxic stress response in soybean.

Can Hospitalization Precipitate Toxic Stress?

* Abbreviation: ACE — : adverse childhood experience During morning rounds, I introduced myself to the parent of a patient with bronchiolitis. As trainees, we are taught the medical management of bronchiolitis and how to set families’ expectations for the course of illness. However, we are not taught how to help families cope with the stress of a hospitalization. As we entered the room to discuss her child’s illness, the mother was on edge. Although her son was due to feed, she firmly requested that we let him sleep. Then she glanced at the textbook in her lap, remarking that her child was finally comfortable. Although she had not slept herself, she needed to catch up with her schoolwork. This interaction prompted our team to consider whether this mother’s stress, the challenge she felt juggling her son’s illness with her own responsibilities, was affecting her son’s clinical course. Could the stress of this hospitalization be toxic to her? To this family? The 2012 American Academy of Pediatrics Policy Statement called on pediatricians to screen for and act on factors that could precipitate toxic stress responses.1 The report introduced positive, tolerable, and toxic physiologic responses to stress.1 Events that trigger positive and tolerable stress may elevate the body’s physiologic response system, but buffers such as social supports make the biological response mild and brief, preventing harm. Events that trigger positive stress provide the opportunity “to observe, learn, and practice healthy, adaptive responses.”2 Alternatively, … Address correspondence to Anita N. Shah, DO, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC 9016, Cincinnati, OH 45229. E-mail: anita.shah{at}cchmc.org

Structural aspects of molecular recognition in the immune system. Part II: Pattern recognition receptors (IUPAC Technical Report)

Abstract The vertebrate immune system uses pattern recognition receptors (PRRs) to detect a large variety of molecular signatures (pathogen-associated molecular patterns, PAMPs) from a broad range of different invading pathogens. The PAMPs range in size from relatively small molecules, to others of intermediate size such as bacterial lipopolysaccharide, lipopeptides, and oligosaccharides, to macromolecules such as viral DNA, RNA, and pathogen-derived proteins such as flagellin. Underlying this functional diversity of PRRs is a surprisingly small number of structurally distinct protein folds that include leucine-rich repeats in Toll-like receptors (TLRs) and NOD-like receptors (NLRs), the DExH box helicase domain in RIG-like receptors (RLRs), and C-type lectin domains (CTLDs) in the C-type lectins. Following PAMP recognition by the PRRs, downstream signaling pathways activate the innate immune system to respond to invading pathogenic organisms. The resulting stimulatory response is also vital for a balanced adaptive immune response to the pathogen, mediated by circulating antibodies and/or cytotoxic T cells. However, an aberrant stimulation of the innate immune system can also lead to excessive inflammatory and toxic stress responses. Exciting opportunities are now arising for the design of small synthetic molecules that bind to PRRs and influence downstream signaling pathways. Such molecules can be useful tools to modulate immune responses, for example, as adjuvants to stimulate adaptive immune responses to a vaccine, or as therapeutic agents to dampen aberrant immune responses, such as inflammation. The design of agonists or antagonists of PRRs can now benefit from a surge in knowledge of the 3D structures of PRRs, many in complexes with their natural ligands. This review article describes recent progress in structural studies of PRRs (TLRs, NLRs, CTLs, and RLRs), which is required for an understanding of how they specifically recognize structurally diverse “foreign” PAMPs amongst a background of other “self” molecules, sometimes closely related in structure, that are present in the human body.

Quantitative High Content Imaging of Cellular Adaptive Stress Response Pathways in Toxicity for Chemical Safety Assessment

Over the past decade, major leaps forward have been made on the mechanistic understanding and identification of adaptive stress response landscapes underlying toxic insult using transcriptomics approaches. However, for predictive purposes of adverse outcome several major limitations in these approaches exist. First, the limited number of samples that can be analyzed reduces the in depth analysis of concentration-time course relationships for toxic stress responses. Second these transcriptomics analysis have been based on the whole cell population, thereby inevitably preventing single cell analysis. Third, transcriptomics is based on the transcript level, totally ignoring (post)translational regulation. We believe these limitations are circumvented with the application of high content analysis of relevant toxicant-induced adaptive stress signaling pathways using bacterial artificial chromosome (BAC) green fluorescent protein (GFP) reporter cell-based assays. The goal is to establish a platform that incorporates all adaptive stress pathways that are relevant for toxicity, with a focus on drug-induced liver injury. In addition, cellular stress responses typically follow cell perturbations at the subcellular organelle level. Therefore, we complement our reporter line panel with reporters for specific organelle morphometry and function. Here, we review the approaches of high content imaging of cellular adaptive stress responses to chemicals and the application in the mechanistic understanding and prediction of chemical toxicity at a systems toxicology level.

BRCA1 involvement in toxicological responses and human cancer etiology

Breast cancer associated gene 1 (BRCA1) gene is located on the long (q) arm of chromosome 17 at position 21. In the nucleus of many types of normal cells, BRCA1 protein interacts with several other proteins to mend strand breaks in DNA. It is generally considered a key regulatory protein participating in cell cycle checkpoint and DNA damage repair networks. Exposure to various environmental and genetic factors can induce a severe impact on life span and lead to neoplastic transformation. BRCA1 through its participation in the control mechanisms of cell growth and DNA repair is lately considered as an important component of mammary homeostasis. In this review we summarize the different cellular functions and roles of this gene, the experimental evidence for its linkage to carcinogenesis and recent evidence tying BRCA1 to environmentally induced toxic-stress responses. Finally, we discuss the new insights in the exploitation of BRCA1 defects for the development of new therapeutic strategies in cancer treatment and clinical applications.