Biomarkers Of Stress Response Research Articles

Evaluation of a probiotic blend on psychosocial health and biomarkers of inflammatory, immune and stress response in adults with subthreshold depression: a double-blind, randomised, placebo-controlled trial.

This study examined the efficacy of a probiotic in reducing depressive symptom severity in people with subthreshold depression. In a double-blind, randomised, placebo-controlled trial, a probiotic (1 × 10^9 live cells per strain: Limosilactobacillus fermentum LF16 (DSM26956), Lacticaseibacillus rhamnosus LR06 (DSM21981), Lactiplantibacillus plantarum LP01 (LMG P-21021) and Bifidobacterium longum 04 (DSM23233)) or placebo was taken daily for 12 weeks. Data were collected at baseline, 6 and 12 weeks including psychological symptom severity (Beck Depression Inventory, BDI; Patient Health Questionnaire, PHQ; Hospital Anxiety Depression Scale, HADS; and Depression Anxiety and Stress Scale, DASS). Biomarkers of glycaemia, inflammation (high-sensitivity C-reactive protein, hs-CRP), antioxidant status (total glutathione (GSH)) and stress (cortisol awakening response, CAR) were also measured. Thirty-nine participants (nineteen probiotic;twenty placebo) were enrolled. There were no significant between-group differences in the examined psychological symptom severity scores, despite certain significant within-group changes observed in both groups from baseline to 6 and/or 12 weeks of follow-up. Regarding biomarkers, the probiotic group showed reduced hs-CRP (-1520; 95 % CI -273·7, -2766·2 ng/dl) and CAR (-0·28; 95 % CI -0·05, -0·51 μg/dl) at 12 weeks, but increased total GSH (3·9; 95 % CI 0·1, 7·5 ng/dl) at 6 weeks, compared with the placebo. The current study reported favourable decreases in depressive symptoms in both groups. Although the within-group changes observed in the probiotic group were supported by favourable inflammatory, antioxidant status and stress biomarker changes compared with the placebo, further research is required to shed more light on the role of gut microbiota modulation on emotional regulation.

Copeptin as an inflammatory marker in diagnosis and prognosis of neonatal sepsis

BackgroundCopeptin is an immediate biomarker of individual stress response; many life-threatening diseases are causing a high elevation of its concentration in plasma, such as myocardial infarction and cardiovascular shock. Moreover, copeptin is a promising marker in sepsis. We aimed to evaluate copeptin as a diagnostic and prognostic marker in neonatal sepsis for the early initiation of appropriate therapy and the prediction of mortality. A prospective case-control study involved 237 neonates (165 cases had neonatal sepsis, and 72 served as controls). Cases were admitted to the neonatal intensive care unit (NICU) and followed up for symptoms and signs of sepsis confirmed by laboratory data: complete blood count (CBC), c-reactive protein (CRP), and cultures. Serum copeptin level by the enzyme-linked immunosorbent assay (ELISA) was measured for all included neonates. We observed that the copeptin level was significantly higher in cases than control (3.51 ± 1.4, 1.61 ± 0.51 pmol/liter, respectively). The cut-off value of copeptin at which we can discriminate between cases and controls was above 2.065 pmol/liter. Among cases, copeptin was higher in early-onset sepsis (EOS) than late-onset sepsis (LOS) neonates, and there was a significant correlation between its level and all the following: age at admission, birth weight, gestational age, history of perinatal asphyxia, maternal chorioamnionitis, and premature rupture of membrane (PROM). Also, copeptin was strongly associated with CRP level and the poor prognosis of patients. Copeptin can predict the death of cases at a cut-off value above 2.995 pmol/liter.ConclusionSerum copeptin level can be used as a diagnostic and prognostic marker in neonatal sepsis.

Seasonal and Sexual Variations in Corticosterone and Total Triiodothyronine: A Pilot Study in Mediterranean Tortoises (Testudo hermanni).

The Mediterranean tortoise Testudo hermanni inhabits different regions bordering the northwestern Mediterranean. This species is vulnerable, protected by legislation, and involved in various breeding and reintroduction programs. Wild populations face numerous environmental and anthropogenic stressors that can potentially interfere with their conservation. While seasonal changes in stress-response biomarkers, such as glucocorticoids and thyroid hormones, have been widely studised in mammals and birds, there is a paucity of research in reptile species. Therefore, the present study aimed to evaluate the seasonal fluctuations in corticosterone and total triiodothyronine levels in adult and juvenile Hermann's tortoises (Testudo hermanni) as a measure of the physiological stress response. Blood samples were collected seasonally (winter, spring, summer, and autumn) and posteriorly analyzed by using a specific and validated enzyme immunoassay for both hormones, respectively. The results showed that corticosterone levels varied seasonally and differed between sexes, whereas total triiodothyronine levels changed seasonally but did not differ between sexes. Notably, juveniles exhibited no seasonal changes in either corticosterone or total triiodothyronine levels. Additionally, no correlation between blood extraction duration and hormonal concentrations was observed. This study is pioneering in its comprehensive evaluation of corticosterone and total triiodothyronine changes across all four seasons, including winter, and its focus on juvenile Hermann's tortoises.

Benzalkonium chloride induced acute toxicity and its multifaceted implications on growth, hematological metrics, biochemical profiles, and stress-responsive biomarkers in tilapia (Oreochromis mossambicus).

This study aimed to investigate the toxic effects of benzalkonium chloride (BAC) on Oreochromis mossambicus, a freshwater fish species. Probit analysis was used to determine the lethal concentration (LC50) of BAC for different exposure periods (24, 48, 72, and 96h). The viability of fish exposed to BAC was assessed using the general threshold survival models (GUTS) and confirmed with relevant datasets to evaluate model accuracy. Experimental groups of fish were exposed to BAC concentrations equivalent to 10% and 20% of the 96-h LC50 for 45days. The study revealed significant alterations in various parameters during sublethal BAC exposure. These effects included decreased specific growth rate (SGR), red blood cell count (RBC), hemoglobin (Hb) concentration, hematocrit (Ht) value, plasma protein, and albumin levels, as well as acetylcholinesterase (AChE) activities in both gills and liver. Additionally, an increase in gastrosomatic index (GSI), feed conversion ratio (FCR), plasma glucose and creatinine concentrations, alanine aminotransferase (ALT), aspartate aminotransferase (AST) enzymatic activities, catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) levels were observed in the exposed fish's gills and liver. Furthermore, the study found that glutathione S-transferase (GST) and glutathione peroxidase (GPx) levels initially increased and then decreased in both gills and liver after exposure to BAC. Correlation matrix analysis, multivariate multiple regression (MMR), canonical correspondence analysis (CCA), integrated biomarker response (IBR), and biomarker response index (BRI) were utilized to assess the impact of BAC on fish, highlighting significant effects on multiple biomarkers in O. mossambicus following surfactant exposure. Thus, the study provides valuable insights into the toxic effects of BAC on this fish species, emphasizing the importance of monitoring such pollutants in aquatic environments.

Cell stiffening is a label-free indicator of reactive oxygen species-induced intracellular acidification

Reactive oxygen species (ROS) are important secondary messengers involved in a variety of cellular processes, including activation, proliferation, and differentiation. Hydrogen peroxide (H2O2) is a major ROS typically kept in low nanomolar range that causes cell and tissue damage at supraphysiological concentrations. While ROS have been studied in detail at molecular scale, little is known about their impact on cell mechanical properties as label-free biomarker for stress response. Here, we exposed human myeloid precursor cells, T-lymphoid cells and neutrophils to varying concentrations of H2O2 and show that elevated levels of mitochondrial superoxide are accompanied by an increased Young’s modulus. Mechanical alterations do not originate from global modifications in filamentous actin and microtubules but from cytosolic acidification due to lysosomal degradation. Finally, we demonstrate our findings to be independent of the presence of H2O2 and that stiffening seems to be a general response of cells to stress factors lowering cytosolic pH.

Elevated stress-responsive biomarkers are associated with HIV acquisition in young women in rural South Africa: A HPTN 068 case cohort study.

Biological markers of stress have been associated with HIV progression and pathogenesis but not with HIV incidence. We sought to determine if elevated stress-responsive biomarkers would be associated with incident HIV among adolescent girls and young women (AGYW). We conducted a case-cohort study within the HIV Prevention Trials Network (HPTN) 068 study among 949 AGYW in South Africa. Cases were AGYW who tested HIV-positive during the eight-year follow-up. Unmatched controls were randomly selected from the HIV-negative population at enrollment. Dried blood spots from cases and controls were tested from enrollment (2011-2012) for C-reactive protein (CRP), herpes simplex virus type-1 (HSV-1) antibody titers, and cytomegalovirus (CMV) antibody titers. Cox proportional hazards models estimated the association between each biomarker and time to incident HIV. Compared to AGYW with the lowest CRP levels, those with medium and high CRP levels had a higher hazard ratio (HR) of incident HIV (HR: 1.45, 95% CI: 0.95, 2.21; HR: 1.50, 95% CI: 0.98,2.30, respectively), although not statistically significant. The relative hazard of incident HIV was also higher among AGYW who were CMV seropositive vs. seronegative (low antibodies HR: 2.18, 95% CI: 1.2,3.87; medium HR: 2.25, 95% CI: 1.28,3.95; high HR: 1.78, 95% CI: 0.99,3.21). Those with the highest HSV-1 antibody levels experienced an increased hazard of HIV compared to those who were HSV-1 seronegative (HR: 1.58, 95% CI: 1.03,2.44). Biological stress may increase AGYW's susceptibility to HIV acquisition through changes in immune function, viral infection, and increased biological vulnerability to disease.

Feasibility of replacing fish oil with sunflower oil on the growth, body composition, fatty acid profile, antioxidant activity, stress response, and blood biomarkers of Labeo rohita.

A 90-day study was conducted to investigate the effects of substituting sunflower oil (SFO) for fish oil (FO) on various parameters in Labeo rohita (initial weight 18.21 ± 0.22 g). Five experimental diets with different levels of SFO (up to 7%) substitution for FO (0%, 25%, 50%, 75%, and 100%) were formulated, ensuring equal levels of nitrogen and lipids. The results indicated that even with 100% substitution of SFO with FO, there were no significant differences (P>0.05) were observed in growth performance. The survival rate (SR), hepato-somatic index (HSI), and viscero-somatic index (VSI) as well as whole-body composition were also nonsignificant by SFO substitution. However, the fatty acid profiles in both muscle and liver were influenced (P<0.05) by dietary substitution. Saturated fats (SFA) decreased, while monounsaturated fats (MUFA), and linoleic acid (LA) increased (P<0.05). On the other hand, the contribution of linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) decreased (P<0.05) as the amount of SFO in the diet increased. Hematology parameters, including red blood cells (RBCs), hemoglobin (Hb), and hematocrit (Hct), were not affected. Globulin (GLO) levels decreased significantly (P<0.05), while alanine transaminase (ALT) and aspartate transaminase (AST) activity showed nonsignificant increases (P>0.05). Total protein (TP) increased (P<0.05) at 100% SFO inclusion in the diet, and albumin (ALB) levels increased (P<0.05) at 75% and 100% SFO inclusion in the diet. Cholesterol (CHOL), triacylglycerol (TG), and high-density lipids (HDL) were not significantly affected (P>0.05), while low-density lipids (LDL) were significantly increased (P<0.05) compared to the control group. Cortisol (CORT) and glucose (GLU) levels showed nonsignificant (P>0.05) changes. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities in the liver and serum were not significantly (P>0.05) affected, while malondialdehyde (MDA) status was significantly (P<0.05) reduced. In conclusion, the fatty acid profile of the muscle and liver of fish was modified by the diets, and FO can be substituted with SFO up to 100% for L. rohita, which is beneficial for growth and immunity while marinating the lipid contents in fish. Our study revealed that fully replacing fish oil with SFO shows promise in fully replacing FO without compromising the growth and overall health status of the fish.

Proteome profiling reveals opportunities to investigate biomarkers of oxidative stress and immune responses in blubber biopsies from free-ranging baleen whales.

Over 25% of cetacean species worldwide are listed as critically endangered, endangered or vulnerable by the International Union for Conservation of Nature. Objective and widely applicable tools to assess cetacean health are therefore vital for population monitoring and to inform conservation initiatives. Novel blubber biomarkers of physiological state are examples of such tools that could be used to assess overall health. Proteins extracted from blubber likely originate from both the circulation and various cell types within the tissue itself, and their expression is responsive to signals originating from other organs and the nervous system. Blubber proteins can therefore capture information on physiological stressors experienced by individuals at the time of sampling. For the first time, we assess the feasibility of applying shotgun proteomics to blubber biopsy samples collected from free-ranging baleen whales. Samples were collected from minke whales (Balaenoptera acutorostrata) (n = 10) in the Gulf of St Lawrence, Canada. Total protein was extracted using a RIPA cell lysis and extraction buffer-based protocol. Extracted proteins were separated and identified using nanoflow Liquid Chromatography Electrospray Ionization in tandem with Mass Spectrometry. We mapped proteins to known biological pathways and determined whether they were significantly enriched based on the proteome profile. A pathway enrichment map was created to visualize overlap in tissue-level biological processes. Amongst the most significantly enriched biological pathways were those involved in immune system function: inflammatory responses, leukocyte-mediated immunity and the humoral immune response. Pathways associated with responses to oxidative stress were also enriched. Using a suite of such protein biomarkers has the potential to better assess the overall health and physiological state of live individuals through remote biopsy sampling. This information is vital for population health assessments to predict population trajectories, and ultimately guide and monitor conservation priorities and initiatives.

Salivary kallikrein-8 as a favorable biomarker for stress response

Background/Aim. Kallikreins (KLKs) are a group of serine protease enzymes capable of cleaving protein peptide bonds. Besides, they are proteolytic enzymes that mediate the conversion of kininogen (alpha 2-globulin) to bradykinin or kallidin. The aim of the study was to examine whether KLK8 might serve as a novel stress biomarker. Methods. Twenty-four students (17 female and 7 male) were included in the study. The general and dental health of the students were evaluated in the appropriate anamnesis format. Unstimulated samples were collected by Sarstedt ? saliva collection tubes as recommended: 08.00- 09.00 am, 12.00, and 2.00-3.00 pm on the exam day. KLK levels were measured by a KLK8 Human ELISA kit. Results. The salivary KLK8 levels in the morning (1.25 ? 0.26 pg/mL) were statistically significantly lower than the KLK8 levels pre-exam [at 12.00 (2.89 ? 0.85 pg/mL)] (p = 0.0006). There is also a significant difference in salivary KLK8 levels between pre- and post-exam (1.69 ? 0.39) time points (p = 0.0005). Conclusion. These results show that the differences in salivary KLK8 levels might be related to the degree of stress, indicating that KLK8 may serve as a novel stress biomarker.

P134: Immediate stress responses to music during psychomotor stimulation in 2 study cases with dementia.

Background:The use of music in older people with advanced dementia is possible because perception, sensitivity, emotion, and memory of music may remain intact after other types of memory disappear. Previous literature is controversial about stress biomarkers response to music introduction in therapy routines for people with severe cognitive impairment and neural-behavioural disorders. Particularly, for these patients, it is possible that they feel lower pleasure levels with music-based therapies.Objective:To characterize the immediate physiological effects of listening to music during psychomotor stimulation in an old participant with combined dementia and depression disorder and in a participant with a dementia diagnosis.Methods:Two study cases with dementia diagnosis participated in this study (P1: 84yrs; male Parkinson; FAB=9; P2: 85 yrs; female; Alzheimer; FAB=11; depression diagnosis) and were submitted to psychomotor stimulation (2 sessions). The first 20 min. of each session was dedicated to psychomotor stimulation without music (A), followed by 20 minutes with music (B). Heart rate was monitored (H10 Polar sensor) in a continuous mode. Cortisol levels were collected at the beginning of the session (T0) and then repeated at periods A and B (μg/dL). The range between minimum and maximum HR values (beats per minute- bpm) and mean values for cortisol levels were considered for the stress response analysis.Results:Salivary cortisol levels were higher at T0 for P1 (0.393 vs 0.203). During period A, the P1 slightly decreased their values (↓0,076) and P2 had no changes. After introducing music, both P1 and P2 increased cortisol levels (↑0,085; 0,162↑). For both P1 and P2, a wide range of HR was detected during period B (P1: 13 vs 23 bpm) vs (P2: 15 vs 41 bpm).Conclusion:Immediate responses to the music inclusion in a psychomotor intervention caused an augmented stress response in elderly participants with dementia, especially in P2. In specific, the depression diagnosis in this participant may be associated with a low capacity to handle emotions during new experiences, causing a higher stress response.

Muscle Transcriptome Sequencing Revealed Thermal Stress-Responsive Regulatory Genes in Farmed Rohu, Labeo rohita (Hamilton, 1822).

Rohu, Labeo rohita, is one of the most important aquaculture species in the Indian subcontinent. Understanding the molecular-level physiological responses to thermal stress or climate change is essential. In the present work, transcriptome sequencing was carried out in the muscle tissue of the rohu in response to heat stress (35°C) in comparison with the control (28°C). A total of 125Gb of sequence data was generated, and the raw-reads were filtered and trimmed, which resulted in 484 million quality reads. Reference-based assembly of reads was performed using L. rohita genome, and a total of 90.17% of reads were successfully mapped. A total of 37,462 contigs were assembled with an N50 value of 1854. The differential expression analysis revealed a total of 107 differentially expressed genes (DEGs) (15 up-, 37 down-, and 55 neutrally regulated) as compared to the control group (Log2FC > 2, P < 0.05). Gene enrichment analysis of DEGs indicates that transcripts were associated with molecular, biological, and cellular activities. The randomly selected differentially expressed transcripts were validated by RT-qPCR and found consistent expression patterns in line with the RNA-seq data. Several transcripts such as SERPINE1(HSP47), HSP70, HSP90alpha, Rano class II histocompatibility A beta, PGC-1 and ERR-induced regulator, proto-oncogene c-Fos, myozenin2, alpha-crystallin B chain-like protein, angiopoietin-like protein 8, and acetyl-CoA carboxylases have been identified in muscle tissue of rohu that are associated with stress/immunity. This study identified the key biomarker SERPINE1 (HSP47), which showed significant upregulation (~ 2- to threefold) in muscle tissue of rohu exposed to high temperature. This study can pave a path for the identification of stress-responsive biomarkers linked with thermal adaptations in the farmed carps.

Effect of the dipeptide retro-analog of cholecystokinin tetrapeptide (GB-115) on the behavior of rhesus monkeys in isolation

Introduction. The developed domestic dipeptide retro-analog of cholecystokinin (CCK) tetrapeptide (N-(6-phenylhexanoyl)-glycyltryptophan amide, compound GB-115) with antagonistic properties towards CCK1 receptors has anxiolytic activity, previously shown in preclinical and clinical studies. Purpose of the study. Evaluation of the anxiolytic effect of GB-115 in tablet dosage form with subchronic oral administration in comparison with phenazepam in laboratory primates. Methods. The experiment was performed on four male rhesus monkeys (Macaca mulatta) aged 5.7–6.7 years. After a 30-day period of adaptation to the conditions of individual housing, an experiment was performed with GB-115 (0.001 g tablets) and then with phenazepam (0.0005 g tablets). Both drugs were given one at a time (7 days), and then 2 tablets (7 days). Behavior was assessed by observing the object with registration according to the “Yes-No” principle of ethogram elements in the background periods, during the administration of drugs and during their withdrawal. Using enzyme immunoassay, the content of stress response biomarkers: cortisol and dehydroepiandrosterone sulfate (DHEA-S) was determined in blood serum. Results. GB-115 (0.001 g each) and phenazepam (0.001 g each) reduced the stay of animals in the upper part of the cage compared to the background period, which indicates a decrease in the stress response. GB-115 (0.002 g each) decreased the cortisol/DHEA-S ratio. Phenazepam dose-dependently reduced serum cortisol levels without affecting DHEA-S levels; with the administration of phenazepam (0.001 g), a decrease in the cortisol/DHEA-S ratio was also recorded. Conclusion. A positive effect of GB-115, when administered subchronically, on the weakening of the emotional stress reaction and restoration of adaptive behavior in rhesus monkeys was revealed, comparable to the effect of phenazepam, which confirms the possibility of using blockade of CCK1 receptors as one of the approaches for the treatment of anxiety disorders.

Potential of in vivo stress reporter models to reduce animal use and provide mechanistic insights in toxicity studies

Chemical risk assessment ensures protection from the toxic effects of drugs and manmade chemicals. To comply with regulatory guidance, studies in complex organisms are required, as well as mechanistic studies to establish the relevance of any toxicities observed to man. Although in vitro toxicity models are improving, in vivo studies remain central to this process. Such studies are invariably time-consuming and often involve large numbers of animals. New regulatory frameworks recommend the implementation of “smart” in vivo approaches to toxicity testing that can effectively assess safety for humans and comply with societal expectations for reduction in animal use. A major obstacle in reducing the animals required is the time-consuming and complexity of the pathological endpoints used as markers of toxicity. Such endpoints are prone to inter-animal variability, subjectivity and require harmonisation between testing sites. As a consequence, large numbers of animals per experimental group are required. To address this issue, we propose the implementation of sophisticated stress response reporter mice that we have developed. These reporter models provide early biomarkers of toxic potential in a highly reproducible manner at single-cell resolution, which can also be measured non-invasively and have been extensively validated in academic research as early biomarkers of stress responses for a wide range of chemicals at human-relevant exposures. In this report, we describe a new and previously generated models in our lab, provide the methodology required for their use and discuss how they have been used to inform on toxic risk (likelihood of chemical causing an adverse health effect). We propose our in vivo approach is more informative (refinement) and reduces the animal use (reduction) compared to traditional toxicity testing. These models could be incorporated into tiered toxicity testing and used in combination with in vitro assays to generate quantitative adverse outcome pathways and inform on toxic potential.

Salivary secretory immunoglobulin A as a potential biomarker of psychosocial stress response during the first stages of life: A systematic review

Mucosal secretory immunoglobulin A (s-IgA) has been recognized as a key component of human first line defense against infection. However, its reactivity to psychosocial stressors is poorly understood. This systematic review aimed to explore whether s-IgA levels changed after psychosocial stress in subjects under the age of 18. Fifteen articles were included. s-IgA basal levels are increased in children older than 9 years old exposed to stress. Furthermore, s-IgA seems to follow a circadian rhythm, which is altered under stress conditions. Finally, the collective evidence suggests that salivary s-IgA rapidly increases under acute stress after puberty. Overall, our review indicates that s-IgA could be considered a potential psychosocial stress biomarker of interest for pediatric and child-juvenile psychiatric population. Further studies are needed to validate the role of s-IgA circadian rhythm and basal levels as psychosocial stress biomarkers and disentangle the role of age and type of stressor.

A randomized controlled trial on the effects and acceptability of individual mindfulness techniques – meditation and yoga – on anxiety and depression in people with Parkinson’s disease: a study protocol

BackgroundBetween 40 and 50% of patients with Parkinson’s disease (PD) experience anxiety and depression, associated with impaired physical function, high care dependency and mortality. Recently, the United States National Institutes of Health has urged the implementation of mindfulness practices in chronic illness care. Most research to date has examined the effects on chronically ill patients of complex interventions using a combination of mindfulness techniques. In PD patients, however, such complex modalities appear to hinder the technique mastery. Hence, the aim of this trial is to investigate the effects and underlying mechanism of individual mindfulness techniques among PD patients, as well as exploring participants’ experience in using individual mindfulness techniques as a lifestyle intervention for stress and symptom management.MethodsWe will conduct an assessor-blind three-arm randomized waitlist-controlled trial with a descriptive qualitative evaluation. Up to 168 PD patients will be recruited from community settings and out-patient clinics, and randomized to meditation, yoga, or usual care group. Meditation and yoga sessions of 90-minute are held weekly for 8 weeks. Primary outcomes include anxiety and depression. Secondary outcomes include PD-related motor and non-motor symptoms and quality-of-life; and level of mindfulness and biomarkers of stress and inflammatory responses will be measured as mediating variables. All outcome evaluations will be assessed at baseline, 8 weeks, and 24 weeks. Following the intention-to-treat principle, generalized estimating equation models and path analysis will be used to identify the treatment effects and the mediating mechanisms. A subsample of 30 participants from each intervention group will be invited for qualitative interviews.DiscussionThe study would also generate important insights to enhance the patients’ adaptation to debilitating disease. More specifically, symptom management and stress adaptation are highly prioritized healthcare agenda in managing PD. The research evidence will further inform the development of community-based, nurse-led compassionate care models for neurodegenerative conditions, which is complementary to existing health services.Trial registrationWHO Primary Registry – Chinese Clinical Trials Registry number: ChiCTR2100045939; registered on 2021/04/29 (https://www.chictr.org.cn/showproj.html?proj=125878).

Assessment of the Accumulation of Trace Metals and Oxidative Stress Response Biomarkers in the Portunid Portunus segnis

The invasive blue crab Portunus segnis, which was collected from two sites on the Gulf of Gabès, is the subject of this work. This study is based on demonstrating the accumulation capacity of P. segnis by measuring the concentrations of cadmium, zinc, lead, and copper in the gills and hepatopancreas. The enzymatic activities of catalase, glutathione-S-transferase, reduced glutathione, and lipid peroxidase were assessed in this region for the first time. The main results show that the metals have high bioaccumulation potentials in P. segnis tissues between different sites. The possible adaptation of P. segnis in the Gulf of Gabès and the variations in the studied biomarkers and metal concentrations at different sites confirm the usefulness of the invasive blue crab as a sentinel species.

Evidence that the Biomarker-Behavior Relationship Depends on Negative Evaluation Level: Development and Initial Application of a Scale for Behavioral Engagement During the TSST

Behavioral engagement is integral to mental health, but little is known about the relationship of lab-based stress and behavioral engagement. This talk will report on the development and validation of an observer-rated measure of behavioral engagement for lab-based stress inductions, and on the relationship of stress-responsive biomarkers and affect to behavioral engagement during the Trier Social Stress Test (TSST). Young adults (N=109) completed one of three TSST versions—a non-stressful Control, an ambiguously evaluative Intermediate, or the explicitly negative-evaluative Challenge condition. They provided self-reports of positive and negative affect and saliva samples for cortisol and salivary alpha-amylase (sAA) at four timepoints; research assistants rated behavior. Psychometric inspection and EFA of the behavioral engagement items yielded an 8-item measure with good interrater reliability and well-fitting 2-factor structure, capturing Persistence (4 items; loadings=.41-.89), and Quality of Speech (4 items; loadings=.53-.92). Growth curve modeling indicated that as negative evaluation level increased, behavioral engagement became more tightly associated with relative preservation of positive affect, in the context of positive affect decline for most participants across the protocol. For both cortisol and sAA, the relationship between biomarker baseline levels—but not biomarker reactivity—and behavioral engagement varied by condition. Under milder conditions (Control for sAA, Intermediate for cortisol), elevated biomarkers predicted greater engagement, but under explicit negative evaluation, they predicted less engagement, that is, behavioral withdrawal. Findings support the critical role of context—especially negative evaluation—in the relationship of biomarkers to behavioral engagement.

Stress-responsive Gdf15 counteracts renointestinal toxicity via autophagic and microbiota reprogramming

The integrated stress response (ISR) plays a pivotal role in the cellular stress response, primarily through global translational arrest and the upregulation of cellular adaptation-linked molecules. Growth differentiation factor 15 (Gdf15) is a potent stress-responsive biomarker of clinical inflammatory and metabolic distress in various types of diseases. Herein, we assess whether ISR-driven cellular stress contributes to pathophysiological outcomes by modulating Gdf15. Clinical transcriptome analysis demonstrates that PKR is positively associated with Gdf15 expression in patients with renal injury. Gdf15 expression is dependent on protein kinase R (PKR)-linked ISR during acute renointestinal distress in mice and genetic ablation of Gdf15 aggravates chemical-induced lesions in renal tissues and the gut barrier. An in-depth evaluation of the gut microbiota indicates that Gdf15 is associated with the abundance of mucin metabolism-linked bacteria and their enzymes. Moreover, stress-responsive Gdf15 facilitates mucin production and cellular survival via the reorganization of the autophagy regulatory network. Collectively, ISR-activated Gdf15 counteracts pathological processes via the protective reprogramming of the autophagic network and microbial community, thereby providing robust predictive biomarkers and interventions against renointestinal distress.

Relationship of cortisol and alpha amylase to behavioral engagement under three levels of negative evaluative psychosocial stress

Despite that behavioral engagement is integral to mental health, surprisingly little is known about the relationship of psychosocial stress and behavioral engagement. The current study developed an observer-rated measure of behavioral engagement for lab-based stress inductions, then examined its relationship with stress-responsive biomarkers and affect. Young adults (N = 109, Mage=19.4, SDage=1.59, 57% female) completed one of three Trier Social Stress Test (TSST) conditions—non-stressful Control, Intermediate, or an Explicit Negative Evaluative—and at four timepoints provided self-reports of positive and negative affect and saliva samples for cortisol and salivary alpha-amylase (sAA). Trained study staff (experimenters and TSST judges) completed a programmed questionnaire measure of the novel behavioral engagement measure after the participants completed the TSST. Psychometric review and EFA of the behavioral engagement items resulted in a final 8-item measure with good interrater reliability and well-fitting 2-factor structure, capturing Persistence (4 items; loadings=.41–.89), and Quality of Speech (4 items; loadings=.53–.92). Results indicated that the relationship of positive affect growth and biomarker level to behavioral engagement varied substantially as a function of context: As negative evaluation level strengthened, behavioral engagement became more tightly associated with relative preservation of positive affect. For both cortisol and sAA, the relationship between biomarker levels (but not reactivity) and behavioral engagement varied significantly by condition, such that under milder conditions and elevated levels of biomarkers, engagement was greater, but under Explicit Negative Evaluation, and elevated levels of biomarkers, engagement was less, suggesting behavioral withdrawal. Findings reveal the critical role of context—especially negative evaluation—in the relationship of biomarkers with behavioral engagement.

Defining the in vivo mechanism of air pollutant toxicity using murine stress response biomarkers

Air pollution can cause a wide range of serious human diseases. For the informed instigation of interventions which prevent these outcomes there is an urgent need to develop robust in vivo biomarkers which provide insights into mechanisms of toxicity and relate pollutants to specific adverse outcomes. We exemplify for a first time the application of in vivo stress response reporters in establishing mechanisms of air pollution toxicity and the application of this knowledge in epidemiological studies. We first demonstrated the utility of reporter mice to understand toxicity mechanisms of air pollutants using diesel exhaust particles compounds. We observed that nitro-PAHs induced Hmox1 and CYP1a1 reporters in a time- and dose-dependent, cell- and tissue-specific manner. Using in vivo genetic and pharmacological approaches we confirmed that the NRF2 pathway mediated this Hmox1-reporter induction stress reporter activity. We then correlated the activation of stress-reporter models (oxidative stress/inflammation, DNA damage and Ah receptor -AhR- activity) with responses in primary human nasal cells exposed to chemicals present in particulate matter (PM; PM2.5-SRM2975, PM10-SRM1648b) or fresh roadside PM10. To exemplify their use in clinical studies, Pneumococcal adhesion was assessed in exposed primary human nasal epithelial cells (HPNEpC). The combined use of HPNEpC and in vivo reporters demonstrated that London roadside PM10 particles induced pneumococcal infection in HPNEpC mediated by oxidative stress responses. The combined use of in vivo reporter models with human data thus provides a robust approach to define the relationship between air pollutant exposure and health risks. Moreover, these models can be used in epidemiological studies to hazard ranking environmental pollutants by considering the complexity of mechanisms of toxicity. These data will facilitate the relationship between toxic potential and the level of pollutant exposure in populations to be established and potentially extremely valuable tools for intervention studies for disease prevention.