Chronic Stress Research Articles

Exploring the anti-depressant effects and nitric oxide modulation of quercetin: A preclinical study in Socially Isolated mice.

This study investigates the effects of quercetin, an antioxidant and nitric oxide (NO) modulator, on depressive-like behaviours triggered by social isolation stress (SIS) in mice. SIS, known to harm psychosocial functioning and increase the risk of depression, involves oxidative stress and NO in its pathophysiology. 72 male mice were divided into nine groups, including the social (SC) group as the control group (stress-free with normal saline intake). The isolation (IC) groups received normal saline, quercetin at doses of 10, 20, and 40 mg/kg, the nitric oxide synthetase inhibitor L-NAME at a dose of 5 mg/kg, the NO precursor L-arginine at a dose of 100 mg/kg, an ineffective dose of quercetin combined with L-NAME and an effective dose of quercetin combined with L-arginine. Behavioural tests (open-field, forced swimming, and splash tests) were conducted, followed by measuring hippocampal nitrite levels. Quercetin significantly reduced immobility in the forced swimming test, increased activity in the open-field test, and enhanced grooming behaviour, particularly at 40 mg/kg. Co-administration of an ineffective dose of quercetin (10 mg/kg) with L-NAME increased immobility and grooming activity time. Interestingly, co-administration of the effective dose of quercetin (40 mg/kg) with L-arginine increased immobility time in the FST. Additionally, administration of quercetin at doses of 20 and 40 mg/kg significantly reduced the nitrite level in the hippocampus of SIS mice. Furthermore, co-administration of L-NAME and L-arginine with ineffective and effective doses of quercetin decreased and increased nitrite levels in the hippocampus and increased immobility time in the FST compared to their respective counterparts administered alone. These results suggest quercetin's potential in alleviating depression by modulating NO levels, pointing to its promise in treating depression associated with chronic stressors like social isolation.

Mitochondrial Functioning: Front and Center in Defining Psychosomatic Mechanisms of Allostasis in Health and Disease.

There is increased awareness among basic and clinical scientists that psychological and social stress can have detrimental effects on physical, cognitive, and mental health. Data have been published indicating that social, economic, psychological, and physical environmental stress can influence behavior that has biological and physiological consequences-yet there are major gaps in understanding the physiological and cellular processes that drive increased morbidity and mortality. The potential role of mitochondria has been highlighted in psychosomatic medicine, as their functionality in various biological and physiological processes has earned recognition. This review outlines the essential role of mitochondria by considering the numerous intracellular, extracellular, and physiological functions it regulates that position the organelle as a central mediator in responses to psychological stress. We then connect these functions to mitochondrial allostasis and allostatic load for further examination of the limitations of mitochondria to an adaptive psychological stress response where mitochondrial allostatic load may eventually lead to systemic pathophysiology. This review emphasizes how chronic social, economic, and psychological stress can contribute to mitochondrial dysfunction and predispose individuals to poorer health outcomes and death. Mitochondrial capacity, function, and activity may therefore serve as biomarkers for identifying individuals at high risk for developing comorbid conditions related to their psychosocial environment.

Sex-specific GABAergic microcircuits that switch vulnerability into resilience to stress and reverse the effects of chronic stress exposure.

Clinical and preclinical studies have identified somatostatin (SST)-positive interneurons as critical elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, disinhibition of SST neurons in mice results in resilience to the behavioral effects of chronic stress. Here, we established a low-dose chronic chemogenetic protocol to map these changes in positively and negatively motivated behaviors to specific brain regions. AAV-hM3Dq-mediated chronic activation of SST neurons in the prelimbic cortex (PLC) had antidepressant drug-like effects on anxiety- and anhedonia-like motivated behaviors in male but not female mice. Analogous manipulation of the ventral hippocampus (vHPC) had such effects in female but not male mice. Moreover, the activation of SST neurons in the PLC of male mice and the vHPC of female mice resulted in stress resilience. Activation of SST neurons in the PLC reversed prior chronic stress-induced defects in motivated behavior in males but was ineffective in females. Conversely, activation of SST neurons in the vHPC reversed chronic stress-induced behavioral alterations in females but not males. Quantitation of c-Fos+ and FosB+ neurons in chronic stress-exposed mice revealed that chronic activation of SST neurons leads to a paradoxical increase in pyramidal cell activity. Collectively, these data demonstrate that GABAergic microcircuits driven by dendrite targeting interneurons enable sex- and brain-region-specific neural plasticity that promotes stress resilience and reverses stress-induced anxiety- and anhedonia-like motivated behavior. The data provide a rationale for the lack of antidepressant efficacy of benzodiazepines and superior efficacy of dendrite-targeting, low-potency GABAA receptor agonists, independent of sex and despite striking sex differences in the relevant brain substrates.

Personality and Psychoneuroimmunology: A Systems Biology Perspective.

Research in psychoneuroimmunology (PNI) underscores the intricate connections within the "whole mind-body system." Personality plays a pivotal role, with specific traits linked to stress influencing neural behavior and psychophysiological disorders. Gene expression networks associated with personality affect neuronal plasticity, epigenetic processes, and adaptive behaviors, highlighting the importance of systems biology mechanisms. Systemic inflammation correlates with key personality traits. Understanding the roles of inflammatory and oxidative biomarkers in personality traits and disorders can help identify diagnostic and therapeutic targets for various diseases. Neurobiological features contribute to our understanding of personality disorders and related conditions. Personality traits are linked to distributed neuroendocrine networks, particularly the hypothalamic-pituitary-adrenal (HPA) axis, rather than localized brain areas. Correlations have also been identified between personality traits and thyroid hormones. Disrupted hypothalamic-pituitary-thyroid (HPT) axis functions may be associated with disease severity, depression, and distress, highlighting the need for comprehensive endocrinological and psychopathological evaluations. The gut-brain axis influences personality traits, emotions, stress, and social behaviors. Altered gut microbiota is common in psychiatric conditions, suggesting potential treatments targeting the microbiota. Chronic stress impacts cognitive functions and correlates with personality and mental health, emphasizing the need for comprehensive, multi-dimensional patient profiles for effective prevention and therapy. A biopsychosocial model integrating personality traits will advance personalized and systems medicine.

Transcriptome signatures of the medial prefrontal cortex underlying GABAergic control of resilience to chronic stress exposure.

Analyses of postmortem human brains and preclinical studies of rodents have identified somatostatin (SST)-positive, dendrite-targeting GABAergic interneurons as key elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, genetically induced disinhibition of SST neurons (induced by Cre-mediated deletion of the γ2 GABAA receptor subunit gene selectively from SST neurons, SSTCre:γ2f/f mice) results in stress resilience. Similarly, chronic chemogenetic activation of SST neurons in the medial prefrontal cortex (mPFC) results in stress resilience but only in male and not in female mice. Here, we used RNA sequencing of the mPFC of SSTCre:γ2f/f mice to characterize the transcriptome changes underlying GABAergic control of stress resilience. We found that stress resilience of male but not female SSTCre:γ2f/f mice is characterized by resilience to chronic stress-induced transcriptome changes in the mPFC. Interestingly, the transcriptome of non-stressed SSTCre:γ2f/f (stress-resilient) male mice resembled that of chronic stress-exposed SSTCre (stress-vulnerable) mice. However, the behavior and the serum corticosterone levels of non-stressed SSTCre:γ2f/f mice showed no signs of physiological stress. Most strikingly, chronic stress exposure of SSTCre:γ2f/f mice was associated with an almost complete reversal of their chronic stress-like transcriptome signature, along with pathway changes suggesting stress-induced enhancement of mRNA translation. Behaviorally, the SSTCre:γ2f/f mice were not only resilient to chronic stress-induced anhedonia - they also showed an inversed, anxiolytic-like behavioral response to chronic stress exposure that mirrored the chronic stress-induced reversal of the chronic stress-like transcriptome signature. We conclude that GABAergic dendritic inhibition by SST neurons exerts bidirectional control over behavioral vulnerability and resilience to chronic stress exposure that is mirrored in bidirectional changes in the expression of putative stress resilience genes, through a sex-specific brain substrate.

The Effect of Psilocybe cubensis on Spatial Memory and BDNF Expression in Male Rats Exposed to Chronic Unpredictable Mild Stress

ABSTRACT Psilocybin-containing mushrooms, commonly known as magic mushrooms, drastically affect mental processing, cognitive functioning, and the mood state. In the present study, we investigated the effect of the Psilocybe cubensis extract on spatial memory and the brain-derived neurotrophic factor (BDNF) in rats exposed to chronic unpredictable mild stress (CUMS). The duration of CUMS was 4 weeks. Spatial learning and memory were measured using the Morris water maze apparatus. The Psilocybe cubensis extract was intraperitoneally injected (20 mg/kg) in different time periods: 5 min before training, 24 h before training, 48 h before training, 5 min after training, and 5 min before the probe test. Results showed that CUMS impaired spatial learning and memory, and decreased BDNF in the hippocampus. Psilocybe cubensis (24 and 48 h before training) restored spatial learning, while (48 h before training) restored spatial memory impairment in CUMS rats. Psilocybe cubensis (24 and 48 h before training) increased BDNF in CUMS rats. Psilocybe cubensis administrations (expect 48 h before training) impaired spatial learning and memory and decreased BDNF levels in controls. In conclusion, we suggested that Psilocybe cubensis may be beneficial for the improvement of memory deficits induced by CUMS, while the time of injection seems to be an important factor in its final effect.

Activation of Hippocampal Neuronal NADPH Oxidase NOX2 Promotes Depressive-Like Behaviour and Cognition Deficits in Chronic Restraint Stress Mouse Model.

Nicotinamide adenosine dinucleotide phosphate oxidases (NOX) play important roles in mediating stress-induced depression. Three NOX isotypes are expressed mainly in the brain: NOX2, NOX3 and NOX4. In this study, the expression and cellular sources of these NOX isoforms was investigated in the context of stress-induced depression. Chronic restraint stress (CRS)-induced depressive-like behaviour and cognitive deficits were evaluated by tail suspension tests, forced swimming tests and the Morris water maze test. Hippocampal NOX expression was determined by immunofluorescence staining and western blotting. The hippocampal levels of the brain-derived neurotrophic factor (BDNF) mRNA were determined via quantitative real-time -polymerase chain reaction. Glucocorticoid levels in the hippocampus were measured using ELISA kits. In the mouse CRS model, a significant increase in NOX2 expression was observed in the hippocampus, whereas no significant changes in NOX3 and NOX4 expression were detected. Next, NOX2 expression was primarily localised to neurons (NeuN+) but not microglia (Iba-1+) or astrocytes (GFAP+). Treatment with gp91ds-tat, a specific NOX2 inhibitor, effectively mitigated the behavioural deficits induced by CRS. The decreased expression of the BDNF mRNA in the hippocampus of CRS mice was restored upon gp91ds-tat treatment. A positive correlation was identified between neuronal NOX2 expression and serum glucocorticoid levels. Our study indicated that neuronal NOX2 may be a critical mediator of depression-like behaviours and spatial cognitive deficits in mice subjected to CRS. Blockade of NOX2 signalling may be a promising therapeutic strategy for depression.

Life Course Stressors, Latent Coping Strategies, Alcohol Use, and Latent Coping Strategies Among People with HIV.

People with HIV (PWH) have often experienced chronic stressors across their lifespan, including adverse childhood experiences (ACES), lifetime economic hardship (LEH), and concurrent stressors associated with living in urban areas (urban stress). Prolonged exposure to stressors might result in differential coping patterns among PWH that can impact care trajectories. We utilized a life course-informed approach to examine chronic stressors as antecedents of latent coping strategies among PWH in care. High-risk alcohol use and non-adherence to anti-retroviral therapy (ART) were examined as consequences of latent coping strategies. Data were utilized from the baseline and interim follow-up visit of the New Orleans Alcohol Use in HIV (NOAH) study. Three latent classes of coping strategies were identified: avoidance coping (31%), low-frequency coping (43%), and problem-solving coping (25%). Exposure to ACES was associated with greater use of avoidance versus low-frequency coping class at wave II. Urban stress was associated with greater use of avoidance coping compared to problem-solving or low-frequency coping classes at wave II. LEH was associated with greater use of low-frequency coping at wave II. Those utilizing low-frequency coping had a two-fold increase in ART non-adherence compared to problem-solving coping. PWH utilizing avoidance and low-frequency coping had a nearly two-fold increase in high-risk alcohol use versus problem-solving coping. These findings reveal important coping classifications that are linked to stressors across the life course of PWH. An understanding of coping styles and stressors may aid in improving the continuum of care among PWH by reducing alcohol use and improving medication adherence.

Aging, ROS, and cellular senescence: a trilogy in the progression of liver fibrosis.

Ageing is an inevitable and multifaceted biological process that impacts a wide range of cellular and molecular mechanisms, leading to the development of various diseases, such as liver fibrosis. Liver fibrosis progresses to cirrhosis, which is an advanced form due to high amounts of extracellular matrix and restoration of normal liver structure with failure to repair damaged tissue and cells, marking the end of liver function and total liver failure, ultimately death. The most important factors are reactive oxygen species (ROS) and cellular senescence. Oxidative stress is defined as an impairment by ROS, which are by-products of the mitochondrial electron transport chain and other key molecular pathways that induce cell damage and can activate cellular senescence pathways. Cellular senescence is characterized by pro-inflammatory cytokines, growth factors, and proteases secreted by senescent cells, collectively known as the senescence-associated secretory phenotype (SASP). The presence of senescent cells, which disrupt tissue architecture and function and increase senescent cell production in liver tissues, contributes to fibrogenesis. Hepatic stellate cells (HSCs) are activated in response to chronic liver injury, oxidative stress, and senescence signals that drive excessive production and deposition of extracellular matrix. This review article aims to provide a comprehensive overview of the pathogenic role of ROS and cellular senescence in the aging liver and their contribution to fibrosis.

The impact of long-term isolation on anxiety, depressive-like and social behavior in aging Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) male rats.

Aging is a complex process associated with multimorbidity. Hypertension, one of widespread states, is among main causes of age-related alterations in behavior, emotionality and sociability. We studied the effects of long-term isolated housing on anxiety, depressive-like and social behavior as well as changes in the adrenocortical and sympathetic systems in the aging normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Ten-month-old male rats of both strains were subjected to 90-day isolated or group housing. Surprisingly, social isolation induced only mild effect on anxiety without influencing other affective-related behaviors. No effects of isolated housing on sociability or social novelty preferences were revealed. Despite the adrenal gland hypertrophy in the SHRs, corticosterone levels remained stable within the period of isolation but the expression of nuclear glucocorticoid receptor (Nr3c1) mRNA in the adrenals was lower in the SHR as compared to WKY rats. Pre-existing hypertension, associated with SHR genotype, did not significantly contribute to the effects of social isolation. The data suggest that the aged WKY and SHR rats are relatively resilient to chronic social stress associated with isolated housing.

HOW THE ENDOCRINE SYSTEM AND MICROBIOTA EXPLAIN THE EMOTIONS BIOCHEMISTRY AND THEIR IMPACT IN HEALTH

Emotional reactions stimulate neural circuits and biological pathways that produce neurotransmitters, affecting homeostasis and promoting disease. Health and emotions communicate, establishing a bidirectional cause-and-effect pathway. The composition of the microbiota also affects health and emotions, interacting through metabolites, such as short-chain fatty acids (SCFA), with the host's biochemistry. Certain genera of bacteria act in different ways on the host's homeostasis, keeping the immune system constantly vigilant and acting on the synthesis of neurotransmitters, such as serotonin and dopamine, which are responsible for well-being. When the host is in homeostasis, the synthesis of neurotransmitters is normal, which keeps the intestinal microbiota in balance. However, when the organism is out of balance, this synthesis is impaired; decreasing the concentration of the initial compounds for the production of neurotransmitters, which leads to a reduction in the concentration of neurotransmitters and exaggerated activation of the HPA axis, inducing an imbalance in the intestinal microbiota, generating dysbiosis. Due to dysbiosis, the synthesis of neurotransmitters is impaired, leading the host to develop mental disorders such as depression, anxiety and chronic stress; which contributes to the state of imbalance of the organism, harming mental and physical health. By adequately restoring the intestinal microbiota, the hyperactivation of the HPA axis decreases, returning the body to homeostasis, resulting in the improvement of symptoms of depression, anxiety and chronic stress; leaving the organism healthy, both mentally and physically. Therefore, in this study we contextualize emotional research from a historical and descriptive perspective and present the main models of emotional identification. Focusing on basic emotions, we research the relationship of emotional states with the HPA axis and the microbiota, as well as how the bacteria present in the intestine affect the well-being of the host. Finally, we discuss our analysis presenting the bidirectional relationship between the endocrine system, microbiota and emotions.

Neuroprotective Effects of Thymol and p-Cymene in Immobilized Male rats through Alterations in Molecular, Biochemical, Histological, and Behavioral Parameters.

The research was conducted to examine the neuroprotective effect of thymol and its precursor p-cymene on chronic immobility stress in adult male Wistar rats. The rats were subjected to 2.5h of stress every day for 14 consecutive days by placing them inside a restrainer. Thymol (10mg/kg) and p-cymene (50mg/kg) were given to the rats during the same period. The results showed that thymol and p-cymene prevented the increase of MDA level, decline of GSH level, and decrease of SOD and GPx activity in the hippocampus of rats exposed to stress. These monoterpenes also prevented the increase in the expression of Tnfa, Il1b, Tlr4, and Nfkb, and the decrease in the expression of Nrf2, Ho1, and Bdnf. In addition, thymol and p-cymene inhibited the increase in the expression and activity of acetylcholinesterase in the hippocampus of animals exposed to immobility and enhanced the expression of A7nachr. They also reduced neuronal death in the CA1 region of stressed animals and improved their performance in the Morris water maze and elevated plus maze tests. Based on these findings, thymol and p-cymene may be effective in preventing neurodegenerative diseases as they reduce oxidative stress and neuroinflammation, strengthen ACh signaling, and stimulate Bdnf expression.

Logistic regression analysis of risk factors for anxiety and depression in patients with coronary heart disease and subclinical hypothyroidism.

We sought to explore the risk factors for anxiety and depression in patients with coronary heart disease and subclinical hypothyroidism through logistic regression analysis. A retrospective analysis was conducted on 168 patients with coronary heart disease and subclinical hypothyroidism admitted to the Department of Cardiology of our hospital from February 2020 to November 2022. Patients were categorized into the control group, anxiety group, and depression group based on the Hamilton Anxiety Scale (HAMA) and Hamilton Depression Rating Scale (HAMD) scores. All participants were informed about the protocol and provided signed informed consent upon inclusion. The study examined influencing factors for anxiety and depression in patients with coronary heart disease and subclinical hypothyroidism. Collect patients' gender, age, presence or absence of chronic diseases (including Diabetes, hypertension and hyperthyroidism), sleep quality, dietary habits, psychosocial stress, living environment, social support, education level, and blood TSH levels. The linear relationship between anxiety, depression, and each influencing factor was quantified using the Pearson correlation coefficient. Blood level of TSH and free T4 were detected by chemiluminescence immunoassay. Multiple logistic regression was applied to analyze the factors influencing anxiety and depression in these patients. Various factors were identified as significant influencers of anxiety and depression in patients with coronary heart disease and subclinical hypothyroidism. For anxiety, presence or absence of chronic diseases, sleep quality, dietary habits, psychosocial pressure, living environment, and blood TSH levels were found to be influential (P < 0.05). Similarly, for depression, presence or absence of chronic diseases, sleep quality, social support, quality of life, social support, education level, and blood TSH levels were identified as significant factors (P < 0.05). The study revealed positive correlations between presence or absence of chronic diseases, psychosocial stress, and TSH levels with anxiety symptoms in patients with coronary heart disease and subclinical hypothyroidism (P < 0.05). Conversely, sleep quality, dietary patterns, and living environment showed negative correlations with anxiety symptoms (P < 0.05).Gender and age had no correlation with anxiety levels (P > 0.05). Presence or absence of chronic diseases and TSH levels were positively correlated with depressive symptoms in patients with coronary heart diseaseand subclinical hypothyroidism (P < 0.05). On the other hand, sleep quality, social support, quality of life, and educational level were negatively correlated with anxiety symptoms (P < 0.05). Gender and age had no correlation with depression (P > 0.05). Notably, TSH levels in both the anxiety and depression groups were higher than those in the control group (P < 0.05), with no significant difference in free T4 levels among the groups (P > 0.05). The combination of chronic illness types, living habits (sleep quality, dietary habits), psychosocial pressure, living environment, and TSH levels emerged as risk factors for anxiety in patients with coronary heart disease and subclinical hypothyroidism (P < 0.05). Similarly, the combination of chronic illness types, sleep quality, social support, quality of life, education level, and TSH levels were identified as risk factors for depression in these patients (P < 0.05). This logistic regression analysis underscores the significant impact of factors such as types of chronic illness, sleep quality, social support, living environment, education level, and TSH levels on anxiety and depression symptoms in patients with coronary heart disease and subclinical hypothyroidism. These findings highlight the importance of considering these multiple risk factors collectively when devising treatment and management strategies to reduce the risk of mental health issues in this patient population.

Nonselective beta blockade enhances gut microbiome diversity in a rodent model of trauma, hemorrhage, and chronic stress

BACKGROUND Traumatic injury leads to gut dysbiosis with changes in microbiome diversity and conversion toward a “pathobiome” signature characterized by a selective overabundance of pathogenic bacteria. The use of non-selective beta antagonism in trauma patients has been established as a useful adjunct to reduce systemic inflammation. We sought to investigate whether beta-adrenergic blockade following trauma would prevent the conversion of microbiome to a “pathobiome” phenotype. METHODS Sprague-Dawley rats (n = 6–8/group) were subjected to routine daily handling (naïve), lung contusion with hemorrhagic shock (LCHS), or LCHS with daily chronic stress (LCHS/CS), each with or without administration of intraperitoneal propranolol (BB) (10 mg/kg/day). Fecal microbiome was measured on Days 0, 7, and 14 using high-throughput 16S rRNA sequencing and QIIME2 bioinformatics analyses. Alpha- and beta-diversity and microbiome composition were assessed with significance defined as *p &lt; 0.05. RESULTS Use of propranolol following LCHS or LCHS/CS demonstrated a significant increase in the number of bacterial species (Chao1 index), as well as overall richness and evenness (Shannon index) compared with their untreated counterparts at Day 7. By Day 14, these differences were no longer apparent between BB and untreated groups subjected to LCHS/CS. There was an abundance of commensal bacteria such as Oscillospiraceae and Clostridia in LCHS and LCHS/CS treated with BB after 7 days which persisted at 14 days. CONCLUSION These findings suggest a role for beta-antagonism in altering the diversity of the gut microbiome and the need for further studies to elucidate the cellular and molecular mechanisms underlying this intriguing connection of microbiome with trauma and beta-blockade.

Healthcare costs and resource utilization of patients with chronic post-traumatic stress disorder: a retrospective US claims analysis of commercially insured patients.

Aim: Exploring the healthcare costs and resource use among privately insured US patients with post-traumatic stress disorder (PTSD). Methods: This study used Merative MarketScan data. The index date was defined as the first PTSD claim. Study period included a 1-year pre-index and 2-year post-index follow-up. Cases with only acute PTSD, cancer, or insurance gap during the study period were excluded. The PTSD with (PwC) and PTSD without comorbidities (PwoC) cohorts were defined by the presence/absence of comorbid mental health conditions (schizophrenia, bipolar and major depressive disorder). Baseline PTSD (BP) cohort included PwoC cases with only index PTSD event and without FDA-approved PTSD medications or psychotherapy. Sub-analysis is conducted among patients with PTSD and substance/alcohol use disorder. Study cohorts were matched in a 1:1:1 ratio. Results: The matched sample included 5076 patients (1681 PwC, 1681 PwoC, 1714 BP). PwC patients had higher 2-year PTSD-related costs than PwoC and BP patients ($3762 vs $1750 and $841; all p<0.001). The same trend was noted among all-cause and anxiety-related costs. PwC patients had higher 2-year PTSD-related inpatient and emergency department (ED) rates than PwoC (10.2% vs 1.7% and 6.8% vs 2.6%, all p<0.001) and inpatient and outpatient rates than BP (10.2% vs 2.1% and 98.0% vs 93.1%; all p≤0.004). The sub-analysis had 3776 patients (3154 PwC, 537 PwoC, 85 BP). PwC had higher 2-year PTSD-related costs than PwoC and BP ($7668 vs $2919 and $1,483; all p<0.001). The same trend was noted in all-cause and anxiety-related costs. PwC also had higher 2-year PTSD-related inpatient and ED rates than PwoC (25.6% vs 10.4% and 12.7% vs 5.2%; all p<0.001) and inpatient and outpatient rates than BP (25.6% vs 8.2% and 95.5% vs 84.7%; all p<0.001). Conclusion: PTSD is associated with high healthcare costs and resource use. The highest economic burden was observed in patients with PTSD and mental health comorbidities.

Abstract 4137735: Chronic Oxidative Stress Induces Hypertension and Abdominal Aortic Aneurysm in Chemogenetic Mice Model

Background: Aortic aneurysms account for ~10,000 deaths annually in the USA. Oxidative stress is implicated in both abdominal (AAA) and thoracic (TAA) aneurysm formation, but the mechanisms are incompletely understood. We used a chemogenetic approach to modulate oxidative stress in the vascular wall by creating a transgenic mouse (DAAO-TG Tie2 ) that expresses yeast D-amino acid oxidase (DAAO) driven by the endothelial Tie2 promoter. DAAO generates the reactive oxygen species hydrogen peroxide from D-amino acids. Vascular tissues contain L-amino acids, so yeast DAAO is quiescent until DAAO-TG Tie2 mice are provided with D-amino acids. Here we characterize the cellular and molecular consequences of vascular oxidative stress in DAAO-TG Tie2 mice. Hypothesis: Chronic oxidative stress in the vascular wall causes arterial dysfunction. Aim: To characterize the phenotype of DAAO-TG Tie2 mice after oxidative stress induction in vascular endothelium. To identify the mechanisms whereby vascular oxidative stress causes arterial dysfunction and hypertension. Methods: Systolic blood pressure and aortic sonography were measured weekly in D-alanine-fed DAAO-TG Tie2 . Proteomic analyses were used to identify mechanistic targets, which were validated using biochemical and immunohistochemical methods. Results: D-alanine-fed DAAO-TG Tie2 mice develop systolic hypertension and abdominal but not thoracic aortic aneurysms; treated mice die in &gt;3 months with burst abdominal aortic aneurysms. Transgene expression is similar in abdominal and thoracic endothelium. Levels of oxidative stress markers (oxidized proteins, lipid, and DNA) were similar in thoracic and abdominal aorta. Proteomic analyses established phenotypic switching in abdominal but not thoracic aorta, and also revealed activation of the oxidant-activated kinase ASK1 and of the MAP kinase cascade in abdominal but not thoracic aorta. Immunoblot analyses showed a marked decrease in JNK1 phosphorylation by phosphatase DUSP3 and an increase in vascular KLF4, leading to phenotypic switching of contractile to synthetic VSMCs. Conclusion: Chronic chemogenetic oxidative stress induces hypertension and abdominal aortic aneurysm formation caused by KLF4-dependent VSMC phenotypic switching.

Abstract 4125025: Association between Marital Status and Major Adverse Cardiovascular Events: Role of Stress-Related Neural-Immune Mechanisms

Background: Chronic stress is associated with cardiovascular disease (CVD) in part through neural mechanisms that potentiate inflammation. Disrupted social connections are associated with higher chronic stress. As such, we hypothesized that: 1) previously married (divorced, separated) individuals have higher major adverse cardiovascular event (MACE) risk compared to married individuals and 2) that greater activation of stress-related neural-immune mechanisms contributes to this relationship. Methods: Participants (N=75,638) enrolled in the Mass General Brigham Biobank were studied. Marital status and MACE were identified using survey data and ICD-10 codes, respectively. A subset (N=1,121) underwent clinical 18 F-FDG-PET imaging, enabling assessment of stress-related neural activity as the ratio of the amygdala to prefrontal cortex activity (AmygAc). Clinical high-sensitivity C-reactive protein (hs-CRP) levels were assessed in another subset of the cohort (N=10,358). Linear and Cox regression and mediation analyses were used. Results: Among participants (median age 62 years; 53% female), 2,978 subjects developed MACE after Biobank enrollment. Previously married (vs. currently married) individuals had greater MACE risk (HR 1.33 [95% CI: 1.20,1.57], p=&lt;0.001, Figure 1A ) , higher AmygAc (B=0.23 [95% CI: 0.06-0.40], p=0.009) and higher hs-CRP (B=0.19 [95% CI: 0.13-0.25], p=&lt;0.001). MACE risk remained significant after adjustment for key confounders ( Table 1 ), and both the AmygAc and CRP were higher among divorced or separated individuals ( Figure 1B and 1C ). Moreover, increased AmygAc and hs-CRP associated with increased MACE risk (HR=1.24 [1.14-1.36], p=&lt;0.001 and 1.13 [1.09-1.16], p=&lt;0.001, respectively), and both AmygAc and hs-CRP mediated the relationship between marital status and MACE (p&lt;0.05). Conclusions: Our findings suggest that divorced and separated individuals are at an increased risk for MACE. This relationship appears to be driven in part by stress-related neural-immune mechanisms.

4-Phenylbutyric acid mitigates ER stress-induced neurodegeneration in the spinal cords of a GM2 gangliosidosis mouse model.

Sandhoff disease (SD), a fatal and rare lysosomal storage disorder (LSD), is caused by a deficiency of the enzyme β-hexosaminidase B and leads to severe accumulation of GM2 gangliosides in lysosomes, primarily within the central nervous system (CNS). This accumulation results in severe neurological impairment, lower motor neuron disease, and death. Currently, there are no effective therapies available for SD. Here, we explored the role of endoplasmic reticulum (ER) stress in the spinal cord during disease progression in an established mouse model of SD and revealed the beneficial outcome of off-label treatment with the FDA-approved drug, 4-phenylbutyric acid (4-PBA). We analyzed the expression and localization of ER stress and cellular apoptosis markers, which revealed significant upregulation of these factors within motor neurons. Additionally, we observed a > 50% reduction in neuronal numbers throughout all spinal cord regions. Our studies also tested the impact of the chemical chaperone 4-PBA on ER stress in mice, and following administration, we observed significant improvements in motor neuromuscular function and life span throughout disease progression. 4-PBA treatment significantly reduced apoptosis in spinal cord neurons and increased the number of choline acetyltransferase (ChAT)-positive neurons, with little effect on astrogliosis or sensory interneurons. Overall, this study provides strong evidence for the role of chronic ER stress in the pathophysiology of SD and highlights 4-PBA as a promising therapeutic treatment for SD and potentially other related LSDs.

Persistent elevation of plasma markers of cellular senescence after hip fracture: a pilot longitudinal study

IntroductionHip fractures may result from and contribute to accelerated biological aging. We aimed to evaluate the impact of hip fracture and its surgery on the senescence-associated secretory phenotype (SASP) index, a composite of peripheral protein markers where higher scores are thought to indicate greater levels of cellular senescence and accelerated aging.MethodsWe examined the SASP index in plasma over 12 weeks post-surgery and its prediction of long-term post-surgical functional outcomes. We included 60 older adults: 20 recruited immediately after hip fracture surgery, and 40 comparison individuals who were either healthy or suffering chronic psychosocial stress (caregiving). We assessed 22 SASP biomarkers and calculated the SASP index score for each hip fracture participant immediately following fracture surgery and 4 and 12 weeks later. Functional recovery was assessed at 12, 26, and 52 weeks after hip replacement surgery.ResultsThe hip fracture group had higher SASP index scores than the comparison groups, after adjusting for potential confounding variables (p = 0.021). SASP index scores in hip fracture patients increased further by week 4 after surgery (p &amp;lt; 0.001), declining by week 12 but remaining elevated overall. However, the SASP index scores were not significantly associated with functional recovery after hip replacement surgery at 26 or 52 weeks after surgery. In conclusion, after hip fracture surgery SASP scores are elevated, continue to rise over time, and do not return to normal by 12 weeks post-surgery.DiscussionOur findings support the need to investigate this phenomenon of post-operative senescence, including whether novel interventions such as senolytics would help older adults facing major surgery.

Adaptive emotion regulation might prevent burnout in emergency healthcare professionals: an exploratory study.

Emergency department (ED) professionals face a high risk of physical, mental, and emotional strain, which can lead to burnout. Burnout arises from chronic work-related stress, which negatively impacts ED professionals, the healthcare system, as well as patient outcomes. Effective adaptive emotion regulation strategies (ERS) are crucial for handling stress in healthcare workplaces and mitigating the risk of burnout. High-quality patient-professional relationships, including empathy, significantly improve patient compliance and disease outcomes. This cross-sectional exploratory study aims to investigate the relationship between mental distress, burnout, adaptive and maladaptive ERS among healthcare professionals in an ED. A total of 159 ED workers participated in an online survey. Emotion regulation was assessed using the Cognitive Emotion Regulation Questionnaire, while burnout and mental distress were measured using the Maslach Burnout Inventory and the Depression, Anxiety, and Stress Scale. The findings revealed that more than 20% of participants displayed severe symptoms of stress (N = 35), anxiety (N = 36), and depression (N = 31), and only 10.7% (N = 27) had no signs of burnout. Despite these findings, it appears that the majority of ED professionals primarily utilise adaptive ERS (91.8%, N = 146). However, as burnout levels increased, the use of adaptive ERS declined compared to maladaptive strategies. Regression analysis identified several significant predictors of Emotional Exhaustion, Depersonalisation, and reduced Personal Accomplishment, including gender, age, physical exercise, smoking, sedative usage, stress, depression, maladaptive strategies and adaptive strategies such as positive reappraisal. These study results highlight the urgent need to address workplace stress, burnout, and mental distress among healthcare professionals in EDs. Implementing effective strategies for adaptive emotion regulation and promoting a supportive work environment can help mitigate burnout and enhance the well-being of ED workers, ultimately benefiting patient care and outcomes.