Chronic Psychological Stress Research Articles

Diminished ovarian reserve induced by chronic unpredictable stress in C57BL/6 mice

Chronic psychological stress has been considered to be a remarkable contributor to diminished ovarian reserve (DOR). However, there is a lack of a psychological stress-induced DOR animal model. We aim to validate the effects of an 8-week chronic unpredictable stress (CUS) paradigm on the ovarian reserve and reproductive hormone secretion of C57BL/6 mice. We found that after an 8-week CUS exposure, the numbers of primordial and preantral follicles and corpus luteum were significantly decreased in CUS model mice. Model mice also presented higher serum follicle-stimulating hormone, corticosterone levels and lower luteinizing hormone, estradiol, testosterone, anti-Müllerian hormone levels compared to those of control mice. Furthermore, we found that FSH receptor and AMH proteins were downregulated in model mouse ovaries. Although a significant litter size difference between the two groups was not found, the ovarian reserve remained significantly lower in the model group 6 weeks after CUS exposure. These results validated the hypothesis that the 8-week CUS paradigm that we adopted could induce the DOR phenotype in C57BL/6 mice and probably had a long-term adverse effect on ovarian reserve. Therefore, our results indicate that we have successfully established an animal model of psychological stress-induced DOR that can be used for further study.

Abstract 3020: Natural & synthetic glucocorticoids induce therapy resistance in breast cancer in vitro

Abstract BACKGROUND: Research indicates that chronic psychological stress, mediated by the excessive release of glucocorticoid (GC) cortisol, may play a role in cancer progression and patient survival. Thus, synthetic GCs, such as dexamethasone, are widely used in conjugation with cancer therapy due to their ability to induce apoptosis. Surprisingly, recent evidence suggest that GCs can induce therapy-resistance in solid tumors, although the precise mechanisms are not well defined. Therefore, there is an urgent need for both clinical and detailed mechanistic studies elucidating the role of GCs in cancer treatment. The goal of this study was to investigate the role of natural and synthetic GCs on resistance to cytotoxic therapy in breast cancer in vitro. METHODS: We either pre-treated or co-treated human breast cancer cells (MCF7, MDA-MB-231) with physiological and therapeutic doses of cortisol and dexamethasone (0.1-10 µM) alone or in combination with chemotherapy drug Fluorouracil (5FU) for 48-96 hours. We performed cell viability, proliferation, cell cycle and apoptosis assays. Thus, we used the glucocorticoid receptor (GR) antagonist (RU-486) to assess the role of GC receptor signaling. The expression of GR was confirmed by western blots. RESULTS: Our results indicate that GCs alone or in combination with 5FU enhanced cell proliferation, especially in MDA-MB-231 cells (p<0.01). Furthermore, GCs also modulated cell cycle and apoptosis. Finally, RU-486, which antagonizes the action of GR, restored the apoptosis sensitivity of the GCs treated cells. CONCLUSIONS: Our study suggests that in contrast to the pro-apoptotic effect of GCs in lymphoid cells, co-treatment of GCs protected breast cancer cells from 5FU-induced apoptosis. Given our results, it is difficult to conclude whether the primary detrimental effect of GCs is on cell viability and apoptosis. We cannot rule out the possibility that GCs my enhance resistance to chemotherapeutic drugs by modifying inflammation, angiogenesis or cell migration. Therefore, our current studies are aimed at investigating the possible pathways mediating GCs induced resistance to therapy in vitro. Our ultimate goal is to elucidate the molecular mechanisms of the glucocorticoids mediated inhibition of chemotherapy-induced cell death thereby proposing the ways of reversing this process. The literature suggest that around 35-45 % of cancer patients experience significant level of stress which manifests in elevated production of natural GC cortisol. Furthermore, given that GCs are widely accepted as an adjuvant treatment during chemotherapy or radiotherapy for reducing side effects, it is critical to investigate the conditions upon which they exert either pro-apoptotic or anti-apoptotic action in different cancer types. Although more data is needed, our findings imply careful consideration for the profligate use of GCs combination therapy in the treatment of cancer patients. Citation Format: Kristina Andrijauskaite, Michael J. Wargovich. Natural & synthetic glucocorticoids induce therapy resistance in breast cancer in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3020.

Assessment of psychological stress during sleep using digital devices and its clinical relevance to future occupational health practice

Psychophysiological decompensation as a result of occupational stress leads to impairment of occupational performance. Adequate recovery from psychological stress is necessary to maintain occupational performance. It is possible to measure the psychophysiological status and recovery during sleep with health data streamed from biomedical digital devices. Such data, with reference to heart and sleep parameters, could be processed to reflect health status and whether there is a risk of psychophysiological decompensation. This article describes the interpretation of resting heart rate measures, heart rate variability, and actigraphy measures during regular sleep in relation to psychological stress. Interpretation of the health data should be done by informed health-care professionals in combination with clinical history taking. The article does not cover digital measurements while awake and active. The aim of this review article is to provide an evidence-based rationale to health professionals how to interpret digital health data profiles from biomedical devices in appraising psychological stress and recovery. The objective is to prevent the adverse impact of psychological stress on health. Specific lifestyle measures and therapy to manage psychological stress, such as exercise, diet, and cognitive behavioral therapy for insomnia, are not discussed in this article. Applications are especially relevant in the field of occupational health in preventing occupational burnout, achieving a healthy work-life balance, and sustaining a healthy working life. There are future implications with regard to disease prevention as a large proportion of chronic diseases, for example, hypertension, diabetes depression, and ischemic heart disease, are related to chronic psychological stress. Stress monitoring with biomedical devices should occur over periods of work and nonwork days.

Chronic psychological stress during adolescence induces sex-dependent adulthood inflammation, increased adiposity, and abnormal behaviors that are ameliorated by selective inhibition of soluble tumor necrosis factor with XPro1595

Physical and psychosocial maltreatment experienced before the age of 18, termed early life adversity (ELA), affects an estimated 39% of the world’s population, and has long-term detrimental health and psychological outcomes. While adult phenotypes vary following ELA, inflammation and altered stress responsivity are pervasive. Cytokines, most notably tumor necrosis factor (TNF), are elevated in adults with a history of ELA. While soluble TNF (solTNF) drives chronic inflammatory disease, transmembrane TNF facilitates innate immunity. Here, we test whether solTNF mediates the behavioral and molecular outcomes of adolescent psychological stress by administering a brain permeable, selective inhibitor of solTNF, XPro1595. Male and female C57BL/6 mice were exposed to an aggressive rat through a perforated translucent ball (‘predatory stress’) or transported to an empty room for 30 min for 30 days starting on postnatal day 34. Mice were given XPro1595 or vehicle treatment across the last 15 days. Social interaction, sucrose preference, and plasma inflammation were measured at 2 and 4 weeks, and open field behavior, adiposity, and neuroinflammation were measured at 4 weeks. Chronic adolescent stress resulted in increased peripheral inflammation and dysregulated neuroinflammation in adulthood in a sex-specific manner. Abnormal social and open field behavior, fat pad weight, and fecal boli deposition were noted after 30 days; solTNF antagonism ameliorated the effects of stress. Together, these data support our hypothesis, and suggest that targeting solTNF with XPro1595 may improve quality of life for individuals with a history of adolescent stress.

Acupuncture improved depressive behavior by regulating expression of hippocampal apoptosis-related factors in psychological stress-induced depression rats

To investigate the effect of acupuncture on behavior changes and the expression of reactive oxygen species (ROS), cytochrome C, cysteine-containing aspartate-specific proteases-3 (caspase-3), apoptosis inducing factor (AIF) in the hippocampus of rats exposed to chronic restraint stress (CRS), so as to provide experimental evidence for the prevention and treatment of depression. Thirty two male SD rats were equally randomized into control, model, acupuncture and medication (Fluoxetine) groups according to the random number table. The depression model was established by chronic psychological stress stimulation (fasting, water deprivation, chronic restraint combined with solitary raising for 28 days). Manual acupuncture stimulation (2 circles/s) was applied to "Baihui" (GV20), "Yintang" (GV29) and bilateral "Sanyinjiao" (SP6) for 2 min, followed by retaining the needles for 20 min. Rats in the medication group were treated by gavage of Fluoxetine (0.18 mg/mL, 1 mL/100 g body weight). The treatment was conducted once daily for 28 days. The depression-like behavior was evaluated by using open-field test, sucrose preference test, and body weight. The content of ROS of the right hippocampus tissue was detected by using dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay, and the expression levels of cytochrome C, caspase-3 and AIF proteins of hippocampus were determined by using Western blot. After 28 days' stress procedure, the depression rats in the model group showed a significant decrease in the numbers of crossing and rearing of open-field test, sucrose preference index and the body weight compared to the control group (P<0.01). The content of ROS and expression levels of cytochrome C, caspase-3 and AIF in the hippocampus of the model group were significantly increased relevant to the control group (all P<0.01). After the intervention and compared with the model group, the decreased levels of the numbers of crossing and rearing, body weight and sucrose preference index, and the up-regulated levels of content of ROS and expression of cytochrome C, caspase-3 and AIF proteins were all reversed in both acupuncture and medication groups (P<0.01，P<0.05), displaying an anti-depressant effect. The effect of acupuncture was significantly superior to that of medication in up-regulating the numbers of crossing and rearing (P<0.01, P<0.05), and in down-regulating the expression of caspase-3 (P<0.01). No significant differences were found between the medication and acupuncture groups in increasing the body weight and sucrose preference index, and in down-regulating the expression of cytochrome C and AIF proteins (P>0.05). Acupuncture intervention can significantly reduce ROS content and expression level of cytochrome C, caspase-3 and AIF proteins in the hippocampus possibly by inhibiting the chronic psychological stress-hippocampal oxidative stress-mitochondrial apoptotic pathway in psychological stress-induced depression rats, which may contribute to its effect in relieving depression.

Linking Water Scarcity to Mental Health: Hydro–Social Interruptions in the Lake Urmia Basin, Iran

Alterations of water flows resulting from the manifestation of powerful hydro–social imaginaries often produce an uneven distribution of burdens and benefits for different social groups or regions, reflecting their social and political power. Marginalized regions can suffer manufactured territorialized water scarcity, which disturbs the natural, economic and socio-political order of water users, and as this article shows, inevitably affects their psychological wellbeing. Set in the context of the surroundings of Lake Urmia in Iran, once one of the largest hypersaline lakes in the world and now a severely degraded ecosystem mainly as a result of water overuse in its watershed, this article explores how and through which pathways this manufactured water scarcity impacted the mental health of the water users in the region. The research findings reveal that alterations in this local hydro–social territory and the resulting biophysical, financial and social changes, as well as impacts on physical health of water users, relate to chronic psychological stress, social isolation, intra-community conflicts, despair, hopelessness, depression and anxiety.

Hematopoietic stem progenitor cells prevent chronic stress-induced Tregs expansion in an IL12-dependent manner

Abstract Physical or psychological chronic stress induces the expansion of regulatory T cells (Tregs) to contribute to immunosuppression. However, the mechanisms remain to be defined. Recent studies from us and others have shown that hematopoietic stem progenitor cells (HSPCs) significantly modulate the immune system. Since allogeneic hematopoietic stem progenitor cell transplantation contributes to chronic graft-versus-host disease (cGVHD), but attenuation of cGvHD is associated with increased frequency of Treg. We hypothesized that HSPCs prevented the over-expansion of Tregs induced by chronic restraint stress to alleviate immunosuppression. Here we demonstrate that administration of HSPCs prevent Tregs expansion and alleviate the suppressive activity of Tregs following chronic stress. Moreover, we found this protective effect is dependent on IL-12. IL-12/STAT4 signal provides a critical role against the expansion of Tregs in chronic stress. When neutralizing antibody against IL-12 or treatment with selective STAT4 inhibitor was co-administered with HSPCs in chronic stressed mice, the protective effect of HSPCs was abrogated. Additionally, HSPCs treatment promotes IL-12 production by splenocytes in chronic stressed mice. These results suggest that HSPCs can prevent chronic stress-induced Tregs expansion in an IL-12-dependent manner, which might offer a novel strategy against immunosuppression.

Early Blood Profile of C57BL/6 Mice Exposed to Chronic Unpredictable Stress.

Physiological responses to psychological stressors are protective in acute fight or flight situations; however, there is increasing evidence suggesting the detrimental impact of chronic psychological stress on disease. Chronic stress has been associated with inflammation, poor prognosis, increased morbidity, and poor outcome in many diseases including atherosclerosis, cancer, and pulmonary disease. Given the systemic impact of stress, and the role of the hematopoietic system as a rapid responder to homeostatic insults, we hypothesized that early blood profile changes and biochemical alterations could be detected in a model of chronic stress. To test this hypothesis, a variation of the chronic unpredictable stress (CUS) model was employed. Following 10 days of CUS, C57BL/6 mice exhibited a chronic-stress-associated corticosterone profile. Complete blood count (CBC) revealed mild normochromic, normocytic anemia, and reduced monocyte and lymphocyte count. Serum analysis demonstrated hypoferremia with unchanged total iron binding capacity and serum ferritin levels. These findings are consistent with clinical diagnostic parameters for anemia of chronic disease and indicate that CUS results in significant changes in blood and serum biochemical profile in C57BL/6 mice. These studies identify early changes in blood parameters in response to CUS and identify hematopoietic and biochemical alterations that are often associated with increased morbidity in patients experiencing chronic-stress-associated mental health disease.

A test of the epidemiological paradox in a context of forced migration: low birthweight among Syrian newborns in Lebanon.

Background Studies on immigrants revealed an epidemiological paradox whereby low-socioeconomic status (SES) immigrant mothers exhibit favourable birth outcomes compared with native-born mothers. We tested the epidemiological paradox in a context of forced migration, comparing associations of low birthweight (LBW) and maternal SES between Syrian and Lebanese newborns in Lebanon. Methods We used data from the National Collaborative Perinatal Neonatal Network (NCPNN) of 31 Lebanese hospitals, including 45 442 Lebanese and 4910 Syrian neonates born 2011-13. We assessed associations between LBW and maternal SES for both groups. Logistic regression models examined interactions between maternal origin and SES. Results Syrian births increased exponentially between 2011 and 2013, along with the group's forced migration into Lebanon. Although Syrian mothers are more socioeconomically disadvantaged compared with Lebanese mothers, Syrian LBW (6.2%) was only marginally higher than Lebanese LBW (5.6%; P = 0.059). Only 20-24-years-old Syrian women [odds ratio (OR) = 1.70 (1.22-2.36)] and those with ≥ university education [OR = 2.02 (0.98-4.16)] exhibited higher odds of delivering an LBW baby compared with Lebanese women of the same age and education. Conclusions The findings do not provide strong evidence for the epidemiological paradox in a forced migration context. However, the relatively advantageous LBW profile among Syrian neonates, despite their mothers' low SES and exposure to acute and chronic psychological stress, points to protective mechanisms. One of these mechanisms may be a collective response by the displaced population to improve neonatal outcomes as a way of recovering from loss and death.

Stress-sensitive antidepressant-like effects of ketamine in the mouse forced swim test.

Major depression is a stress-linked disease with significant morbidity and the anesthetic drug ketamine is of growing interest in the treatment of depression, since in responsive individuals a single dose has rapid (within hours) antidepressant effects that can be sustained for over a week in some instances. This combination of fast action and a therapeutic effect that lasts far beyond the drug’s half-life points to a unique mechanism of action. In this reverse translational study, we investigate the degree to which ketamine counteracts stress-related depression-like behavioral responses by determining whether it affects unstressed animals similarly to stressed mice. To test this, male C57BL/6J mice were given a single injection of vehicle (0.9% saline; i.p.), 10 mg/kg ketamine, or 30 mg/kg ketamine, and were tested in the forced swim test (FST) 24 hours and 7 days later, as well as in the open field test on the eighth day. Unstressed mice had normal group housing, environmental enrichment, and experimenter pre-handling (5 days), whereas stressed animals were subjected to chronic mild stress (single housing, reduced enrichment and minimal handling), where some mice also had daily two-week unpredictable chronic stress (UCS). We find that ketamine (24 hours post-injection) decreases immobility and increases mobile (swimming) behavior (antidepressant-like effects) in UCS animals but does the opposite in unstressed mice, similar to recent human findings. In summary, these data suggest that chronic psychological stress interacts with ketamine treatment to modulate its effects in the C57BL/6J mouse FST, which reinforces the relevance of this test, and this strain of mice, to human, stress-induced depression.

Impacts of Psychological Stress on Osteoporosis: Clinical Implications and Treatment Interactions.

The significant biochemical and physiological effects of psychological stress are beginning to be recognized as exacerbating common diseases, including osteoporosis. This review discusses the current evidence for psychological stress-associated mental health disorders as risk factors for osteoporosis, the mechanisms that may link these conditions, and potential implications for treatment. Traditional, alternative, and adjunctive therapies are discussed. This review is not intended to provide therapeutic recommendations, but, rather, the goal of this review is to delineate potential interactions of psychological stress and osteoporosis and to highlight potential multi-system implications of pharmacological interventions. Review of the current literature identifies several potentially overlapping mechanistic pathways that may be of interest (e.g., glucocorticoid signaling, insulin-like growth factor signaling, serotonin signaling) for further basic and clinical research. Current literature also supports the potential for cross-effects of therapeutics for osteoporosis and mental health disorders. While studies examining a direct link between osteoporosis and chronic psychological stress are limited, the studies reviewed herein suggest that a multi-factorial, personalized approach should be considered for improved patient outcomes in populations experiencing psychological stress, particularly those at high-risk for development of osteoporosis.

Stress - (self) eating: Epigenetic regulation of autophagy in response to psychological stress.

Autophagy is a constitutive and cytoprotective catabolic process. Aberrations in autophagy lead to a multitude of degenerative disorders, with neurodegeneration being one of the most widely studied autophagy-related disorders. While the field has largely been focusing on the cytosolic constituents and processes of autophagy, recent studies are increasingly appreciating the role of chromatin modifications and epigenetic regulation in autophagy maintenance. Autophagy has been implicated in the regulation of neurogenesis, and disruption of neurogenesis in response to psychological stress is a proximal risk factor for development of neuropsychiatric disorders such as major depressive disorder (MDD). In this review, we will discuss the regulation of autophagy in normal neurogenesis as well as during chronic psychological stress, focusing on the epigenetic control of autophagy in these contexts, and also highlight the lacunae in our understanding of this process. The systematic study of these regulatory mechanisms will provide a novel therapeutic strategy, based on the use epigenetic regulators of autophagy to enhance neurogenesis and potentially alleviate stress-related behavioral disorders.

Exposure to Microbial Infection In Utero Has Long‐Term Effects on the Cardiovascular Response to Angiotensin II and Forebrain Gene Expression in Rats

Prenatal stressors, such as low protein diet, maternal smoking, and chronic psychological stress, predispose offspring to cardiovascular disease later in life. Microbial infection during pregnancy also increases the risk of adverse offspring health outcomes, but it remains to be determined whether this form of prenatal “stress” also triggers long‐term changes in offspring cardiovascular health. Thus, the present study was undertaken to evaluate whether the cardiovascular response to angiotensin II (ANGII) is altered in adult offspring born to mothers exposed to a microbial infection late in pregnancy when compared to non‐exposed controls (CON). Using an established rodent model of prenatal maternal infection (INF), dams were exposed to the rat pathogen Mycoplasma pulmonis or to vehicle via intravenous injection, on day 14 of pregnancy. Following natural birth, pups were cross‐fostered to non‐infected dams. Preliminary data (n=6–8/group) demonstrate that INF modestly elevated body weight by ~25 gm, significantly reduced resting heart rate (HR) by ~30 bpm in both sexes (P&lt;0.001), but did not change resting blood pressure (BP) at 14 wks of age compared to CON. When subjected to a subcutaneous injection of ANGII, the rise in BP was significantly elevated in both female (48±6 vs 18±3 mmHg; P&lt;0.002) and male (51±4 vs 39±5 mmHg; P&lt;0.03) INF offspring compared to CON. The compensatory drop in HR was not significant between INF vs CON in either sex, suggesting INF induces baroreflex dysfunction. Gene expression analysis of the amygdala identified significant changes in corticotrophin system gene expression in females but not males. These results indicate that prenatal stress associated with INF significantly alters both cardiovascular function and gene expression in the forebrain later in life, potentially increasing the likelihood for offspring to develop cardiovascular disease when exposed to a second chronic stressor.Support or Funding InformationFunded by FL‐DOH James and Esther King Biomedical Research Grant (LH &amp; MB).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

RNA-Sequencing and Bioinformatics Analysis of Long Noncoding RNAs and mRNAs in the Prefrontal Cortex of Mice Following Repeated Social Defeat Stress.

Background Repeated or continuous chronic psychological stress may induce diverse neuropsychiatric disorders; however, the underlying mechanisms remain unclear. In this study, we explored the expression profiles of long noncoding RNAs (lncRNAs) and mRNAs, along with their biological function and regulatory network, in mice after repeated social defeat (RSD) stress to explore their potential involvement in the development of anxiety-like behaviors. Main Methods RNA-sequencing was used to screen all differentially expressed (DE) lncRNAs and mRNAs between the RSD and control groups. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for confirmation of the RNA-sequencing results. The function of DE lncRNAs was predicted by Gene Ontology (GO) enrichment and pathway analyses of target mRNAs. In addition, the functional regulatory network of the target mRNAs was constructed to reveal potential relationships between lncRNAs and their target genes with bioinformatics approaches. Key Findings In mice experiencing RSD, 373 and 454 lncRNAs, along with 1142 and 654, mRNAs were significantly upregulated and downregulated, respectively. The detailed regulatory network included 126 eligible lncRNA-mRNA pairs. Among them, 14 genes such as Arhgef1, Chchd2, Fam107a, Dlg1, Nova2, Dpf1, and Shank3 involved in neurite growth, neural development, and synaptic plasticity were direct targets of the DE lncRNAs. qRT-PCR of four of the DE lncRNAs and mRNAs confirmed the reliability of RNA-sequencing. GO clustering analyses showed that the top enriched biological process, cellular component, and molecular function terms were synaptic transmission, neuron spine, and glutamate receptor binding, respectively. Further, the top three significant enriched pathways were synaptic adhesion-like molecule (SALM) protein interactions at the synapses, trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as glutamate binding, activation of AMPA receptors, and synaptic plasticity. Significance Hundreds of lncRNAs and mRNAs are dysregulated after RSD, and many of these lncRNAs might participate in the development of anxiety-like behaviors via multiple complex mechanisms such as target regulation. Available informatics evidence highlighted the likely role of synapse dysfunction and abnormal synaptic neurotransmission in these behaviors. Thus, our findings provide potential candidate biomarkers or intervention targets for chronic psychological stress-induced neuropsychiatric disorders.

Association of oxidative stress and inflammatory markers with chronic stress in patients with newly diagnosed type 2 diabetes.

Chronic stress is associated with increased risk of type 2 diabetes. Oxidative stress and inflammation are potential mediators of this risk. This study was conducted to investigate the association of oxidative stress and inflammatory markers with chronic stress and newly diagnosed type 2 diabetes. Oxidative stress/antioxidant status (malondialdehyde [MDA], reduce glutathione [GSH], glutathione reductase [GR], glutathione peroxidase [GPx], catalase [CAT], superoxide dismutase [SOD]), inflammatory markers (highly sensitive C-reactive protein [hsCRP], adiponectin, leptin), chronic stress levels as assessed by stress scales-presumptive stressful life events scale (PSLES), perceived stress scale (PSS), sense of coherence (SOC) and stress biomarker-salivary cortisol in 125 subjects with newly detected diabetes mellitus (NDDM) were compared with an equal number of age and sex matched subjects with normal glucose tolerance (NGT). NDDM subjects as compared with NGT had significantly increased MDA (P<0.001), hsCRP (P<0.001), and leptin (P=0.014) levels and increased GR (P=0.043) and SOD (P<0.001) activity along with decreased GSH (P<0.001) and adiponectin (P<0.001) levels. They also had significantly higher PSLES-LT and PSS and lower SOC scores along with elevated levels of 10:00pm salivary cortisol and post dexamethasone salivary cortisol as compared with NGT. In stepwise logistic regression analysis, variables GSH (OR: 0.805), SOD (OR: 1.004), and adiponectin (OR: 0.771) along with PSLES-LT (OR: 1.007), PSS (OR: 1.147), SOC (OR: 0.667), salivary cortisol 10:00pm (OR: 1.382), WC (OR: 1.087), and HOMA-IR (OR: 2.721) emerged as significant predictors of NDDM. The findings of this study indicate that chronic psychological stress and stress responses are associated significantly with inflammation and oxidative stress, which could act as mediating stress related risk factors for type 2 diabetes.

Neuroimmune crosstalk in the pathophysiology of hypertension.

Hypertension is an important risk factor for cardiovascular morbidity and mortality andfor events such as myocardial infarction, stroke, heart failure and chronic kidney disease and is a major determinant of disability-adjusted life-years. Despite the importance of hypertension, the pathogenesis of essential hypertension, which involves the complex interaction of several mechanisms, is still poorly understood. Evidence suggests that interplay between bone marrow, microglia and immune mediators underlies the development of arterial hypertension, in particular through mechanisms involving cytokines and peptides, such as neuropeptide Y, substance P, angiotensin II and angiotensin-(1-7). Chronic psychological stress also seems to have a role in increasing the risk of hypertension, probably through the activation of neuroimmune pathways. In this Review, we summarize the available data on the possible role of neuroimmune crosstalk in the origin and maintenance of arterial hypertension and discuss the implications of this crosstalk for recovery and rehabilitation after cardiac and cerebral injuries.

P156 PSYCHOLOGICAL STRESS INDUCES ALTERATIONS IN BEHAVIOR AND THE MUCOSAL IMMUNE SYSTEM IN A SPONTANEOUS MOUSE MODEL OF ILEITIS

Patients with Crohn’s disease (CD) suffer from abnormally high rates of depression and anxiety. Depression among patients with CD are higher than other debilitating chronic medical conditions, such as cancer. Behavioral co-morbidities are associated with increased rates of flares, more severe disease course, and increased rate of corticosteroid prescription. Psychological stress, even among CD patients in remission, is recognized as a risk factor for flare-ups. Despite the well-established relationship between stress and symptom relapse, a rigorous mechanistic explanation remains elusive. Here we demonstrate alterations in the behavioral profile and the mucosal immune system in the SAMP1/YitFc (SAMP1) mouse, a spontaneous model of CD-like ileitis, following exposure to acute and chronic psychological stress. SAMP1 littermates were sex matched and divided into two groups (n=8). The first group was subjected to restraint stress (RS) for seven days. Mice were restrained for 180 minutes per day in a 50mL conical tube with air holes drilled for adequate ventilation. Stool samples were collected each day. Subsequently, each group was subjected to behavioral testing to determine anxiety-like behavior (open field and elevated plus maze), depressive-like behavior (tail suspension), motor deficits (line crossings and rota-rod), and cognitive deficits (Y-maze). Immediately after, mice were sacrificed and tissue samples were collected for immunological analysis. Mice subjected to RS displayed increased immobility time during tail suspension indicating a depressive-like phenotype (p < 0.05). All other behavioral characteristics remained unchanged compared to control. Interestingly, FACS analysis revealed that RS mice had a marked increase in mesenteric lymph node (MLN) dendritic cells (p < 0.01) despite similar T-cell populations. Further analysis, including histopathology, serum cytokine ELISA, fecal corticosterone, 16s rRNA analysis of the microbiome, and RT-PCR analysis of ileum and spleen are currently underway and will be ready by the end of the year. The marked difference in the MLN dendritic cell (DC) population suggests increased luminal sampling of intestinal bacteria. Determining how the microbiome affects or is affected by the altered DC population is of particular interest to us. Is the DC population altered because of the microbiome or is the DC population altering the microbiome? Our preliminary data has suggested that depressive states are associated with alterations in the microbiome. Again, whether the changes are a cause or an effect of depression is yet to be answered but is our immediate goal.

Inflammation is a Basis for Most of All Diseases

inflammation is the body’s defensive action against noxious stimuli. If the inflammation is aggravated chronically, by various agents such as chronic psychological stress, chemical agents, infectious agents, physical injury results in release of various inflammatory mediators such as cytokines, chemokine’s, growth factors from inflammatory cells activate key transcription factors such as NF-KB and STAT-3, results in tissue damage, immune modulation, and cellular changes involved in many diseases such as auto-immune disease, cancer, diabetes, Alzheimer’s disease, heart disease. Hence, chronic inflammation is considered as a basis for almost all diseases. This article briefs about the role of chronic inflammation in pathogenesis of various diseases.

Chronic Psychological Stress Induces Gastritis in C57BL/6 Mice with Decreased Production of Hydrogen Sulphide (H 2S) and Microbial Dysbiosis

Background: Chronic persistent stress is an important cause of gastritis, but its mechanism still needs research. Methods: Here we have used a mouse model and the water avoidance stress (WAS) test as a model for chronic stress-induced gastritis to investigate underlying mechanisms of this disease; The effect of stress on gastric flora was analyzed based on 16sRNA sequencing; the changes of hydrogen sulfide (H2S) and inflammatory cytokines from gastric tissues were detected by western blotting, Elisa, immunofluorescence and qRT-PCR; H&E (Haemotoxylin and Eosin) staining was used for the gastritis histology score. Findings: Consistent with the results of previous studies, gastric H2S was negatively associated with the inflammatory index and may protect the gastrointestinal tract from inflammation. WAS-induced gastritis was associated with a reduction in H2S release, which appeared to affect the homeostasis of the gastric microbiota of mice. Inflammation and microbial dysbiosis were partially reversed by sodium hydrosulfide (NaHS) and vitamin B6 (VB6) supplementation, suggesting that VB6 supplementation may have a therapeutic potential for stress-induced gastritis. Interpretation: The secretory disease gastritis can have a serious effect on health and quality of life, with an increasing number of people suffering from chronic gastritis that is linked to a high-stress lifestyle. Our research provides clues to the prevention and treatment of strss-induced gastritis. Funding: The present research was supported by the National Natural Science Foundation of China (No. 81671978, 81471991, 81772143, 81670486, and 81374101). Declaration of Interest: The authors declare no conflicts of interest. Ethical Approval: All animal experiments were approved by the Animal Care Committee and Ethics Commission of Shandong University (LL-201602047).

Stress-induced autonomic dysregulation of mitochondrial function in the rat urothelium.

Chronic stress exacerbates the symptoms of most pain disorders including interstitial cystitis/bladder pain syndrome (IC/BPS). Abnormalities in urothelial cells (UTC) occur in this debilitating bladder condition. The sequence of events that might link stress (presumably through increased sympathetic nervous system-SNS activity) to urothelial dysfunction are unknown. Since autonomic dysregulation, mitochondrial dysfunction, and oxidative stress all occur in chronic pain, we investigated whether chronic psychological stress initiated a cascade linking these three dysfunctions. Adult female Wistar Kyoto rats were exposed to 10 days of water avoidance stress (WAS). Bladders were then harvested for Western blot and single cell imaging in UTC cultures. UTC from WAS rats exhibited depolarized mitochondria membrane potential (Ψm ∼30% more depolarized compared to control), activated AMPK and altered UT mitochondria bioenergetics. Expression of the fusion protein mitofusion-2 (MFN-2) was upregulated in the mucosa, suggesting mitochondrial structural changes consistent with altered cellular metabolism. Intracellular calcium levels were elevated in cultured WAS UTC, consistent with impaired cellular function. Stimulation of cultured UTC with alpha-adrenergic (α-AR) receptor agonists increased reactive oxidative species (ROS) production, suggesting a direct action of SNS activity on UTC. Treatment of rats with guanethidine to block SNS activity prevented most of WAS-induced changes. Chronic stress results in persistent sympathetically mediated effects that alter UTC mitochondrial function. This may impact the urothelial barrier and signaling, which contributes to bladder dysfunction and pain. This is the first demonstration, to our knowledge, of a potential autonomic mechanism directly linking stress to mitochondrial dysfunction.