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  1. Kalinichenko LS, Smaga I, Filip M, Lenz B, Kornhuber J, Müller CP
    Behav Brain Res, 2023 Feb 15;439:114225.
    PMID: 36435218 DOI: 10.1016/j.bbr.2022.114225
    Prenatal stress is a critical life event often resulting in mental illnesses in the offspring. The critical developmental processes, which might trigger a cascade of molecular events resulting in mental disorders in adulthood, are still to be elucidated. Here we proposed that sex hormones, particularly testosterone, might determine the "developmental programming" of long-term consequences of prenatal stress in foetuses of both sexes. We observed that severe prenatal stress in the model of repeated corticosterone injections enhanced brain levels of corticosterone and testosterone in male foetuses. The expression of GluN1 and GluN2A, but not GluN2B NMDA receptor subunits were significantly reduced in the brain of stressed male foetuses. However, female foetuses were protected against stress effects on the brain corticosterone and testosterone levels. More moderate types of stress, such as repeated restraint stress and chronic unpredictable stress, did not induce an increase in brain corticosterone in dams and testosterone concentrations in foetuses of both sexes. Moreover, chronic unpredictable stress reduced brain testosterone concentration in male foetuses. Altogether, changes in brain testosterone level might be one of the crucial mechanisms determining the development of long-term consequences of severe prenatal stress in male, but not in female foetuses. Targeting this mechanism might allow to develop principally new prediction and therapeutic approaches for prenatal stress-associated psychiatric disorders.
    Matched MeSH terms: Stress, Psychological/metabolism
  2. Aimie-Salleh N, Malarvili MB, Whittaker AC
    Med Biol Eng Comput, 2019 Jun;57(6):1229-1245.
    PMID: 30734153 DOI: 10.1007/s11517-019-01958-3
    Adverse childhood experiences have been suggested to cause changes in physiological processes and can determine the magnitude of the stress response which might have a significant impact on health later in life. To detect the stress response, biomarkers that represent both the Autonomic Nervous System (ANS) and Hypothalamic-Pituitary-Adrenal (HPA) axis are proposed. Among the available biomarkers, Heart Rate Variability (HRV) has been proven as a powerful biomarker that represents ANS. Meanwhile, salivary cortisol has been suggested as a biomarker that reflects the HPA axis. Even though many studies used multiple biomarkers to measure the stress response, the results for each biomarker were analyzed separately. Therefore, the objective of this study is to propose a fusion of ANS and HPA axis biomarkers in order to classify the stress response based on adverse childhood experience. Electrocardiograph, blood pressure (BP), pulse rate (PR), and salivary cortisol (SCort) measures were collected from 23 healthy participants; 11 participants had adverse childhood experience while the remaining 12 acted as the no adversity control group. HRV was then computed from the ECG and the HRV features were extracted. Next, the selected HRV features were combined with the other biomarkers using Euclidean distance (ed) and serial fusion, and the performance of the fused features was compared using Support Vector Machine. From the result, HRV-SCort using Euclidean distance achieved the most satisfactory performance with 80.0% accuracy, 83.3% sensitivity, and 78.3% specificity. Furthermore, the performance of the stress response classification of the fused biomarker, HRV-SCort, outperformed that of the single biomarkers: HRV (61% Accuracy), Cort (59.4% Accuracy), BP (78.3% accuracy), and PR (53.3% accuracy). From this study, it was proven that the fused biomarkers that represent both ANS and HPA (HRV-SCort) able to demonstrate a better classification performance in discriminating the stress response. Furthermore, a new approach for classification of stress response using Euclidean distance and SVM named as ed-SVM was proven to be an effective method for the HRV-SCort in classifying the stress response from PASAT. The robustness of this method is crucial in contributing to the effectiveness of the stress response measures and could further be used as an indicator for future health. Graphical abstract ᅟ.
    Matched MeSH terms: Stress, Psychological/metabolism*
  3. Soga T, Nakajima S, Kawaguchi M, Parhar IS
    PMID: 32739332 DOI: 10.1016/j.pnpbp.2020.110053
    Extreme stress is closely linked with symptoms of depression. Chronic social stress can cause structural and functional changes in the brain. These changes are associated with dysfunction of neuroprotective signalling that is necessary for cell survival, growth, and maturation. Reduced neuronal numbers and volume of brain regions have been found in depressed patients, which may be caused by decreased cell survival and increased cell death. Elucidating the mechanism underlying the degeneration of the neuroprotective system in social stress-induced depression is important for developing neuroprotective measures. The Repressor Element 1 Silencing Transcription Factor (REST) also known as Neuron-Restrictive Silencing Factor (NRSF) has been reported as a neuroprotective molecule in certain neurological disorders. Decreased expression levels of REST/NRSF in the nucleus can induce death-related gene expression, leading to neuronal death. Under physiological stress conditions, REST/NRSF over expression is known to activate neuronal survival in the brain. Alterations in REST/NRSF expression in the brain has been reported in stressed animal models and in the post-mortem brain of patients with depression. Here, we highlight the neuroprotective function of REST/NRSF and discuss dysregulation of REST/NRSF and neuronal damage during social stress and depression.
    Matched MeSH terms: Stress, Psychological/metabolism*
  4. Li P, Huang W, Chen Y, Aslam MS, Cheng W, Huang Y, et al.
    Neural Plast, 2023;2023:1474841.
    PMID: 37179843 DOI: 10.1155/2023/1474841
    PURPOSE: To explore the therapeutic efficiency of acupuncture and the related molecular mechanism of neural plasticity in depression.

    METHODS: Chronic unpredictable mild stress- (CUMS-) induced rats were established for the depression animal model. There were a total of four rat groups, including the control group, the CUMS group, the CUMS+acupuncture group, and the CUMS+fluoxetine group. The acupuncture group and the fluoxetine group were given a 3-week treatment after the modeling intervention. The researcher performed the open-field, elevated plus maze, and sucrose preference tests to evaluate depressive behaviors. The number of nerve cells, dendrites' length, and the prefrontal cortex's spine density were detected using Golgi staining. The prefrontal cortex expression, such as BDNF, PSD95, SYN, and PKMZ protein, was detected using the western blot and RT-PCR.

    RESULTS: Acupuncture could alleviate depressive-like behaviors and promote the recovery of the neural plasticity functions in the prefrontal cortex, showing the increasing cell numbers, prolonging the length of the dendrites, and enhancing the spine density. The neural plasticity-related proteins in the prefrontal cortex, including BDNF, PSD95, SYN, and PKMZ, were all downregulated in the CUMS-induced group; however, these effects could be partly reversed after being treated by acupuncture and fluoxetine (P < 0.05).

    CONCLUSION: Acupuncture can ameliorate depressive-like behaviors by promoting the recovery of neural plasticity functions and neural plasticity-related protein upregulation in the prefrontal cortex of CUMS-induced depressed rats. Our study provides new insights into the antidepressant approach, and further studies are warranted to elucidate the mechanisms of acupuncture involved in depression treatment.

    Matched MeSH terms: Stress, Psychological/metabolism
  5. Lee CY
    Clin Exp Pharmacol Physiol, 2013 Jun;40(6):385-91.
    PMID: 23586523 DOI: 10.1111/1440-1681.12096
    Psychosocial stress is reported to be one of the main causes of obesity. Based on observations in studies that relate stress and gut inflammation to obesity, the present study hypothesized that chronic stress, via inflammation, alters the expression of nutrient transporters and contributes to the development of metabolic syndrome. Rats were exposed to restraint stress for 4 h/day for 5 days/week for eight consecutive weeks. Different segments of rat intestine were then collected and analysed for signs of pathophysiological changes and the expression of Niemann-Pick C1-like-1 (NPC1L1), sodium-dependent glucose transporter-1 (SLC5A1, previously known as SGLT1) and facilitative glucose transporter-2 (SLC2A2, previously known as GLUT2). In a separate experiment, the total anti-oxidant activity (TAA)-time profile of control isolated intestinal segments was measured. Stress decreased the expression of NPC1L1 in the ileum and upregulated SLC5A1 in both the jejunum and ileum and SLC2A2 in the duodenum. Inflammation and morphological changes were observed in the proximal region of the intestine of stressed animals. Compared with jejunal and ileal segments, the rate of increase in TAA was higher in the duodenum, indicating that the segment contained less anti-oxidants; anti-oxidants may function to protect the tissues. In conclusion, stress alters the expression of hexose and lipid transporters in the gut. The site-specific increase in the expression of SLC5A1 and SLC2A2 may be correlated with pathological changes in the intestine. The ileum may be protected, in part, by gut anti-oxidants. Collectively, the data suggest that apart from causing inflammation, chronic stress may promote sugar uptake and contribute to hyperglycaemia.
    Matched MeSH terms: Stress, Psychological/metabolism*
  6. Lee MT, Chiu YT, Chiu YC, Hor CC, Lee HJ, Guerrini R, et al.
    J Biomed Sci, 2020 Jan 09;27(1):7.
    PMID: 31915019 DOI: 10.1186/s12929-019-0590-1
    BACKGROUND: Stress-induced analgesia (SIA) is an evolutionarily conserved phenomenon during stress. Neuropeptide S (NPS), orexins, substance P, glutamate and endocannabinoids are known to be involved in stress and/or SIA, however their causal links remain unclear. Here, we reveal an unprecedented sequential cascade involving these mediators in the lateral hypothalamus (LH) and ventrolateral periaqueductal gray (vlPAG) using a restraint stress-induced SIA model.

    METHODS: Male C57BL/6 mice of 8-12 week-old were subjected to intra-cerebroventricular (i.c.v.) and/or intra-vlPAG (i.pag.) microinjection of NPS, orexin-A or substance P alone or in combination with selective antagonists of NPS receptors (NPSRs), OX1 receptors (OX1Rs), NK1 receptors (NK1Rs), mGlu5 receptors (mGlu5Rs) and CB1 receptors (CB1Rs), respectively. Antinociceptive effects of these mediators were evaluated via the hot-plate test. SIA in mice was induced by a 30-min restraint stress. NPS levels in the LH and substance P levels in vlPAG homogenates were compared in restrained and unrestrained mice.

    RESULTS: NPS (i.c.v., but not i.pag.) induced antinociception. This effect was prevented by i.c.v. blockade of NPSRs. Substance P (i.pag.) and orexin-A (i.pag.) also induced antinociception. Substance P (i.pag.)-induced antinociception was prevented by i.pag. Blockade of NK1Rs, mGlu5Rs or CB1Rs. Orexin-A (i.pag.)-induced antinociception has been shown previously to be prevented by i.pag. blockade of OX1Rs or CB1Rs, and here was prevented by NK1R or mGlu5R antagonist (i.pag.). NPS (i.c.v.)-induced antinociception was prevented by i.pag. blockade of OX1Rs, NK1Rs, mGlu5Rs or CB1Rs. SIA has been previously shown to be prevented by i.pag. blockade of OX1Rs or CB1Rs. Here, we found that SIA was also prevented by i.c.v. blockade of NPSRs or i.pag. blockade of NK1Rs or mGlu5Rs. Restrained mice had higher levels of NPS in the LH and substance P in the vlPAG than unrestrained mice.

    CONCLUSIONS: These results suggest that, during stress, NPS is released and activates LH orexin neurons via NPSRs, releasing orexins in the vlPAG. Orexins then activate OX1Rs on substance P-containing neurons in the vlPAG to release substance P that subsequently. Activates NK1Rs on glutamatergic neurons to release glutamate. Glutamate then activates perisynaptic mGlu5Rs to initiate the endocannabinoid retrograde inhibition of GABAergic transmission in the vlPAG, leading to analgesia.

    Matched MeSH terms: Stress, Psychological/metabolism*
  7. Khor YM, Soga T, Parhar IS
    Gen Comp Endocrinol, 2016 Feb 1;227:84-93.
    PMID: 26686318 DOI: 10.1016/j.ygcen.2015.12.004
    Early-life stress can cause long-term effects in the adulthood such as alterations in behaviour, brain functions and reproduction. DNA methylation is a mechanism of epigenetic change caused by early-life stress. Dexamethasone (DEX) was administered to zebrafish larvae to study its effect on reproductive dysfunction. The level of GnRH2, GnRH3, Kiss1 and Kiss2 mRNAs were measured between different doses of DEX treatment groups in adult zebrafish. Kiss1 and GnRH2 expression were increased in the 200mg/L DEX treated while Kiss2 and GnRH3 mRNA levels were up-regulated in the 2mg/L DEX-treated zebrafish. The up-regulation may be related to programming effect of DEX in the zebrafish larvae, causing overcompensation mechanism to increase the mRNA levels. Furthermore, DEX treatment caused negative impact on the development and maturation of the testes, in particular spermatogenesis. Therefore, immature gonadal development may cause positive feedback by increasing GnRH and Kiss. This indicates that DEX can alter the regulation of GnRH2, GnRH3, Kiss1 and Kiss2 in adult zebrafish, which affects maturation of gonads. Computer analysis of 1.5 kb region upstream of the 5' UTR of Kiss1, Kiss2, GnRH2 and GnRH3 promoter showed that there are putative binding sites of glucocorticoid response element and transcription factors involved in stress response. GnRH3 promoter analysed from pre-optic area, ventral telencephalon and ventral olfactory bulb showed higher methylation at CpG residues located on -1410, -1377 and -1355 between control and 2mg/L DEX-treated groups. Hence, early-life DEX treatment can alter methylation of GnRH3 gene promoter, which subsequently affects gene regulation and reproductive functions.
    Matched MeSH terms: Stress, Psychological/metabolism
  8. Shen J, Hao C, Yuan S, Chen W, Tong T, Chen Y, et al.
    Brain Res, 2024 Mar 01;1826:148715.
    PMID: 38142722 DOI: 10.1016/j.brainres.2023.148715
    BACKGROUND: The treatment of depression with acupuncture has been documented. The mechanism behind acupuncture's curative and preventative effects is still unknown.

    METHODS: The current study examined the effects of acupuncture on depression-like behaviors in a rat model of chronic unpredictable mild stress (CUMS), while also exploring its potential mechanisms. A total of six groups of rats were randomly assigned: control, CUMS, acupuncture, fluoxetine, acupoint catgut embedding and sham acupoint catgut embedding. Fluoxetine (2.1 mg/kg) and acupoint catgut embedding were used for comparative research to acupuncture. The modelling evaluation is measured by body weight and behavior tests. Western blotting and reverse transcription-polymerase chain reaction were used to detect the proteins and mRNA expression of Silent information regulator 1 (Sirt1)/ nuclear factor-erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1)/ Glutathione peroxidase 4 (GPX4) pathway in the hippocampus. The expression of oxidative stress (OS)-related proteins and inflammatory cytokines in the serum was detected with ELISA. Immunofluorescence showed microglia and astrocytes activity in the hippocampus.

    RESULTS: Acupuncture and fluoxetine could alleviate CUMS-induced depression-like behaviors. Acupuncture was also found to effectively reverse the levels of MDA, SOD, GSH, GSH-PX and T-AOC, IL-1β, IL-6 and TNF-α in the serum of CUMS-induced rats. Rats with CUMS showed decreased levels of Sirt1, Nrf2, HO-1 and GPX4 in the hippocampus, while acupuncture treatment could partly reverse the diminished effects. In addition, acupuncture treatment significantly reduced the activation of hippocampal microglia and astrocytes in CUMS-induced rats.

    CONCLUSION: The study's findings indicate that acupuncture has the potential to mitigate depression-like behaviors in rats induced with CUMS by mitigating OS and reducing neuroinflammation.

    Matched MeSH terms: Stress, Psychological/metabolism
  9. Kapitonova MY, Kuznetsov SL, Khlebnikov VV, Zagrebin VL, Morozova ZCh, Degtyar YV
    Neurosci. Behav. Physiol., 2010 Jan;40(1):97-102.
    PMID: 20012496 DOI: 10.1007/s11055-009-9217-4
    Quantitative immunohistochemical methods were used to assess activation of the hypothalamo-hypophyseal-adrenocortical system at the level of its central component - the adenohypophysis - in the growing body during chronic exposure to psychoemotional stressors of different strengths. Sprague-Dawley rats aged 30 days were subjected to "mild" or "severe" immobilization stress for 5 h per day for seven days. Animals were decapitated at the end of the last stress session and the endocrine glands (hypophysis, adrenals) were harvested, weighed, and embedded in paraffin; sections were stained with hematoxylin and eosin, and also immunohistochemically using monoclonal antibodies to adrenocorticotropic hormone (ACTH) and proliferating cell nuclear antigen (PCNA) following by automated image analysis. These studies showed that stress-associated hyperplasia of corticotropocytes in rats of pubertal age was due more to the differentiation of existing immature precursor cells than to cell proliferation.
    Matched MeSH terms: Stress, Psychological/metabolism*
  10. Arffin F, Al-Bayaty FH, Hassan J
    Arch Gynecol Obstet, 2012 Nov;286(5):1187-91.
    PMID: 22718098 DOI: 10.1007/s00404-012-2417-0
    BACKGROUND: Exposure of pregnant women to environmental tobacco smoke has been shown to be associated with low birth weight. Many studies have suggested that stress have a role in the etiology of preterm birth.

    AIMS: This study carried out from June 2008 to March 2009 to find the relation between environmental tobacco smoke, stress and miscarriage and preterm births.

    METHODS: A total of 33 subjects consisted of multiparous pregnant women that were in their early third trimester were chosen for this investigation. Subjects were divided into test group women with adverse pregnancy outcome, control group women with successful pregnancy. Four ml of unstimulated whole saliva were collected. The concentrations of cotinine and cortisol were evaluated using commercially available ELISA kit.

    RESULTS: Pregnancies in which the average standardized cortisol during history of previous miscarriage(s) which occurred within 6th-27th week or/and history of preterm labor which occurred within 28th-36th weeks of gestation, demonstrated higher cortisol level (1.0201 ± 0.1855 ng/ml) compared to control group 0.9757 ± 0.2860 ng/ml (P = 0.323); statistical analysis showed no significant differences. Women of control group were more likely to be environmental tobacco smoke exposed (1.2714 ± 1.7639 ng/ml) than women with miscarriage and preterm births (0.9889 ± 0.5498 ng/ml).

    CONCLUSION: The results from this primarily study demonstrated no association between cotinine, cortisol, miscarriage and preterm births.

    Matched MeSH terms: Stress, Psychological/metabolism
  11. Ng JS, Chin KY
    Int J Med Sci, 2021;18(3):604-614.
    PMID: 33437195 DOI: 10.7150/ijms.50680
    Chronic psychological stress affects many body systems, including the skeleton, through various mechanisms. This review aims to provide an overview of the factors mediating the relationship between psychological stress and bone health. These factors can be divided into physiological and behavioural changes induced by psychological stress. The physiological factors involve endocrinological changes, such as increased glucocorticoids, prolactin, leptin and parathyroid hormone levels and reduced gonadal hormones. Low-grade inflammation and hyperactivation of the sympathetic nervous system during psychological stress are also physiological changes detrimental to bone health. The behavioural changes during mental stress, such as altered dietary pattern, cigarette smoking, alcoholism and physical inactivity, also threaten the skeletal system. Psychological stress may be partly responsible for epigenetic regulation of skeletal development. It may also mediate the relationship between socioeconomic status and bone health. However, more direct evidence is required to prove these hypotheses. In conclusion, chronic psychological stress should be recognised as a risk factor of osteoporosis and stress-coping methods should be incorporated as part of the comprehensive osteoporosis-preventing strategy.
    Matched MeSH terms: Stress, Psychological/metabolism
  12. Mohamad Shalan NA, Mustapha NM, Mohamed S
    Food Chem, 2016 Dec 01;212:443-52.
    PMID: 27374554 DOI: 10.1016/j.foodchem.2016.05.179
    Morinda citrifolia fruit, (noni), enhanced performances in athletes and post-menopausal women in clinical studies. This report shows the edible noni leaves water extract enhances performance in a weight-loaded swimming animal model better than the fruit or standardized green tea extract. The 4weeks study showed the extract (containing scopoletin and epicatechin) progressively prolonged the time to exhaustion by threefold longer than the control, fruit or tea extract. The extract improved (i) the mammalian antioxidant responses (MDA, GSH and SOD2 levels), (ii) tissue nutrient (glucose) and metabolite (lactate) management, (iii) stress hormone (cortisol) regulation; (iv) neurotransmitter (dopamine, noradrenaline, serotonin) expressions, transporter or receptor levels, (v) anti-inflammatory (IL4 & IL10) responses; (v) skeletal muscle angiogenesis (VEGFA) and (v) energy and mitochondrial biogenesis (via PGC, UCP3, NRF2, AMPK, MAPK1, and CAMK4). The ergogenic extract helped delay fatigue by enhancing energy production, regulation and efficiency, which suggests benefits for physical activities and disease recovery.
    Matched MeSH terms: Stress, Psychological/metabolism
  13. Ogawa S, Parhar IS
    Int J Mol Sci, 2020 Apr 15;21(8).
    PMID: 32326396 DOI: 10.3390/ijms21082724
    Gonadotropin-releasing hormone (GnRH) is essential for the initiation and maintenance of reproductive functions in vertebrates. To date, three distinct paralogue lineages, GnRH1, GnRH2, and GnRH3, have been identified with different functions and regulatory mechanisms. Among them, hypothalamic GnRH1 neurons are classically known as the hypophysiotropic form that is regulated by estrogen feedback. However, the mechanism of action underlying the estrogen-dependent regulation of GnRH1 has been debated, mainly due to the coexpression of low levels of estrogen receptor (ER) genes. In addition, the role of sex steroids in the modulation of GnRH2 and GnRH3 neurons has not been fully elucidated. Using single-cell real-time PCR, we revealed the expression of genes for estrogen, androgen, glucocorticoid, thyroid, and xenobiotic receptors in GnRH1, GnRH2, and GnRH3 neurons in the male Nile tilapia Oreochromis niloticus. We further quantified expression levels of estrogen receptor genes (ERα, ERβ, and ERγ) in three GnRH neuron types in male tilapia of two different social statuses (dominant and subordinate) at the single cell level. In dominant males, GnRH1 mRNA levels were positively proportional to ERγ mRNA levels, while in subordinate males, GnRH2 mRNA levels were positively proportional to ERβ mRNA levels. These results indicate that variations in the expression of nuclear receptors (and possibly steroid sensitivities) among individual GnRH cells may facilitate different physiological processes, such as the promotion of reproductive activities through GnRH1 neurons, and the inhibition of feeding and sexual behaviors through GnRH2 neurons.
    Matched MeSH terms: Stress, Psychological/metabolism
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