Antidepressant effects of Peiyuan Jieyu formula in a mouse model of chronic stress in conjunction with lipopolysaccharide-induced depression

Objective:To explore the mechanism of the Peiyuan Jieyu formula in treating depression by assessing its impact on a lipopolysaccharide-induced(LPS-induced)depression mouse model.Methods:We created a mouse model of depression by exposing mice that had previously received chronic stress to intraperitoneal LPS injections.The mice were divided into the following groups:control,model,fluoxetine,Tiansi Yin,Sini powder,and low-,medium-,and high-dose Peiyuan Jieyu formula groups.Forced swim and tail suspension tests were used to assess the efficacy of the depression(despair)model,and weight gain rates were also measured.Furthermore,serum levels of various depression and inflammation-associated molecules,including tumor necrosis factor-a(TNF-a),interferon-γ(IFN-γ),tryptophan,5-hydroxytryptamine,kynurenine(KYN),and kynurenic acid(KA)were assessed.Furthermore,the expression levels of ionic calcium-binding adaptor molecule-1(IBA-1)and indoleamine 2,3-dioxygenase(IDO)mRNA in hippocampal microglia were measured.Results:The model group displayed greater despair-associated immobility,which was shortened in response to various doses of Peiyuan Jieyu formula.Furthermore,formula administration significantly reduced serum TNF-a levels and hippocampal IDO mRNA expression.The high formula dose also reduced IFN-γand IBA-1 levels,the latter was also decreased in response to the medium formula dose.However,the low formula dose reduced serum KYN level and KYN/tryptophan(TRP)and KYN/KA ratios.Conclusion:The Peiyuan Jieyu formula holds immense potential in treating depression in a mouse model,potentially inhibiting inflammation and improving TRP-KYN metabolic disorders.

Effects of Shuyusan on monoamine neurotransmitters expression in a rat model of chronic stress-induced depression

Shuyusan, a traditional Chinese medicine, was shown to improve depression symptoms and behavioral scores, as well as increase 5-hydroxytryptamine （5-HT）, 5-hydroxyindoleacetic acid, and 5-hydroxytryptophan levels, in a rat model of chronic stress-induced depression. However, dopamine, noradrenalin, and 3-methoxy-4-hydroxyphenylglycol expressions remained unchanged following Shuyusan treatment. Compared with the model group, the number of 5-HT-positive neurons in layers 4-5 of the frontal cortex, as well as hippocampal CA1 and CA3 regions, significantly increased following Shuyusan treatment. These results suggested that Shuyusan improved symptoms in a rat model of chronic stress-induced depression with mechanisms that involved 5-HT, 5-HT metabolite, 5-HT precursor expressions.

Chronic stress induces ageing-associated degeneration in rat Leydig cells

Several studies have suggested that stress and ageing exert inhibitory effects on rat Leydig cells. In a pattern similar to the normal process of Leydig cell ageing, stress-mediated increases in glucocorticoid levels inhibit steroidogenic enzyme expression that then results in decreased testosterone secretion. We hypothesized that chronic stress accelerates the degenerative changes associated with ageing in Leydig cells. To test this hypothesis, we established a model of chronic stress to evaluate stress-induced morphological and functional alterations in Brown Norway rat Leydig cells; additionally, intracellular lipofuscin levels, reactive oxygen species （ROS） levels and DNA damage were assessed. The results showed that chronic stress accelerated ageing-related changes： ultrastructural alterations associated with ageing, cellular lipofuscin accumulation, increased ROS levels and more extensive DNA damage were observed. Additionally, testosterone levels were decreased. This study sheds new light on the idea that chronic stress contributes to the degenerative changes associated with ageing in rat Leydig cells in vivo.

Hippocampal activation of c-Jun N-terminal kinase,protein kinase B,and p38 mitogen-activated protein kinase in a chronic stress rat model of depression

Recent studies have shown that varied stress stimuli activate c-Jun N-terminal kinase （JNK）, protein kinase B （Akt）, and p38 mitogen-activated protein kinase （p38） signal transduction pathway, and also regulate various apoptotic cascades. JNK and p38 promote apoptosis, but Akt protects against apoptosis, in hippocampal neurons. However, changes in the transduction pathway in different regions of brain tissues in a chronic stress rat model of depression remain poorly understood. Results from this study showed that JNK phosphorylation levels were significantly greater in the stress group hippocampus compared with the control group （P 〈 0.05）. No significant difference in JNK phosphorylation levels was detected in the rat cerebral cortex between stress and control groups, and no significant difference in Akt and p38 phosphorylation levels was detected in the rat hippocampus and cerebral cortex between stress and control groups （P 〉 0.05）. These results suggested that the JNK signal pathway is activated by JNK phosphorylation and participates in pathophysiological changes in rat models of depression.

Molecular mechanism of non-alcoholic fatty liver disease induced and aggravated by chronic stress through HSL/ATGL-FFA which promotes fat mobilization

Objective:To study the effects of social stress(CS)and social stress combined with high-fat diet on fat mobilization as a candidate mechanism for the induction or aggravation of non-alcoholic fatty liver disease(NAFLD).Methods:Thirty-two male Wistar rats(250±10 g)were randomly allocated to a blank control group(BC),a high-fat diet group(HFD),a CS group,and a combined CS and high-fat diet group(CS t HFD).Rats were sacrificed and tissues were collected after 8 weeks.Liver and body mass were measured and used to calculate the liver index.Serum aspartate aminotransferase(AST),alanine aminotransferase(ALT),and free fatty acids(FFAs)were measured.Liver sections were examined microscopically after oil red O and hematoxylin and eosin staining.The relative mRNA expression of acetyl-CoA carboxylase(ACCase),hydroxymethylglutaryl coenzyme A(HMG-CoA)reductase in liver,and hormone-sensitive lipase(HSL),and adipose triglyceride lipase(ATGL)in subcutaneous adipose tissue,were measured by real-time PCR.The liver concentrations of triglyceride,reactive oxygen species,and ACCase were measured by ELISA and HSL activity was determined using turbidimetry.Results:NAFLD developed in the CS,HFD,and CS t HFD groups,with the most severe NAFLD being in the CS t HFD group.Serum AST,ALT,and FFA,liver index,and hepatic triglyceride,FFA,and tumor necrosis factor-a were significantly higher in both the CS and CS t HFD groups.However,food intake and ACCase mRNA expression were lower.The mRNA expression of HSL and ATGL in adipose tissue was much higher,and HSL activity was higher in the CS group than in the BC group,and in the CS t HFD group than in the HFD group.Conclusion:We have successfully established two models of stress-induced NAFLD,suggesting stress can induce and aggravate NAFLD by promoting fat mobilization through upregulation of HSL and ATGL.

Basic fibroblast growth factor improves learning and memory functions in chronic stress mice

Four weeks of uncertain stress was used to establish an animal model of chronic stress. Basic fibroblast growth factor was injected daily for 15 days following stress induction. Cell morphology in the hippocampal CA3 region of chronic stress mice revealed cell damage. Nitric oxide content and calcium concentration were significantly increased in the hippocampus, and learning and memory functions were significantly decreased. After basic fibroblast growth factor intervention, Ca2~ overload was decreased and neuronal damage was relieved in hippocampal neurons, which improved learning and memory functions in chronic stress mice. Latency was prolonged and the number of errors was decreased in a passive avoidance test.

Chronic Stress Induced Proliferation and Activation of Mast Cells of Gastric Antrum in Rats

To explore chronic eration and activation of mast heterotypic stressors induced prolifcells in gastric antrum mucosa by ultrastructure alterations of mast cells, chronic unpredictable heterotypic stressors were used as a study model. The mean immunofluorescence magnitude of mast cell protease 1 （MCP-1） taken from chronic stress rats were 37.4±7.7, significantly higher （p〈0.05） than the value of normal control group （24.8±5.6）. Chronic unpredictable haterotypic stressors appeared also to induce ultrastructure alterations of mast cells. It indicated that mast cells were proliferated and activated, while mast cell granules were hyperplasiaed. Most granules had obvious intragranular changes with loss of electron-dense material. The morphologic evidence showed that macrophages and leukocytes infiltrated in chronic stress rats. Some granules of leukocytes adhered to the surface of mast cell, and formed a bridge. Macrophages phagocytized the mast cell granules.

Antidepressant Effect of Shenwei Ningyu Tablets on Rat Chronic Stress Model and Mouse Tail Suspension Model

[Objectives]To explore the antidepressant effect of Shenwei Ningyu Tablet,a new antidepressant traditional Chinese medicine,on rat chronic stress depression model and mouse tail suspension models.[Methods]Rat chronic stress model:except for the normal group,the rats in other groups were given corresponding chronic stress,and administered by gavage 1 h before modeling,for a total of 21 d.The changes of each indicator before and after the experiment were observed through the body weight change,the sugar water test,and open field test.The relevant hormone levels were detected by radioimmunoassay.Mouse tail suspension depression model:after continuous administration for 7 d,the activity times was recorded with the mouse automatic recorder,and the mouse immobility time was recorded after tail suspension,to explore the effects of each administration group on the tail suspension immobility time of mice.[Results]Chronic stress depression model:21 d after modeling,compared with the normal group,rats in the model group exhibited significantly reduced body weight,sucrose preference index,and horizontal and vertical movement scores(P<0.05).Compared with the model group,the low-dose Shenwei Ningyu Tablets group had significant differences in the sugar water test,horizontal and vertical movement scores(P<0.05).In addition,all three dose groups of Shenwei Ningyu Tablets could effectively reduce the content of CRF in chronic stress model rats,and the low dose group could significantly reduce the ACTH level in model rats(P<0.05).Mouse tail suspension depression model:the immobility time after tail suspension in each administration group was significantly different from that in the model group(P<0.05).[Conclusions]Shenwei Ningyu Tablets has a certain anti-depression effect on both the rat chronic stress depression model and the mouse tail suspension depression model.

Comparative proteomic analysis of hippocampal proteins from chronic stressed rats

Chronic stress can induce hippocampus injury such as neuron loss and dendrite atrophy,but its mechanism and molecular basis remain unclear up to now.To understand the molecular mechanism on protein level and find the crucial proteins which correlated with chronic

L-tyrosine improves neuroendocrine function in a mouse model of chronic stress

Adult BALB/c mice, individually housed, were stimulated with nine different stressors, arranged randomly, for 4 continuous weeks to generate an animal model of chronic stress. In chronically stressed mice, spontaneous locomotor activity was significantly decreased, escape latency in the Morris water maze test was prolonged, serum levels of total thyrotropin and total triiodothyronine were significantly decreased, and dopamine and norepinephrine content in the pallium, hippocampus and hypothalamus were significantly reduced. All of these changes were suppressed, to varying degrees, by L-tyrosine supplementation. These findings indicate that the neuroendocrine network plays an important role in chronic stress, and that L-tyrosine supplementation has therapeutic effects.

Beneficial Effects of <i>Fumaria indica</i>on Chronic Stress-Induced Neurobehavioral and Biochemical Perturbations in Rats

Objective: To evaluate the anti-stress activity of standardized extract of Fumaria indica (FI) through validated beha-vioral models of rodents followed by estimation of biochemical changes associated with chronic stress. Methods: Fifty percent ethanolic extract of FI used in this study was standardized on its contents of fumaric acid and its conjugates (0.45% and 0.35% respectively). Stressed Charles Foster rats received unpredictable foot shocks (2 mA, 1 hr, 14 days) through electric grid. FI was given orally as 0.3% carboxymethyl cellulose (CMC) suspension in 100, 200 and 400 mg/kg doses. For comparison, Panax ginseng (PG) extract (100 mg/kg, p.o.) was used as standard adaptogen. Incidence of gastric ulceration, changes in weight of adrenal and spleen, behavioral depression, cognitive dysfunction test and suppression of sexual behavior in male rats were used as validated behavioral models. Plasma corticosterone, brain levels of lipid peroxides (LPO), superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH), and expression of cytokines IL-1β, TNF-α and IL-10 in circulating white blood cells (WBC) were quantified for ascertaining biochemical changes accompanying stress. Results: As compared to vehicle treated stressed rats, the FI and PG treated rats showed fewer incidence of gastric ulceration, reversal of changes in weight of adrenal gland and spleen, reversal of behavioral depression, better performance in passive and active avoidance tests for cognitive function and increased sexual activity. FI and PG significantly decreased chronic unpredictable stress induced elevation of corticosterone, and both extracts normalized also the abnormal oxidative status of the brain observed in stressed rats. FI treatment also suppressed the elevated level of IL-1β, TNF-α and IL-10 in stressed animals. Conclusions: FI could be another adaptogenic herb and fumaric acid and its conjugates are possibly involved in observed bioactivity of its extract.

EFFECTS OF CHRONIC STRESS ON THE ACTIVITIES OF SOD, GSH-Px AND MDA LEVEL IN FEMALE RATS' BRAIN

Objective To observe the effects of chronic emotional stress on the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and malonialdehyde (MDA) level in female rats’ brain. Methods The rats were randomly divided into 4 groups: normal control group (group N), emotional stress group (group E), emotional stress + pregnancy group (group E+P) and regularly drinking group (group R). Emotional stress in rats was induced by training rats with empty drinking bottles. Having been finished the stress procedure, the brain was taken out and homogenized. Then the activities of SOD, GSH-Px and MDA level were measured. Results Compared to group N, both the activities of SOD in brain tissues of group E and group E+P were significantly decreased ( P <0.05 and P <0.01, respectively) while the MDA level increased ( P <0.05). However, the extent of changes in group E+P was more obvious than that in E. GSH-Px activities in E+P and E were significantly changed. However, the GSH-Px activity in E+P was decreased ( P <0.05) while the activity in E increased ( P <0.05).Conclusion The chronic emotional stress can reduce the antioxidative system by decreasing the antioxidative enzyme activity and potentiating the lipid peroxidation in the brain. It is also suggested that the combination of emotional stress and pregnancy can augment the oxidative damage in rats’ brain.

Chronic stress as an emerging risk factor for the development and progression of glioma

Gliomas tend to have a poor prognosis and are the most common primary malignant tumors of the central nervous system.Compared with patients with other cancers,glioma patients often suffer from increased levels of psychological stress,such as anxiety and fear.Chronic stress(CS)is thought to impact glioma profoundly.However,because of the complex mechanisms underlying CS and variability in individual tolerance,the role of CS in glioma remains unclear.This review suggests a new proposal to redivide the stress system into two parts.Neuronal activity is dominant upstream.Stress-signaling molecules produced by the neuroendocrine system are dominant downstream.We discuss the underlying molecular mechanisms by which CS impacts glioma.Potential pharmacological treatments are also summarized from the therapeutic perspective of CS.

Transcriptome analysis reveals the mechanism of chronic heat stress on meat quality of broilers

Background:Chronic heat stress has a negative impact on poultry meat quality.Although this has been extensively investigated,previous studies have primarily focused on metabolic alterations and oxidative stress in the pectoralis major(PM)muscle under chronic heat stress,and not all of the underlying molecular mechanisms are completely understood.Methods:A total of 144 male Arbor Acres broilers(28 d old)were randomly allocated into 3 treatment groups:(1)the normal control(NC)group,with broilers raised at 22℃and fed a basal diet;(2)the heat stress(HS)group,with birds raised at 32℃and fed a basal diet;and(3)the pair-fed(PF)group,with birds raised at 22℃and fed the amount of feed equal to the feed consumed on the previous day by the HS group.The experiment lasted for 14 d.Results:Chronic heat stress decreased the average daily feed intake and average daily gain,increased feed:gain ratio(P<0.05);and increased drip loss,cooking loss,shear force,hardness,and decreased p H,redness(a*);and springiness of PM muscle(P<0.05).Furthermore,chronic heat stress decreased muscle fiber density,increased connective tissue,and led to intracellular vacuolation.The transcriptome analyses indicated that the effect of chronic heat stress on meat quality was not only related to metabolism and oxidative stress,but also to signal transduction,immune system,transport and catabolism,cell growth and death,and muscle structure.Conclusions:Chronic heat stress has a negative impact on the growth performance,meat quality,and the PM muscle structure of broilers.Transcriptome analysis revealed a comprehensive understanding of the mechanism of the chronic heat stress-induced deterioration of broiler meat quality at the transcriptional level.

Shuganheweitang Ameliorates Chronic Unpredictable Mild Stress-Induced Depression-Like Behaviors in Rats through the PI3K/AKT/mTOR Pathway: Involvement of Amino Acids, Glycerophospholipids, and Energy Metabolism

Background: Depression is a typical psychosomatic disease. Shuganheweitang (SGHWT) is a clinical formula that effectively treats depression. However, the potential mechanism used by SGHWT to ameliorate depression-like behaviors is still unclear. This study investigated the effects of SGHWT on metabolic change in the liver and hypothalamus with signaling pathways involved in chronic unpredictable mild stress (CUMS)-induced depression in rats to explore the mechanism of the anti-depressive effect. Methods: A total of 52 rats were used to create a model of depression by CUMS combined with solitary rearing for 6 weeks. Open field test (OFT), sucrose preference test (SPT), forced swim test (FST), and body weight (BW) were performed to analyze the pharmacodynamic effects of SGHWT. H&E staining, Nissl staining, immunofluorescence, immunohistochemistry, and western blot were used to evaluate the mechanism of action. Untargeted metabolomics techniques by ultra-performance liquid chromatography-quantitative time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) were used to analyze all the metabolic differences in the liver and hypothalamus. Results: SGHWT improved CUMS-induced depression-like behaviors in vivo. SGHWT reduced hepatic c-Fos protein expression and increased hypothalamic c-Fos protein expression. Moreover, p-PI3K, p-AKT473, p-AKT308, and p-mTOR protein expressions were significantly downregulated in the liver and hypothalamus of CUMS rats. Notably, these alterations were reversed by the SGHWT administration. Furthermore, the metabolomic analysis identified 15 and 5 key differential SPT-associated metabolites in the liver and hypothalamus, respectively. Conclusion: This study suggests that SGHWT ameliorates chronic unpredictable mild stress-induced depression-like behaviors, by the involvement of amino acids, glycerophospholipids, energy metabolism, and the PI3K/AKT/mTOR pathway. Highlights: 1) Shuganheweitang was derived from the TCM herbal formula Sinisan. 2) SGHWT treatment reverses depression-like behaviors in CUMS-induced rats. 3) The mechanism of SGHWT on depression by the liver and hypothalamus metabolomics. 4) SGHWT regulates amino acids, glycerophospholipids, and energy metabolism. 5) SGHWT exerts antidepressant effects through the PI3K/AKT/mTOR pathway.

Brain region-specific roles of brain-derived neurotrophic factor in social stress-induced depressive-like behavior

Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region–specific,particularly involving the corticolimbic system,including the ventral tegmental area,nucleus accumbens,prefrontal cortex,amygdala,and hippocampus.Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology.In this review,we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression.We focused on associated molecular pathways and neural circuits,with special attention to the brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling pathway and the ventral tegmental area–nucleus accumbens dopamine circuit.We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature,severity,and duration of stress,especially in the above-mentioned brain regions of the corticolimbic system.Therefore,BDNF might be a biological indicator regulating stress-related processes in various brain regions.

Resolving Specific Psychological Stressors Can Instantly Reduce or Relieve Chronic Neck Pain and Upper Back Pain: Case Reports

Introduction: The goal of this study was to use a novel approach to pain relief which includes a participant using their mind to reduce or relieve their neck pain in a matter of minutes and taking continuous thermal medical imaging scans during the process to capture any concurrent temperature changes at the location of the self-reported pain. Previous studies using multidisciplinary approaches have shown that it is possible for a person to achieve a moderate reduction in pain over a period of time (typically two or more months). However, in this innovative study, the goal was to demonstrate rapid pain relief (in a matter of minutes) using only the mind. Case report: For this study, six subjects were selected, all of whom were experiencing long-term chronic neck pain. The subjects consisted of five adult females and one adult male. Several of the subjects also had pain that radiated into their upper back region. Each subject participated in one talk therapy session during which the subject’s neck was actively scanned by a thermal imaging (TI) camera that was programmed to take a new thermal image every thirty (30) seconds. The goal of the talk therapy session was to create a strong emotional shift by encouraging the subject to let go of negative emotions and replace buried painful feelings with feelings of positive expectation and optimism. Then, as the subject created this emotional shift, the goal was to observe if this change affected the subject’s self-reported physical pain, as well as noting any visible effects in thermal images. Results: All six subjects reported that they were able to relieve some or all of their pain by the end of the talk therapy session. As they did, there was simultaneously a significant decrease in temperature recorded on the TI images in the corresponding location in their neck and upper back region. This suggested that the pain relief the subjects reported was not merely “mind over matter”, since there were marked physiological changes taking place. Discussion and Conclusion: It’s worth noting that three of the subjects had moments during their talk therapy session where they thought about a specific painful memory that increased their negative emotions. At that moment, their self-reported pain also increased, and simultaneously, the infrared camera detected an increase in temperature in the corresponding location where the subjects reported increased pain. Subsequently, when the subjects were able to change the painful memory and once again move towards feelings of optimism, they reported pain relief, and simultaneously, the TI camera reported a decrease in temperature. Neither this potential outcome nor any other potential outcome was discussed with the subjects before or during the session. This research shows that talk therapy may be used as a new therapeutic option for people not only with neck pain, but possibly other types of pain, and that under certain circumstances, the results can be rapid.

Effect of an Ilex asprella root decoction on the related genes of lipid metabolism from chronic stress and hyperlipidemic fatty liver in rats

Background The gradually increasing changes in a human hyperlipidemic diet along with chronic stress might play an important role in the increased numbers of fatty liver. This study investigated the effects of Ilex asprella root decoction on related genes of lipid metabolism in chronic stress in hyperlipidemic fatty liver in rats. Methods Forty-eight male Wistar rats were randomly divided into four groups： normal control group, model control group, simvastatin group, and Ilex asprella root group. To establish chronic stress and hyperlipidemic fatty liver models in rats, the levels of serum lipids, glucose, liver index, insulin （INS）, insulin resistant （IR） index, adiponectin, superoxide dismutase （SOD）, glutathione peroxidase （GSH-pX）, glutathione （GSH）, liver X receptor （LXR）, and sterol responsive element binding protein （$REBP）-lc in rats were measured. Results When compared to the normal control group, the levels of serum lipids, glucose, liver index, INS, IR index, and GSH in the model control group significantly increased （P 〈0.01）. The protein levels of LXRa and SREBP-lc increased （P 〈0.05）, and the serum adiponectin and the SOD and GSH-pX decreased significantly （P 〈0.01）. When compared to the model control group, the levels of serum lipids, glucose, liver index, INS, IR index, SOD, and GSH-pX in the simvastatin group and Ilex asprella root group increased in varying degrees （P 〈0.01 or 0.05）; the serum adiponectin and GSH decreased （P 〈0.05）, while the protein levels of LXRa and SREBP-lc decreased in varying degrees （P 〈0.01 or 0.05）. When compared to the simvastatin group, the IR index and protein levels of LXRa in the Ilex asprella root group decreased （P 〈0.05）, and the serum adiponectin and SOD increased （P 〈0.05）. Conclusion The Ilex asprella root decoction has some protective effects on regulating the related genes of lipid metabolism caused by chronic stress and hyperlipidemic fatty liver in rats.

Effects of Yulangsan polysaccharide on monoamine neurotransmitters, adenylate cyclase activity and brain-derived neurotrophic factor expression in a mouse model of depression induced by unpredictable chronic mild stress

The present study established a mouse model of depression induced by unpredictable chronic mild stress. The model mice were treated with Yulangsan polysaccharide （YLSPS; 150, 300 and 600 mg/kg） for 21 days, and compared with fluoxetine-treated and normal control groups. Enzyme-linked immunosorbent assay, radioimmunity and immunohistochemical staining showed that following treatment with YLSPS （300 and 600 mg/kg）, monoamine neurotransmitter levels, prefrontal cortex adenylate cyclase activity and hippocampal brain-derived neurotrophic factor expression were significantly elevated, and depression-like behaviors were improved. Open-field and novelty-suppressed feeding tests showed that mouse activity levels were increased and feeding latency was shortened following treatment. Our results indicate that YLSPS inhibits depression by upregulating monoamine neurotransmitters, prefrontal cortex adenylate cyclase activity and hippocampal brain-derived neurotrophic factor expression.

Mechanism of Chronic Stress-induced Reduced Atherosclerotic Medial Area and Increased Plaque Instability in Rabbit Models of Chronic Stress

Background： Chronic stress contributes to increased risks ofatherosclerotic diseases including heart disease, stroke, and transient ischemic attack. However, its underline mechanisms are poorly understood. This study aimed to elucidate the mechanism via which chronic stress exerts its effect on atherosclerosis （AS）. Methods： Fifty male New Zealand white rabbits were used. Aortic balloon-injury model was applied. Both social stress and physical stress methods were adopted to establish chronic stress models. The lumen stenotic degree, intimal and medial areas, maximum fibrous cap thickness, and plaque contents were measured with histological sections. Proteomic methods were applied to detect protein changes in abdominal aortas to identify the specialized mediators. Real-time reverse transcription-polymerase chain reaction was used for further verification and investigation. Results： The stress rabbits exhibited lower body weight, worse fur state, more inactivity behavior, and higher serum cortisol level. Chronic stress was significantly associated with the decreased medial area and increased plaque instability, which was manifested by thinner fibrous caps, larger lipid cores, more macrophages, and new vessels but fewer smooth muscle cells and elastic fibers. After chronic stress, the apoptosis-related genes UBE2K, BAX, b）~S, Ca.v^ase 3, Caspase 9, and P53 were upregulated, and B^Z-2/BAX was down-regulated; the angiogenesis-related genes ANG and VEGF-A were also highly expressed in atherosclerotic arteries. Conclusions： Rabbit models of chronic stress were successfully established by applying both social stress and physical stress for 8 weeks. Chronic stress can reduce AS tunica media and accelerate plaque instability by promoting apoptosis and neovascularization.