Liuwei Dihuang decoction(LW), a classic formula in traditional Chinese medicine(TCM), has been used for nearly one thousand years for various diseases with characteristic features of kidney yin deficiency. LW consists...Liuwei Dihuang decoction(LW), a classic formula in traditional Chinese medicine(TCM), has been used for nearly one thousand years for various diseases with characteristic features of kidney yin deficiency. LW consists of 6herbs including Dihuang[prepared root of Rehmannia glutinosa(Gaertn) DC], Shanyao(rhizome of Dioscorea polystachya Turcz), Shanzhuyu(fruit of Cornus officinalis Siebold Zucc), Mudanpi(root bark of Paeonia × suffruticosa Andrews),Zexie(rhizome of Alisma plantago-aquatica L) and Fuling(scleorotia of Wolfiporia extensa(Peck) Ginns)LW-active fraction combination(LW-AFC) is extracted from LW, it is effective for the treatment of kidney yin deficiency in many animal models. There are 3 fractions in LW-AFC, a polysaccharide fraction(LWB-B), a glycoside fraction(LWD-b) and an oligosaccharide fraction(CA-30). Our previous results indicate that LW-AFC has similar pharmacological effects to LW, modulating the balance of the NIM network. LW-AFC has positive effects in many animal models of kidney deficiency or disturbance of the NIM network. LW-AFC could improve the cognitive ability in Alzheimer′s disease(AD) animal models(APP/PS1, SAMP8), where modulating immune function and balancing the NIM network may play an important role in its cognition improving effects. Our study also showed that LW-AFC had protective effects on stress-induced disturbances of the NIM network. However, the underlying mechanisms remain elusive and need further investigation. OBJECTIVE This study evaluated the effects of LW-AFC and the active fractions(polysaccharide, LWB-B;glycoside, LWD-b;oligosaccharide,CA-30) on corticosterone(Cort)-induced long-term potentiation(LTP) impairment in vivo. METHODS LTP was used to evaluate the synaptic plasticity. LW-AFC was orally administered for seven days. The active fractions were given by either chronic administration(ig, ip, 7 d) or single administration(icv, ig, ip). Cort was injected subcutaneously 1 h before the high-frequency stimulation(HFS) to induce LTP impairment. Moreover, in order to research on the possible effective pathways, an antibiotic cocktail and an immunosuppressant were also used. RESULTS Chronic administration(ig) of LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Single administration(icv, ig, ip) of any of the active fractions had no effect on Cort-induced LTP impairment, while chronic administration(ig, ip) of LWB-B or LWD-b showed positive effects against Cort. Interestingly, CA-30 only showed protective effects via ig administration,and there was little effect when CA-30 was administered ip In addition, when the intestinal microbiota was disrupted by application of the antibiotic cocktail, CA-30 showed little protective effects against Cort. The effects of LW-AFC were also abolished when the immune function was inhibited. In the hippocampal tissue, Cort treatment increased corticosterone and glutamate, and LW-AFC could inhibit the Cort-induced elevation of corticosterone and glutamate;there was little change in D-serine in Cort-treated animals, but LW-AFC could increase the D-serine levels. CONCLUSION LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Their protective effects are unlikely by a direct way, and immune modulation might be the common pathway. CA-30 could protect LTP from impairment via modulating the intestinal microbiota. Decreasing corticosterone and glutamate and increasing D-serine in the Cort-treated animals’ hippocampal tissue might be one of the mechanisms for the neural protective effects of LW-AFC. Further study is needed to understand the underlying mechanisms.展开更多
Background: Bringing free-living animals into captivity subjects them to the stress of both capture and captivity, leading to the alteration of normal physiological processes and behaviors through activation of the hy...Background: Bringing free-living animals into captivity subjects them to the stress of both capture and captivity, leading to the alteration of normal physiological processes and behaviors through activation of the hypothalamic– pituitary–adrenal axis. In free-living birds, although elevated plasma corticosterone (CORT) is an important adaptation regulating physiological and behavioral responses during the process of capture and captivity stress, little information is currently available on the effects of such stress on plasma metabolite levels. Methods: We examined the effects of immediate capture and 24-h captivity on body mass, body condition, plasma CORT, and metabolite levels including glucose (Glu), triglyceride (TG), total cholesterol (TC), uric acid (UA), in breeding Eurasian Tree Sparrows (Passer montanus). Results: CORT and Glu levels were increased significantly by the stress of capture, whereas TC and UA levels decreased. Body mass, body condition declined notably after 24 h in captivity, but CORT, Glu, and UA levels increased. Furthermore, male sparrows had lower TG levels after both capture and captivity than those of females. The relationships between plasma CORT and metabolite levels varied between sexes. Conclusions: Our results revealed that the metabolic status of Eurasian Tree Sparrows could be dramatically altered by capture and captivity. Monitoring the dynamic effects of both capture and captivity on plasma CORT, metabolite levels in a free-living bird contributes to a better understanding of the stress-induced pathways involved in sexdependent energy mobilization.展开更多
Background:Laying hens supplemented with betaine demonstrate activated adrenal steroidogenesis and deposit higher corticosterone(CORT)in the egg yolk.Here we further investigate the effect of maternal betaine on the p...Background:Laying hens supplemented with betaine demonstrate activated adrenal steroidogenesis and deposit higher corticosterone(CORT)in the egg yolk.Here we further investigate the effect of maternal betaine on the plasma CORT concentration and adrenal expression of steroidogenic genes in offspring pullets.Results:Maternal betaine significantly reduced(P<0.05)plasma CORT concentration and the adrenal expression of vimentin that is involved in trafficking cholesterol to the mitochondria for utilization in offspring pullets.Concurrently,voltage-dependent anion channel 1 and steroidogenic acute regulatory protein,the two mitochondrial proteins involved in cholesterol influx,were both down-regulated at m RNA and protein levels.However,enzymes responsible for steroid syntheses,such as cytochrome P450 family 11 subfamily A member 1 and cytochrome P450 family 21 subfamily A member 2,were significantly(P<0.05)up-regulated at m RNA or protein levels in the adrenal gland of pullets derived from betaine-supplemented hens.Furthermore,expression of transcription factors,such as steroidogenic factor-1,sterol regulatory element-binding protein 1 and c AMP response element-binding protein,was significantly(P<0.05)enhanced,together with their downstream target genes,such as 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase,LDL receptor and sterol regulatory element-binding protein cleavage-activating protein.The promoter regions of most steroidogenic genes were significantly(P<0.05)hypomethylated,although methyl transfer enzymes,such as AHCYL,GNMT1 and BHMT were up-regulated.Conclusions:These results indicate that the reduced plasma CORT in betaine-supplemented offspring pullets is linked to suppressed cholesterol trafficking into the mitochondria,despite the activation of cholesterol and corticosteroid synthetic genes associated with promoter hypomethylation.展开更多
Exercise is recommended for the treatment of type 2 diabetes because of its benefits on body weight and glycemic control. Our recent work using the db/db mouse, a model that mimics the phenotype of type 2 diabetes, de...Exercise is recommended for the treatment of type 2 diabetes because of its benefits on body weight and glycemic control. Our recent work using the db/db mouse, a model that mimics the phenotype of type 2 diabetes, demonstrated that forced treadmill training exerted detrimental effects on obesity, hyperglycemia and insulin resistance. We investigated whether this response is explained by increased corticosterone and norepinephrine secretion, measured as urinary byproducts, since these hormones are known to alter glucose homeostasis. Male db/db mice and lean littermates serving as controls, were assigned to sedentary, voluntary wheel, and forced treadmill training groups for a period of 5 weeks. After 5 weeks of treadmill running, db/db mice remained hyperglycemic compared to sedentary db/db mice and were hyperinsulinemic compared to db/db voluntary runners. Urine glucose and corticosterone levels were also highest in db/db treadmill runners compared to all groups. Urine normetanephrine levels, although lower in db/db mice compared to control mice, were increased after treadmill running. Our results indicate that treadmill running leads to perturbations in plasma levels of hormones associated with glucose homeostasis. A greater stress response may be invoked by treadmill training, worsening glycemic control in this model of type 2 diabetes.展开更多
The present study aimed to investigate the effect of relative humidity(RH) at either acute or chronic moderate ambient temperature(Ta) on growth performance and droppings' corticosterone metabolites of broilers.Tw...The present study aimed to investigate the effect of relative humidity(RH) at either acute or chronic moderate ambient temperature(Ta) on growth performance and droppings' corticosterone metabolites of broilers.Two experiments were conducted: effect of RH(35,60 or 85%) on average daily feed intake(ADFI) and droppings' corticosterone metabolites at acute(1 d: 20–26 or 31–20°C,26 or 31°C for 6 h d–1 at 10:00–16:00) moderate Ta(experiment 1) and effect of RH(35,60 or 85%) on growth performance and droppings' corticosterone metabolites at chronic(step-wisely increasing temperature by 3°C every 3 d from 20 to 32°C within 15 d: 20–23–26–29–32°C) moderate Ta(experiment 2).Droppings were collected at the 2,4,6,8,and 22 h after Ta-RH controlled in experiment 1 and at the 2,4,6,and 22 h after Ta controlled to 32°C in experiment 2.The results showed that: 1) In experiment 1,85% RH increased(P<0.05) the droppings' corticosterone metabolites at the 2,6,8,and 22 h and 35% RH increased(P<0.05) it at the 2 and 22 h compared to the 60% RH.Moreover,85% RH further increased(P<0.05) it compared to the 35% RH,however,no difference(P>0.05) was found in ADFI among the three RH groups at acute moderate 26°C; 35 and 85% RH increased(P<0.05) droppings' corticosterone metabolites at the 2,6,8 and 22 h and decreased(P<0.05) ADFI compared to the 60% RH,moreover,85% RH further increased(P<0.05) droppings' corticosterone metabolites and further decreased(P<0.05) ADFI compared to the 35% RH at acute moderate 31°C; and the average of droppings' corticosterone metabolites in the whole period had a negative correlation(P<0.02) with the ADFI.2) In experiment 2,85% RH increased(P<0.01) droppings' corticosterone metabolites only at the 2 h and decreased(P<0.02) ADFI and average daily gain(ADG) compared to the 60% RH,no difference(P>0.05) in droppings' corticosterone metabolites was found between the 35 and 60% RH,however,35% RH decreased(P<0.01) ADG compared to the 60% RH,and the average of droppings' corticosterone metabolites in the whole period also had a negative correlation(P<0.02) with ADFI and ADG.In conclusion,droppings' corticosterone metabolites could be used as a RH stress index and low and high RH,especially high RH,reduced growth performance possibly through inducing RH stress at moderate temperature.展开更多
OBJECTIVE Chronic stress is one of the important factors in the development of many mental and neurological diseases,and cause damage to the central nervous system,affect animal emotions and damage the immune function...OBJECTIVE Chronic stress is one of the important factors in the development of many mental and neurological diseases,and cause damage to the central nervous system,affect animal emotions and damage the immune function of the body.The purpose of this study was to investigate the effects of LW-AFC which extracting from traditional Chinese medicine prescription Liuwei Dihuang decoctionon the anxiety-like behaviorand immune dysfunction abnormalities caused by chronic stress,and whether immune intervention affect the action of LW-AFC.METHODS Male BALB/c mice were subcutaneously injected with corticosterone(25 mg·kg^-1)for 28 d to establish a chronic stress model.Cyclophos⁃phamide(Cy,80 mg·kg^-1)was injected continuously for the initial three days,followed by once a week,LW-AFC(1.6 g·kg^-1)was given continuously for 28 d.Then investigate the emotion changes by open field and elevated plus maze tests,and detected the lymphocyte proliferation,lymphocyte subsets in peripheral blood,microglia and astrocyte expression,and inflammatory cytokines in peripheral blood and brain tissue.RESULTS The mice showed obvious depressive-like behaviorafter 28 d of continuous corticosterone injection.LW-AFC could significantly improve the anxietybehavior induced by corticosterone injection,but LW-AFC could not improve the anxietybehavior of mice by Cy intervention.The expression of glial cells in hippocampus of corticosterone-induced mice showed an upward trend,and the activation of microglia and astrocytes have significantly increase in corticosterone and Cy injected mice.LW-AFC significantly decreased the activation of microglia and astrocytes in corticosterone-induced mice with Cy intervention.This suggested that LW-AFC can reduce the damage of stress on the immune function of central nervous system under immunosuppres⁃sive state.Furthermore,LW-AFC could significantly up-regulate the proliferation of splenic lymphocyte stimulated by LPS and ConA,up-regulate the proportion of CD3+CD8+cells,reduce the proportion of CD4+/CD8+cells,decrease the secretion of inflammatory factors IL-6 and MCP-1 in plasma,and increase the level of anti-inflammatory factor IL-10 in plasma of mice induced by chronic corticosteroneinjection.While LW-AFC could promote the inflammatory factors TNF-α and IL-6in plasma,inhibit the secretion of anti-inflammatory factor IL-10 and inflammatory cytokine MCP-1 in hippocampus of corticosterone-induced mice with Cy intervention.CONCLUSION LW-AFC can improve anxiety-likebehavior induced by chronic stress,the Cy intervention affects the alleviation of anxiety-like behavior by LW-AFC as well as the regulation of immune function.The regulation of immune function might be the main way for LW-AFC to improve the function of central nervous system.展开更多
Background:Corticotropin-releasing hormone(CRH),the major secretagogue of the hypothalamic-pituitary-adrenal(HPA)axis,is intricately intertwined with the clock genes to regulate the circadian rhythm of various body fu...Background:Corticotropin-releasing hormone(CRH),the major secretagogue of the hypothalamic-pituitary-adrenal(HPA)axis,is intricately intertwined with the clock genes to regulate the circadian rhythm of various body functions.N6-methyladenosine(m^(6)A)RNA methylation is involved in the regulation of circadian rhythm,yet it remains unknown whether CRH expression and m^(6)A modification oscillate with the clock genes in chicken hypothalamus and how the circadian rhythms change under chronic stress.Results:Chronic exposure to corticosterone(CORT)eliminated the diurnal patterns of plasma CORT and melatonin levels in the chicken.The circadian rhythms of clock genes in hippocampus,hypothalamus and pituitary are all disturbed to different extent in CORT-treated chickens.The most striking changes occur in hypothalamus in which the diurnal fluctuation of CRH mRNA is flattened,together with mRNA of other feeding-related neuropeptides.Interestingly,hypothalamic m^(6)A level oscillates in an opposite pattern to CRH mRNA,with lowestm^(6)A level after midnight(ZT18)corresponding to the peak of CRH mRNA before dawn(ZT22).CORT diminished the circadian rhythm of m^(6)A methylation with significantly increased level at night.Further site-specific m^(6)A analysis on 3’UTR of CRH mRNA indicates that higher m^(6)A on 3’UTR of CRH mRNA coincides with lower CRH mRNA at night(ZT18 and ZT22).Conclusions:Our results indicate that chronic stress disrupts the circadian rhythms of CRH expression in hypothalamus,leading to dysfunction of HPA axis in the chicken.RNA m^(6)A modification is involved in the regulation of circadian rhythms in chicken hypothalamus under both basal and chronic stress conditions.展开更多
OBJECTIVE Previous studies showed that over activation of NMDA receptors may be a crucial cause of long-term potentiation(LTP)and cognitive impairment induced by stress or corticosterone.However,other studies showed t...OBJECTIVE Previous studies showed that over activation of NMDA receptors may be a crucial cause of long-term potentiation(LTP)and cognitive impairment induced by stress or corticosterone.However,other studies showed that the function of NMDA receptors is insufficient since the NMDA receptors co-agonist D-serine could improve stress-induced cognitive impairment.The purpose of this study is to clarify whether over activation of NMDA receptors or hypofunction of NMDA receptors is involved in hippocampal impairment of LTP by corticosterone and the underlying mechanisms.METHODS Cort was injected subcutaneously 1 h before the high-frequency stimulation(HFS)to induce LTP impairment.NMDA receptor antagonists and agonists were administrated by icv.RESULTS Hippocampal LTP and object location recognition memory were impaired in corticosterone-treated mice.Corticosterone increased the glutamate level in hippocampal tissues,neither NMDA receptors antagonist nor its subtype antagonists alleviated impairment of LTP,while enhancing the function of NMDA receptors by D-serine did alleviate impairment of LTP by corticosterone,suggesting that hypofunction of NMDA receptors might be one of the main reasons for impairment of LTP by corticosterone.Further results showed that the level of D-serine and its precursor L-serine did not change.D-serine release-related protein Na+-independent alanine-serine-cysteine transporter-1(ASC-1)in the cell membrane was decreased and increasing D-serine release by the selective activator of ASC-1 antiporter activity alleviated impairment of LTP by corticosterone.CONCLUSION Taken together,this study demonstrates that hypofunction of NMDA receptors may be involved in impairment of LTP by corticosterone and reduced D-serine release may be an important reason for its hypofunction,which is an important complement to existing mechanisms of corticosterone-induced LTP and cognitive impairment.展开更多
Objective:Xiaobuxintang-2(XBXT-2)has antidepressant effects,but the underlying mechanism is still unclear.In this study,we used the corticosterone-induced depression mouse model to study the antidepressant effect of X...Objective:Xiaobuxintang-2(XBXT-2)has antidepressant effects,but the underlying mechanism is still unclear.In this study,we used the corticosterone-induced depression mouse model to study the antidepressant effect of XBXT-2and its underlying mechanisms.Methods:A mouse model of depression was induced by corticosterone.The mice were divided into 5 groups:(i)control group,(ii)corticosterone group(CORT),(iii)corticosterone+XBXT-2(CORT+XBXT-2)group,(iv)corticosterone+XBXT-2+lentiviral empty group(CORT+XBXT-2+no-load),(v)corticosterone+XBXT-2+lentivirus GSK3βOverexpression group(CORT+XBXT-2+GSK3β).The expression level of GSK3βin the hippocampus was detected by immunoblotting,and the depression status of the mice was evaluated by forced swimming test and tail suspension test.Results:The GSK3βlentivirus induced the high expression of GSK3βin the hippocampus of mice,and the mRNA and protein levels were significantly increased compared with the control group.The immobility time is significantly increased in corticosterone injection-induced depression model mice(CORT group),and XBXT-2 can effectively reduce the immobility time of depression model mice.Overexpression of GFP empty lentivirus did not affect mouse behavior,whereas overexpression of GSK3βsignificantly increased immobility time in depression model mice according to forced swimming and tail suspension experiments.Conclusion:High expression of GSK3βin the hippocampus of mice can inhibit the therapeutic effect of XBXT-2 on the corticosterone-induced depression in mice.展开更多
Social interaction is known to alter behavior and emotional responses to various events. It has been reported that when fear-conditioned animals are put in a fear extinction paradigm with non-fearful conspecifics (pai...Social interaction is known to alter behavior and emotional responses to various events. It has been reported that when fear-conditioned animals are put in a fear extinction paradigm with non-fearful conspecifics (pair-exposure), freezing behavior decreases compared to a solitary situation. However, it remains unclear whether pair-exposure during fear extinction is persistently effective in reducing the freezing response. In this study, we examined whether the effect of pair-exposure could be persistently effective on cued and contextual fear extinction. The reduction of the fear compared to the solitary condition was transiently observed only in the cued fear extinction with no difference in the subsequent recall session. We also found that the correlation between corticosterone levels and freezing behavior during extinction was disrupted in the pair-exposure situation. These results suggest that pair-exposure reduces freezing behavior in cued fear extinction, although this fear response reduction is not persistent. The pair-exposure changed an association between corticosterone levels and freezing behavior during extinction.展开更多
The renin angiotensin system (RAS) participates in inflammatory processes, as either a pro-inflammatory or an anti-inflammatory mediator. Components of RAS, such as angiotensin-converting enzyme (ACE), have been detec...The renin angiotensin system (RAS) participates in inflammatory processes, as either a pro-inflammatory or an anti-inflammatory mediator. Components of RAS, such as angiotensin-converting enzyme (ACE), have been detected locally in the gut epithelium. In addition, the anti-inflammatory steroid, corticosterone, is produced in the gut. Hypertension and aging evoke a low-grade inflammatory process in the vascular endothelium. It is not known whether they induce a similar low-grade inflammation in the intestine and if the low-grade inflammation would evoke an activation of ACE and an elevation of corticosterone production. These two variables were measured in ileum and colon of 9- and 26-week old spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WK) controls. ACE-activity, measured via the formation of histidyl-leucine from hippuryl-histidyl-leucine in the tissue homogenate samples, was similar in the ileum and colon of young animals although the ileum of the young normotensive animals displayed the lowest level. In the old animals, the ACE activity was higher in the ileum than in the colon, especially in normotensive rats. Corticosterone production was measured as corticosterone concentration in the supernatants of ileum or colon after a 90-min ex vivo incubation. Corticosterone production was higher in ileum than in colon in both SHR and WK. No clear evidence was seen for age-dependency or for an effect of hypertension in the measured variables in the intestine. Thus, the putative low-grade inflammation in the intestine in aging or hypertension is not a strong enough stimulus to elevate corticosterone production or activate ACE.展开更多
We have examined acute effects of corticosterone (CORT) on N-methyl-D-aspartate (NMDA) receptor-mediated Ca2+ signals in adult mouse hippocampal slices. We found so far that the 30 min preincubation of CORT induced a ...We have examined acute effects of corticosterone (CORT) on N-methyl-D-aspartate (NMDA) receptor-mediated Ca2+ signals in adult mouse hippocampal slices. We found so far that the 30 min preincubation of CORT induced a signifcant decrease of the peak amplitude of NMDA-induced Ca2+ elevation in the CA1 region. The membrane non-permeable bovine serum albumin-conjugated CORT also induced a similar effect in the CA1 region. Therefore the acute CORT effects should be induced via putative surface CORT receptors. A possible candidate is a classical intracellular glucocorticoid receptor (GR). To confirm this speculation, we here examined the effects of dexamethasone (DEX: an agonist of GR) and CORT with RU38486 (an antagonist of GR) on NMDA-induced Ca2+ signals. As a result, DEX induced a similar effect to the suppressive CORT effect in the CA1 region, and RU38486 inhibited the suppressive CORT effect. These results indicate that the surface CORT receptor should be GR bound to plasma mem- brane.展开更多
Atractylenolide Ⅲ(ATL-Ⅲ), a sesquiterpene compound isolated from Rhizoma Atractylodis Macrocephalae, has revealed a number of pharmacological properties including anti-inflammatory, anti-cancer activity, and neuropr...Atractylenolide Ⅲ(ATL-Ⅲ), a sesquiterpene compound isolated from Rhizoma Atractylodis Macrocephalae, has revealed a number of pharmacological properties including anti-inflammatory, anti-cancer activity, and neuroprotective effect. This study aimed to evaluate the cytoprotective efficiency and potential mechanisms of ATL-Ⅲ on corticosterone injured rat phaeochromocytoma(PC12) cells. Our results demonstrate that ATL-Ⅲ increases cell viability and reduces the release of lactate dehydrogenase(LDH). The results suggest that ATL-Ⅲ protects PC12 cells from corticosterone-induced injury by inhibiting the intracellular Ca^(2+) overloading, inhibiting the mitochondrial apoptotic pathway and modulating the MAPK/NF-κB inflammatory pathways. These findings provide a novel insight into the molecular mechanism by which ATL-Ⅲ protected the PC12 cells against corticosterone-induced injury for the first time. Our results provide the evidence that ATL-Ⅲ may serve as a therapeutic agent in the treatment of depression.展开更多
Nicotinicα4β2 receptor antagonists have drawn increasing attention in the development of new antidepressants.In this study,we aimed to investigate the protective effect of VMY-2-95,the new selective antagonist ofα4...Nicotinicα4β2 receptor antagonists have drawn increasing attention in the development of new antidepressants.In this study,we aimed to investigate the protective effect of VMY-2-95,the new selective antagonist ofα4β2 nicotinic acetylcholine receptor(nAChR)on corticosterone(CORT)injured mice and cellular models.Fluoxetine was applied as a positive control,and the effects of VMY-2-95 were investigated with three different doses or concentrations(1,3,10 mg/kg in mice,and 0.003,0.03,0.1μmol/L in cells).As a result,VMY-2-95 showed significant antidepressant-like effects in the CORT injured mice by improving neuromorphic function,promoting hippocampal nerve proliferation,and regulating the contents of monoamine transmitters.Meanwhile,VMY-2-95 exhibited protective effects on cell viability,cell oxidant,cell apoptosis,and mitochondrial energy metabolism on corticosterone-impaired SH-SY5 Y cells.Also,the PKA-CREB-BDNF signaling pathway was up-regulated by VMY-2-95 both in vitro and in vivo,and pathway blockers were also combined with VMY-2-95 to verify the effects furtherly.Therefore,we preliminarily proved that VMY-2-95 had protective effects in depressed mice and SH-SY5 Y cells against injuries induced by corticosterone.This work indicated that the application of VMY-2-95 is a potential pharmacological solution for depression.This study also supported the development ofα4β2 nAChR antagonists towards neuropsychiatric dysfunctions.展开更多
When vertebrates face stressful events,the hypothalamic–pituitary–adrenal(HPA)axis is activated,generating a rapid increase in circulating glucocorticoid(GC)stress hormones followed by a return to baseline levels.Ho...When vertebrates face stressful events,the hypothalamic–pituitary–adrenal(HPA)axis is activated,generating a rapid increase in circulating glucocorticoid(GC)stress hormones followed by a return to baseline levels.However,repeated activation of HPA axis may lead to increase in oxidative stress.One target of oxidative stress is telomeres,nucleoprotein complexes at the end of chromosomes that shorten at each cell division.The susceptibility of telomeres to oxidizing molecules has led to the hypothesis that increased GC levels boost telomere shortening,but studies on this link are scanty.We studied if,in barn swallows Hirundo rustica,changes in adult erythrocyte telomere length between 2 consecutive breeding seasons are related to corticosterone(CORT)(the main avian GC)stress response induced by a standard capture-restraint protocol.Within-individual telomere length did not significantly change between consecutive breeding seasons.Second-year individuals showed the highest increase in circulating CORT concentrations following restraint.Moreover,we found a decline in female stress response along the breeding season.In addition,telomere shortening covaried with the stress response:a delayed activation of the negative feedback loop terminating the stress response was associated with greater telomere attrition.Hence,among-individual variation in stress response may affect telomere dynamics.展开更多
Objective: [WT5BZ]To investigate the effects of Tiaojining granule (调激宁, TJNG) combined with corticosterone (CS) in treating infantile primary nephrotic syndrome (IPNS). Methods: [WT5BZ]Sixty inpatients with IPNS w...Objective: [WT5BZ]To investigate the effects of Tiaojining granule (调激宁, TJNG) combined with corticosterone (CS) in treating infantile primary nephrotic syndrome (IPNS). Methods: [WT5BZ]Sixty inpatients with IPNS were divided into two groups, 30 cases as the treated group treated by TJNG combined with CS, and the other 30 cases as the control group treated by CS alone for 8 weeks. The changes of urinary protein, serum albumin, blood cholesterol, platelet and blood pressure before and after treatment were observed. Results: [WT5BZ]The total effective rate of the treated group was significantly higher than that of the control group ( P <0.01). The time for urinary protein disappearance of the treated group was significantly shorter than that of the control group ( P <0.05). In preventing hypertension, lowering lipidemia and platelets, TJNG were obviously better than CS used in the control group ( P <0.01). Conclusion: [WT5BZ]TJNG could enhance the therapeutic effects of CS on IPNS and safely and effectively reduce the side effects of CS. [WT5FZ]展开更多
Previous studies have shown that models of depression exhibit structural and functional changes to the neurovascular unit. Thus, we hypothesized that diabetes-related depression might be associated with damage to the ...Previous studies have shown that models of depression exhibit structural and functional changes to the neurovascular unit. Thus, we hypothesized that diabetes-related depression might be associated with damage to the hippocampal neurovascular unit. To test this hypothesis, neurons, astrocytes and endothelial cells were isolated from the brain tissues of rat embryos and newborn rats. Hippocampal neurovascular unit co-cultures were produced using the Transwell chamber co-culture system. A model of diabetes-related depression was generated by adding 150 mM glucose and 200 μM corticosterone to the culture system and compared with the neuron + astrocyte and astrocyte + endothelial cell co-culture systems. Western blot assay was used to measure levels of structural proteins in the hippocampal neurovascular unit co-culture system. Levels of basic fibroblast growth factor, angiogenic factor 1, glial cell line–derived neurotrophic factor, transforming growth factor β1, leukemia inhibitory factor and 5-hydroxytryptamine in the hippocampal neurovascular unit co-culture system were measured by enzyme-linked immunosorbent assay. Flow cytometry and terminal deoxynucleotidyl transferase(TdT)-mediated dUTP nick end labeling staining was used to assess neuronal apoptosis in the hippocampal neurovascular unit. The neurovascular unit triple cell co-culture system had better barrier function and higher levels of structural and secretory proteins than the double cell co-culture systems. In comparison, in the model of diabetes-related depression, the neurovascular unit was damaged with decreased barrier function, poor structural integrity and impaired secretory function. Moreover, neuronal apoptosis was markedly increased, and 5-hydroxytryptamine levels were reduced. These results suggest that diabetes-related depression is associated with structural and functional damage to the neurovascular unit. Our findings provide a foundation for further studies on the pathogenesis of diabetes-related depression.展开更多
The progress of modern medicine would be impossible without the use of general anesthetics(GAs).Despite advancements in refining anesthesia approaches,the effects of GAs are not fully reversible upon GA withdrawal.Neu...The progress of modern medicine would be impossible without the use of general anesthetics(GAs).Despite advancements in refining anesthesia approaches,the effects of GAs are not fully reversible upon GA withdrawal.Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly.Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research,but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects.The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents,which are far more extensively studied than any other species.Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated.Specifically,we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities(somatic effects),but also epigenetic reprogramming of germ cells(germ cell effects).The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring,who may be affected even at levels of anesthesia that are not harmful to the exposed parents.The large number of patients who require general anesthesia,the even larger number of their future unexposed offspring whose health may be affected,and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs.In this mini review,we discuss emerging experimental findings on neuroendocrine,epigenetic,and intergenerational effects of GAs.展开更多
文摘Liuwei Dihuang decoction(LW), a classic formula in traditional Chinese medicine(TCM), has been used for nearly one thousand years for various diseases with characteristic features of kidney yin deficiency. LW consists of 6herbs including Dihuang[prepared root of Rehmannia glutinosa(Gaertn) DC], Shanyao(rhizome of Dioscorea polystachya Turcz), Shanzhuyu(fruit of Cornus officinalis Siebold Zucc), Mudanpi(root bark of Paeonia × suffruticosa Andrews),Zexie(rhizome of Alisma plantago-aquatica L) and Fuling(scleorotia of Wolfiporia extensa(Peck) Ginns)LW-active fraction combination(LW-AFC) is extracted from LW, it is effective for the treatment of kidney yin deficiency in many animal models. There are 3 fractions in LW-AFC, a polysaccharide fraction(LWB-B), a glycoside fraction(LWD-b) and an oligosaccharide fraction(CA-30). Our previous results indicate that LW-AFC has similar pharmacological effects to LW, modulating the balance of the NIM network. LW-AFC has positive effects in many animal models of kidney deficiency or disturbance of the NIM network. LW-AFC could improve the cognitive ability in Alzheimer′s disease(AD) animal models(APP/PS1, SAMP8), where modulating immune function and balancing the NIM network may play an important role in its cognition improving effects. Our study also showed that LW-AFC had protective effects on stress-induced disturbances of the NIM network. However, the underlying mechanisms remain elusive and need further investigation. OBJECTIVE This study evaluated the effects of LW-AFC and the active fractions(polysaccharide, LWB-B;glycoside, LWD-b;oligosaccharide,CA-30) on corticosterone(Cort)-induced long-term potentiation(LTP) impairment in vivo. METHODS LTP was used to evaluate the synaptic plasticity. LW-AFC was orally administered for seven days. The active fractions were given by either chronic administration(ig, ip, 7 d) or single administration(icv, ig, ip). Cort was injected subcutaneously 1 h before the high-frequency stimulation(HFS) to induce LTP impairment. Moreover, in order to research on the possible effective pathways, an antibiotic cocktail and an immunosuppressant were also used. RESULTS Chronic administration(ig) of LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Single administration(icv, ig, ip) of any of the active fractions had no effect on Cort-induced LTP impairment, while chronic administration(ig, ip) of LWB-B or LWD-b showed positive effects against Cort. Interestingly, CA-30 only showed protective effects via ig administration,and there was little effect when CA-30 was administered ip In addition, when the intestinal microbiota was disrupted by application of the antibiotic cocktail, CA-30 showed little protective effects against Cort. The effects of LW-AFC were also abolished when the immune function was inhibited. In the hippocampal tissue, Cort treatment increased corticosterone and glutamate, and LW-AFC could inhibit the Cort-induced elevation of corticosterone and glutamate;there was little change in D-serine in Cort-treated animals, but LW-AFC could increase the D-serine levels. CONCLUSION LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Their protective effects are unlikely by a direct way, and immune modulation might be the common pathway. CA-30 could protect LTP from impairment via modulating the intestinal microbiota. Decreasing corticosterone and glutamate and increasing D-serine in the Cort-treated animals’ hippocampal tissue might be one of the mechanisms for the neural protective effects of LW-AFC. Further study is needed to understand the underlying mechanisms.
基金supported by the National Natural Science Foundation of China(NSFC,31672292)the Natural Science Foundation of Hebei Province(C2017205059)+1 种基金the foundation of China Scholarship Council(201408130068) to D.Lithe NSFC(31770445)to Y.Wu,the NSFC(31372201)to X.Gao
文摘Background: Bringing free-living animals into captivity subjects them to the stress of both capture and captivity, leading to the alteration of normal physiological processes and behaviors through activation of the hypothalamic– pituitary–adrenal axis. In free-living birds, although elevated plasma corticosterone (CORT) is an important adaptation regulating physiological and behavioral responses during the process of capture and captivity stress, little information is currently available on the effects of such stress on plasma metabolite levels. Methods: We examined the effects of immediate capture and 24-h captivity on body mass, body condition, plasma CORT, and metabolite levels including glucose (Glu), triglyceride (TG), total cholesterol (TC), uric acid (UA), in breeding Eurasian Tree Sparrows (Passer montanus). Results: CORT and Glu levels were increased significantly by the stress of capture, whereas TC and UA levels decreased. Body mass, body condition declined notably after 24 h in captivity, but CORT, Glu, and UA levels increased. Furthermore, male sparrows had lower TG levels after both capture and captivity than those of females. The relationships between plasma CORT and metabolite levels varied between sexes. Conclusions: Our results revealed that the metabolic status of Eurasian Tree Sparrows could be dramatically altered by capture and captivity. Monitoring the dynamic effects of both capture and captivity on plasma CORT, metabolite levels in a free-living bird contributes to a better understanding of the stress-induced pathways involved in sexdependent energy mobilization.
基金supported by the National Natural Science Foundation of China(31672512)the Fundamental Research Funds for the Central Universities(KYZ201212)+1 种基金the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)Jiangsu Collaborative Innovation Centre of Meat Production and Processing,Quality and Safety Control.
文摘Background:Laying hens supplemented with betaine demonstrate activated adrenal steroidogenesis and deposit higher corticosterone(CORT)in the egg yolk.Here we further investigate the effect of maternal betaine on the plasma CORT concentration and adrenal expression of steroidogenic genes in offspring pullets.Results:Maternal betaine significantly reduced(P<0.05)plasma CORT concentration and the adrenal expression of vimentin that is involved in trafficking cholesterol to the mitochondria for utilization in offspring pullets.Concurrently,voltage-dependent anion channel 1 and steroidogenic acute regulatory protein,the two mitochondrial proteins involved in cholesterol influx,were both down-regulated at m RNA and protein levels.However,enzymes responsible for steroid syntheses,such as cytochrome P450 family 11 subfamily A member 1 and cytochrome P450 family 21 subfamily A member 2,were significantly(P<0.05)up-regulated at m RNA or protein levels in the adrenal gland of pullets derived from betaine-supplemented hens.Furthermore,expression of transcription factors,such as steroidogenic factor-1,sterol regulatory element-binding protein 1 and c AMP response element-binding protein,was significantly(P<0.05)enhanced,together with their downstream target genes,such as 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase,LDL receptor and sterol regulatory element-binding protein cleavage-activating protein.The promoter regions of most steroidogenic genes were significantly(P<0.05)hypomethylated,although methyl transfer enzymes,such as AHCYL,GNMT1 and BHMT were up-regulated.Conclusions:These results indicate that the reduced plasma CORT in betaine-supplemented offspring pullets is linked to suppressed cholesterol trafficking into the mitochondria,despite the activation of cholesterol and corticosteroid synthetic genes associated with promoter hypomethylation.
文摘Exercise is recommended for the treatment of type 2 diabetes because of its benefits on body weight and glycemic control. Our recent work using the db/db mouse, a model that mimics the phenotype of type 2 diabetes, demonstrated that forced treadmill training exerted detrimental effects on obesity, hyperglycemia and insulin resistance. We investigated whether this response is explained by increased corticosterone and norepinephrine secretion, measured as urinary byproducts, since these hormones are known to alter glucose homeostasis. Male db/db mice and lean littermates serving as controls, were assigned to sedentary, voluntary wheel, and forced treadmill training groups for a period of 5 weeks. After 5 weeks of treadmill running, db/db mice remained hyperglycemic compared to sedentary db/db mice and were hyperinsulinemic compared to db/db voluntary runners. Urine glucose and corticosterone levels were also highest in db/db treadmill runners compared to all groups. Urine normetanephrine levels, although lower in db/db mice compared to control mice, were increased after treadmill running. Our results indicate that treadmill running leads to perturbations in plasma levels of hormones associated with glucose homeostasis. A greater stress response may be invoked by treadmill training, worsening glycemic control in this model of type 2 diabetes.
基金funded by the Key National Research and Development Program Project of China (2016YFD0500509)the National Science and Technology Support Plan Project of China (2012BAD39B02)the Chinese Academy of Agricultural Science and Technology Innovation Team Project (ASTIPIAS07)
文摘The present study aimed to investigate the effect of relative humidity(RH) at either acute or chronic moderate ambient temperature(Ta) on growth performance and droppings' corticosterone metabolites of broilers.Two experiments were conducted: effect of RH(35,60 or 85%) on average daily feed intake(ADFI) and droppings' corticosterone metabolites at acute(1 d: 20–26 or 31–20°C,26 or 31°C for 6 h d–1 at 10:00–16:00) moderate Ta(experiment 1) and effect of RH(35,60 or 85%) on growth performance and droppings' corticosterone metabolites at chronic(step-wisely increasing temperature by 3°C every 3 d from 20 to 32°C within 15 d: 20–23–26–29–32°C) moderate Ta(experiment 2).Droppings were collected at the 2,4,6,8,and 22 h after Ta-RH controlled in experiment 1 and at the 2,4,6,and 22 h after Ta controlled to 32°C in experiment 2.The results showed that: 1) In experiment 1,85% RH increased(P<0.05) the droppings' corticosterone metabolites at the 2,6,8,and 22 h and 35% RH increased(P<0.05) it at the 2 and 22 h compared to the 60% RH.Moreover,85% RH further increased(P<0.05) it compared to the 35% RH,however,no difference(P>0.05) was found in ADFI among the three RH groups at acute moderate 26°C; 35 and 85% RH increased(P<0.05) droppings' corticosterone metabolites at the 2,6,8 and 22 h and decreased(P<0.05) ADFI compared to the 60% RH,moreover,85% RH further increased(P<0.05) droppings' corticosterone metabolites and further decreased(P<0.05) ADFI compared to the 35% RH at acute moderate 31°C; and the average of droppings' corticosterone metabolites in the whole period had a negative correlation(P<0.02) with the ADFI.2) In experiment 2,85% RH increased(P<0.01) droppings' corticosterone metabolites only at the 2 h and decreased(P<0.02) ADFI and average daily gain(ADG) compared to the 60% RH,no difference(P>0.05) in droppings' corticosterone metabolites was found between the 35 and 60% RH,however,35% RH decreased(P<0.01) ADG compared to the 60% RH,and the average of droppings' corticosterone metabolites in the whole period also had a negative correlation(P<0.02) with ADFI and ADG.In conclusion,droppings' corticosterone metabolites could be used as a RH stress index and low and high RH,especially high RH,reduced growth performance possibly through inducing RH stress at moderate temperature.
基金National Natural Science Foundation of China(81473191)National Key Research and Development Program(2016YFC1306300)
文摘OBJECTIVE Chronic stress is one of the important factors in the development of many mental and neurological diseases,and cause damage to the central nervous system,affect animal emotions and damage the immune function of the body.The purpose of this study was to investigate the effects of LW-AFC which extracting from traditional Chinese medicine prescription Liuwei Dihuang decoctionon the anxiety-like behaviorand immune dysfunction abnormalities caused by chronic stress,and whether immune intervention affect the action of LW-AFC.METHODS Male BALB/c mice were subcutaneously injected with corticosterone(25 mg·kg^-1)for 28 d to establish a chronic stress model.Cyclophos⁃phamide(Cy,80 mg·kg^-1)was injected continuously for the initial three days,followed by once a week,LW-AFC(1.6 g·kg^-1)was given continuously for 28 d.Then investigate the emotion changes by open field and elevated plus maze tests,and detected the lymphocyte proliferation,lymphocyte subsets in peripheral blood,microglia and astrocyte expression,and inflammatory cytokines in peripheral blood and brain tissue.RESULTS The mice showed obvious depressive-like behaviorafter 28 d of continuous corticosterone injection.LW-AFC could significantly improve the anxietybehavior induced by corticosterone injection,but LW-AFC could not improve the anxietybehavior of mice by Cy intervention.The expression of glial cells in hippocampus of corticosterone-induced mice showed an upward trend,and the activation of microglia and astrocytes have significantly increase in corticosterone and Cy injected mice.LW-AFC significantly decreased the activation of microglia and astrocytes in corticosterone-induced mice with Cy intervention.This suggested that LW-AFC can reduce the damage of stress on the immune function of central nervous system under immunosuppres⁃sive state.Furthermore,LW-AFC could significantly up-regulate the proliferation of splenic lymphocyte stimulated by LPS and ConA,up-regulate the proportion of CD3+CD8+cells,reduce the proportion of CD4+/CD8+cells,decrease the secretion of inflammatory factors IL-6 and MCP-1 in plasma,and increase the level of anti-inflammatory factor IL-10 in plasma of mice induced by chronic corticosteroneinjection.While LW-AFC could promote the inflammatory factors TNF-α and IL-6in plasma,inhibit the secretion of anti-inflammatory factor IL-10 and inflammatory cytokine MCP-1 in hippocampus of corticosterone-induced mice with Cy intervention.CONCLUSION LW-AFC can improve anxiety-likebehavior induced by chronic stress,the Cy intervention affects the alleviation of anxiety-like behavior by LW-AFC as well as the regulation of immune function.The regulation of immune function might be the main way for LW-AFC to improve the function of central nervous system.
基金supported by the National Natural Science Foundation of China (31972638)the National Key Research and Development Program of China (2016YFD0500502)+2 种基金the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)the Postgraduate Research&Practice Innovation Program of Jiangsu Province (KYCX18_0716)Jiangsu Collaborative Innovation Center of Meat Production and Processing,Quality,Safety Control
文摘Background:Corticotropin-releasing hormone(CRH),the major secretagogue of the hypothalamic-pituitary-adrenal(HPA)axis,is intricately intertwined with the clock genes to regulate the circadian rhythm of various body functions.N6-methyladenosine(m^(6)A)RNA methylation is involved in the regulation of circadian rhythm,yet it remains unknown whether CRH expression and m^(6)A modification oscillate with the clock genes in chicken hypothalamus and how the circadian rhythms change under chronic stress.Results:Chronic exposure to corticosterone(CORT)eliminated the diurnal patterns of plasma CORT and melatonin levels in the chicken.The circadian rhythms of clock genes in hippocampus,hypothalamus and pituitary are all disturbed to different extent in CORT-treated chickens.The most striking changes occur in hypothalamus in which the diurnal fluctuation of CRH mRNA is flattened,together with mRNA of other feeding-related neuropeptides.Interestingly,hypothalamic m^(6)A level oscillates in an opposite pattern to CRH mRNA,with lowestm^(6)A level after midnight(ZT18)corresponding to the peak of CRH mRNA before dawn(ZT22).CORT diminished the circadian rhythm of m^(6)A methylation with significantly increased level at night.Further site-specific m^(6)A analysis on 3’UTR of CRH mRNA indicates that higher m^(6)A on 3’UTR of CRH mRNA coincides with lower CRH mRNA at night(ZT18 and ZT22).Conclusions:Our results indicate that chronic stress disrupts the circadian rhythms of CRH expression in hypothalamus,leading to dysfunction of HPA axis in the chicken.RNA m^(6)A modification is involved in the regulation of circadian rhythms in chicken hypothalamus under both basal and chronic stress conditions.
文摘OBJECTIVE Previous studies showed that over activation of NMDA receptors may be a crucial cause of long-term potentiation(LTP)and cognitive impairment induced by stress or corticosterone.However,other studies showed that the function of NMDA receptors is insufficient since the NMDA receptors co-agonist D-serine could improve stress-induced cognitive impairment.The purpose of this study is to clarify whether over activation of NMDA receptors or hypofunction of NMDA receptors is involved in hippocampal impairment of LTP by corticosterone and the underlying mechanisms.METHODS Cort was injected subcutaneously 1 h before the high-frequency stimulation(HFS)to induce LTP impairment.NMDA receptor antagonists and agonists were administrated by icv.RESULTS Hippocampal LTP and object location recognition memory were impaired in corticosterone-treated mice.Corticosterone increased the glutamate level in hippocampal tissues,neither NMDA receptors antagonist nor its subtype antagonists alleviated impairment of LTP,while enhancing the function of NMDA receptors by D-serine did alleviate impairment of LTP by corticosterone,suggesting that hypofunction of NMDA receptors might be one of the main reasons for impairment of LTP by corticosterone.Further results showed that the level of D-serine and its precursor L-serine did not change.D-serine release-related protein Na+-independent alanine-serine-cysteine transporter-1(ASC-1)in the cell membrane was decreased and increasing D-serine release by the selective activator of ASC-1 antiporter activity alleviated impairment of LTP by corticosterone.CONCLUSION Taken together,this study demonstrates that hypofunction of NMDA receptors may be involved in impairment of LTP by corticosterone and reduced D-serine release may be an important reason for its hypofunction,which is an important complement to existing mechanisms of corticosterone-induced LTP and cognitive impairment.
文摘Objective:Xiaobuxintang-2(XBXT-2)has antidepressant effects,but the underlying mechanism is still unclear.In this study,we used the corticosterone-induced depression mouse model to study the antidepressant effect of XBXT-2and its underlying mechanisms.Methods:A mouse model of depression was induced by corticosterone.The mice were divided into 5 groups:(i)control group,(ii)corticosterone group(CORT),(iii)corticosterone+XBXT-2(CORT+XBXT-2)group,(iv)corticosterone+XBXT-2+lentiviral empty group(CORT+XBXT-2+no-load),(v)corticosterone+XBXT-2+lentivirus GSK3βOverexpression group(CORT+XBXT-2+GSK3β).The expression level of GSK3βin the hippocampus was detected by immunoblotting,and the depression status of the mice was evaluated by forced swimming test and tail suspension test.Results:The GSK3βlentivirus induced the high expression of GSK3βin the hippocampus of mice,and the mRNA and protein levels were significantly increased compared with the control group.The immobility time is significantly increased in corticosterone injection-induced depression model mice(CORT group),and XBXT-2 can effectively reduce the immobility time of depression model mice.Overexpression of GFP empty lentivirus did not affect mouse behavior,whereas overexpression of GSK3βsignificantly increased immobility time in depression model mice according to forced swimming and tail suspension experiments.Conclusion:High expression of GSK3βin the hippocampus of mice can inhibit the therapeutic effect of XBXT-2 on the corticosterone-induced depression in mice.
文摘Social interaction is known to alter behavior and emotional responses to various events. It has been reported that when fear-conditioned animals are put in a fear extinction paradigm with non-fearful conspecifics (pair-exposure), freezing behavior decreases compared to a solitary situation. However, it remains unclear whether pair-exposure during fear extinction is persistently effective in reducing the freezing response. In this study, we examined whether the effect of pair-exposure could be persistently effective on cued and contextual fear extinction. The reduction of the fear compared to the solitary condition was transiently observed only in the cued fear extinction with no difference in the subsequent recall session. We also found that the correlation between corticosterone levels and freezing behavior during extinction was disrupted in the pair-exposure situation. These results suggest that pair-exposure reduces freezing behavior in cued fear extinction, although this fear response reduction is not persistent. The pair-exposure changed an association between corticosterone levels and freezing behavior during extinction.
文摘The renin angiotensin system (RAS) participates in inflammatory processes, as either a pro-inflammatory or an anti-inflammatory mediator. Components of RAS, such as angiotensin-converting enzyme (ACE), have been detected locally in the gut epithelium. In addition, the anti-inflammatory steroid, corticosterone, is produced in the gut. Hypertension and aging evoke a low-grade inflammatory process in the vascular endothelium. It is not known whether they induce a similar low-grade inflammation in the intestine and if the low-grade inflammation would evoke an activation of ACE and an elevation of corticosterone production. These two variables were measured in ileum and colon of 9- and 26-week old spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WK) controls. ACE-activity, measured via the formation of histidyl-leucine from hippuryl-histidyl-leucine in the tissue homogenate samples, was similar in the ileum and colon of young animals although the ileum of the young normotensive animals displayed the lowest level. In the old animals, the ACE activity was higher in the ileum than in the colon, especially in normotensive rats. Corticosterone production was measured as corticosterone concentration in the supernatants of ileum or colon after a 90-min ex vivo incubation. Corticosterone production was higher in ileum than in colon in both SHR and WK. No clear evidence was seen for age-dependency or for an effect of hypertension in the measured variables in the intestine. Thus, the putative low-grade inflammation in the intestine in aging or hypertension is not a strong enough stimulus to elevate corticosterone production or activate ACE.
文摘We have examined acute effects of corticosterone (CORT) on N-methyl-D-aspartate (NMDA) receptor-mediated Ca2+ signals in adult mouse hippocampal slices. We found so far that the 30 min preincubation of CORT induced a signifcant decrease of the peak amplitude of NMDA-induced Ca2+ elevation in the CA1 region. The membrane non-permeable bovine serum albumin-conjugated CORT also induced a similar effect in the CA1 region. Therefore the acute CORT effects should be induced via putative surface CORT receptors. A possible candidate is a classical intracellular glucocorticoid receptor (GR). To confirm this speculation, we here examined the effects of dexamethasone (DEX: an agonist of GR) and CORT with RU38486 (an antagonist of GR) on NMDA-induced Ca2+ signals. As a result, DEX induced a similar effect to the suppressive CORT effect in the CA1 region, and RU38486 inhibited the suppressive CORT effect. These results indicate that the surface CORT receptor should be GR bound to plasma mem- brane.
基金supported by the National Nature Science Foundation of China(No.81673572)the Applied basic research project of Shanxi Province(No.201601D021164)+2 种基金the Innovation project of higher education institutions in Shanxi Province(No.2016120)the Construction of the Science and Technology Basic Condition Platform of Shanxi Province(No.2014091022)the Program of Science and Technology of Shanxi Province(No.20140313008-14)
文摘Atractylenolide Ⅲ(ATL-Ⅲ), a sesquiterpene compound isolated from Rhizoma Atractylodis Macrocephalae, has revealed a number of pharmacological properties including anti-inflammatory, anti-cancer activity, and neuroprotective effect. This study aimed to evaluate the cytoprotective efficiency and potential mechanisms of ATL-Ⅲ on corticosterone injured rat phaeochromocytoma(PC12) cells. Our results demonstrate that ATL-Ⅲ increases cell viability and reduces the release of lactate dehydrogenase(LDH). The results suggest that ATL-Ⅲ protects PC12 cells from corticosterone-induced injury by inhibiting the intracellular Ca^(2+) overloading, inhibiting the mitochondrial apoptotic pathway and modulating the MAPK/NF-κB inflammatory pathways. These findings provide a novel insight into the molecular mechanism by which ATL-Ⅲ protected the PC12 cells against corticosterone-induced injury for the first time. Our results provide the evidence that ATL-Ⅲ may serve as a therapeutic agent in the treatment of depression.
基金supported by the National Natural Science Foundation of China(No.81603100)the Drug Innovation Major Project(2018ZX09711001-003-005,2018ZX09711001-012,China)+1 种基金CAMS Innovation Fund for Medical Sciences(2017-I2M1-010,China)Peking Union Medical College Graduate Innovation Fund Project(2017-1007-11,China)
文摘Nicotinicα4β2 receptor antagonists have drawn increasing attention in the development of new antidepressants.In this study,we aimed to investigate the protective effect of VMY-2-95,the new selective antagonist ofα4β2 nicotinic acetylcholine receptor(nAChR)on corticosterone(CORT)injured mice and cellular models.Fluoxetine was applied as a positive control,and the effects of VMY-2-95 were investigated with three different doses or concentrations(1,3,10 mg/kg in mice,and 0.003,0.03,0.1μmol/L in cells).As a result,VMY-2-95 showed significant antidepressant-like effects in the CORT injured mice by improving neuromorphic function,promoting hippocampal nerve proliferation,and regulating the contents of monoamine transmitters.Meanwhile,VMY-2-95 exhibited protective effects on cell viability,cell oxidant,cell apoptosis,and mitochondrial energy metabolism on corticosterone-impaired SH-SY5 Y cells.Also,the PKA-CREB-BDNF signaling pathway was up-regulated by VMY-2-95 both in vitro and in vivo,and pathway blockers were also combined with VMY-2-95 to verify the effects furtherly.Therefore,we preliminarily proved that VMY-2-95 had protective effects in depressed mice and SH-SY5 Y cells against injuries induced by corticosterone.This work indicated that the application of VMY-2-95 is a potential pharmacological solution for depression.This study also supported the development ofα4β2 nAChR antagonists towards neuropsychiatric dysfunctions.
文摘When vertebrates face stressful events,the hypothalamic–pituitary–adrenal(HPA)axis is activated,generating a rapid increase in circulating glucocorticoid(GC)stress hormones followed by a return to baseline levels.However,repeated activation of HPA axis may lead to increase in oxidative stress.One target of oxidative stress is telomeres,nucleoprotein complexes at the end of chromosomes that shorten at each cell division.The susceptibility of telomeres to oxidizing molecules has led to the hypothesis that increased GC levels boost telomere shortening,but studies on this link are scanty.We studied if,in barn swallows Hirundo rustica,changes in adult erythrocyte telomere length between 2 consecutive breeding seasons are related to corticosterone(CORT)(the main avian GC)stress response induced by a standard capture-restraint protocol.Within-individual telomere length did not significantly change between consecutive breeding seasons.Second-year individuals showed the highest increase in circulating CORT concentrations following restraint.Moreover,we found a decline in female stress response along the breeding season.In addition,telomere shortening covaried with the stress response:a delayed activation of the negative feedback loop terminating the stress response was associated with greater telomere attrition.Hence,among-individual variation in stress response may affect telomere dynamics.
文摘Objective: [WT5BZ]To investigate the effects of Tiaojining granule (调激宁, TJNG) combined with corticosterone (CS) in treating infantile primary nephrotic syndrome (IPNS). Methods: [WT5BZ]Sixty inpatients with IPNS were divided into two groups, 30 cases as the treated group treated by TJNG combined with CS, and the other 30 cases as the control group treated by CS alone for 8 weeks. The changes of urinary protein, serum albumin, blood cholesterol, platelet and blood pressure before and after treatment were observed. Results: [WT5BZ]The total effective rate of the treated group was significantly higher than that of the control group ( P <0.01). The time for urinary protein disappearance of the treated group was significantly shorter than that of the control group ( P <0.05). In preventing hypertension, lowering lipidemia and platelets, TJNG were obviously better than CS used in the control group ( P <0.01). Conclusion: [WT5BZ]TJNG could enhance the therapeutic effects of CS on IPNS and safely and effectively reduce the side effects of CS. [WT5FZ]
基金supported by the National Natural Science Foundation of China,No.81373578(to YHW),81573965(to YHW)the Natural Science Foundation of Hunan Province of China,No.2017JJ3241(to JL)the Education Department Scientific Research Foundation of Hunan Province of China,No.17C1229(to JL)
文摘Previous studies have shown that models of depression exhibit structural and functional changes to the neurovascular unit. Thus, we hypothesized that diabetes-related depression might be associated with damage to the hippocampal neurovascular unit. To test this hypothesis, neurons, astrocytes and endothelial cells were isolated from the brain tissues of rat embryos and newborn rats. Hippocampal neurovascular unit co-cultures were produced using the Transwell chamber co-culture system. A model of diabetes-related depression was generated by adding 150 mM glucose and 200 μM corticosterone to the culture system and compared with the neuron + astrocyte and astrocyte + endothelial cell co-culture systems. Western blot assay was used to measure levels of structural proteins in the hippocampal neurovascular unit co-culture system. Levels of basic fibroblast growth factor, angiogenic factor 1, glial cell line–derived neurotrophic factor, transforming growth factor β1, leukemia inhibitory factor and 5-hydroxytryptamine in the hippocampal neurovascular unit co-culture system were measured by enzyme-linked immunosorbent assay. Flow cytometry and terminal deoxynucleotidyl transferase(TdT)-mediated dUTP nick end labeling staining was used to assess neuronal apoptosis in the hippocampal neurovascular unit. The neurovascular unit triple cell co-culture system had better barrier function and higher levels of structural and secretory proteins than the double cell co-culture systems. In comparison, in the model of diabetes-related depression, the neurovascular unit was damaged with decreased barrier function, poor structural integrity and impaired secretory function. Moreover, neuronal apoptosis was markedly increased, and 5-hydroxytryptamine levels were reduced. These results suggest that diabetes-related depression is associated with structural and functional damage to the neurovascular unit. Our findings provide a foundation for further studies on the pathogenesis of diabetes-related depression.
基金Supported by National Institutes of Health,No.R01NS091542National Natural Science Foundation of China,No.81771149,No.U1704165。
文摘The progress of modern medicine would be impossible without the use of general anesthetics(GAs).Despite advancements in refining anesthesia approaches,the effects of GAs are not fully reversible upon GA withdrawal.Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly.Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research,but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects.The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents,which are far more extensively studied than any other species.Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated.Specifically,we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities(somatic effects),but also epigenetic reprogramming of germ cells(germ cell effects).The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring,who may be affected even at levels of anesthesia that are not harmful to the exposed parents.The large number of patients who require general anesthesia,the even larger number of their future unexposed offspring whose health may be affected,and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs.In this mini review,we discuss emerging experimental findings on neuroendocrine,epigenetic,and intergenerational effects of GAs.
