Jianqiang Lu

Swimming exercise ameliorates depression-like behavior in chronically stressed rats: Relevant to proinflammatory cytokines and IDO activation

Chronic stress is involved in development of depression and causes immune alterations. Indoleamine-2,3-dioxygenase (IDO) plays a pivotal role in mediating the depression-like behaviors in response to immune activation. Physical exercise has been shown to reduce the stress impairment and ameliorate depressive symptoms. The objectives of present study were to confirm that chronic unpredictable mild stress (CUMS) induces depression-like behavior and inflammatory responses within the brain, and then investigate whether swimming exercise alleviates the depression-like behaviors induced by CUMS through proinflammatory cytokine-induced alteration of IDO in brain. It has been found that CUMS exposure induced depression-like behavior, increased serum corticosterone (CORT) level, decreased 5-HT level, increased IFN-γ and TNF-α levels and elevated IDO activity in prefrontal cortex. Moreover, the level of 5-HT was inversely correlated with IDO level. Regular swimming exercise ameliorated depressive symptoms induced by CUMS. The exercise reduced serum CORT level, increased 5-HT level as well as decreased levels of IFN-γ, TNF-α and IDO in prefrontal cortex in CUMS rats. These findings suggested that CUMS activate HPA axis and induce immune activation, which may stimulate IDO activity, leading to the reduction of 5-HT level in brain, thereby resulting in depression. Swimming exercise may inhibit activation of inflammation/IDO pathways induced by CUMS, thereby ameliorating depression.

Estrogens increase cystathionine-γ-lyase expression and decrease inflammation and oxidative stress in the myocardium of ovariectomized rats.

Objective Hydrogen sulfide (H2S), generated in the myocardium predominantly via cystathionine-&ggr;-lyase (CSE), is cardioprotective. The objectives of the present study were to investigate the effects of estrogens on CSE expression and H2S generation in the myocardium and to examine whether serum 17&bgr;-estradiol (E2) level is associated with CSE activity and H2S generation and whether H2S or E2 level is associated with proinflammatory cytokines and oxidative stress status. Methods Ovariectomized Sprague-Dawley rats received subcutaneous E2 (30 &mgr;g/kg/d) or vehicle for 12 weeks. At the end of the 12-week treatment, CSE expression, H2S generation, reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, catalase (CAT) activity, interleukin (IL)-6 concentration, and tumor necrosis factor-&agr; (TNF-&agr;) concentration in the left ventricle were determined. Results E2 increased CSE expression and H2S generation in the myocardium of ovariectomized rats. H2S production rate and serum E2 were positively correlated. E2 increased GSH/GSSG ratio, T-AOC, CAT, and SOD activity but decreased IL-6 and TNF-&agr; levels. Serum E2 level was positively correlated with GSH/GSSG ratio, T-AOC, CAT, and SOD activity, and inversely correlated with IL-6 and TNF-&agr; levels. H2S generation rate was positively correlated with T-AOC and GSH/GSSG ratio, and inversely correlated with IL-6 and TNF-&agr; levels. Conclusions E2 increases CSE expression and endogenous H2S generation in the myocardium. The effects of E2 are associated with decreased oxidative stress and inflammatory status. Our data suggest that estrogens might exert cardioprotective effects through up-regulation of CSE expression and H2S generation.

Exercise ameliorates depression-like behavior and increases hippocampal BDNF level in ovariectomized rats

The aims of the present study were to investigate whether exercise can improve the depression-like behavior caused by estrogen deficiency. Given that decreased level of brain-derived neurotrophic factor (BDNF) in many brain areas including hippocampus and prefrontal cortex is associated with estrogen deficiency-induced depression-like behavior, we also determined whether exercise affects the levels of BDNF and its receptor in hippocampus and prefrontal cortex (PFC). It was found that ovariectomy (OVX) caused an increase in depression-like behavior in rats and a decrease in BDNF level in hippocampus but not in PFC. The expression of TrkB, a high affinity BDNF receptor in hippocampus and PFC was not affected by OVX. 17β-estradiol (E2) treatment ameliorated depression-like behavior and increased BDNF level in hippocampus in OVX rats. Serum E2 level inversely correlated to depression-like behavior and positively correlated to BDNF level in hippocampus. Exercise ameliorated depression-like behavior, increased serum E2 level and BDNF level in hippocampus in OVX rats. The increased E2 level did not correlate to BDNF level but correlated with some of the behaviors in the rats subjected to exercise. Our results suggested that E2 maintains BDNF in hippocampus, thereby ameliorating depression-like behavior. Exercise amelioration of depression-like behavior in OVX rats is partly due to increased serum E2 level.

Inflammation and increased IDO in hippocampus contribute to depression-like behavior induced by estrogen deficiency.

Estrogen deficiency is involved in the development of depression. However, the mechanism underlying estrogen modulates depression-like behavior remains largely unknown. Inflammation and indoleamine-2,3-dioxygenase (IDO) have been shown to play pivotal roles in various depression models. The objective of the present study was to investigate whether estrogen deficiency-induced depression-like behavior is associated with inflammation and IDO activation in brain. The results showed that ovariectomy resulted in depression-like behavior in female rats and caused a decrease in 5-HT content and an increase in levels of IDO, IFN-γ, IL-6, toll like receptor (TLR)-4 and phosphorylated NF-κB (p65 subunit) in hippocampus but not in prefrontal cortex (PFC). 17β-Estradiol (E2) treatment ameliorated depression-like behavior and restored above neurochemical alternations in hippocampus in ovariectomized rats. Partial correlation analysis showed that the levels of phosphorylated p65, IFN-γ and IL-6 in hippocampus correlated to serum E2 level. Our study suggests that estrogen inhibits inflammation and activates of IDO and maintains 5-HT level in hippocampus, thereby ameliorating depression-like behavior.

Upregulation of microRNA-22 contributes to myocardial ischemia-reperfusion injury by interfering with the mitochondrial function

Mitochondrial oxidative damage is critically involved in cardiac ischemia reperfusion (I/R) injury. MicroRNA-22 (miR-22) has been predicted to potentially target sirtuin-1 (Sirt1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), both of which are known to provide protection against mitochondrial oxidative injury. The present study aims to investigate whether miR-22 is involved in the regulation of cardiac I/R injury by regulation of mitochondrial function. We found that miR-22 level was significantly increased in rat hearts subjected to I/R injury, as compared with the sham group. Intra-myocardial injection of 20 ug miR-22 inhibitor reduced I/R injury as evidenced by significant decreases in cardiac infarct size, serum lactate dehydrogenase (LDH) and creatine kinase (CK) levels and the number of apoptotic cardiomyocytes. H9c2 cardiomyocytes exposed to hypoxia/reoxygenation (H/R) insult exhibited an increase in miR-22 expression, which was blocked by reactive oxygen species (ROS) scavenger and p53 inhibitor. In addition, miR-22 inhibitor attenuated, whereas miR-22 mimic aggravated H/R-induced injury in H9c2 cardiomyocytes. MiR-22 inhibitor per se had no significant effect on cardiac mitochondrial function. Mitochondria from rat receiving miR-22 inhibitor 48h before ischemia were found to have a significantly less mitochondrial superoxide production and greater mitochondrial membrane potential and ATP production as compared with rat receiving miR control. In H9c2 cardiomyocyte, it was found that miR-22 mimic aggravated, whilst miR-22 inhibitor significantly attenuated H/R-induced mitochondrial damage. By using real time PCR, western blot and dual-luciferase reporter gene analyses, we identified Sirt1 and PGC1α as miR-22 targets in cardiomyocytes. It was found that silencing of Sirt1 abolished the protective effect of miR-22 inhibitor against H/R-induced mitochondrial dysfunction and cell injury in cardiomyocytes. Taken together, our findings reveal a novel molecular mechanism for cardiac mitochondrial dysfunction during myocardial I/R injury at the miRNA level and demonstrate the therapeutic potential of miR-22 inhibition for acute myocardial I/R injury by maintaining cardiac mitochondrial function.

Exercise amelioration of depression-like behavior in OVX mice is associated with suppression of NLRP3 inflammasome activation in hippocampus

Exercise has benefit for perimenopause women in many ways, such as affective disorders. Our previous study has demonstrated that inflammation in hippocampus contributes to development of depression-like behavior in ovariectomized (OVX) rats. Recently, oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has been implicated to be involved in lipopolysaccharide (LPS)- and chronic stress-induced depression-like behavior in rodents. We sought to investigate whether ovariectomy-induced depression-like behavior is associated with NLRP3 inflammasome activation in brain and the effect of exercise on NLRP3 inflammasome activation in this model. The results showed that ovariectomy resulted in depression-like behavior in mice and an increase in levels of IL-1β and IL-18 in hippocampus. Exercise ameliorated the depression-like behavior and decreased levels of IL-1β and IL-18 in hippocampus. The level of IL-1β and IL-18 in hippocampus correlated to depression-like behavior in OVX mice. The levels of NLRP3, cleaved caspase-1 P10 and CD11b in hippocampus were increased in OVX mice compared with control group. Exercise could reduce the levels of NLRP3, cleaved caspase-1 P10 and CD11b in OVX mice. Our study suggests that NLRP3 inflammasome activation contribute to inflammation in hippocampus upon to deprivation of ovary. Exercise amelioration of depression-like behavior is associated with suppression of NLRP3 inflammasome activation in hippocampus of this model.

Cardioprotection of 17β-estradiol against hypoxia/reoxygenation in cardiomyocytes is partly through up-regulation of CRH receptor type 2.

Estrogens have been suggested to exert cardioprotection through maintaining endogenous cardioprotective mechanisms. In the present study, we investigated whether estrogens protect cardiomyocytes against hypoxia/reoxygenation (H/R) via modulating urocortins (UCNs) and their receptor corticotrophin-releasing hormone receptor type 2 (CRHR2). We found that 17β-estradiol (E2) enhanced UCN cardioprotection against H/R and increased CRHR2 expression in neonatal rat cardiomyocytes. E2 protected cardiomyocytes against H/R, which was impaired by CRHR2 antagonist or knockdown of CRHR2. Estrogen receptor α (ERα) antagonist treatment or ERα knockdown could abolish E2-induced CRHR2 up-regulation. Moreover, knockdown of Sp1 also attenuated E2-induced CRHR2 up-regulation. Ovariectomy resulted in down-regulation of CRHR2 and Sp-1 in myocardium of mice, which was restored by E2 or ERα agonist treatment. These results suggest that estrogens act on ERα to up-regulate CRHR2 expression in cardiomyocytes, thereby enhancing cardioprotection of UCNs against H/R.

Exercise Increases Cystathionine- γ -lyase Expression and Decreases the Status of Oxidative Stress in Myocardium of Ovariectomized Rats

Exercise could be a therapeutic approach for cardiovascular dysfunction induced by estrogen deficiency. Our previous study has shown that estrogen maintains cystathionine-γ-lyase (CSE) expression and inhibits oxidative stress in the myocardium of female rats. In the present study, we investigated whether exercise improves CSE expression and oxidative stress status and ameliorates isoproterenol (ISO)-induced cardiac damage in ovariectomized (OVX) rats. The results showed that treadmill training restored the ovariectomy-induced reduction of CSE and estrogen receptor (ER)α and decrease of total antioxidant capacity (T-AOC) and increase of malondialdehyde (MDA). The level of CSE was positively correlated to T-AOC and ERα while inversely correlated to MDA. OVX rats showed increases in the serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH) and the percentage of TUNEL staining in myocardium upon ISO insult compared to sham rats. Exercise training significantly reduced the serum levels of LDH and CK and the percentage of TUNEL staining in myocardium upon ISO insult in OVX rats. In cultured cardiomyocytes, ISO treatment decreased cell viability and increased LDH release, while overexpression of CSE increased cell viability and decreased LDH release in the cells upon ISO insult. The results suggest that exercise training improves the oxidative stress status and ameliorates the cardiac damage induced by oxidative stress in OVX rats. The improvement of oxidative stress status by exercise might be at least partially due to upregulation of CSE/H2S signaling.

Estrogen enhancement of SGK1 expression induced by urocortin contributes to its cardioprotection against ischemia/reperfusion insult

☆ This work is supported by the National Natural Sci 31000516 and No. 31371197), Key Laboratory of Exe Ministry of Education, Shanghai University of Sport and I Undergraduates, and Education Commission of Shanghai ⁎ Correspondence to: J. Lu, School of Kinesiology, Sha Changhai Road, Shanghai 200438, China. ⁎⁎ Correspondence to: X. Ni, Department of Physiol University, Shanghai 200433, China. E-mail addresses: lujianqiang@sus.edu.cn (J. Lu), nixin

CRH/CRHR1 mediates prenatal synthetic glucocorticoid programming of depression-like behavior across 2 generations

Pregnant women at risk of preterm labor usually receive synthetic glucocorticoids (sGCs) to promote fetal lung development. Emerging evidence indicates that antenatal sGC increases the risk of affective disorders in offspring. Data from animal studies show that such disorders can be transmitted to the second generation. However, the molecular mechanisms underlying the intergenerational effects of prenatal sGC remain largely unknown. Here we show that prenatal dexamethasone (Dex) administration in late pregnancy induced depression‐like behavior in first‐generation (F1) offspring, which could be transmitted to second‐generation (F2) offspring with maternal dependence. Moreover, corticotropin‐releasing hormone (CRH) and CRH receptor type 1 (CRHR1) expression in the hippocampus was increased in F1 Dex offspring and F2 offspring from F1 Dex female rats. Administration of a CRHR1 antagonist to newborn F1 Dex offspring alleviated depression‐like behavior in these rats at adult. Furthermore, we demonstrated that increased CRHR1 expression in F1 and F2 offspring was associated with hypo‐methylation of CpG islands in Crhr1 promoter. Our results revealed that prenatal sGC exposure could program Crh and Crhr1 gene expression in hippocampus across 2 generations, thereby leading to depression‐like behavior. Our study indicates that prenatal sGC can cause epigenetic instability, which increases the risk of disease development in the offsprings later life.—Xu, Y.‐J., Sheng, H., Wu, T.‐W., Bao, Q.‐Y., Zheng, Y., Zhang, Y.‐M., Gong, Y.‐X., Lu, J.‐Q., You, Z.‐D., Xia, Y., Ni, X. CRH/CRHR1 mediates prenatal synthetic glucocorticoid programming of depressionlike behavior across 2 generations. FASEB J. 32, 4258–4269 (2018). www.fasebj.org