It has been documented that stress or glucocorticoids have conflicting effects on memory under different conditions. However, it is not fully understood why stress can either impair or enhance memory. Here, we have examined the performance of six age groups of Wistar rats in a water maze spatial task to evaluate the effects of stress under different conditions. We found that the impairment or enhancement effect of an 'elevated platform' (EP) stress on memory was dependent on previous stress experience and on age. EP stress impaired memory retrieval in water maze naive animals, but enhanced rather than impaired memory retrieval in young water maze stress-experienced animals. Furthermore, exogenously applied corticosterone or foot shock stress before water maze training prevented the impairment of memory retrieval that should be induced by treatment with corticosterone or foot shock before the 'probe trial'. Again, memory retrieval was enhanced in young animals under these conditions, and this enhancement can be prevented by the glucocorticoid receptor antagonist RU 38486. Thus, glucocorticoid receptor activation not only induced impairment of memory but also increased the capacity of young animals to overcome a later stress. The present findings suggest that the effect of stress on memory can be switched from impairment to enhancement dependent on both stress experience and age.
Y Yang, J Cao, W Xiong, J Zhang, Q Zhou, H Wei, C Liang, J Deng, T Li, S Yang, L Xu, and L Xu
Xiuli Men, Liang Peng, Haiyan Wang, Wenjian Zhang, Shiqing Xu, Qing Fang, Honglin Liu, Wenying Yang, and Jinning Lou
The calcium-regulated transcription coactivator, Ca2 +-responsive transactivator (CREST) was expressed in pancreatic β-cells. Moreover, CREST expression became significantly increased in pancreatic islets isolated from hyperglycemic Goto–Kakizaki rats compared with normoglycemic Wistar controls. In addition, culture of β-cells in the presence of high glucose concentrations also increased CREST expression in vitro. To further investigate the role of this transactivator in the regulation of β-cell function, we established a stable β-cell line with inducible CREST expression. Hence, CREST overexpression mimicked the glucotoxic effects on insulin secretion and cell growth in β-cells. Moreover, high glucose-induced apoptosis was aggravated by upregulation of the transactivator but inhibited when CREST expression was partially silenced by siRNA technology. Further investigation found that upregulation of Bax and downregulation of Bcl2 was indeed induced by its expression, especially under high glucose conditions. In addition, as two causing factors leading to β-cell apoptosis under diabetic conditions, endoplasmic reticulum stress and high free fatty acid, mimicked the high glucose effects on CREST upregulation and generation of apoptosis in β-cells, and these effects were specifically offset by the siRNA knockdown of CREST. These results indicated that CREST is implicated in β-cell apoptosis induced by culture in high glucose and hence that CREST may become a potential pharmacological target for the prevention and treatment of type 2 diabetes mellitus.
Yuriko Sakai, Hideyuki Arie, Yinhua Ni, Fen Zhuge, Liang Xu, Guanliang Chen, Naoto Nagata, Takuya Suzuki, Shuichi Kaneko, Tsuguhito Ota, and Mayumi Nagashimada
Intestinal mucosal barrier dysfunction is closely related to the pathogenesis of nonalcoholic steatohepatitis (NASH). Gut immunity has been recently demonstrated to regulate gut barrier function. The Lactobacillus pentosus strain S-PT84 activates helper T cells and natural killer/natural killer T cells. In this study, we examined the effect of S-PT84 on NASH progression induced by high-cholesterol/high-fat diet (CL), focusing on the immune responses involved in gut barrier function. C57BL/6 mice were fed a normal chow or CL diet with or without 1 × 1010 S-PT84 for 22 weeks. S-PT84 administration improved hepatic steatosis by decreasing triglyceride and free fatty acid levels by 34% and 37%, respectively. Furthermore, S-PT84 inhibited the development of hepatic inflammation and fibrosis, suppressed F4/80+ macrophage/Kupffer cell infiltration, and reduced liver hydroxyproline content. Administration of S-PT84 alleviated hyperinsulinemia and enhanced hepatic insulin signalling. Compared with mice fed CL diet, mice fed CL+S-PT84 had 71% more CD11c-CD206+ M2 macrophages, resulting in a significantly decreased M1/M2 macrophage ratio in the liver. Moreover, S-PT84 inhibited the CL diet-mediated increase in intestinal permeability. Additionally, S-PT84 reduced the recruitment of interleukin-17-producing T cells and increased the levels of intestinal tight junction proteins, including zonula occludens-1, occludin, claudin-3, and claudin-7. In conclusion, our findings suggest that S-PT84 attenuates diet-induced insulin resistance and subsequent NASH development by maintaining gut permeability. Thus, S-PT84 represents a feasible approach to prevent the development of NASH.
Yingxin Xian, Zonglan Chen, Hongrong Deng, Mengyin Cai, Hua Liang, Wen Xu, Jianping Weng, and Fen Xu
Obesity-associated chronic inflammation in adipose tissue is partly attributed to hypoxia with insufficient microcirculation. Previous studies have shown that exenatide, a glucagon-like peptide 1 (GLP-1) receptor agonist, plays an anti-inflammatory role. Here, we investigate its effects on inflammation, hypoxia and microcirculation in white adipose tissue of diet-induced obese (DIO) mice. DIO mice were injected intraperitoneally with exenatide or normal saline for 4 weeks, while mice on chow diet were used as normal controls. The mRNA and protein levels of pro-inflammatory cytokines, hypoxia-induced genes and angiogenic factors were detected. Capillary density was measured by laser confocal microscopy and immunochemistry staining. After 4-week exenatide administration, the dramatically elevated pro-inflammatory cytokines in serum and adipose tissue and macrophage infiltration in adipose tissue of DIO mice were significantly reduced. Exenatide also ameliorated expressions of hypoxia-related genes in obese fat tissue. Protein levels of endothelial markers and pro-angiogenic factors including vascular endothelial growth factor and its receptor 2 were augmented in accordance with increased capillary density by exenatide in DIO mice. Our results indicate that inflammation and hypoxia in adipose tissue can be mitigated by GLP-1 receptor agonist potentially via improved angiogenesis and microcirculation in obesity.
Wu Luo, Lan Huang, Jingying Wang, Fei Zhuang, Zheng Xu, Haimin Yin, Yuanyuan Qian, Guang Liang, Chao Zheng, and Yi Wang
Emerging evidence implicates elevated activity of STAT3 transcription factor in driving the development and progression of diabetic cardiomyopathy (DCM). We hypothesized that the fibrosis-promoting and hypertrophic actions of STAT3 are linked to the activation by epidermal growth factor receptor (EGFR). We tested this hypothesis by challenging cultured cardiomyocytes to high-concentration glucose and heart tissues of streptozotocin (STZ)-induced type 1 diabetic mice. Our results indicated that, in diabetic mice, the blockade of STAT3 or EGFR using selective inhibitors S3I-201 and erlotinib, respectively, abrogated the increased activating STAT3 phosphorylation and the induction of genes regulating fibrosis and hypertrophy in myocardial tissue. S3I-201 and erlotinib significantly reduced myocardial structural and functional deficits in diabetic mice. In cultured cardiomyocytes, high-concentration glucose induced EGFR-mediated STAT3 phosphorylation. We further showed that blockade of STAT3 or EGFR using selective inhibitors and siRNAs significantly reduced the increased expression of genes known to promote fibrosis and hypertrophy in cardiomyocytes. These results provide novel evidence that the EGFR-STAT3 signaling axis likely plays a crucial role in the development and progression of DCM.
Shisan Xu, Fangjing Xie, Li Tian, Samane Fallah, Fatemeh Babaei, Sinai H C Manno, Francis A M Manno III, Lina Zhu, Kin Fung Wong, Yimin Liang, Rajkumar Ramalingam, Lei Sun, Xin Wang, Robert Plumb, Lee Gethings, Yun Wah Lam, and Shuk Han Cheng
Sexual differences have been observed in the onset and prognosis of human cardiovascular diseases, but the underlying mechanisms are not clear. Here, we found that zebrafish heart regeneration is faster in females, can be accelerated by estrogen and is suppressed by the estrogen-antagonist tamoxifen. Injuries to the zebrafish heart, but not other tissues, increased plasma estrogen levels and the expression of estrogen receptors, especially esr2a. The resulting endocrine disruption induces the expression of the female-specific protein vitellogenin in male zebrafish. Transcriptomic analyses suggested heart injuries triggered pronounced immune and inflammatory responses in females. These responses, previously shown to elicit heart regeneration, could be enhanced by estrogen treatment in males and reduced by tamoxifen in females. Furthermore, a prior exposure to estrogen preconditioned the zebrafish heart for an accelerated regeneration. Altogether, this study reveals that heart regeneration is modulated by an estrogen-inducible inflammatory response to cardiac injury. These findings elucidate a previously unknown layer of control in zebrafish heart regeneration and provide a new model system for the study of sexual differences in human cardiac repair.