The Role of the CREB Protein Family Members and the Related Transcription Factors in Radioresistance Mechanisms

In the framework of space flight, the risk of radiation carcinogenesis is considered a “red” risk due to the high likelihood of occurrence as well as the high potential impact on the quality of life in terms of disease-free survival after space missions. The cyclic AMP response element-binding protein (CREB) is overexpressed both in haematological malignancies and solid tumours and its expression and function are modulated following irradiation. The CREB protein is a transcription factor and member of the CREB/activating transcription factor (ATF) family. As such, it has an essential role in a wide range of cell processes, including cell survival, proliferation, and differentiation. Among the CREB-related nuclear transcription factors, NF-κB and p53 have a relevant role in cell response to ionising radiation. Their expression and function can decide the fate of the cell by choosing between death or survival. The aim of this review was to define the role of the CREB/ATF family members and the related transcription factors in the response to ionising radiation of human haematological malignancies and solid tumours.

Activation of CREB Protein With Tabersonine Attenuates STAT3 During Atherosclerosis in Apolipoprotein E-Deficient Mice

Objective: Atherosclerosis is a pathological condition of fat deposition in the arteries, which causes cardiovascular disorders. Management of atherosclerosis remains a challenge and conventional drugs used for its management have several limitations. This study evaluated the protective effect of tabersonine against atherosclerosis and assessed its molecular mechanism of action. Methods: Atherosclerosis was induced by feeding apolipoprotein E (ApoE)-deficient mice a high-fat diet. Mice were treated with 20 or 40 mg/kg of tabersonine intraperitoneally for the 12-week duration of the study. Atherosclerosis markers and nitric oxide were measured in the sera of ApoE-deficient mice. Mediators of inflammation and markers of oxidative stress were assessed using enzyme-linked immunosorbent assays. Western blotting, quantitative reverse transcriptase polymerase chain reaction, and immunohistochemistry analyses were conducted to determine the protein expression in aortic tissue. Results: The tabersonine-treatment groups had an improved lipid profile and enhanced liver function, compared to the ApoE treatment group. Tabersonine treatment resulted in reduced levels of nitric oxide, cytokines, and oxidative stress, compared to the ApoE group. The altered expression levels of protein inhibitor activated STAT-3 (PIAS3), signal transducer and activator of transcription-3 (STAT-3), and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkBα) in ApoE-deficient mice were ameliorated by tabersonine treatment. Moreover, cAMP-response-element-binding (CREB) expression was elevated in aortic tissue of tabersonine treatment groups, compared to the ApoE group. Conclusion: These results suggested that tabersonine ameliorates the expression of STAT-3 by activating CREB protein in atherosclerotic ApoE-deficient mice.

Timing-Dependent Protection of Swimming Exercise against d-Galactose-Induced Aging-Like Impairments in Spatial Learning/Memory in Rats

This study was designed to investigate beneficial effects of swimming exercise training on learning/memory, synaptic plasticity and CREB (cAMP response element binding protein) expression in hippocampus in a rat model of d-galactose-induced aging (DGA). Eighty adult male rats were randomly divided into four groups: Saline Control (group C), DGA (group A), Swimming exercise before DGA (group S1), and Swimming during DGA (group S2). These four groups of animals were further divided into Morris water maze training group (M subgroup) and sedentary control group (N subgroup). Spatial learning/memory was tested using Morris water maze training. The number and density of synaptophysin (Syp) and metabotropic glutamate receptor 1 (mGluR1) in hippocampal dentate gyrus area, CREB mRNA and protein expression and DNA methylation levels were determined respectively with immunohistochemistry, western blot, real-time PCR, and MassArray methylation detection platform. We found that compared with group C, DGA rats showed aging-like poor health and weight loss as well as hippocampal neurodegenerative characteristics. Exercise training led to a time-dependent decrease in average escape latency and improved spatial memory. Exercise training group (S2M) had significantly increased swim distance as compared with controls. These functional improvements in S2M group were associated with higher Syp and mGluR1 values in hippocampus (p < 0.01) as well as higher levels of hippocampal CREB protein/mRNA expression and gene methylation. In conclusion, swimming exercise training selectively during drug-induced aging process protected hippocampal neurons against DGA-elicited degenerative changes and in turn maintained neuronal synaptic plasticity and learning/memory function, possibly through upregulation of hippocampal CREB protein/mRNA and reduction of DGA-induced methylation of CREB.

Lactobacillus Rhamnosus GG and Bifidobacterium Bifidum TMC3115 Can Affect the Development of Hippocampal Neurons Cultured in Vitro in a Strain-dependent Manner (P20-009-19)

Objectives This study aimed to examine whether probiotics could morphologically or physiologically influence hippocampal neuron development. Methods Hippocampal neurons cultured in vitro were exposed to live or heat-inactivated Lactobacillus rhamnosus GG (LGG), or live or heat-inactivated Bifidobacterium bifidum TMC3115 (TMC3115), for either 6 or 24 h. Neuron viability was then tested using the methyl thiazolyl tetrazolium assay. Neuronal morphological changes and drebrin (DRB) and synaptophysin (SYP) protein levels were monitored using immunofluorescence. And the levels of DRB, SYP, and brain-derived neurotrophic factor (BDNF), and cAMP-response element binding protein (CREB) mRNA were detected using RT-PCR. The BDNF, CREB and phosphorylated-CREB (P-CREB) protein levels were detected by ELISA or Western blot assays. Results We found exposure to probiotics could enhance neuron viability, although no significant differences were found in neuronal morphology among the groups following exposure to the test bacteria. However, the synapse development-related proteins, DRB and SYP, as well as BDNF and P-CREB protein levels, were significantly altered in this specific culture system. Conclusions These results demonstrated that LGG and TMC3115 exposure can affect neuronal viability, along with synaptic and brain function development, in a strain-dependent manner, which may also be closely associated with the physiological and cultural conditions of each strain, The up-regulated P-CREB protein level may be one of the underlying mechanisms by which the tested bacteria, especially live TMC3115 following exposure for 24 h, are able to regulate neuronal BDNF protein production. Further studies are needed to explore other possible effects probiotic exposure may have on hippocampal neurons, as well as the corresponding mechanisms that underlie them. Funding Sources This work was funded by the National Natural Science Foundation of China (Grant number 81872606).

Influence of Diallyl disulphide on Hepatic Gluconeogenesis suppression by CREB Binding protein phosphorylation

Diabetes is an important human ailment affecting many lives in different countries. Diallyl disulfide (DADS), the antidiabetic compound found in garlic, acts as a therapeutic agent in diabetes mellitus condition. This research aimed to investigate the role of DADS on the gluconeogenic mechanism in the liver tissue and the potential involvement of CREB in glucose homeostasis in a Wistar rat model. The alteration in the body weight, liver weight and glycogen content in diabetic rats were prevented by this therapeutic compound: the cAMP-responsive element-binding protein (CREB), an important transcriptional regulator of the gluconeogenic mechanism. The glucose uptake potential was studied by the expression of CREB protein in DADS treated diabetic rats using the western blotting technique. A high level of hepatic CREB protein expression was noted in diabetic status in the chronic hyperglycemic model which was reversed by DADS. The antihyperglycemic effect of DADS was almost similar to that of known antidiabetic drug metformin. The therapeutic action of DADS on diabetic status is due to the control of the glycemic imbalance in liver tissue.

PO-233 The Neuroprotective Effects of Aerobic Exercise and Oral Resveratrol on Hippocampal Neurons in Diabetic Rats

Objective The purpose of this study is to explore the effects of aerobic exercise combined with oral resveratrol on ethology and BDNF and CREB proteins of hippocampus neurons in diabetic rats, in order to provide a theoretical basis for revealing the neuroprotective mechanism of exercise and resveratrol. Methods 45 male Sprague Dawley rats, aged 8 weeks, were randomly divided into 5 groups: normal control (NC), diabetes control (DC), diabetes exercise (DE), diabetes resveratrol (DR) and diabetes exercise and resveratrol (DER). Exercise-related groups performed 8-week swimming training (60min/d，5d/week). Morris maze test, 7d. Escape latency time, strategy of finding platform performance, the protein expression of BDNF and CREB from hippocampus neurons were measured. Results 1）Compared with DM, DR and RE groups, the escape latency of DRE group was significantly shortened (p<0.01), and the strategy of finding platform performance was remarkably improved (p<0.05). 2) Compared with NC group, the protein expression of BDNF of DM group was obviously decreased (p <0.01), while in DRE group was improved significantly than that in DE group (p< 0.05). 3) The level of CREB expression in DM group clearly lower than in group NC (p<0.01), and the expression of CREB in DER and DE groups were remarkably increased (P <0.01) . Conclusions Eight weeks of swimming training and/or oral resveratrol could increase the expression level of BDNF and CREB protein in the hippocampal neurons of diabetic rats, and improve the ability of spatial learning from behavioral study. It is suggested that the aerobic exercise training and the SIRT1 mechanism of resveratrol perhaps improve the situation of high glucose and indirectly stimulate the expression of BDNF and CREB protein. As a result, that leads to improve the impair of learning and memory which caused by diabetes.