camp response element
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Nutrients ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 117
Author(s):  
Lijin Song ◽  
Meibo He ◽  
Qinghua Sun ◽  
Yujing Wang ◽  
Jindong Zhang ◽  
...  

Intestinal melatonin exerts diverse biological effects on the body. Our previous research showed that the abundance of the butyrate-producing bacteria, Roseburia, is positively related to the expression of colonic mucosal melatonin. However, the detailed relationship is unclear. Therefore, we aimed to explore whether Roseburia regulates intestinal melatonin and its underlying mechanisms. Male Sprague–Dawley germfree rats were orally administered with or without Roseburia hominis. R. hominis treatment significantly increased the intestinal melatonin level. The concentrations of propionate and butyrate in the intestinal contents were significantly elevated after gavage of R. hominis. Propionate or butyrate treatment increased melatonin, 5-hydroxytryptamine (5-HT), arylalkylamine N-acetyltransferase (AANAT), and phosphorylated cAMP-response element-binding protein (p-CREB) levels. When pretreated with telotristat ethyl, the inhibitor of tryptophan hydroxylase (TPH), or siRNA of Aanat, or 666-15, i.e., an inhibitor of CREB, propionate, or butyrate, could not promote melatonin production in the pheochromocytoma cell line BON-1. Metabolomics analysis showed that propionate and butyrate stimulation regulated levels of some metabolites and some metabolic pathways in BON-1 cell supernatants. In conclusion, propionate and butyrate, i.e., metabolites of R. hominis, can promote intestinal melatonin synthesis by increasing 5-HT levels and promoting p-CREB-mediated Aanat transcription, thereby offering a potential target for ameliorating intestinal diseases.


2021 ◽  
Vol 14 ◽  
Author(s):  
Lynette A. Desouza ◽  
Madhurima Benekareddy ◽  
Sashaina E. Fanibunda ◽  
Farhan Mohammad ◽  
Balaganesh Janakiraman ◽  
...  

Psychedelic compounds that target the 5-HT2A receptor are reported to evoke psychoplastogenic effects, including enhanced dendritic arborization and synaptogenesis. Transcriptional regulation of neuronal plasticity-associated genes is implicated in the cytoarchitectural effects of serotonergic psychedelics, however, the transcription factors that drive this regulation are poorly elucidated. Here, we addressed the contribution of the transcription factor cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) in the regulation of neuronal plasticity-associated genes by the hallucinogenic 5-HT2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI). In vitro studies with rat cortical neurons indicated that DOI enhances the phosphorylation of CREB (pCREB) through mitogen-activated protein (MAP) kinase and calcium/calmodulin dependent kinase II (CaMKII) pathways, with both cascades contributing to the DOI-evoked upregulation of Arc, Bdnf1, Cebpb, and Egr2 expression, whilst the upregulation of Egr1 and cFos mRNA involved the MAP kinase and CaMKII pathway respectively. We observed a robust DOI-evoked increase in the expression of several neuronal plasticity-associated genes in the rat neocortex in vivo. This DOI-evoked upregulation of neuronal plasticity-associated genes was completely blocked by the 5-HT2A receptor antagonist MDL100,907 in vitro and was also abrogated in the neocortex of 5-HT2A receptor deficient mice. Further, 5-HT2A receptor stimulation enhanced pCREB enrichment at putative cAMP response element (CRE) binding sites in the Arc, Bdnf1, Cebpb, cFos, but not Egr1 and Egr2, promoters in the rodent neocortex. The DOI-mediated transcriptional induction of Arc, cFos and Cebpb was significantly attenuated in the neocortex of CREB deficient/knockout (CREBαδ KO) mice. Collectively, these results indicate that the hallucinogenic 5-HT2A receptor agonist DOI leads to a rapid transcriptional upregulation of several neuronal plasticity-associated genes, with a subset of them exhibiting a CREB-dependent regulation. Our findings raise the intriguing possibility that similar to slow-acting classical antidepressants, rapid-action serotonergic psychedelics that target the 5-HT2A receptor may also recruit the transcription factor CREB to enhance the expression of neuronal plasticity-associated genes in the neocortex, which could in turn contribute to the rapid psychoplastogenic changes evoked by these compounds.


Author(s):  
Kuai Yu ◽  
Linju Kuang ◽  
Tianmei Fu ◽  
Congkai Zhang ◽  
Yuru Zhou ◽  
...  

The transcriptional repressor cAMP response element modulator (CREM) has an important role in T-cell development. In this study, we used the integrated Bioinformatics Methods to explore the role of CREM in gastric adenocarcinoma (GAC). Our results showed that high CREM expression was closely related with poorer overall survival in GAC. By GSEA cluster analysis, we found that the high expression of CREM was associated with the cancer-associated pathway in GAC. Moreover, single-cell sequencing data showed that CREM is mainly localized in exhausted CD8+ T cells. Its prognostic value and the potential function lead to T-cell exhaustion in the tumor microenvironment (TME). Similar results were also obtained in glioma and lung cancer. High expression of CREM, correlated with clinical relevance of GAC, was associated with T-cell exhaustion and M2 polarization in GAC. These findings suggest that CREM can be used as a prognostic biomarker in GAC, which might provide a novel direction to explore the pathogenesis of GAC.


2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Malk Eun Pak ◽  
You-Chang Oh ◽  
Yeo Jin Park ◽  
Jae Kwang Kim ◽  
Min-Gyeong Shin ◽  
...  

Since ancient times, Banhasasim-tang (BHS) has been used to treat functional dyspepsia in East Asia. Here, we aimed to determine the protective action of BHS on hippocampal neurons against oxidative stress. We investigated the functional effect of BHS on a scopolamine-induced mouse model, and molecular analysis was performed in glutamate-induced HT22 cells. We observed that BHS administration ameliorated memory dysfunction in scopolamine-treated mice. BHS administration also increased neuronal survival and acetylcholine activity and phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus of mice. In hippocampal cells, BHS treatment rescued glutamate-induced cytotoxicity, apoptosis, and oxidative stress. We observed an increase of HO-1 and a decrease of Nrf2 protein expression in glutamate-induced oxidative stress; however, the expression level of these proteins was significantly rescued by BHS treatment. BHS treatment also regulated phosphorylation of p38, p53, ERK, and CREB. Therefore, our data indicated that BHS may reduce oxidative stress through regulation of ERK-CREB and p38-p53 signaling in the hippocampus, resulting in decreased neuronal damage and improved memory in rodent models of neurodegenerative disease.


2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Pit Shan Chong ◽  
Chi Him Poon ◽  
Jaydeep Roy ◽  
Ka Chun Tsui ◽  
Sze Yuen Lew ◽  
...  

Abstract Background Depression is a severe neuropsychiatric disorder that affects more than 264 million people worldwide. The efficacy of conventional antidepressants are barely adequate and many have side effects. Hericium erinaceus (HE) is a medicinal mushroom that has been reported to have therapeutic potential for treating depression. Methods Animals subjected to chronic restraint stress were given 4 weeks HE treatment. Animals were then screened for anxiety and depressive-like behaviours. Gene and protein assays, as well as histological analysis were performed to probe the role of neurogenesis in mediating the therapeutic effect of HE. Temozolomide was administered to validate the neurogenesis-dependent mechanism of HE. Results The results showed that 4 weeks of HE treatment ameliorated depressive-like behaviours in mice subjected to 14 days of restraint stress. Further molecular assays demonstrated the 4-week HE treatment elevated the expression of several neurogenesis-related genes and proteins, including doublecortin, nestin, synaptophysin, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), phosphorylated extracellular signal-regulated kinase, and phosphorylated cAMP response element-binding protein (pCREB). Increased bromodeoxyuridine-positive cells were also observed in the dentate gyrus of the hippocampus, indicating enhanced neurogenesis. Neurogenesis blocker temozolomide completely abolished the antidepressant-like effects of HE, confirming a neurogenesis-dependent mechanism. Moreover, HE induced anti-neuroinflammatory effects through reducing astrocyte activation in the hippocampus, which was also abolished with temozolomide administration. Conclusion HE exerts antidepressant effects by promoting neurogenesis and reducing neuroinflammation through enhancing the BDNF-TrkB-CREB signalling pathway.


Stroke ◽  
2021 ◽  
Author(s):  
Jun Yan ◽  
Weilin Xu ◽  
Cameron Lenahan ◽  
Lei Huang ◽  
Jing Wen ◽  
...  

Background and Purpose: Neuronal pyroptosis is a type of regulated cell death triggered by proinflammatory signals. CCR5 (C-C chemokine receptor 5)-mediated inflammation is involved in the pathology of various neurological diseases. This study investigated the impact of CCR5 activation on neuronal pyroptosis and the underlying mechanism involving cAMP-dependent PKA (protein kinase A)/CREB (cAMP response element binding)/NLRP1 (nucleotide-binding domain leucine-rich repeat pyrin domain containing 1) pathway after experimental intracerebral hemorrhage (ICH). Methods: A total of 194 adult male CD1 mice were used. ICH was induced by autologous whole blood injection. Maraviroc (MVC)—a selective antagonist of CCR5—was administered intranasally 1 hour after ICH. To elucidate the underlying mechanism, a specific CREB inhibitor, 666-15, was administered intracerebroventricularly before MVC administration in ICH mice. In a set of naive mice, rCCL5 (recombinant chemokine ligand 5) and selective PKA activator, 8-Bromo-cAMP, were administered intracerebroventricularly. Short- and long-term neurobehavioral assessments, Western blot, Fluoro-Jade C, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and immunofluorescence staining were performed. Results: The brain expression of CCL5 (chemokine ligand 5), CCR5, PKA-Cα (protein kinase A-Cα), p-CREB (phospho-cAMP response element binding), and NLRP1 was increased, peaking at 24 hours after ICH. CCR5 was expressed on neurons, microglia, and astrocytes. MVC improved the short- and long-term neurobehavioral deficits and decreased neuronal pyroptosis in ipsilateral brain tissues at 24 hours after ICH, which were accompanied by increased PKA-Cα and p-CREB expression, and decreased expression of NLRP1, ASC (apoptosis-associated speck-like protein containing a CARD), C-caspase-1, GSDMD (gasdermin D), and IL (interleukin)-1β/IL-18. Such effects of MVC were abolished by 666-15. At 24 hours after injection in naive mice, rCCL5 induced neurological deficits, decreased PKA-Cα and p-CREB expression in the brain, and upregulated NLRP1, ASC, C-caspase-1, N-GSDMD, and IL-1β/IL-18 expression. Those effects of rCCL5 were reversed by 8-Bromo-cAMP. Conclusions: CCR5 activation promoted neuronal pyroptosis and neurological deficits after ICH in mice, partially through the CCR5/PKA/CREB/NLRP1 signaling pathway. CCR5 inhibition with MVC may provide a promising therapeutic approach in managing patients with ICH.


Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 3686
Author(s):  
Ashley Jazzar ◽  
Danielle Jacques ◽  
Ghassan Bkaily

Although insulin-induced cardiac hypertrophy is reported, very little information is available on the hypertrophic effect of insulin on ventricular cardiomyocytes and the regulation of sodium and calcium homeostasis. Taurine is a non-essential amino acid synthesized by cardiomyocytes and the brain and is present in low quantities in many foods, particularly seafood. The purpose of this study was to investigate whether chronic exposure to insulin induces hypertrophy of ventricular cardiomyocytes that are associated with changes in Na+ and Ca2+ homeostasis and whether taurine pre-treatment prevents these effects. Our results showed that chronic treatment with insulin leads to cardiomyocyte hypertrophy that is associated with an increase in basal intracellular Na+ and Ca2+ levels. Furthermore, long-term taurine treatment prevents morphological and ionic remodeling induced by insulin. In addition, blocking the Na+-taurine co-transporter prevented the taurine antihypertrophic effect. Finally, the insulin-induced remodeling of cardiomyocytes was associated with a decrease in the ratio of phospho-CREB (pCREB) to total cAMP response element binding protein (CREB); taurine prevented this effect. In conclusion, our results show that insulin induces ventricular cardiomyocyte hypertrophy via downregulation of the pCREB/tCREB level and that chronic taurine treatment prevents this effect.


2021 ◽  
Author(s):  
Lynette A. Desouza ◽  
Madhurima Benekareddy ◽  
Sashaina E. Fanibunda ◽  
Farhan Mohammad ◽  
Tamar Gur ◽  
...  

AbstractPsychedelic compounds that target the 5-HT2A receptor are reported to evoke psychoplastogenic effects, including enhanced dendritic arborization and synaptogenesis. Transcriptional regulation of neuronal plasticity-associated genes is implicated in the cytoarchitectural effects of serotonergic psychedelics, however the transcription factors that drive this regulation are poorly elucidated. Here, we addressed the contribution of the transcription factor cAMP response element binding protein (CREB) in the regulation of neuronal plasticity-associated genes by the hallucinogenic 5-HT2A receptor agonist, DOI. In vitro studies with rat cortical neurons indicated that DOI enhances the phosphorylation of CREB (pCREB) through the MAP kinase and CaMKII pathways, with both cascades contributing to the DOI-evoked upregulation of Arc, Bdnf1, Cebpb and Egr2 expression, whilst the upregulation of Egr1 and cFos mRNA involved the MAP kinase and CaMKII pathway respectively. We observed a robust DOI-evoked increase in the expression of several neuronal plasticity-associated genes in the rat neocortex in vivo. Further, 5-HT2A receptor stimulation enhanced pCREB enrichment at putative cAMP response element (CRE) binding sites in the Arc, Bdnf1, Cebpb, cFos, but not Egr1 and Egr2, promoters in the rodent neocortex. The DOI-mediated transcriptional induction of Arc, cFos and Cebpb was significantly attenuated in the neocortex of CREB deficient (CREBαδ KO) mice. Collectively, these results indicate that the hallucinogenic 5-HT2A receptor agonist DOI leads to a rapid transcriptional upregulation of several neuronal plasticity-associated genes, with a subset of them exhibiting a CREB-dependent regulation. Our findings raise the intriguing possibility that similar to slow-acting classical antidepressants, rapid-action serotonergic psychedelics that target the 5-HT2A receptor may also recruit the transcription factor CREB to enhance the expression of neuronal plasticity-associated genes in the neocortex, which could in turn contribute to the rapid psychoplastogenic changes evoked by these compounds.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Tianyu Zheng ◽  
Jinrong Huang ◽  
Xi Xiang ◽  
Siyuan Li ◽  
Jiaying Yu ◽  
...  

AbstractThe transcription factor cyclic-AMP response element-binding protein 1 (CREB1) responds to cAMP level and controls the expression of target genes, which regulates nutrition partitioning. The promoters of CREB1-targeted genes responsive to cAMP have been extensively investigated and characterized with the presence of both cAMP response element and TATA box. Compelling evidence demonstrates that CREB1 also plays an essential role in promoting tumor development. However, only very few genes required for cell survival, proliferation and migration are known to be constitutively regulated by CREB1 in tumors. Their promoters mostly do not harbor any cAMP response element. Thus, it is very likely that CREB1 regulates the expressions of distinct sets of target genes in normal tissues and tumors. The whole gene network constitutively regulated by CREB1 in tumors has remained unrevealed. Here, we employ a systematical and integrative approach to decipher this gene network in the context of both tissue cultured cancer cells and patient samples. We combine transcriptomic, Rank-Rank Hypergeometric Overlap, and Chipseq analysis, to define and characterize CREB1-regulated genes in a multidimensional fashion. A strong cancer relevance of those top-ranked targets, which meet the most stringent criteria, is eventually verified by overall survival analysis of cancer patients. These findings strongly suggest the importance of genes constitutively regulated by CREB1 for their implicative involvement in promoting tumorigenesis.


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