Prevention of vascular smooth muscle cell proliferation and injury-induced neointimal hyperplasia by CREB-mediated p21 induction: An insight from a plant polyphenol

Lazarovici

et al. 2018

Front. Mol. Neurosci.

301

204

Dopamine is a brain neurotransmitter involved in the pathology of schizophrenia. The dopamine hypothesis states that, in schizophrenia, dopaminergic signal transduction is hyperactive. The cAMP-response element binding protein (CREB) is an intracellular protein that regulates the expression of genes that are important in dopaminergic neurons. Dopamine affects the phosphorylation of CREB via G protein-coupled receptors. Neurotrophins, such as brain derived growth factor (BDNF), are critical regulators during neurodevelopment and synaptic plasticity. The CREB is one of the major regulators of neurotrophin responses since phosphorylated CREB binds to a specific sequence in the promoter of BDNF and regulates its transcription. Moreover, susceptibility genes associated with schizophrenia also target and stimulate the activity of CREB. Abnormalities of CREB expression is observed in the brain of individuals suffering from schizophrenia, and two variants (-933T to C and -413G to A) were found only in schizophrenic patients. The CREB was also involved in the therapy of animal models of schizophrenia. Collectively, these findings suggest a link between CREB and the pathophysiology of schizophrenia. This review provides an overview of CREB structure, expression, and biological functions in the brain and its interaction with dopamine signaling, neurotrophins, and susceptibility genes for schizophrenia. Animal models in which CREB function is modulated, by either overexpression of the protein or knocked down through gene deletion/mutation, implicating CREB in schizophrenia and antipsychotic drugs efficacy are also discussed. Targeting research and drug development on CREB could potentially accelerate the development of novel medications against schizophrenia.

Section: Molecular Structure Of Crebmentioning

confidence: 99%

cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia

Lazarovici

et al. 2018

Front. Mol. Neurosci.

301

204

“…In vivo, salvianolic acid A inhibits atherosclerosis stimulated by a high-fat diet in ApoE -/mice, and angiotensin II (Ang II)-induced aortic aneurysm formation [131,132]. Salvianolic acid A also inhibits platelet-derived growth factor-BB (PDGF-BB)-stimulated VSMC proliferation and migration by regulating the ERK and PKA signaling pathways [133,134]. In macrophages, salvianolic acid-A inhibits LPS-stimulated proinflammatory cytokines (TNFα, IL-6 and iNOS) by inhibiting NF-κB activity [135,136].…”

Section: Experimental Studies and Molecular Mechanismsmentioning

confidence: 99%

Danhong injection in cardiovascular and cerebrovascular diseases: Pharmacological actions, molecular mechanisms, and therapeutic potential

Feng

Pharmacological Research

et al. 2019

Cardiovascular and cerebrovascular diseases are the main cause of mortality worldwide, currently with less than optimum therapeutic options. Danhong injection (DHI) is a medicinal preparation based on two eminent Chinese herbal medicines, Salviae Miltiorrhizae (Dan Shen; family: Lamiaceae) and Flos Carthami (Hong Hua; family: Compositae/Asteraceae). DHI has been mainly used in the clinical therapy of cardiovascular (such as acute coronary syndrome and angina pectoris) and cerebrovascular diseases (such as stroke) in China for many years. The pharmacological properties of DHI include anti-inflammatory, anti-oxidant, anti-coagulatory, hypolipidemic, anti-apoptotic, vasodilatory, and angiogenesis-promoting actions. DHI offers a safe and effective therapeutic agent against cardiovascular and cerebrovascular diseases by modulating multiple disease-relevant signaling pathways and molecular targets. Herein, we provide a comprehensive review of the phytochemistry, therapeutic effects, molecular mechanisms, and adverse reactions of DHI in cardiovascular and cerebrovascular diseases. We also highlight the latest pharmacological advances and therapeutic potential of this promising herb-derived cardiovascular drug preparation.

“…cAMP response element binding protein (CREB) is a phosphorylation‐dependent transcription factor that is phosphorylated by multiple protein kinases and participates in different protein kinase signal transduction pathways . Activation of the CREB signalling pathway and phosphorylation of CREB were shown to fulfill numerous cellular functions ranging from cell proliferation and the cell cycle to cell differentiation and cytokine production by binding of phosphorylated‐CREB to the cAMP response element (CRE) in target genes and promoting their transcription . A CRE site has been identified in the TGF‐β gene promoter, and p‐CREB induces TGF‐β expression in both normal cells and cancer cells by directly binding to the TGF‐β gene promoter, which contributes to tissue fibrosis or tumour progression …”

Section: Introductionmentioning

confidence: 99%

“…10 Activation of the CREB signalling pathway and phosphorylation of CREB were shown to fulfill numerous cellular functions ranging from cell proliferation and the cell cycle to cell differentiation and cytokine production by binding of phosphorylated-CREB to the cAMP response element (CRE) in target genes and promoting their transcription. [11][12][13][14] A CRE site has been identified in the TGF-β gene promoter, [15][16][17] and p-CREB induces TGF-β expression in both normal cells and cancer cells by directly binding to the TGF-β F I G U R E 1 Autophagy contributes to degradation of PDE4A in hepatocarcinoma cells. Starvation of HepG2 and BEL7402 cells in Hank's balanced salt solution (HBSS) for 24 h-induced autophagy, which was shown by the LC3-I to LC3-II conversion and P62 degradation.…”

mentioning

confidence: 99%

Autophagy induces transforming growth factor‐β‐dependent epithelial‐mesenchymal transition in hepatocarcinoma cells through cAMP response element binding signalling

J Cellular Molecular Medi

Zhang

et al. 2018

Autophagy promotes invasion of hepatocarcinoma cells through transforming growth factor (TGF)‐β‐dependent epithelial‐mesenchymal transition (EMT). This study investigated the mechanism by which autophagy induces TGF‐β‐triggered EMT and invasion of hepatocarcinoma cells. Autophagy was induced in HepG2 and BEL7402 cells by starvation in Hank's balanced salt solution. Induction of autophagy degraded phosphodiesterase (PDE) 4A and increased intracellular cAMP, PKA activity and PKA phosphorylation, resulting in increased cAMP response element binding (CREB) phosphorylation in hepatocarcinoma cells. Autophagy‐induced activation of cAMP/PKA/CREB signalling further enhanced TGF‐β1 expression, downregulated the expression of epithelial markers and upregulated the expression of mesenchymal markers, accelerating invasion of hepatocarcinoma cells. Inhibition of autophagy by Atg3 and Atg7 knockdown or by chloroquine treatment prevented degradation of PDE4A and activation of cAMP/PKA/CREB signalling, suppressing TGF‐β1 expression, EMT and invasion in hepatocarcinoma cells. In addition, inhibition of cAMP/PKA/CREB signalling also blocked autophagy‐induced TGF‐β1 expression and prevented EMT and invasion of hepatocarcinoma cells under starvation. Furthermore, exogenous inhibition of PDE4A or activation of cAMP/PKA/CREB signalling rescued TGF‐β1 expression, EMT and invasion in autophagy‐deficient hepatocarcinoma cells. These findings suggest that autophagy induces TGF‐β1 expression and EMT in hepatocarcinoma cells via cAMP/PKA/CREB signalling, which is activated by autophagy‐dependent PDE4A degradation.