CREB Signaling Pathway Research Articles

Exploring the Connection Between BDNF/TrkB and AC/cAMP/PKA/CREB Signaling Pathways: Potential for Neuroprotection and Therapeutic Targets for Neurological Disorders.

The BDNF/TrkB and AC/cAMP/PKA/CREB signaling pathways play a vital role in neuroplasticity, neuronal survival, and cognitive functions. This review explores its physiological and pathological implications in neurological disorders, with a focus on neurodegenerative diseases (NDDs) and neuropsychiatric disorders (NPDs). Neurological conditions increasingly burden public health, making understanding the biochemical mechanisms that underpin these diseases critical. BDNF, a neurotrophic factor, binds to the TrkB receptor, activating multiple intracellular signaling cascades that regulate cellular responses essential for neurogenesis, memory, and learning. Dysregulation within this pathway has been linked to various NDDs, as well as NPDs. Key components of the path, including adenylyl cyclase and cyclic AMP, mediate the effects of neurotransmitters and growth factors, influencing downstream targets like PKA and CREB, which are crucial for gene expression and synaptic changes. Furthermore, the review discusses the challenges of targeting this pathway for therapeutic interventions, including receptor isoform diversity, blood-brain barrier penetration, and potential side effects. Future strategies may include the development of selective TrkB modulators, nanoparticle carriers for drug delivery, and innovative gene therapy techniques. Advancing the understanding of this complex signaling network holds promise for effective interventions in treating neurological and psychiatric disorders, ultimately enhancing neuroprotection and cognitive resilience.

Esketamine mitigates endotoxin-induced hippocampal injury by regulating calcium transient and synaptic plasticity via the NF-α1/CREB pathway.

Esketamine mitigates endotoxin-induced hippocampal injury by regulating calcium transient and synaptic plasticity via the NF-α1/CREB pathway.

Abstract 3617: Distinct immune signature and regulated genes in prostate cancer disparity

Abstract Prostate cancer is a biologically and clinically diverse disease, with incidence and mortality rates varying significantly among different racial and ethnic groups. In African American (AA) men, the incidence of prostate cancer is approximately 60% higher, and the mortality rate is two to three times greater compared to Caucasian American (CA) men. These disparities are complex and encompass various biological and social determinants, including genetic predisposition, comorbid conditions, socioeconomic status, and environmental influences. The interplay of these elements has a clear association with disease outcomes. Recent research highlights the role of the tumor immune landscape and its associated genes in regulating prostate cancer biology at every stage of progression, ultimately impacting patient outcomes. We hypothesize that variations in immune cell gene signatures within tumors across different racial groups may influence prostate cancer outcomes. To investigate this, we analyzed transcriptomic data from 35 radical prostatectomy specimens obtained from treatment-naive patients, comprising 20 AA men and 15 CA men with prostate cancer. This analysis focused on the gene expression profiles of primary prostate tumors and adjacent normal tissues. We specifically selected immune-related genes to assess the immune-oncological differences between AA and CA prostate tumors, utilizing bioinformatics platforms such as EPIC, xCell, and IPA. To evaluate race-specific differential gene expression, we employed a rank test, and the effect of each gene’s expression on overall survival was further analyzed using a univariate Cox regression model. Prostate tumors in AA patients exhibit significant enrichment in the tumor microenvironment and a distinct gene immune profile compared to those in CA men. In AA patients we observed elevated z-scores in pathways such as CREB signaling, Th1 and Th2 pathways, dendritic cell maturation, IL-17 signaling, TREM1 signaling, and cytokine production in macrophage and T Helper cells mediated by IL-17A and IL-17F. We also noted increased cytokine levels in epithelial cells influenced by IL-17A and IL-17F. Conversely, pathways like PD-1, PD-L1, ILK, IL-3, chemokine signaling, adrenomedullin, erythropoietin signaling, IGF-1, VEGF, and B-cell receptor signaling exhibited low z-scores in AA prostate tumors. Additionally, our analysis identified 13 major immune cell types, and 27 genes significantly associated with immune cell infiltration in AA prostate cancer. The expression levels of ARSL, BAALC, CCL23, EPHA2, IGFL2, KRT5, NTM, and NDP (p < 0.05) were linked to overall survival in AA prostate cancer patients. Taken together, prostate cancer in AA patients demonstrates a unique immune repertoire and gene profile, characterized by significant enrichment in pro-inflammatory immune pathways that correlate with poorer outcomes. Citation Format: Shiv Shankar Verma, Pingfu Fu, Gregory T MacLennan, Lee E Ponsky, Chen-Han Wilfred Wu, Jonathan E Shoag, Sanjay Gupta. Distinct immune signature and regulated genes in prostate cancer disparity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3617.

Deciphering the Pharmacological Mechanisms of Wen-Jing-Zhi-Tong Decoction in Treating Primary Dysmenorrhea by UPLC-Q-ExactiveOrbitrap-MS/MS with GC-MS and Network Pharmacology.

Primary dysmenorrhea (PDM) is a prevalent menstrual disorder among women, often underreported and undertreated. Wen-Jing-Zhi-Tong Decoction (WJZTD), a patented Traditional Chinese Medicine (TCM) herbal decoction, has shown efficacy in treating PDM. However, the underlying therapeutic mechanism of WJZTD in PDM treatment remains to be elucidated. This study aimed to employ integrative pharmacology and experimental validation to investigate the potential therapeutic mechanisms of WJZTD in treating PDM. The bioactive compounds of WJZTD were identified by UPLC-Q-Exactive-Orbitrap MS/MS and GC-MS. Putative targets of WJZTD were obtained from Swiss Target Prediction, STITCH, and BATMAN-TCM databases. Known targets of PDM were retrieved from Gene Cards and Drug Bank databases. Protein-to-protein interactions were constructed to screen key targets using the STRING database. Subsequently, GO and KEGG pathway enrichment analyses were performed based on Metascape. Finally, a PDM rat model was established to validate the potential therapeutic mechanisms of WJZTD using Western Blot, PCR, and ELISA. 390 bioactive compounds in WJZTD were identified through UPLC-Q-ExactiveOrbitrap MS/MS and GC-MS. Network pharmacology revealed 7 key compounds with 20 targets and pathways that are crucial for WJZTD in treating PDM. Behavioral tests confirmed that WJZTD can effectively ameliorate menstrual pain in PDM. WJZTD also inhibited prostaglandin production, thereby relieving uterine smooth muscle contraction. The downregulation of the BDNF/TrkB/ERK/CREB signaling pathway, identified as the key target and pathway through network pharmacology, may be crucial to the anti-nociceptive and anti-inflammatory effects of WJZTD in treating PDM. This study provides the first comprehensive analysis of the key compounds, targets, and pathways of WJZTD, laying a solid foundation for future pharmacological studies on PDM. The anti-nociceptive and anti-inflammatory effect may be attributed to the downregulation of the BDNF/TrkB/ERK/CREB signaling pathway.

Wuzhuyu Decoction Relieves Chronic Migraine by Regulating 5-HT1A and 3A Receptors-Mediated CREB Signaling Pathway in Brain and Intestine.

Background: Chronic migraine (CM) is a common complex nervous system disease, often accompanied by symptoms of the digestive tract that interact with each other, leading to prolonged and difficult-to-cure migraines. These symptoms are associated with abnormalities in 5-HT and its receptors. Wuzhuyu decoction (WZYD) is a traditional Chinese medicine prescription commonly used in clinics to treat CM; it relieves gastrointestinal symptoms, such as nausea and vomiting; however, its mechanism is still unclear. Investigating the differences in the role of WZYD compared to existing drugs targeting 5-HT receptors in the treatment of CM not only helps elucidate its pathogenesis but also provides possibilities for the development of new therapeutic approaches. Methods: An inflammation soup (IS)-induced CM male rat model was established. Based on a preliminary experiment, the target of WZYD in treating CM was determined by network pharmacology, and verified by molecular docking. ELISA, immunofluorescence, western blot, and real-time quantitative polymerase chain reaction (RT-qPCR) were used to evaluate the expression levels of CM-related indicators (5-HT, calcitonin gene-related peptide (CGRP), and c-Fos) to ensure the successful establishment of the CM model and the effectiveness of the drug. On this basis, the protein expression levels of 5-HT1A/3A receptors and their cAMP-response element binding protein (CREB) signaling pathway were detected by western blot and immunohistochemistry. The role of 5-HT1A/3A receptors in the treatment of CM by WZYD was validated using a 5-HT1A receptor antagonist (WAY 100635) and a 5-HT3A receptor agonist (SR 57227). Results: The results showed that WZYD increased the expression of 5-HT in the brain, decreased the expression of CGRP, c-Fos, ionized calcium-binding adapter molecule 1 (Iba1), and relieved CM. At the same time, WZYD also increased the expression of the 5-HT1A receptor and decreased the expression of the 5-HT3A receptor in the brain and colon of CM rats. Subsequently, WZYD further exerted its brain-gut integrated therapeutic effects by regulating the CREB signaling pathway mediated by 5-HT1A/3A receptors in the brain and colon of CM rats. Conclusions: WZYD not only regulates neurotransmitters in the brain and colon at the same time, but also specifically regulates 5-HT1A/3A receptors in the brain and colon, which explains the characteristics and advantages of WZYD from a new perspective. While effectively relieving headache symptoms, it also improves related gastrointestinal symptoms, which is more conducive to the treatment of CM.

Tanshinone IIA Reverses Osteogenic Differentiation of Bone Marrow Mesenchymal Stromal Cells Impaired by Glucocorticoids via the ERK1/2-CREB Signaling Pathway.

Glucocorticoids-induced osteoporosis poses a critical health issue due to its detrimental impact on bone marrow mesenchymal stem cells (BMSCs); Tanshinone IIA (TSA) emerges as a promising therapeutic intervention, demonstrating its capacity to reverse osteogenic differentiation impairment. The aim is to determine whether TSA enhances the osteogenic differentiation of BMSCs damaged by dexamethasone (DEX) through the ERK1/2 -CREB signaling pathway. BMSCs were treated with varying concentrations of DEX (0.1-30 μM) and TSA (0.04-5 μM) for 18 or 36 h. Cell viability was assessed using the MTT assay. Osteogenic differentiation was evaluated through Alizarin Red S staining and quantified by qRT-PCR for osteogenic markers such as Runx2 and ALP. Apoptosis was measured by Annexin V-FITC/PI staining and TUNEL/DAPI co-staining. The ERK1/2-CREB signaling pathway was examined using Western blot and immunofluorescence. TSA at 5 μM significantly bolstered BMSCs viability and osteogenic differentiation, reversing the deleterious effects of 30 μM DEX. TSA pre-treatment decreased apoptosis and ROS levels, and importantly, it enhanced the ERK1/2-CREB signaling pathway, as evidenced by increased phosphorylation of ERK1/2 and CREB. The ERK1/2 inhibitor PD98059 and siCREB abrogated TSA's protective effects, highlighting the pathway's significance. These findings indicate that TSA, through the ERK1/2-CREB axis, provides a protective strategy against DEX-induced impairment in BMSCs. TSA's modulation of the ERK1/2 -CREB pathway reverses DEX-induced osteogenic inhibition and apoptosis in BMSCs, suggesting its therapeutic efficacy against glucocorticoid-induced bone disorders.

The PDE4DIP-AKAP9 axis promotes lung cancer growth through modulation of PKA signalling

Phosphodiesterase 4D interacting protein (PDE4DIP) is a Golgi/centrosome-associated protein that plays critical roles in the regulation of microtubule dynamics and maintenance of the Golgi structure. However, its biological role in human cancer remains largely unknown. In this study, we showed that PDE4DIP is overexpressed in human non-small cell lung cancer (NSCLC) tissues and that upregulated PDE4DIP expression is associated with poor prognosis in patients with lung cancer. We demonstrated that PDE4DIP knockdown inhibits NSCLC cell proliferation in vitro and tumorigenicity in vivo. We further demonstrated that PDE4DIP knockdown triggers apoptosis and cell cycle arrest in NSCLC cells by activating the Protein kinase A (PKA) /CREB signalling pathway. PDE4DIP coordinates with A-kinase anchoring proteins 9 (AKAP9) to enhance the Golgi localization and stability of PKA RIIα. Depletion of PDE4DIP mislocalizes PKA RIIα from the Golgi and leads to its degradation, thereby compromising its negative regulatory effect on PKA signalling. Overall, our findings provide novel insights into the roles of the PDE4DIP-AKAP9 complex in regulating PKA signalling and NSCLC growth and highlight PDE4DIP as a promising therapeutic target for NSCLC.

Exploring the Analgesic Effect of Acupuncture on Knee Osteoarthritis Based on MLT/cAMP/PKA/CREB Signaling Pathway.

Acupuncture is an effective treatment for knee osteoarthritis (KOA), reducing pain and improving function. While melatonin (MLT) has notable pain relief benefits, the analgesic mechanism of acupuncture in KOA and its relationship with melatonin are still unknown. This study aims to explore this mechanism. In this work, the KOA rabbit model was constructed using the traditional Hulth method, and the therapeutic effect was assessed by the Lequesne MG score and Pain assessment by hot plate test. The pathological alterations of cartilage tissue were observed using hematoxylin and eosin (H&E) staining, Safranin O-fast green and MASSON staining to observe the pathological changes in cartilage tissue, and the efficacy was evaluated according to the principles of Mankin score and Osteoarthritis Research Society International (OARSI) score. Meanwhile, MLT in serum, cyclic adenosine monophosphate (cAMP) in cartilage, and matrix metalloproteinase-3 (MMP-3) in joint fluid were detected by enzyme-linked immunosorbent assay. In addition, the expression of aromatic L-amino acid N-acetyltransferase (AANAT), melatonin receptor 1 (MT1) and 2 (MT2) mRNAs in cartilage was determined by real-time quantitative reverse transcription-polymerase chain reaction, and the levels of proteins related to PKA/CREB signaling pathway were detected by Western blotting. Based on the results of Lequesne MG score and Pain assessment by hot plate test experimental data, the treatment group presented significant improvements in knee pain and overall function relative to OA (Osteoarthritis) group. Besides, according to results of histologic staining, Mankin and OARSI scores, articular cartilage degeneration of treatment group remarkably improved. In addition, acupuncture significantly reduced the expression of the inflammatory factor MMP-3 in knee joint fluid and significantly increased the levels of MLT, AANAT, MT1, MT2, cAMP, PKA and CREB. By regulating sympathetic excitability, acupuncture may activate the MLT/cAMP/PKA/CREB signaling pathway, decrease inflammatory factor expression and slow down degradation of articular cartilage, resulting in the relief of knee pain.

Epigenetics in Learning and Memory.

In animals, memory formation and recall are essential for their survival and for adaptations to a complex and often dynamically changing environment. During memory formation, experiences prompt the activation of a selected and sparse population of cells (engram cells) that undergo persistent physical and/or chemical changes allowing long-term memory formation, which can last for decades. Over the past few decades, important progress has been made on elucidating signaling mechanisms by which synaptic transmission leads to the induction of activity-dependent gene regulation programs during the different phases of learning (acquisition, consolidation, and recall). But what are the molecular mechanisms that govern the expression of immediate-early genes (IEGs; c-fos, Npas4) and plasticity-related genes (PRGs; Dlg4/PSD95 and Grin2b/NR2B) in memory ensemble? Studies in relatively simple in vitro and in vivo neuronal model systems have demonstrated that synaptic activity during development, or when induced by chemical stimuli (i.e., cLTP, KCl, picrotoxin), activates the NMDAR-Ca2+-CREB signaling pathway that upregulates gene expression through changes in the epigenetic landscape (i.e., histone marks and DNA methylation) and/or 3D chromatin organization. The data support a model in which epigenetic modifications in promoters and enhancers facilitate the priming and activation of these regulatory regions, hence leading to the formation of enhancer-promoter interactions (EPIs) through chromatin looping. The exploration of whether similar molecular mechanisms drive gene expression in learning and memory has presented notable challenges due to the distinct phases of learning and the activation of only sparse population of cells (the engram). Consequently, such studies demand precise temporal and spatial control. By combining activity-dependent engram tagging strategies (i.e., TRAP mice) with multi-omics analyses (i.e., RNA-seq, ChiP-seq, ATAC-seq, and Hi-C), it has been recently possible to associate changes in the epigenomic landscape and/or 3D genome architecture with transcriptional waves in engram cells of mice subjected to contextual fear conditioning (CFC), a relevant one-shot Pavlovian learning task. These studies support the role of specific epigenetic mechanisms and of the 3D chromatin organization during the control of gene transcription waves in engram cells. Advancements in our comprehension of the molecular mechanisms driving memory ensemble will undoubtedly play a crucial role in the development of better-targeted strategies to tackle cognitive diseases, including Alzheimer's disease and frontotemporal dementia, among other information-processing disorders.

CREB: A Promising Therapeutic Target for Treating Psychiatric Disorders.

Psychiatric disorders are complex, multifactorial illnesses. It is challenging for us to understand the underlying mechanism of psychiatric disorders. In recent years, the morbidity of psychiatric disorders has increased yearly, causing huge economic losses to the society. Although some progress, such as psychotherapy drugs and electroconvulsive therapy, has been made in the treatment of psychiatric disorders, including depression, anxiety, bipolar disorder, obsessive-compulsive and autism spectrum disorders, antidepressants and psychotropic drugs have the characteristics of negative effects and high rate of relapse. Therefore, researchers continue to seek suitable interventions. cAMP response element binding protein (CREB) belongs to a protein family and is widely distributed in the majority of brain cells that function as a transcription factor. It has been demonstrated that CREB plays an important role in neurogenesis, synaptic plasticity, and neuronal growth. This review provides a 10-year update of the 2013 systematic review on the multidimensional roles of CREB-mediated transcriptional signaling in psychiatric disorders. We also summarize the classification of psychiatric disorders and elucidate the involvement of CREB and related downstream signalling pathways in psychiatric disorders. Importantly, we analyse the CREB-related signal pathways involving antidepressants and antipsychotics to relieve the pathological process of psychiatric disorders. This review emphasizes that CREB signalling may have a vast potential to treat psychiatric disorders like depression. Furthermore, it would be helpful for the development of potential medicine to make up for the imperfection of current antidepressants and antipsychotics.

Lipoteichoic Acid Rescued Age-Related Bone Loss by Enhancing Neuroendocrine and Growth Hormone Secretion Through TLR2/COX2/PGE2 Signalling Pathway.

The phenomenon of brain-bone crosstalk pertains to the intricate interaction and communication pathways between the central nervous system and the skeletal system. Disruption in brain-bone crosstalk, particularly in disorders such as osteoporosis, can result in skeletal irregularities. Consequently, investigating and comprehending this communication network holds paramount importance in the realm of bone disease prevention and management. In this study, we found that Staphylococcus aureus lipoteichoic acid promoted the conversion of arachidonic acid to PGE2 by interacting with TLR2 receptors acting on the surface of microglial cells in the pituitary gland, leading to the upregulation of COX-2 expression. Subsequently, PGE2 bound to the EP4 receptor of growth hormone-secreting cells and activated the intracellular CREB signalling pathway, promoting GH secretion and ameliorating age-related bone loss.

The role of CREB and MAPK signaling pathways in ATLL patients

BackgroundHTLV-1 is a worldwide distribution retrovirus with 10–20 million infected individuals. ATLL is an Adult T-cell leukaemia lymphoma caused by aggressive T-cell proliferation that is infected by HTLV-1 and is associated with an inferior prognosis. The exact molecular pathogenesis has yet to be fully understood. CREB, a transcription factor, acts as a molecular switch that controls the expression of numerous genes in response to various extracellular signals. Its activation is primarily mediated through phosphorylation by multiple kinases, including MAPKs. MAPKs, a family of serine/threonine kinases, serve as crucial mediators of intracellular signaling cascades.Method and materialThis study investigated, 38 HTLV-I-infected individuals, including 18 HTLV-1 asymptomatic carriers (ACs) and 20 ATLL subjects. mRNA was extracted and converted to cDNA from Peripheral blood mononuclear cells (PBMCs), and then the expression of TAX, HBZ, CREB, and MAPK was analyzed by TaqMan qPCR. The genomic HTLV-1 Proviral loads were examined among the study group.ResultsThe data analysis showed a significant difference in the mean of CREB expression amongst study groups (ATLL and carriers, (p = 0.002). There is no statistical difference between the MAPK gene expression (p = 0.35). HBZ, TAX, and HTLV-1 proviral load weree significantly higher in ATLL subjects compared to ACs (p = 0.002, 0.000, and 0.000), respectively. Moreover, our results, demonstrated a direct positive correlation among HBZ, CREB, and TAX gene expression in ATLL patients (p = 0.001), whilst between the ACs, TAX gene expression had a positive significant correlation with HBZ and HTLV-1 proviral load (p = 0.007 and p = 0.004, respectively).ConclusionThe present study demonstrated that CREB gene expression was higher in the ATLL group than ACs, while there was no difference for MAPK. Therefore, this pathway may not strongly involve in the activation of CREB. The CREB may be a prognostic factor for the development of HTLV-I-associated diseases and can be used as a monitoring marker for the efficiency of the therapeutic regime and prognosis.

Neuroprotective Effect of Ixeris dentata Extract on Trimethyltin-Induced Memory Impairment in Rats.

Alzheimer's disease (AD) is a representative neurodegenerative disease characterized by the structural and functional degeneration of neurons. The present study investigated the neuroprotective effect of Ixeris dentata (ID) extract on trimethyltin (TMT)-induced memory deficit in the rat. Cognitive improving effect and neuronal activity of ID were assessed by using Morris water maze (MWM) test and choline acetyltransferase (ChAT), cAMP-response element-binding protein (CREB) immunohistochemistry. Seven days after TMT injection (8.0 mg/kg, i.p.), each group of rats was administered saline, water extract of ID (WID, 400 or 800 mg/kg, p.o.), ethanol extract of ID (EID, 400 or 800 mg/kg, p.o.), or caffeic acid (CAF, 30 mg/kg, i.p.) daily for fourteen days. Results: Treatment with EID and CAF produced a significant improvement in escape latency time of the acquisition, and retention time in the target area of the MWM task. Additionally, administration of EID or CAF markedly alleviated TMT-induced loss of ChAT- and CREB-immunoreactive cells in the hippocampus. The results demonstrated that EID has a protective effect against TMT-induced memory deficit, partly through increasing the CREB and cholinergic signaling pathway in the hippocampus. These results suggest that ethanol extracts of ID might be useful for improving cognitive functions in neurodegenerative diseases such as Alzheimer's disease.

Effect of recombinant irisin on recombinant human bone morphogenetic protein-2 induced osteogenesis and osteoblast differentiation

Effect of recombinant irisin on recombinant human bone morphogenetic protein-2 induced osteogenesis and osteoblast differentiation

Oxysterol Sensing Through GPR183 Triggers Endothelial Senescence in Hypertension.

Despite endothelial dysfunction being an initial step in the development of hypertension and associated cardiovascular/renal injuries, effective therapeutic strategies to prevent endothelial dysfunction are still lacking. GPR183 (G protein-coupled receptor 183), a recently identified G protein-coupled receptor for oxysterols and hydroxylated metabolites of cholesterol, has pleiotropic roles in lipid metabolism and immune responses. However, the role of GPR183 in the regulation of endothelial function remains unknown. Endothelial-specific GPR183 knockout mice were generated and used to examine the role of GPR183 in endothelial senescence by establishing 2 independent hypertension models: desoxycorticosterone acetate/salt-induced and Ang II (angiotensin II)-induced hypertensive mice. Echocardiography, transmission electron microscopy, blood pressure measurement, vasorelaxation response experiments, flow cytometry analysis, and chromatin immunoprecipitation analysis were performed in this study. Endothelial GPR183 was significantly induced in hypertensive mice, which was further confirmed in renal biopsies from subjects with hypertensive nephropathy. Endothelial-specific deficiency of GPR183 markedly alleviated cardiovascular and renal injuries in hypertensive mice. Moreover, we found that GPR183 regulated endothelial senescence in both hypertensive mice and aged mice. Mechanistically, GPR183 disrupted circadian signaling by inhibiting PER1 (period circadian regulator 1) expression, thereby facilitating endothelial senescence and dysfunction through the cAMP (cyclic adenosine monophosphate)/PKA (protein kinase A)/CREB (cAMP-response element binding protein) signaling pathway. Importantly, pharmacological inhibition of the oxysterol-GPR183 axis by NIBR189 or clotrimazole ameliorated endothelial senescence and cardiovascular/renal injuries in hypertensive mice. This study discovers a previously unrecognized role of GPR183 in promoting endothelial senescence. Pharmacological targeting of GPR183 may be an innovative therapeutic strategy for hypertension and its associated complications.

Linking activation of synaptic NMDA receptors-induced CREB signaling to brief exposure of cortical neurons to oligomeric amyloid-beta peptide.

Amyloid-beta peptide oligomers (AβO) have been considered "primum movens" for a cascade of events that ultimately cause selective neuronal death in Alzheimer's disease (AD). However, initial events triggered by AβO have not been clearly defined. Synaptic (Syn) N-methyl-d-aspartate receptors (NMDAR) are known to activate cAMP response element-binding protein (CREB), a transcriptional factor involved in gene expression related to cell survival, memory formation and synaptic plasticity, whereas activation of extrasynaptic (ESyn) NMDARs was linked to excitotoxic events. In AD brain, CREB phosphorylation/activation was shown to be altered, along with dyshomeostasis of intracellular Ca2+ (Ca2+ i). Thus, in this work, we analyze acute/early and long-term AβO-mediated changes in CREB activation involving Syn or ESyn NMDARs in mature rat cortical neurons. Our findings show that acute AβO exposure produce early increase in phosphorylated CREB, reflecting CREB activity, in a process occurring through Syn NMDAR-mediated Ca2+ influx. Data also demonstrate that AβO long-term (24 h) exposure compromises synaptic function related to Ca2+-dependent CREB phosphorylation/activation and nuclear CREB levels and related target genes, namely Bdnf, Gadd45γ, and Btg2. Data suggest a dual effect of AβO following early or prolonged exposure in mature cortical neurons through the activation of the CREB signaling pathway, linked to the activation of Syn NMDARs.

Ginsenoside Re Prevents Depression-like Behaviors via Inhibition of Inflammation, Oxidative Stress, and Activating BDNF/TrkB/ERK/CREB Signaling: An In Vivo and In Vitro Study.

Depression is a widespread disease, with high mortality and recurrence rates. Recent studies have shown that elevated cytokine levels are implicated in the molecular mechanisms of depression. Oxidative stress contributes to the stimulation of cytokine production. Growing evidence suggests that ginsenoside Re (Gs-Re) exerts a neuroprotective effect on the hippocampus by suppressing oxidative stress and inflammation. However, the effect and mechanism of Gs-Re in the treatment of depression remain understudied. This study aimed to evaluate the neuroprotective and antidepressant-like effects of Gs-Re and the possible underlying mechanisms. In this article, the antidepressant-like effect of the Gs-Re was studied both in vitro (H2O2-induced oxidative stress in HT-22 cells) and in vivo (reserpine-induced depressive model mice). Our results indicated that, at the cellular level, Gs-Re effectively enhanced cell survival following H2O2 stimulation, inhibited the mass production of oxidative stress markers (MDA and ROS), and prevented the occurrence of apoptosis. Moreover, Gs-Re significantly reduced the levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α and restored the abnormal mitochondrial membrane potential. Subsequently, Gs-Re treatment reversed reserpine-induced neuroinflammation and depressive-like behaviors in vivo and inhibited microglia overactivation. Furthermore, the alterations in the BDNF/TrkB/ERK/CREB signaling pathway induced by H2O2 or reserpine in HT-22 cells or in the mouse hippocampus were significantly reversed by Gs-Re. K252a blocked the improvement of Gs-Re on depression-like behavior and eliminated the inhibition of oxidative stress and neuroinflammation in vivo. This study suggested that Gs-Re produces neuroprotective and depressive effects by inhibiting oxidative stress and inflammation and activating the BDNF/TrkB/ERK/CREB pathway.

The Anti-Melanogenic Effects of Ganodermanontriol from the Medicinal Mushroom Ganoderma lucidum through the Regulation of the CREB and MAPK Signaling Pathways in B16F10 Cells.

Ganoderma lucidum, a member of the Basidiomycetes family, is attracting attention for its medicinal potential due to its biological activity and the presence of numerous bioactive compounds. Although it is known that extracts of this mushroom inhibit melanin production, there are few reports on a single substance associated with this effect. In this study, we identified ganodermanontriol (GT), a novel compound from G. lucidum, that effectively inhibited melanin biosynthesis in B16F10 cells. GT inhibits melanin production by suppressing the expression of cellular tyrosinase proteins and microphthalmia-related transcription factor (MITF). Furthermore, GT affects the phosphorylation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and mitogen-activated protein kinase (MAPK) signaling molecules, which are involved in melanogenesis in B16F10 cells. Finally, the biosynthesis of GT and other substances by G. lucidum was evaluated using HPLC analysis. Thus, this study revealed the mechanism by which GT in G. lucidum inhibits melanin production in B16F10 cells, and these findings will contribute to promoting the potential use of this mushroom in the future.

Mahuang Fuzi Xixin decoction: A potent analgesic for neuropathic pain targeting the NMDAR2B/CaMKIIα/ERK/CREB pathway

Mahuang Fuzi Xixin decoction: A potent analgesic for neuropathic pain targeting the NMDAR2B/CaMKIIα/ERK/CREB pathway

The Role of the CREB Signaling Pathway in Tumor Development and Therapeutic Potential

Review The Role of the CREB Signaling Pathway in Tumor Development and Therapeutic Potential Qunlong Jin 1,2,†, Youheng Jiang 1,2,†, Zhiheng Zhang 1,3,†, Yanming Yang 1, Zhang Fu 1, Yunfeng Gao 1,4, Ningning Li 1,5, Yulong He 2,*, and Changxue Li 1,2,* 1 Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China 2 Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China 3 The Affiliated High School of Shenzhen University, Shenzhen, 518066, China 4 Department of Otolaryngology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China 5 China-UK Institute for Frontier Science, Shenzhen, 518107, China † These authors contributed equally to this work. * Correspondence: heyulong@mail.sysu.edu.cn (Y.L.H.); lichx59@mail2.sysu.edu.cn (C.X.L.) Received: 2 May 2024; Revised: 19 May 2024; Accepted: 20 May 2024; Published: 11 June 2024 Abstract: The cAMP response element-binding protein (CREB) is a multifunctional transcription factor belonging to the basic leucine zipper (bZIP) family of proteins. It regulates the expression of target genes by binding to the cAMP response element (CRE) on DNA. The activation of CREB in cells typically depends on its phosphorylation, mediated by kinases activated by various signaling pathways, such as the cAMP-dependent protein kinase A (PKA) pathway and the PI3K-AKT pathway. CREB regulates genes involved in various cellular functions, including cell growth, differentiation, survival, as well as the development and plasticity of the nervous system. Therefore, CREB plays a key role in the development of neurological diseases, oncology, and other diseases. This review aims to systematically elucidate the structure and regulatory mechanisms of CREB, its biological function in tumors, and the potential of targeting the CREB signaling pathway in anti-tumor therapy, with the hope of providing new strategies and targets for cancer treatment.