CREB Research Articles

Memory Decline and Aberration of Synaptic Proteins in X-Linked Moesin Knockout Male Mice

Objective This study aims to investigate may moesin deficiency resulted in neurodevelopmental abnormalities caused by negative impact on synaptic signaling ultimately leading to synaptic structure and plasticity.Methods Behavioral assessments measured neurodevelopment (surface righting, negative geotaxis, cliff avoidance), anxiety (open field test, elevated plus maze test), and memory (passive avoidance test, Y-maze test) in moesin-knockout mice (KO) compared to wild-type mice (WT). Whole exome sequencing (WES) of brain (KO vs. WT) and analysis of synaptic proteins were performed to determine the disruption of signal pathways downstream of moesin. Risperidone, a therapeutic agent, was utilized to reverse the neurodevelopmental aberrance in moesin KO.Results Moesin-KO pups exhibited decrease in the surface righting ability on postnatal day 7 (p<0.05) and increase in time spent in the closed arms (p<0.01), showing increased anxiety-like behavior. WES revealed mutations in pathway aberration in neuron projection, actin filament-based processes, and neuronal migration in KO. Decreased cell viability (p<0.001) and expression of soluble NSF adapter protein 25 (SNAP25) (p<0.001) and postsynaptic density protein 95 (PSD95) (p<0.01) was observed in days in vitro 7 neurons. Downregulation of synaptic proteins, and altered phosphorylation levels of Synapsin I, mammalian uncoordinated 18 (MUNC18), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB) was observed in KO cortex and hippocampus. Risperidone reversed the memory impairment in the passive avoidance test and the spontaneous alternation percentage in the Y maze test. Risperidone also restored the reduced expression of PSD95 (p<0.01) and the phosphorylation of Synapsin at Ser605 (p<0.05) and Ser549 (p<0.001) in the cortex of moesin-KO.Conclusion Moesin deficiency leads to neurodevelopmental delay and memory decline, which may be caused through altered regulation in synaptic proteins and function.

Histone Deacetylation in Alzheimer's Diseases (AD); Hope or Hype.

Histone acetylation is the process by which histone acetyltransferases (HATs) add an acetyl group to the N-terminal lysine residues of histones, resulting in a more open chromatin structure. Histone acetylation tends to increase gene expression more than methylation does. In the central nervous system (CNS), histone acetylation is essential for controlling the expression of genes linked to cognition and learning. Histone deacetylases (HDACs), "writing" enzymes (HATs), and "reading" enzymes with bromodomains that identify and localize to acetylated lysine residues are responsible for maintaining histone acetylation. By giving animals HDAC inhibitors (HDACis), it is possible to intentionally control the ratios of "writer" and "eraser" activity, which will change the acetylation of histones. In addition to making the chromatin more accessible, these histone acetylation alterations re-allocate the targeting of "readers," including the transcriptional co-activators, cAMP response element-binding protein (CBP), and bromodomain-containing protein 4 (Brd4) in the CNS. Conclusive evidence has shown that HDACs slow down the progression of Alzheimer's disease (AD) by reducing the amount of histone acetylation, decreasing the activity of genes linked to memory, supporting cognitive decline and Amyloid beta (Aβ) protein accumulation, influencing aberrant tau phosphorylation, and promoting the emergence of neurofibrillary tangles (NFTs). In this review, we have covered the therapeutic targets and functions of HDACs that might be useful in treating AD.

The Primary Cilia are Associated with the Axon Initial Segment in Neurons.

The primary cilia serve as pivotal mediators of environmental signals and play crucial roles in neuronal responses. Disruption of ciliary function has been implicated in neuronal circuit disorders and aberrant neuronal excitability. However, the precise mechanisms remain elusive. To study the link between the primary cilia and neuronal excitability, manipulation of somatostatin receptor 3 (SSTR3) is investigated, as an example of how alterations in ciliary signaling may affect neuronal activity. It is found that aberrant SSTR3 expression perturbed not only ciliary morphology but also disrupted ciliary signaling cascades. Genetic deletion of SSTR3 resulted in perturbed spatial memory and synaptic plasticity. The axon initial segment (AIS) is a specialized region in the axon where action potentials are initiated. Interestingly, loss of ciliary SSTR3 led to decrease of Akt-dependent cyclic AMP-response element binding protein (CREB)-mediated transcription at the AIS, specifically downregulating AIS master organizer adaptor protein ankyrin G (AnkG) expression. In addition, alterations of other ciliary proteins serotonin 6 receptor (5-HT6R)and intraflagellar transport protein 88 (IFT88) also induced length changes of the AIS. The findings elucidate a specific interaction between the primary cilia and AIS, providing insight into the impact of the primary cilia on neuronal excitability and circuit integrity.

Transcriptional regulation of daily sleep amount by TCF4–HDAC4–CREB complex in mice

Abstract Histone deacetylase HDAC4/5 cooperates with cAMP response element-binding protein (CREB) in the transcriptional regulation of daily sleep amount downstream of LKB1-SIK3 kinase cascade in mice. Here, we report a significant enrichment of the E-box motifs for the basic loop–helix–loop (bHLH) proteins near the CREB- and HDAC4-binding sites in the mouse genome. Adeno-associated virus-mediated expression of class I bHLH transcription factors, such as TCF4, TCF3, or TCF12, across the mouse brain neurons reduces the duration of rapid eye movement sleep (REMS) and non-REMS (NREMS). TCF4 requires its bHLH domain to regulate REMS or NREMS amount, of which the latter is mostly independent of the E-box-binding activity. Consistent with that TCF4 interacts with CREB and HDAC4 via the bHLH domain, TCF4 relies on CREB and partly on HDAC4 to regulate NREMS/REMS amount. Conversely, the ability of CREB to regulate sleep duration also requires its binding to TCF4 and HDAC4. Together, these results indicate that TCF4, HDAC4, and CREB could function cooperatively in the transcriptional regulation of daily sleep amount in mice.

LncRNA SNHG4 enhanced gastric cancer progression by modulating miR-409-3p/CREB1 axis.

Gastric cancer (GC) is a globally common cancer characterized by high incidence and mortality worldwide. Advances in the molecular understanding of GC provide promising targets for GC diagnosis and therapy. Long non-coding RNAs (lncRNAs) and their downstream regulators are regarded to be implicated in the progression of multiple types of malignancies. Studies have shown that the lncRNA small nucleolar RNA host gene 4 (SNHG4) serves as a tumor promoter in various malignancies, while its function in GC has yet to be characterized. Therefore, our study aimed to explore the role and underlying mechanism of SNHG4 in GC. We used qRT-PCR to analyze SNHG4 expression in GC tissues and cells. Kaplan-Meier analysis was used to assess the correlation between SNHG4 expression and the survival rate of GC patients. Cellular function experiments such as CCK-8, BrdU, colony formation, flow cytometry analysis, and transwell were performed to explore the effects of SNHG4 on GC cell proliferation, apoptosis, cell cycle, migration, and invasion. We also established xenograft mouse models to explore the effect of SNHG4 on GC tumor growth. Mechanically, dual luciferase reporter assay was used to verify the interaction between SNHG4 and miR-409-3p and between miR-409-3p and cAMP responsive element binding protein 1 (CREB1). The results indicated that SNHG4 was overexpressed in GC tissues and cell lines, and was linked with poor survival rate of GC patients. SNHG4 promoted GC cell proliferation, migration, and invasion while inhibiting cell apoptosis and cell cycle arrest in vitro. The in vivo experiment indicated that SNHG4 facilitated GC tumor growth. Furthermore, SNHG4 was demonstrated to bind to miR-409-3p. Moreover, CREB1 was directly targeted by miR-409-3p. Rescue assays demonstrated that miR-409-3p deficiency reversed the suppressive impact of SNHG4 knockdown on GC cell malignancy. Additionally, miR-409-3p was also revealed to inhibit GC cell proliferation, migration, and invasion by targeting CREB1. In conclusion, we verified that the SNHG4 promoted GC growth and metastasis by binding to miR-409-3p to upregulate CREB1, which may deepen the understanding of the underlying mechanism in GC development.

GABARAPL1 is essential for ACR-induced autophagic cell death of mouse Leydig cells

Acrylamide (ACR), a chemical extensively utilized in industry and food processing sectors, has been recognized for its potentially irreversible adverse effect on male reproductive system; however, the underlying mechanism remains elusive. Our study reveals that ACR markedly triggers oxidative stress-mediated autophagy and upregulates the expression of GABAA-receptor-associated protein like-1 (GABARAPL1). Intriguingly, overexpression of GABARAPL1 significantly induces autophagy, while its knockdown alleviates ACR-induced autophagic responses, underscoring its pivotal function. Furthermore, we demonstrate that transcription factors cAMP response element-binding protein 1 (CREB1) and POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) synergistically enhance Gabarapl1 gene transcription by interacting with its promoter region, contributing to ACR-induced autophagy in mouse Leydig cells. Notably, our findings suggest a reciprocal regulation between PATZ1 and CREB1. This study suggests the critical role of GABARAPL1 in ACR-induced autophagy of mouse Leydig cells, shedding light on the underlying mechanism of ACR-caused male reproductive impairment.

Effects of Age and Atomoxetine on Olfactory Perception and Learning and Underlying Plasticity Mechanisms in Rats.

The locus coeruleus (LC) plays a vital role in cognitive function through norepinephrine release. Impaired LC neuronal health and function is linked to cognitive decline during ageing and Alzheimer's disease. This study investigates age-related alterations in olfactory detection and discrimination learning, along with its reversal, in Long-Evans rats, and examines the effects of atomoxetine (ATM), a norepinephrine uptake inhibitor, on these processes. Adult (6-9 months) and aged (22-24 months) Long-Evans rats underwent odour detection threshold experiments with saline and two doses of ATM (0.3 and 1 mg/kg). Reward-based odour discrimination learning included simple, difficult and reversal learning tasks. LC neuron density, dopamine beta-hydroxylase and norepinephrine transporter expression in the piriform cortex (PC) and orbitofrontal cortex were measured. Reversal learning and olfactory threat extinction were used to measure behavioural flexibility. Immunohistochemistry and western blotting were used to analyse phosphorylated cAMP response element binding protein (pCREB) and cFos expression and exvivo electrophysiology assessed long-term depression (LTD) in the PC. Whereas adult and aged cohorts showed similar odour detection and discrimination learning, fewer aged rats acquired reversal learning successfully. ATM improved reward-based odour discrimination in adults but hindered learning reversal. A delayed CREB phosphorylation in the posterior PC associated with atomoxetine administration possibly underlies learning enhancement. ATM resulted in less freezing behaviour in a threat conditioning and extinction paradigm at moderate, but not at higher doses. ATM administration exvivo prevented PC LTD. These findings highlight the intricate effects of atomoxetine, influenced by target structures, and suggest potential interactions with other neurotransmitters. Our results contribute to understanding the impact of ageing and norepinephrine enhancers on cognitive processes.

Role of BDNF-TrkB signaling in the improvement of motor function and neuroplasticity after ischemic stroke in rats by transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS) has an impact on improving cognitive and motor dysfunction induced by ischemia-reperfusion injury. However, to use this technology more rationally in clinical practice, a deepened understanding of the molecular mechanisms behind its therapeutic effects is needed. This study explored the role of the brain-derived neurotrophic factor(BDNF) and its associated receptor tropomyosin-receptor kinase B(TrkB) while deciphering the underlying mechanisms in transcranial direct current therapy to treat ischemic stroke. A middle cerebral artery occlusion-reperfusion(MCAO/R) model was established in rats to observe tDCS effects on brain damage. Behavioral tests, the modified neurologic severity score(mNSS), and the Hoffman reflex / the M wave(Hmax/Mmax) ratio helped assess motor function and neurologic deficits. HE and Nissl staining helped observe the morphological changes and count of nerve cells. We tested the expression of growth-associated protein-43(Gap-43) and microtubule-associated protein-2(Map-2), K+-Cl- co-transporter 2(KCC2), γ-aminobutyric acid(GABA), and key BDNF-TrkB downstream signaling, the phospholipase C gamma(PLCγ) / CaMK IV / cAMP response element binding protein(CREB), and extracellular signal-regulated protein kinase(ERK1/2) / ribosomal S6 kinase(RSK) using western blotting. Moreover, BDNF was analyzed in plasma using the enzyme-linked immunosorbent assay (ELISA) to investigate the tDCS effect on human BDNF expression levels. Finally, a BDNF receptor antagonist, ANA-12, was administered to explore the tDCS mechanism mediating BDNF-TrkB signaling. After tDCS treatment, the mNSS was improved, and the motor function was restored. Moreover, tDCS decreased cell swelling after MCAO/R and enhanced the number of neurons. tDCS treatment increased: (1) BDNF, Gap-43, Map-2 expression, (2) KCC2, GABA, and (3) PLCγ, CaMK IV, CREB and ERK1/2, RSK. Furthermore, ELISA results indicate that tDCS elevated human plasma BDNF protein expression. However, the therapeutic effect of tDCS was suppressed to a certain extent by adding ANA-12. Our findings indicate that tDCS may exert a neuroprotective effect by activating the downstream key molecules of BDNF-TrkB expression, for instance, PLCγ/ CaMK IV/ CREB and ERK/ RSK pathway. Moreover, tDCS can control neuronal excitability, promote axonal regeneration, and accelerate motor function recovery in ischemia reperfusion-injured rats.

The effect of Naringin on cognitive function, oxidative stress, cholinergic activity, CREB/BDNF signaling and hippocampal cell damage in offspring rats with utero-placental insufficiency-induced intrauterine growth restriction.

Intrauterine growth restriction (IUGR) induced by utero-placental insufficiency (UPI) results in delayed neural development and impaired brain growth. This study investigates the effects of Naringin (Nar) on memory, learning, cholinergic activity, oxidative stress markers, hippocampal CREB/BDNF signal pathway and cell damage in offspring of rats exposed to UPI. Twenty pregnant Wistar rats were randomly assigned to four groups: control, sham surgery, UPI+NS (UPI + normal saline as a vehicle), and UPI+Nar (UPI + Nar at 100mg/kg/day). UPI was induced by permanently occluding the uterine anterior vessels on embryonic day (ED) 18. Naringin or saline was administered orally from ED15 to ED21. Behavioral assessments of offspring, including working memory, avoidance learning, and anxiety-like behavior, were conducted on a postnatal day (PND) 21. Subsequently, hippocampal acetylcholinesterase (AChE) activity, catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (TAC), malondialdehyde (MDA), hippocampal transcript level of cyclic AMP response element-binding protein (CREB) and brain derived neurotrophic factor (BDNF) and apoptotic neuron density in the hippocampus were evaluated. Naringin-treated rats demonstrated significant improvements in working and avoidance memory, increases in CAT, SOD, and TAC, CREB, BDNF and reductions in AChE activity, MDA levels, apoptotic neuron density, and anxiety-like behaviors compared to the UPI+NS group (p<0.05). Naringin mitigates hippocampal cell damage, cognitive impairments, and anxiety by enhancing antioxidant defenses, modulating cholinergic activity and CREB/BDNF signaling in the brains of UPI-exposed offspring.

Early-life bisphenol A exposure causes detrimental age-related changes in anxiety, depression, learning, and memory in juvenile and adult male rats: Involvement of NMDAR/PSD-95–PTEN/AKT signaling pathway

Bisphenol A (BPA) is an endocrine disruptor monomer that is widely used in the manufacturing of epoxy resins and polycarbonate plastics. Several lines of evidence indicate the function of the pre- or perinatally PI3K/AKT signaling pathway in the development of psychiatric disorders. The present study aimed to evaluate for the first time the effect of modifying the NMDAR/PSD-95–PTEN/AKT signaling pathway on behavioral and synaptic plasticity of early-life BPA exposure and its long-lasting influence on juvenile and adulthood stages of development. We investigated the effects of oral BPA doses of 50 and 125mg/kg/day on the prefrontal cortex (PFC) and hippocampus of male Sprague Dawley rats from postnatal day (PND) 18–60 and PND 18–95, which correspond to juvenile and adolescent stages, respectively. Subsequently, we performed a series of rat behavioral tests, including the open field, elevated plus-maze, forced swimming, and Y-maze. Notably, neurotransmitter levels such as dopamine, serotonin, and gamma-aminobutyric acid, levels of postsynaptic density protein 95 and cAMP response element-binding protein, as well as mRNA levels of N-methyl-D-aspartate receptor subunits, fluctuated between reduction and elevation in the PFC and hippocampus. Furthermore, phosphatase and tensin (PTEN) mRNA and protein levels were upregulated in both brain areas, while PI3K, protein kinase B (AKT) and mammalian target of rapamycin (mTOR) mRNA and protein levels were decreased. Finally, our findings indicate that postnatal BPA exposure promotes long-term anxiety and depressive-like behaviors, as well as cognitive impairment, via modulation of the NMDAR/PSD-95–PTEN/AKT pathway. These findings could help to elucidate the potential developmental and neurobehavioral effects of early-life BPA exposure.

Upregulation of cAMP/PKA/CREB signaling mediated by GABABR might contribute to the amelioration effects of sea cucumber peptides (Acaudina leucoprocta) on cognitive dysfunction in mice

This study aimed to determine the effects and underlying mechanisms of sea cucumber peptides (SCP) obtained from Acaudina leucoprocta in mitigating induced by D-galactose cognitive dysfunction in mice. Additionally, it aimed to validate the cognitive-enhancing potential of peptides identified via in silico and peptidomics using SH-SY5Y cells. The results demonstrated significant improvement in behavioral performance with oral administration of SCP. Additionally, SCP normalized oxidative stress and neurotransmitter imbalances (especially gamma-aminobutyric acid, GABA). Also, SCP effectively rectified gut microbiota dysbiosis. Mechanistically, SCP activated the γ-aminobutyric acid type B receptors (GABABR)/ cyclic adenosine monophosphate (cAMP)/ cAMP-dependent protein kinase A (PKA)/ cAMP response element-binding protein (CREB) axis to promote GABA release and alleviate neuronal and oxidative stress damage, which subsequently ameliorated cognitive dysfunction. Furthermore, docking analysis predicted the binding of fourteen peptides with high abundance and PeptideRanker scores to GABABR. Notably, Lys-Gly-Phe-Pro (KGFP) had the strongest binding affinities and actively interacted with GABABR sites through hydrogen bonds, van der Waals, hydrophobic, and electrostatic interactions. The capacity of KGFP to improve cognitive function was further demonstrated when the SH-SY5Y cells were subjected to D-galactose. These results imply that the implementation of SCP intervention could be a useful tactic for improving cognitive function.

Cilostazol Counteracts Mitochondrial Dysfunction in Hepatic Encephalopathy Rat Model: Insights into the role of cAMP/AMPK/SIRT1/ PINK-1/Parkin hub and p-CREB /BDNF/ TrkB neuroprotective trajectory.

A devasting stage of chronic hepatic dysfunction is strictly correlated with neurological impairment, signifying hepatic encephalopathy (HE). HE is a multifactorial condition; therefore, hyperammonemia, oxidative stress, neuroinflammation, and mitochondrial dysfunction interplay in HE's progressive development. Cilostazol (Clio) has shown promising neuroprotective and hepatoprotective effectiveness in different neuronal and hepatic disorders; however, its efficiency against HE hasn't yet been explored. This study aimed to investigate the protective role of Cilo against thioacetamide (TAA)-induced HE in rats targeting mitochondrial dysfunction via modulation of Adenosine monophosphate-activated protein kinase (AMPK)/ Silent information regulator 1 (SIRT1) dependent pathways. Rats were allocated into three groups: the normal control group, the TAA group received (100 mg/kg, three times per week, for six weeks) to induce HE, and the Cilo group received (Cilo 100 mg/kg/day for six weeks, oral gavage) concurrently with TAA. Cilo counteracted HE indicated in the enhancement of cognitive impairment and the motor performance of rats (P<0.0001), modulation AMPK/SIRT1signaling pathway causing reduction of NF-kB p65 (P<0.0001) evoked inflammation along with histopathological alterations and glial fibrillary acidic protein (GFAP) immunoreactivity (P<0.0001), restoration nuclear factor E2-related factor 2 ( Nrf2 ) (P<0.0001) antioxidant effects, reduction of Bax and elevation of Bcl2 immunoreactivity (P<0.0001) in addition to boosting mitochondrial biogenesis by upregulation of PTEN-induced kinase-1 (PINK-1)/Parkin (P<0.0001)and restoration of Brain-derived neurotrophic factor (BDNF) (P=0.0002)/ tropomyosin-related kinase B (TrkB) (P<0.0001)/ cAMP response element-binding (CREB) (P<0.0001) neuroprotective axis. Collectively, Cilo activates the SIRT1 trajectory to abridge mitochondrial dysfunction invigorated in the HE rat model via restoration of mitochondrial hemostasis.

ZBED3 exacerbates hyperglycemia by promoting hepatic gluconeogenesis through CREB signaling

BackgroundElevated hepatic glucose production (HGP) is a prominent manifestation of impaired hepatic glucose metabolism in individuals with diabetes. Increased hepatic gluconeogenesis plays a pivotal role in the dysregulation of hepatic glucose metabolism and contributes significantly to fasting hyperglycemia in diabetes. Previous studies have identified zinc-finger BED domain-containing 3 (ZBED3) as a risk gene for type 2 diabetes (T2DM), and its single nucleotide polymorphism (SNPs) is closely associated with the fasting blood glucose level, suggesting a potential correlation between ZBED3 and the onset of diabetes. This study primarily explores the effect of ZBED3 on hepatic gluconeogenesis and analyzes the relevant signaling pathways that regulate hepatic gluconeogenesis. MethodsThe expression level of ZBED3 was assessed in the liver of insulin-resistant (IR)-related disease. RNA-seq and bioinformatics analyses were employed to examine the ZBED3-related pathway that modulated HGP. To investigate the role of ZBED3 in hepatic gluconeogenesis, the expression of ZBED3 was manipulated by upregulation or silencing using adeno-associated virus (AAV) in mouse primary hepatocytes (MPHs) and HHL-5 cells. In vivo, hepatocyte-specific ZBED3 knockout mice were generated. Moreover, AAV8 was employed to achieve hepatocyte-specific overexpression and knockdown of ZBED3 in C57BL/6 and db/db mice. Immunoprecipitation and mass spectrometry (IP-MS) analyses were employed to identify proteins that interacted with ZBED3. Co-immunoprecipitation (co-IP), glutathione S-transferase (GST) - pulldown, and dual-luciferase reporter assays were conducted to further elucidate the underlying mechanism of ZBED3 in regulating hepatic gluconeogenesis. ResultsThe expression of ZBED3 in the liver of IR-related disease models was found to be increased. Under the stimulation of glucagon, ZBED3 promoted the expression of hepatic gluconeogenesis-related genes PGC1A, PCK1, G6PC, thereby increasing HGP. Consistently, the rate of hepatic gluconeogenesis was found to be elevated in mice with hepatocyte-specific overexpression of ZBED3 and decreased in those with ZBED3 knockout. Additionally, the knockdown of ZBED3 in the liver of db/db mice resulted in a reduction in hepatic gluconeogenesis. Moreover, the study revealed that ZBED3 facilitated the nuclear translocation of protein arginine methyltransferases 5 (PRMT5) to influence the regulation of PRMT5-mediated symmetrical dimethylation of arginine (s-DMA) of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), which in turn affects the phosphorylation of CREB and ultimately promotes HGP. ConclusionsThis study indicates that ZBED3 promotes hepatic gluconeogenesis and serves as a critical regulator of the progression of diabetes.

Electroacupuncture pretreatment ameliorates Golgi stress and the inflammation response against endotoxin-induced lung injury.

Sepsis is a life-threatening condition involving organ dysfunction characterized by a generalized inflammatory syndrome, and the associated mortality rate is high. Electroacupuncture (EA) exerts benefits in endotoxemia-induced lung injury, mainly through lung inflammation reduction and cellular homeostasis, although the anti-inflammatory mechanisms underlying these benefits remain to be completely understood. Mice were pretreated with EA or sham EA therapy 5days prior to the induction of endotoxemia through the administration of lipopolysaccharide (LPS) and cecal ligation and puncture (CLP). Histopathological changes, systemic inflammation and cell death in the lungs were assessed. Transmission electron microscopy was employed to visually identify the structure of the Golgi complex. We examined proteins involved in maintaining the structural integrity of the Golgi apparatus and proteins associated with Golgi stress. The potential molecular mechanisms were investigated through overexpression of CREB3. EA pretreatment effectively rescued the lung from pathological changes, lung edema, cell apoptosis, and survival rate in septic mice, along with the improvement of physiological parameters. Endotoxemia strongly induces fragmented Golgi stacks, leading to fragmentation and disintegration of its shape, inducing cell apoptosis, and causing the outbreak of a large amount of inflammation in the lungs. EA therapy can significantly inhibit the fragmented process of Golgi stress to rescue the morphological changes and exert anti-inflammatory effects. And this protective effect may be related to upregulation of cAMP responsive element binding protein 3 (CREB3) and ADP-Ribosylation Factor 4 (ARF4), one of the key pathways involved in Golgi stress response. However, Sham EA (SEA) treatment did not substantially improve the fragmentation, stacking, and separation of Golgi organization, and inflammatory damage induced by endotoxin remains. This study discovered that overexpression of CREB3 may diminish the protective efficacy of EA. Administering EA pretreatment at precisely selected acupoints notably improves the survival rate in mice challenged with endotoxemia and concurrently exerts a protective effect against inflammatory lung injury. This salutary impact is speculated to be mediated through the augmentation of the Golgi apparatus's stress response.

Dexmedetomidine Improves Learning Functions in Male Rats Modeling Cognitive Impairment by Modulating the BDNF/TrkB/CREB Signaling Pathway.

Dexmedetomidine (DEX) is a selective alpha-2 adrenergic receptor agonist with sedative and anxiolytic properties. Increasing evidence reports that DEX has a neuroprotective effect. In this study, we investigated the potential effects of DEX on learning and memory functions in rats with experimental cognitive impairment. In the study, 21 adult male rats were used. The rats were divided into three groups, namely control, Scopolamine (SCOP) and SCOP + DEX. Cognitive impairment was induced with 1 mg/kg SCOP daily for 21 days. DEX was administered at a dose of 10 µg/kg between days 14 and 21 of the experiment. Following the injections, a spatial memory test was performed with a Morris Water Maze (MWM). At the end of the experiment, the hippocampus was dissected. The brain-derived neurotrophic factor (BDNF), acetylcholine (ACh) and acetylcholinesterase (AChE) levels were determined by ELISA. The tropomyosin receptor kinase B (TrkB) and Cyclic AMP-Response Element-Binding Protein (CREB) levels were measured by immunohistochemistry. DEX treatment improved the learning performance of rats compared to SCOP for 5 days. However, it did not significantly change memory performance. DEX increased the BDNF and ACh levels in the hippocampus while decreasing the AChE levels. Similarly, DEX treatment significantly increased CREB phosphorylation. No significant difference was observed between the TrkB receptor levels of the groups. This study demonstrated that the role of DEX in reducing SCOP-induced cognitive impairment is partially mediated by the increase in BDNF/TrkB/CREB signaling pathway activity.

Light Treatment Ameliorates Sub-chronic MK-801-Induced Cognitive Deficits in Mice Through Up-regulating BDNF/p-CREB/p-ERK Signaling Pathway.

Cognitive impairment associated with schizophrenia (CIAS) is considered a core symptom of the illness, yet effective treatments remain limited. Light plays an important role in regulating cognitive functions. However, the potential of light treatment (LT) to improve CIAS remains unknown. The current study aimed to investigate the efficacy of LT on CIAS and explore the underlying molecular mechanisms in a CIAS animal model. The CIAS group and the control group were sub-chronically administered MK-801 and saline, respectively. Concurrently, the LT/CIAS group, consisting of CIAS mice, received LT exposure (3000 Lux, 2h/day, for 3weeks). Results showed a significant enhancement in cognitive performance among LT/CIAS mice, as evidenced by improvements in the novel object recognition (NOR) test, novel location recognition (NLR) test, and Morris water maze (MWM) compared to the CIAS group. Remarkably, these beneficial effects of LT persisted for over 4weeks after the termination of LT. Furthermore, Golgi-cox staining unveiled an increased dendritic spine density and enhanced morphological complexity in hippocampal CA1 pyramidal neurons following 3weeks of LT. Subsequent investigations revealed elevated levels of brain-derived neurotrophic factor (BDNF) and heightened phosphorylation of cAMP response element-binding phosphorylation protein (p-CREB) in the hippocampus of the LT/CIAS group compared to the CIAS group. Moreover, LT elevated the phosphorylated extracellular signal-regulated kinase (p-ERK) in the hippocampus of the LT/CIAS group relative to the CIAS group. In conclusion, the current study demonstrates that long-term LT effectively ameliorated sub-chronic MK-801-induced cognitive deficits in mice, and the altered dendritic spine density and morphology of CA1 pyramidal neurons were rescued in the LT/CIAS group, potentially through the up-regulation of the BDNF/p-CREB/p-ERK signaling pathway in LT/CIAS mice.

Exploring the Neuroprotective Effects of Rufinamide in a Streptozotocin-Induced Dementia Model

Due to the complex pathophysiology of AD (Alzheimer’s Disease), there are currently no effective clinical treatments available, except for acetylcholinesterase inhibitors. However, CREB (cyclic AMP-responsive element binding protein) has been identified as the critical factor for the transcription in memory formation. Understanding the effect of potential drugs on the CREB pathway could lead to the development of new therapeutic molecules. Rufinamide has shown promise in improving memory in animal models, and these effects may be associated with modulation of the CREB pathway, however, this has not been previously reported. Thus, the present study aimed to determine the involvement of the CREB pathway in the cognitive improvement effects of rufinamide in STZ (streptozotocin) induced mouse model of dementia. Administration of STZ [3 mg/kg, i.c.v. (intracerebroventricular) bilaterally] significantly impaired cognitive performance in step-down passive avoidance and Morris water maze tests in animals, reduced brain endogenous antioxidant levels (GSH, superoxide dismutase, and catalase), and increased marker of brain oxidative stress [TBARS (thiobarbituric acid reactive substances)] and inflammation [IL-1β (Interleukin-1 beta), IL-6 (Interleukin-6), TNF-α (Tumor necrosis factor alpha) and NF-κB (Nuclear factor kappa B)], along with neurodegeneration. These effects were markedly reversed by rufinamide (50 and 100 mg/kg) when administered to STZ animals. However, the pre-treatment with the CREB inhibitor (666-15) in STZ and rufinamide-administered animals neutralized the beneficial influence of rufinamide. Our data suggest that rufinamide, acting via CREB signaling, reduced oxidative stress and inflammatory markers while elevating anti-oxidant levels. Our study has established that rufinamide may act through CREB signaling in an investigational AD model, which could be crucial for developing new treatments beneficial in progressive neurological disorders.Graphical

Malignant epithelioid tumors with EWSR1::CREB fusion involving the kidney: a report of two cases.

Soft tissue tumors with EWSR1/FUS fusion to genes encoding the cyclic adenosine monophosphate response element-binding (CREB) transcription factor family (ATF1, CREB1, and CREM) are rare and heterogeneous aggressive tumors, often found in the peritoneal cavity. Here, we report two cases of malignant epithelioid tumors with EWSR1::CREB fusion involving the kidney in females in their 30s. Both tumors appeared as solitary masses, measuring 5.4cm and 4.0cm in diameter. Histologically, the tumors were similar, growing invasively with unclear boundaries and composed of epithelial cells with eosinophilic and clear cytoplasm arranged in sheets, nests, and trabeculae. Immunohistochemically, case 1 showed focal AE1/AE3 positivity, whereas case 2 was negative. Anaplastic lymphoma kinase was diffusely positive in case 1 and focally positive in case 2. Both cases were positive for epithelial membrane antigen, mucin-4, and synaptophysin. High-throughput sequencing identified EWSR1::CREM fusion in case 1, whereas fluorescence in situ hybridization detected EWSR1::CREB1 fusion in case 2. These cases expand the morphological and immunophenotypic characteristics of malignant epithelioid tumors with EWSR1::CREB fusion, highlighting the diagnostic challenges of immunohistochemistry and value of molecular testing for accurate diagnosis.

Ameliorating Effect of Fermented Perilla frutescens on Sleep Deprivation-Induced Cognitive Impairment Through Antioxidant and BDNF Signaling in Mice.

Background: Adequate sleep is essential for maintaining cognitive function, as evidenced by literature. Perilla frutescens var. acuta Kudo (PF) is a traditional medicinal herb reported to improve vascular cognitive impairment and induce sedation. However, the effects of PF on cognitive impairment caused by sleep deprivation (SD) have not yet been evaluated. This study aims to evaluate the effects of fermented PF (FPF) and its underlying mechanisms in a model of SD-induced cognitive impairment. Methods: Mice were subjected to SD to establish cognitive impairment, and FPF was administered once daily for 3 days. Cognitive performance was assessed using Y-maze and passive avoidance tests, followed by molecular mechanisms analyses. Results: FPF treatment improved SD-induced cognitive impairment, as evidenced by increased spontaneous alternation and extended latency time. Histological analysis revealed that SD impaired the hippocampus, and this impairment was alleviated by FPF treatment. FPF demonstrated antioxidant activity by increasing glutathione levels and decreasing malondialdehyde levels. Furthermore, the decreased levels of brain-derived neurotrophic factor (BDNF) observed in sleep-deprived mice were restored with FPF treatment. FPF also enhanced the phosphorylation of tropomyosin receptor kinase B, extracellular signal-regulated kinase, and cAMP response element-binding protein. Conclusions: These results indicate that FPF may have beneficial effects on SD-induced cognitive impairment by protecting against oxidative stress and increasing BDNF expression.

Reassessing the involvement of the CREB pathway in the circadian clock of Drosophila melanogaster

Circadian clocks are ubiquitous in almost all organisms on Earth and many key genes are highly conserved among species. In the mammalian suprachiasmatic nucleus, the cAMP response element binding protein (CREB) pathway is known to play a crucial role in conveying light-input to the transcription of clock genes. The fruit fly Drosophila melanogaster also expresses two Creb proteins, CrebA and CrebB, which have been associated with the circadian clock. For example, Drosophila Creb has been suggested to constitute a molecular link between neuronal excitability and clock gene transcription. In this study we subjected flies with clock cell specific CrebA or CrebB mutations to circadian behavioral and bioluminescence assays. Surprisingly, we found that neither loss of CrebA or CrebB did affect free-running locomotor behavior, rhythmic period oscillations in clock neurons, or light-dependent synchronization. In conclusion our findings question the conserved circadian role of the Creb pathway in Drosophila and encourage further studies to elucidate its potential function within insect circadian clocks.