Identification of Methamphetamine Abusers Can Be Supported by EEG-Based Wavelet Transform and BiLSTM Networks.

Methamphetamine (MA) is a neurological drug, which is harmful to the overall brain cognitive function when abused. Based on this property of MA, people can be divided into those with MA abuse and healthy people. However, few studies to date have investigated automatic detection of MA abusers based on the neural activity. For this reason, the purpose of this research was to investigate the difference in the neural activity between MA abusers and healthy persons and accordingly discriminate MA abusers. First, we performed event-related potential (ERP) analysis to determine the time range of P300. Then, the wavelet coefficients of the P300 component were extracted as the main features, along with the time and frequency domain features within the selected P300 range to classify. To optimize the feature set, F_score was used to remove features below the average score. Finally, a Bidirectional Long Short-term Memory (BiLSTM) network was performed for classification. The experimental result showed that the detection accuracy of BiLSTM could reach 83.85%. In conclusion, the P300 component of EEG signals of MA abusers is different from that in normal persons. Based on this difference, this study proposes a novel way for the prevention and diagnosis of MA abuse.

Epigenetic control of SOX9 gene by the histone acetyltransferase P300 in human Sertoli cells.

Background: The transcription factor SOX9 is a key regulator of male sexual development and Sertoli cell differentiation. Altered SOX9 expression has been implicated in the pathogenesis of disorders of sexual development (DSD) in mammals. However, limited information exists regarding the epigenetic mechanisms governing its transcriptional control during sexual development. Methods: This study employed real-time PCR (qPCR), immunofluorescence (IIF), and chromatin immunoprecipitation (ChIP) assays to investigate the epigenetic mechanisms associated with SOX9 gene transcriptional control in human and mouse Sertoli cell lines. To identify the specific epigenetic enzymes involved in SOX9 epigenetic control, functional assays using siRNAs for P300, GCN5, and WDR5 were performed. Results: The transcriptional activation of SOX9 was associated with selective deposition of active histone modifications, such as H3K4me3 and H3K27ac, at its enhancer and promoter regions. Importantly, the histone acetyltransferase P300 was found to be significantly enriched at the SOX9 enhancers, co-localizing with the H3K27ac and the SOX9 transcription factor. Silencing of P300 led to decreased SOX9 expression and reduced H3K27ac levels at the eSR-A and e-ALDI enhancers, demonstrating the crucial role of P300-mediated histone acetylation in SOX9 transcriptional activation. Interestingly, another histone lysine acetyltransferases like GNC5 and methyltransferases as the Trithorax/COMPASS-like may also have a relevant role in male sexual differentiation. Conclusions: Histone acetylation by P300 at SOX9 enhancers, is a key mechanism governing the transcriptional control of this essential regulator of male sexual development. These findings provide important insights into the epigenetic basis of sexual differentiation and the potential pathogenesis of DSDs.

Aerobic training attenuates cardiac remodeling in mice post-myocardial infarction by inhibiting the p300/CBP-associated factor.

Aerobic training (AT), an effective form of cardiac rehabilitation, has been shown to be beneficial for cardiac repair and remodeling after myocardial infarction (MI). The p300/CBP-associated factor (PCAF) is one of the most important lysine acetyltransferases and is involved in various biological processes. However, the role of PCAF in AT and AT-mediated cardiac remodeling post-MI has not been determined. Here, we found that the PCAF protein level was significantly increased after MI, while AT blocked the increase in PCAF. AT markedly improved cardiac remodeling in mice after MI by reducing endoplasmic reticulum stress (ERS). In vivo, similar to AT, pharmacological inhibition of PCAF by Embelin improved cardiac recovery and attenuated ERS in MI mice. Furthermore, we observed that both IGF-1, a simulated exercise environment, and Embelin protected from H2O2-induced cardiomyocyte injury, while PCAF overexpression by viruses or the sirtuin inhibitor nicotinamide eliminated the protective effect of IGF-1 in H9C2 cells. Thus, our data indicate that maintaining low PCAF levels plays an essential role in AT-mediated cardiac protection, and PCAF inhibition represents a promising therapeutic target for attenuating cardiac remodeling after MI.

Investigating the mechanism of tricyclic decyl benzoxazole -induced apoptosis in liver Cancer cells through p300-mediated FOXO3 activation.

OBJECTIVE: To investigate whether tricyclic decylbenzoxazole (TDB) regulates liver cancer cell proliferation and apoptosis through p300-mediated FOXO acetylation. METHODS: Sequencing, adenovirus, and lentivirus transfection were performed in human liver cancer cell line SMMC-7721 and apoptosis was detected by Tunel, Hoechst, and flow cytometry. TEM for mitochondrial morphology, MTT for cell proliferation ability, Western blot, and PCR were used to detect protein levels and mRNA changes. RESULTS: Sequencing analysis and cell experiments confirmed that TDB can promote the up-regulation of FOXO3 expression. TDB induced FOXO3 up-regulation in a dose-dependent manner, promoted the expression of p300 and Bim, and enhanced the acetylation and dephosphorylation of FOXO3, thus promoting apoptosis. p300 promotes apoptosis of cancer cells through Bim and other proteins, while HAT enhances the phosphorylation of FOXO3 and inhibits apoptosis. Overexpression of FOXO3 can increase the expression of exo-apoptotic pathways (FasL, TRAIL), endo-apoptotic pathways (Bim), and acetylation at the protein level and inhibit cell proliferation and apoptotic ability, while FOXO3 silencing or p300 mutation can partially reverse apoptosis. In tumor tissues with overexpression of FOXO3, TDB intervention can further increase the expression of p53 and caspase-9 proteins in tumor cells, resulting in loss of mitochondrial membrane integrity during apoptosis, the release of cytoplasm during signal transduction, activation of caspase-9 and synergistic inhibition of growth. CONCLUSION: TDB induces proliferation inhibition and promotes apoptosis of SMMC-7721 cells by activating p300-mediated FOXO3 acetylation.

Recording the tactile P300 with the cEEGrid for potential use in a brain-computer interface.

Brain-computer interfaces (BCIs) are scientifically well established, but they rarely arrive in the daily lives of potential end-users. This could be in part because electroencephalography (EEG), a prevalent method to acquire brain activity for BCI operation, is considered too impractical to be applied in daily life of end-users with physical impairment as an assistive device. Hence, miniaturized EEG systems such as the cEEGrid have been developed. While they promise to be a step toward bridging the gap between BCI development, lab demonstrations, and home use, they still require further validation. Encouragingly, the cEEGrid has already demonstrated its ability to record visually and auditorily evoked event-related potentials (ERP), which are important as input signal for many BCIs. With this study, we aimed at evaluating the cEEGrid in the context of a BCI based on tactually evoked ERPs. To compare the cEEGrid with a conventional scalp EEG, we recorded brain activity with both systems simultaneously. Forty healthy participants were recruited to perform a P300 oddball task based on vibrotactile stimulation at four different positions. This tactile paradigm has been shown to be feasible for BCI repeatedly but has never been tested with the cEEGrid. We found distinct P300 deflections in the cEEGrid data, particularly at vertical bipolar channels. With an average of 63%, the cEEGrid classification accuracy was significantly above the chance level (25%) but significantly lower than the 81% reached with the EEG cap. Likewise, the P300 amplitude was significantly lower (cEEGrid R2-R7: 1.87 µV, Cap Cz: 3.53 µV). These results indicate that a tactile BCI using the cEEGrid could potentially be operated, albeit with lower efficiency. Additionally, participants' somatosensory sensitivity was assessed, but no correlation to the accuracy of either EEG system was shown. Our research contributes to the growing amount of literature comparing the cEEGrid to conventional EEG systems and provides first evidence that the tactile P300 can be recorded behind the ear. A BCI based on a thus simplified EEG system might be more readily accepted by potential end-users, provided the accuracy can be substantially increased, e.g., by training and improved classification.

Cortical Generators and Connections Underlying Phoneme Perception: A Mismatch Negativity and P300 Investigation.

The cortical generators of the pure tone MMN and P300 have been thoroughly studied. Their nature and interaction with respect to phoneme perception, however, is poorly understood. Accordingly, the cortical sources and functional connections that underlie the MMN and P300 in relation to passive and active speech sound perception were identified. An inattentive and attentive phonemic oddball paradigm, eliciting a MMN and P300 respectively, were administered in 60 healthy adults during simultaneous high-density EEG recording. For both the MMN and P300, eLORETA source reconstruction was performed. The maximal cross-correlation was calculated between ROI-pairs to investigate inter-regional functional connectivity specific to passive and active deviant processing. MMN activation clusters were identified in the temporal (insula, superior temporal gyrus and temporal pole), frontal (rostral middle frontal and pars opercularis) and parietal (postcentral and supramarginal gyrus) cortex. Passive discrimination of deviant phonemes was aided by a network connecting right temporoparietal cortices to left frontal areas. For the P300, clusters with significantly higher activity were found in the frontal (caudal middle frontal and precentral), parietal (precuneus) and cingulate (posterior and isthmus) cortex. Significant intra- and interhemispheric connections between parietal, cingulate and occipital regions constituted the network governing active phonemic target detection. A predominantly bilateral network was found to underly both the MMN and P300. While passive phoneme discrimination is aided by a fronto-temporo-parietal network, active categorization calls on a network entailing fronto-parieto-cingulate cortices. Neural processing of phonemic contrasts, as reflected by the MMN and P300, does not appear to show pronounced lateralization to the language-dominant hemisphere.

Discovery of a peptide proteolysis-targeting chimera (PROTAC) drug of p300 for prostate cancer therapy.

BACKGROUND: The E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways in various cancers, including prostate cancer. This need is particularly significant in prostate cancer. While androgen deprivation therapy (ADT) has demonstrated promising efficacy in prostate cancer, its long-term use can eventually lead to the development of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). Notably, p300 has been identified as an important co-activator of the androgen receptor (AR), highlighting its significance in prostate cancer progression. Moreover, recent studies have revealed the involvement of p300 in AR-independent oncogenes associated with NEPC. Therefore, the blockade of p300 may emerge as an effective therapeutic strategy to address the challenges posed by both CRPC and NEPC. METHODS: We employed AI-assisted design to develop a peptide-based PROTAC (proteolysis-targeting chimera) drug that targets p300, effectively degrading p300 in vitro and in vivo utilizing nano-selenium as a peptide drug delivery system. FINDINGS: Our p300-targeting peptide PROTAC drug demonstrated effective p300 degradation and cancer cell-killing capabilities in both CRPC, AR-negative, and NEPC cells. This study demonstrated the efficacy of a p300-targeting drug in NEPC cells. In both AR-positive and AR-negative mouse models, the p300 PROTAC drug showed potent p300 degradation and tumor suppression. INTERPRETATION: The design of peptide PROTAC drug targeting p300 is feasible and represents an efficient therapeutic strategy for CRPC, AR-negative prostate cancer, and NEPC. FUNDING: The funding details can be found in the Acknowledgements section.

How do anxiety and stress affect soccer referees? An ERPs study.

The decision-making of soccer referees is one of the typical forms influenced by factors such as environmental pressure and individual emotions. While previous studies have explored how common factors like personal anxiety and on-field pressure affect the decisions of soccer referees, the mechanisms by which anxiety influences decision-making under pressure remain unclear. This study developed a penalty task based on real soccer match scenarios and recruited 76 experienced soccer referees. These referees were divided into two groups, high anxiety and low anxiety, based on their anxiety levels, to perform decision-making tasks under different pressure environments simulated to mimic real matches. Additionally, this research employed Event-Related Potential (ERP) technology to compare the brain signals of soccer referees with different levels of anxiety when facing foul play under various pressure environments. It was found that referees with high levels of anxiety displayed larger P300 and N400 amplitudes in a low-pressure environment (p = 0.0059, t = 2.9437). However, no significant differences in P300 and N400 amplitudes were observed between referees with high and low levels of anxiety under high-pressure conditions (p = 0.1890, t = 1.3411). This study not only reveals the complex mechanisms of anxiety in the decision-making process of referees but also emphasizes the importance of understanding and managing the psychological state of referees in competitive sports to improve the quality of their decisions. Our findings provide an empirical basis for future efforts to mitigate the impact of anxiety and optimize the decision-making process in similar high-pressure environments.

Mecp2 promotes the anti-inflammatory effect of alpinetin via epigenetic modification crosstalk.

In recent years, inflammatory disorders have emerged as a significant concern for human health. Through ongoing research on anti-inflammatory agents, alpinetin has shown promising anti-inflammatory properties, including involvement in epigenetic modification pathways. As a crucial regulator of epigenetic modifications, Mecp2 may play a role in modulating the epigenetic effects of alpinetin, potentially impacting its anti-inflammatory properties. To test this hypothesis, two key components, p65 (a member of NF-KB family) and p300 (a type of co-activator), were screened by the expression profiling microarray, which exhibited a strong correlation with the intensity of LPS stimulation in mouse macrophages. Meanwhile, alpinetin demonstrates the anti-inflammatory properties through its ability to disrupt the synthesis of p65 and its interaction with promoters of inflammatory genes, yet it did not exhibit similar effects on p300. Additionally, Mecp2 can inhibit the binding of p300 by attaching to the methylated inflammatory gene promoter induced by alpinetin, leading to obstacles in promoter acetylation and subsequently impacting the binding of p65, ultimately enhancing the anti-inflammatory capabilities of alpinetin. Similarly, in a sepsis mouse model, it was observed that homozygotes overexpressing Mecp2 showed a greater reduction in organ damage and improved survival rates compared to heterozygotes when administered by alpinetin. However, blocking the expression of DNA methyltransferase 3A (DNMT3A) resulted in the loss of Mecp2's anti-inflammatory assistance. In conclusion, Mecp2 may augment the anti-inflammatory effects of alpinetin through epigenetic 'crosstalk', highlighting the potential efficacy of a combined therapeutic strategy involving Mecp2 and alpinetin for anti-inflammatory intervention.

Extracellular C1qbp inhibits myogenesis by suppressing NFATc1.

Aging and lack of exercise are the most important etiological factors for muscle loss. We hypothesized that new factors that contribute to muscle loss could be identified from ones commonly altered in expression in aged and exercise-limited skeletal muscles. Mouse gastrocnemius muscles were subjected to mass spectrometry-based proteomic analysis. The muscle proteomes of hindlimb-unloaded and aged mice were compared to those of exercised and young mice, respectively. C1qbp expression was significantly upregulated in the muscles of both hindlimb-unloaded and aged mice. In vitro myogenic differentiation was not affected by altering intracellular C1qbp expression but was significantly suppressed upon recombinant C1qbp treatment. Additionally, recombinant C1qbp repressed the protein level but not the mRNA level of NFATc1. NFATc1 recruited the transcriptional coactivator p300, leading to the upregulation of acetylated histone H3 levels. Furthermore, NFATc1 silencing inhibited p300 recruitment, downregulated acetylated histone H3 levels, and consequently suppressed myogenic differentiation. The expression of C1qbp was inversely correlated with that of NFATc1 in the gastrocnemius muscles of exercised or hindlimb-unloaded, and young or aged mice. These findings demonstrate a novel role of extracellular C1qbp in suppressing myogenesis by inhibiting the NFATc1/p300 complex. Thus, C1qbp can serve as a novel therapeutic target for muscle loss.

The relationship of aerobic fitness with verbal and spatial working memory: An ERP study.

Working memory (WM) plays an important role in daily life and is known to correlated with aerobic fitness. However, whether the relationship between aerobic fitness and WM is dependent on the stimulus modality or is associated with one or multiple subprocesses involved in WM remains unknown. Accordingly, this study utilized event-related potentials (ERPs) to comprehensively examine the encoding, preparation, and retrieval processes during verbal and spatial WM performance. Eighty-eight young adults aged 18-30years were recruited to participate in two laboratory visits on separate days. On day 1, aerobic fitness was assessed by maximum oxygen consumption (V˙O2max) during a treadmill-based graded exercise test. On day 2, participants completed verbal and spatial WM tasks while P2, contingent negative voltage (CNV), and P3 components of ERP were recorded during the encoding, preparatory, and retrieval stages of WM, respectively. Results of hierarchical regression analysis showed that V˙O2max was positively correlated with response accuracy during the high-demanding condition of spatial WM after controlling for age, sex, and self-reported physical activity. Additionally, a higher level of V˙O2max was associated with larger terminal CNV amplitude at the Cz electrode during the high-demanding condition of spatial WM. These findings suggest that aerobic fitness may have selective beneficial associations with the motor preparatory process and subsequent task performance requiring a greater amount of spatial information but not the encoding and retrieval stages nor the verbal modality of WM.

Associations between physical activity, sedentary time, and neurocognitive function during adolescence: Evidence from accelerometry and the flanker P300.

Physical activity and sedentary behavior are two lifestyle factors related to overall health during adolescence. Public health efforts emphasize the importance of increasing physical activity to improve physical and mental health outcomes, including neurocognitive functioning. However, the unique effects of sedentary behavior on neurocognitive functioning remain unclear. This study aimed to investigate associations between daily moderate-to-vigorous physical activity (MVPA), sedentary time, and neurocognitive functioning during adolescence. Fifty-seven participants (37% female) between the ages of 13 and 17 years wore an accelerometer on their non-dominant wrist for approximately 1 week to quantify daily MVPA and sedentary time prior to completing a flanker task to elicit P300 amplitude at a laboratory visit. Results indicated that daily MVPA and sedentary time exhibited unique, significant associations with P300 amplitude in opposing directions: increased daily MVPA was correlated with larger P300 amplitudes, while increased daily sedentary time was linked to reduced P300 amplitudes. Notably, these associations remained significant even after adjusting for age, sex, and BMI-for-age percentile. These findings underscore the independent influence of daily MVPA and sedentary time on neurocognitive functioning during adolescence. Future research should explore whether modifying MVPA levels can improve neurocognitive outcomes-including the P300-during adolescence, and determine whether reducing sedentary time results in similar or differential effects.

Electrophysiological auditory measures to identify potential cortical markers of tinnitus.

Tinnitus, or the perception of a sound in the absence of an external acoustic stimulus, is a common condition that cannot yet be objectively diagnosed. Current diagnostic tests of tinnitus consist of case history and behavioral measures that rely on subjective responses. This study examined electrophysiological measures, specifically the auditory late response (ALR), mismatch negativity (MMN), and P300 as potential neural biomarkers of tinnitus in both a tinnitus and non-tinnitus control group while utilizing the pitch-matched tinnitus frequencies as the test stimuli. Results of this study found differences in MMN amplitudes and area under the curve, and in P300 topographic maps between tinnitus and control subjects. The differences in MMN responses across groups suggest that dysfunctional processing of acoustic stimuli located near the tinnitus frequency in individuals with tinnitus manifests as soon as 200 ms after initial onset of the stimulus. In addition, results from a global field power analysis and differences in spatial distributions on topographical maps indicate that deficits persist through higher levels of cortical processing. A secondary goal of this study was to determine if electrophysiological measures correlated with reported tinnitus severity on questionnaires. This analysis indicated that P2 latency was a significant predictor of Tinnitus Reaction Questionnaire, Tinnitus Handicap Inventory, and percent of the time participant's tinnitus was considered bothersome, suggesting that this measure could potentially be used to assess the efficacy of treatment programs for tinnitus.

Approach bias in individuals with Internet gaming disorder: Evidence from an event-related potential-based approach-avoid task.

Individuals with Internet gaming disorder (IGD) often exhibit an approach bias towards gaming cues compared to non-gaming cues. Although previous studies suggested a positive correlation between approach bias and the severity of game use, the neuropsychological mechanisms that underpin the automatic action tendencies remain largely unexplored. The present study measured event-related potentials (ERPs) in 22 IGD and 23 healthy control (HC) participants who met the inclusion criteria, both groups conducted the Stimulus-Response Compatibility task (SRC), with their ERPs recorded during the task. Results revealed that the IGD group showed a significantly larger approach bias towards gaming cues (avoidance versus approach reaction time) compared to the HC group. The amplitude of P300 significantly increased, whereas N100 significantly decreased for game-approach compared to game-avoid for IGD compared to HC participants. The findings suggested that the enhanced integrated motivational value under compatible conditions as well as increased stimulus-response conflicts under incompatible conditions may contribute to the approach bias in IGD individuals. Further investigation on the intervention is prompted through longitudinal studies.

Post-stroke aphasia rehabilitation using an adapted visual P300 brain-computer interface training: improvement over time, but specificity remains undetermined.

Introduction: This study aimed to evaluate the efficacy of visual P300 brain-computer interface use to support rehabilitation of chronic language production deficits commonly experienced by individuals with a left-sided stroke resulting in post-stroke aphasia. Methods: The study involved twelve participants, but five dropped out. Additionally, data points were missing for three participants in the remaining sample of seven participants. The participants underwent four assessments-a baseline, pre-assessment, post-assessment, and follow-up assessment. Between the pre-and post-assessment, the participants underwent at least 14 sessions of visual spelling using a brain-computer interface. The study aimed to investigate the impact of this intervention on attention, language production, and language comprehension and to determine whether there were any potential effects on quality of life and well-being. Results: None of the participants showed a consistent improvement in attention. All participants showed an improvement in spontaneous speech production, and three participants experienced a reduction in aphasia severity. We found an improvement in subjective quality of life and daily functioning. However, we cannot rule out the possibility of unspecific effects causing or at least contributing to these results. Conclusion: Due to challenges in assessing the patient population, resulting in a small sample size and missing data points, the results of using visual P300 brain-computer interfaces for chronic post-stroke aphasia rehabilitation are preliminary. Thus, we cannot decisively judge the potential of this approach.

C646 degrades Exportin-1 to modulate p300 chromatin occupancy and function.

Molecular glues can induce proximity between a target protein and ubiquitin ligases to induce target degradation, but strategies for their discovery remain limited. We screened 3,200 bioactive small molecules and identified that C646 requires neddylation-dependent protein degradation to induce cytotoxicity. Although the histone acetyltransferase p300 is the canonical target of C646, we provide extensive evidence that C646 directly targets and degrades Exportin-1 (XPO1). Multiple cellular phenotypes induced by C646 were abrogated in cells expressing the known XPO1C528S drug-resistance allele. While XPO1 catalyzes nuclear-to-cytoplasmic transport of many cargo proteins, it also directly binds chromatin. We demonstrate that p300 and XPO1 co-occupy hundreds of chromatin loci. Degrading XPO1 using C646 or the known XPO1 modulator S109 diminishes the chromatin occupancy of both XPO1 and p300, enabling direct targeting of XPO1 to phenocopy p300 inhibition. This work highlights the utility of drug-resistant alleles and further validates XPO1 as a targetable regulator of chromatin state.

Effect of inverted faces as visual stimuli on the performance of the hybrid SSVEP + P300 brain computer interface.

INTRODUCTION: This study proposes a hybrid brain-computer interface (BCI) system that simultaneously evokes steady-state visual evoked potentials (SSVEP) and event-related potentials (P300). The goal of this study was to improve the performance of the current hybrid SSVEP + P300 BCI systems by incorporating inverted faces into visual stimuli. METHODS: In this study, upright and inverted faces were added to visual stimulus to elicit stronger cortical responses in a hybrid SSVEP + P300 BCI. We also considered triggering the P300 signals with facial stimuli and the SSVEP signals with non-facial stimuli. We have tested four paradigms: the upright face paradigm (UF), the inverted face paradigm (IF), the upright face and flicker paradigm (UFF), and the inverted face and flicker paradigm (IFF). RESULTS AND CONCLUSIONS: The results showed that the IFF paradigm evoked more robust cortical responses, which led to enhanced system accuracy and ITR. The IFF paradigm had an average accuracy of 96.6% and a system communication rate of 26.45 bits per second. The UFF paradigm is the best candidate for BCI applications among other paradigms because it provides maximum comfort while maintaining a reasonable ITR.

PNSC928, a plant-derived compound, specifically disrupts CtBP2-p300 interaction and reduces inflammation in mice with acute respiratory distress syndrome.

BACKGROUND: Prior research has highlighted the involvement of a transcriptional complex comprising C-terminal binding protein 2 (CtBP2), histone acetyltransferase p300, and nuclear factor kappa B (NF-κB) in the transactivation of proinflammatory cytokine genes, contributing to inflammation in mice with acute respiratory distress syndrome (ARDS). Nonetheless, it remains uncertain whether the therapeutic targeting of the CtBP2-p300-NF-κB complex holds potential for ARDS suppression. METHODS: An ARDS mouse model was established using lipopolysaccharide (LPS) exposure. RNA-Sequencing (RNA-Seq) was performed on ARDS mice and LPS-treated cells with CtBP2, p300, and p65 knockdown. Small molecules inhibiting the CtBP2-p300 interaction were identified through AlphaScreen. Gene and protein expression levels were quantified using RT-qPCR and immunoblots. Tissue damage was assessed via histological staining. KEY FINDINGS: We elucidated the specific role of the CtBP2-p300-NF-κB complex in proinflammatory gene regulation. RNA-seq analysis in LPS-challenged ARDS mice and LPS-treated CtBP2-knockdown (CtBP2KD), p300KD, and p65KD cells revealed its significant impact on proinflammatory genes with minimal effects on other NF-κB targets. Commercial inhibitors for CtBP2, p300, or NF-κB exhibited moderate cytotoxicity in vitro and in vivo, affecting both proinflammatory genes and other targets. We identified a potent inhibitor, PNSC928, for the CtBP2-p300 interaction using AlphaScreen. PNSC928 treatment hindered the assembly of the CtBP2-p300-NF-κB complex, substantially downregulating proinflammatory cytokine gene expression without observable cytotoxicity in normal cells. In vivo administration of PNSC928 significantly reduced CtBP2-driven proinflammatory gene expression in ARDS mice, alleviating inflammation and lung injury, ultimately improving ARDS prognosis. CONCLUSION: Our results position PNSC928 as a promising therapeutic candidate to specifically target the CtBP2-p300 interaction and mitigate inflammation in ARDS management.

Does Transcranial Direct Current Stimulation Affect Potential P300-Related Events in Vascular Dementia? Considerations from a Pilot Study.

Vascular dementia, the second most common type of dementia, currently lacks a definitive cure. In the pursuit of therapies aimed at slowing its progression and alleviating symptoms, transcranial direct current stimulation (tDCS) emerges as a promising approach, characterized by its non-invasive nature and the ability to promote brain plasticity. In this study, the primary objective was to investigate the effects of a two-week cycle of tDCS on the dorsolateral prefrontal cortex (DLPFC) and neurophysiological functioning in thirty patients diagnosed with vascular dementia. Each participant was assigned to one of two groups: the experimental group, which received anodal tDCS to stimulate DPCFL, and the control group, which received sham tDCS. Neurophysiological functions were assessed before and after tDCS using P300 event-related potentials (ERPs), while neuropsychological function was evaluated through a Mini-Mental State Examination (MMSE). The results showed a reduction in P300 latency, indicating a faster cognitive process; an increase in P300 amplitude, suggesting a stronger neural response to cognitive stimuli; and a significant improvement in MMSE scores compared to the control group, indicating an overall enhancement in cognitive functions. These findings suggest that tDCS could represent a promising therapeutic option for improving both neurophysiological and cognitive aspects in patients with vascular dementia.

CBP/P300 Inhibition Impairs CD4+ T Cell Activation: Implications for Autoimmune Disorders.

T cell activation is critical for an effective immune response against pathogens. However, dysregulation contributes to the pathogenesis of autoimmune diseases, including Juvenile Idiopathic Arthritis (JIA). The molecular mechanisms underlying T cell activation are still incompletely understood. T cell activation promotes the acetylation of histone 3 at Lysine 27 (H3K27ac) at enhancer and promoter regions of proinflammatory cytokines, thereby increasing the expression of these genes which is essential for T cell function. Co-activators E1A binding protein P300 (P300) and CREB binding protein (CBP), collectively known as P300/CBP, are essential to facilitate H3K27 acetylation. Presently, the role of P300/CBP in human CD4+ T cells activation remains incompletely understood. To assess the function of P300/CBP in T cell activation and autoimmune disease, we utilized iCBP112, a selective inhibitor of P300/CBP, in T cells obtained from healthy controls and JIA patients. Treatment with iCBP112 suppressed T cell activation and cytokine signaling pathways, leading to reduced expression of many proinflammatory cytokines, including IL-2, IFN-γ, IL-4, and IL-17A. Moreover, P300/CBP inhibition in T cells derived from the inflamed synovium of JIA patients resulted in decreased expression of similar pathways and preferentially suppressed the expression of disease-associated genes. This study underscores the regulatory role of P300/CBP in regulating gene expression during T cell activation while offering potential insights into the pathogenesis of autoimmune diseases. Our findings indicate that P300/CBP inhibition could potentially be leveraged for the treatment of autoimmune diseases such as JIA in the future.