Abnormal expression and role of MicroRNA-214-3p/SLC8A1 in neonatal Hypoxic-Ischaemic encephalopathy.

Neonatal hypoxic-ischaemic encephalopathy (HIE) refers to brain damage caused by intra-uterine distress and asphyxia/hypoxia during the perinatal and neonatal periods. MicroRNA (MiR)-214-3p plays a critical role in cell growth and apoptosis. The aim of this study was to investigate the expression and role of miR-214-3p in neonatal HIE development, and to explore the underlying mechanisms. The expression of miR-214-3p was significantly down-regulated, while that of Slc8a1, a direct target of miR-214-3p, was significantly up-regulated, in the brain tissue of neonatal HIE rats. The over-expression of miR-214-3p promoted the proliferation and inhibited the apoptosis of neurones, while its down-regulation had the opposite effect. Our results indicate that miR-214-3p expression was down-regulated in neonatal HIE rats, and the up-regulation of miR-214-3p expression protected against HIE development by inhibiting neuronal apoptosis.

Undersampled Fourier ptychography for reflective-based long range imaging.

Fourier ptychography (FP) can be a promising technique for long-range and high-resolution imaging. In this work, we explore reconstructions with undersampled data for meter-scale reflective based Fourier ptychographic imaging. To reconstruct with under-sampling captures, we propose a novel cost function for FP phase retrieval and design a new optimization algorithm based on gradient descent. To verify the proposed methods, we perform the high-fidelity reconstruction of the targets with sampling parameter less than one. Compared to the state-of-the-art alternative-projectionbased FP algorithm, the proposed one can achieve the same performance but with much less data.

microRNA-200c-3p suppresses proliferation and invasion of nephroblastoma cells by targeting EP300 and inactivating the AKT/FOXO1/p27 pathway.

miR-200c-3p is aberrantly expressed in numerous cancers, but its underlying mechanisms in nephroblastoma are unknown. In our study, the differentially regulated miRNAs between the nephroblastoma tissues and adjacent non-neoplastic renal tissues were screened based on microarray analysis. The miR-200c-3p expression in nephroblastoma tissues and cells was detected by qRT-PCR. Then, the effects of miR-200c-3p mimic or inhibitor on cell proliferation, invasion, and migration were evaluated by CCK-8 assay, plate colony formation assay, soft agar assay, Transwell, and wound-healing assay in SK-NEP-1 and G401 cells. Afterward, the target gene of miR-200c-3p was predicted by TarBase, miRTarBase, miRDB softwares, and then verified by dual-luciferase reporter gene assay. The in vivo effects of miR-200c-3p on pathological changes and tumor volume were investigated in tumor xenograft mice by H&E staining and in vivo fluorescence imaging. ChIP assay was used to evaluate the relationship between histone acetyltransferase E1A-binding protein p300 (EP300) and P27, and the relationship of the role of miR-200c-3p in nephroblastoma and the AKT/FOXO1/p27 signaling pathways was evaluated by western blotting. Our study shows that miR-200c-3p was downregulated in nephroblastoma tissues and cells, and EP300 was a target gene of miR-200c-3p. Furthermore, miR-200c-3p mimic decreased cell proliferation and inhibited cell migration and invasion in nephroblastoma. Mechanistically, miR-200c-3p could inhibit p-AKT activity and enhance p-FOXO1 and p27 expression. Notably, the transcription factor P27 could bind to the EP300 promoter. This study demonstrates a new approach to treat nephroblastoma.

Resilience mediates the effect of self-efficacy on symptoms of prenatal anxiety among pregnant women: a nationwide smartphone cross-sectional study in China.

BACKGROUND: Prenatal anxiety is one of the most prevalent mental disorders during pregnancy. This study assessed the prevalence of prenatal anxiety and examined whether resilience could play the mediating role in the association between self-efficacy and symptoms of prenatal anxiety among pregnant women in China. METHODS: A nationwide smartphone cross-sectional study was carried out in three cities (Shenyang of Liaoning Province, Zhengzhou of Henan Province and Chongqing Municipality) in China from July 2018 to July 2019. The questionnaire consisted of questions on demographic characteristics, the Generalized Anxiety Disorder Scale (GAD-7), the Chinese version of General Self-efficacy Scale (GSES), and the 14-item Wagnild and Young Resilience Scale (RS-14). A total of 665 pregnant women were recruited in this study. A hierarchical multiple regression model was employed to explore the associate factors and mediators of symptoms of prenatal anxiety. A structural equation model was employed to test the hypothesis that resilience mediates the association between self-efficacy and symptoms of prenatal anxiety. RESULTS: The prevalence of symptoms of prenatal anxiety was 36.4% in this study. Self-efficacy was negatively correlated with symptoms of prenatal anxiety (r = -0.366, P < 0.01). Resilience had a significant positive correlation with self-efficacy (r = 0.612, P < 0.01) and had a negative correlation with symptoms of prenatal anxiety (r = -0.427, P < 0.01). The hierarchical multiple regression model indicated that self-efficacy and resilience were the main factors associated with symptoms of prenatal anxiety and contributed to 11.9% and 6.3% to the variance of symptoms of prenatal anxiety, respectively. Resilience served as a mediator between self-efficacy and symptoms of prenatal anxiety (a*b = -0.198, Bias-corrected and accelerated bootstrap 95% Confidence interval: -0.270, -0.126). CONCLUSIONS: Self-efficacy was a negative predictor of symptoms of prenatal anxiety among pregnant women. Moreover, resilience mediated the relation between self-efficacy and symptoms of prenatal anxiety among pregnant women in China. It was observed in this study that psychological interventions might be beneficial for pregnant women to relieve symptoms of prenatal anxiety through improved self-efficacy and resilience.

Design and synthesis of a folate-receptor targeted diazepine-ring-opened pyrrolobenzodiazepine prodrug conjugate.

Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed and synthesized a diazepine-ring-opened bis-PBD prodrug (pro-PBD-PBD) folate conjugate lacking the one of the two imine moieties found in the corresponding free bis-PBD. Upon entering a targeted cell, cleavage of the linker system, including the hydrolysis of an oxazolidine moiety, results in the formation of a reactive intermediate which possesses a newly formed aldehyde as well as an aromatic amine. A fast and spontaneous intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine, and as a result, the diazepine ring, thereby delivering the bis-PBD to the targeted cell. The in vitro and in vivo activity of this conjugate has been evaluated on folate receptor positive KB cells. Sub-nanomolar activity with good specificity and high cure rates with minimal toxicity have been observed.

Downregulation of lncRNA NR2F2 Antisense RNA 1 Induces G1 Arrest of Colorectal Cancer Cells by Downregulating Cyclin-Dependent Kinase 6.

AIMS: Long non-coding RNA (lncRNA) NR2F2 antisense RNA 1 (NR2F2-AS1) is an oncogenic lncRNA in lung cancer. This study aimed to investigate the role of NR2F2-AS1 in colorectal cancer (CRC). METHODS: Tissue specimens were obtained from 63 CRC patients, and gene expression was analyzed by qPCR and western blot. Overexpression was performed to analyze gene interactions. A 5-year follow-up was carried out to perform survival analysis. Cell cycle progression and proliferation were analyzed by cell cycle assay and CCK-8 assay, respectively. RESULTS: We found that NR2F2-AS1 and cyclin-dependent kinase 6 (CDK6) were both upregulated in CRC and were positively correlated. NR2F2-AS1 siRNA silencing led to downregulated CDK6 and induced Gap 1 (G1) arrest of CRC cells. CDK6 overexpression rescued G1 arrest caused by NR2F2-AS1 siRNA silencing. High expression levels of NR2F2-AS1 were closely correlated with low overall 5-year survival rate. NR2F2-AS1 siRNA silencing led to decreased rate of CRC cell proliferation. CDK6 overexpression attenuated the effects of NR2F2-AS1 siRNA silencing on cancer cell proliferation. CONCLUSIONS: Downregulation of NR2F2-AS1 induces G1 arrest of CRC cells by downregulating CDK6.

Clinical Characteristics and Functional Outcomes of Wake-Up Stroke in the Chinese Population.

BACKGROUND: Wake-up stroke (WUS) accounts for up to 25% of all new ischemic strokes, but debate exists regarding whether WUS differs from non-WUS in previous studies. Our study aimed to investigate the proportion of WUS cases and to examine differences in clinical characteristics and outcomes in these two groups. METHODS: Data from acute ischemic stroke patients who presented to the First Affiliated Hospital of Chongqing Medical University between April 2017 and September 2017 were prospectively collected. Admission demographic information, clinical and radiological characteristics, and 3-month functional outcomes were assessed and compared between patients with WUS and those with non-WUS. Poor functional outcome was defined as modified Rankin Scale ≥ 3 at the 90-day follow-up. Risks of poor outcomes for WUS were estimated with logistic regression analysis. RESULTS: A total of 473 eligible patients were included, of which 132 had been diagnosed with WUS (27.9%). Forty WUS patients had poor functional outcomes and 92 WUS patients had good functional outcomes. WUS and non-WUS patients were similar in regard to stroke risk factors, severity, etiology, and prognosis at 90 days (p > 0.05), but WUS patients were more likely to have had previous stroke (p < 0.001) and a tendency of higher albumin levels (p = 0.051). WUS patients show significant differences in terms of age, gender, prior stroke, atrial fibrillation, impaired consciousness at admission, levels of albumin and triglycerides, stroke severity, and stroke etiology between the good outcome group and the poor outcome group (p < 0.05). Multivariate logistic regression analysis showed that age (odds ratio [OR] 1.079, 95% confidence interval [CI] 1.021-1.141; p < 0.05), previous stroke (OR 4.017, 95% CI 1.197-13.484; p < 0.05), and admission National Institutes of Health Stroke Scale (NIHSS) score ≥5 (OR 5.453, 95% CI 1.510-19.696; p < 0.05) were independently associated with an unfavorable outcome of WUS. CONCLUSIONS: WUS accounts for 27.9% of 473 ischemic strokes in the Chinese population. WUS and non-WUS patients were similar in terms of stroke risk factors, severity, etiology, and early outcomes. Age, previous stroke, and a high admission NIHSS score were independent risk factors for unfavorable outcomes in patients with WUS.

Identification of differentially expressed lncRNAs and mRNAs in luminal-B breast cancer by RNA-sequencing.

BACKGROUND: Luminal B cancers show much worse outcomes compared to luminal A. This present study aims to screen key lncRNAs and mRNAs correlated with luminal-B breast cancer. METHODS: Luminal-B breast cancer tissue samples and adjacent tissue samples were obtained from 4 patients with luminal-B breast cancer. To obtain differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) between luminal-B breast cancer tumor tissues and adjacent tissues, RNA-sequencing and bioinformatics analysis were performed. Functional annotation of DEmRNAs and protein-protein interaction networks (PPI) construction were performed. DEmRNAs transcribed within a 100 kb window up- or down-stream of DElncRNAs were searched, which were defined as cis nearby-targeted DEmRNAs of DElncRNAs. DElncRNA-DEmRNA co-expression networks were performed. The mRNA and lncRNA expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database to validate the expression patterns of selected DEmRNAs and DElncRNAs. RESULTS: A total of 1178 DEmRNAs and 273 DElncRNAs between luminal-B breast cancer tumor tissues and adjacent tissues were obtained. Hematopoietic cell lineage, Cytokine-cytokine receptor interaction, Cell adhesion molecules (CAMs) and Primary immunodeficiency were significantly enriched KEGG pathways in luminal-B breast cancer. FN1, EGFR, JAK3, TUBB3 and PTPRC were five hub proteins of the PPI networks. A total of 99 DElncRNAs-nearby-targeted DEmRNA pairs and 1878 DElncRNA-DEmRNA co-expression pairs were obtained. Gene expression results validated in TCGA database were consistent with our RNA-sequencing results, generally. CONCLUSION: This study determined key genes and lncRNAs involved in luminal-B breast cancer, which expected to present a new avenue for the diagnosis and treatment of luminal-B breast cancer.

Cancer immune checkpoint blockade therapy and its associated autoimmune cardiotoxicity.

The immune checkpoint molecules are emerged in the evolution to protect the host from self-attacks by activated T cells. However, cancer cells, as a strategy to survive and expand, can hijack these molecules and mechanisms to suppress T cell-mediated immune responses. Therefore, an idea of blocking the checkpoint molecules to enhance the anti-tumor activities of the host immune system has been developed and applied to the cancer therapy after discovery of the inhibitory T cell co-receptor, cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and further enhanced on the identification of PD-1 and its ligands. Since 2010, several checkpoint inhibitors have been approved by FDA and many more are in clinical trials. In the treatment of advanced cancers, these inhibitors significantly increased response rates and survival benefits. However, accompanied with the striking results, immune-related adverse events (irAEs) that broadly occurred in many organs were observed and reported, some of which were fatal. Herein, we first review the recent progressions in the research of the immune checkpoint molecules and the application of their blocking antibodies in cancer treatment, and then discuss the cardiac toxicity induced by the therapy and the strategy to monitor, manage this adverse event when it occurs.

MicroRNA-320 involves in the cardioprotective effect of insulin against myocardial ischemia by targeting survivin.

It is generally accepted that insulin exerts an antiapoptotic effect against ischemia/reperfusion through the activation of PI3K/Akt/mTOR pathway. MicroRNAs involve in multiple cardiac pathophysiological processes, including ischemia/reperfusion-induced cardiac injury. However, the regulation of microRNAs in the cardioprotective effect of insulin is rarely discussed. In this study, using a cell model of ischemia through culturing H9C2 cardiac myocytes in serum-free medium with hypoxia, we demonstrated that pretreatment with insulin significantly inhibited cell apoptosis and downregulated microRNA-320 (miR-320) expression. Interestingly, miR-320 mimic impaired the cardioprotective effect of insulin against myocardial ischemia injury by targeting survivin, which is a member of the family of inhibitor of apoptosis proteins. Suppression miR-320 expression by miR-320 inhibitor in H9C2 cells with myocardial ischemia mimics the cardioprotective effect of insulin by maintaining survivin expression. Taken together, miR-320-mediated survivin expression involves in cardioprotective effect of insulin against myocardial ischemia injury. SIGNIFICANCE OF THIS STUDY: Myocardial ischemia/reperfusion (I/R) injury remains an important clinical problem with extremely deficient clinical therapies. Insulin exerts an antiapoptotic effect against I/R through the activation of PI3K/Akt/mTOR pathway. Here, we provided evidences to show that microRNA-320 involves in the cardioprotective effect of insulin by targeting survivin, which is an inhibitor of apoptosis protein and functions as a key regulator in cell apoptosis and involves in the tumour genesis and progression. Our findings may provide a new potential therapeutic strategy for I/R injury and ischemic heart disease.

Cycloaddition of Fluorenone N-Aryl Nitrones with Methylenecyclopropanes and Sequential 1,3-Rearrangement: An Entry to Synthesis of Spirofluorenylpiperidin-4-ones.

A facile synthesis of various spirofluorenylpiperidin-4-ones has been achieved in good yields from fluorenone N-aryl nitrones and methylenecyclopropanes. This method involved an initial cycloaddition to form a 5-spirocyclopropane-isoxazoline, which underwent a highly selective 1,3-rearrangement to give the desired product. The stereochemistry of the spirofluorenylpiperidin-4-one could be controlled by the cycloaddition and sequential rearrangement strategy. Furthermore, the spirofluorenylpiperidin-4-ones could be not only prepared in one-pot procedure but also converted to useful scaffolds by reduction or oxidation conditions.

miR-93 promotes TGF-ß-induced epithelial-to-mesenchymal transition through downregulation of NEDD4L in lung cancer cells.

The level of microRNA-93 (miR-93) in tumors has been recently reported to be negatively correlated with survival of lung cancer patients. Considering that the most devastating aspect of lung cancer is metastasis, which can be promoted by transforming growth factor-ß (TGF-ß)-induced epithelial-to-mesenchymal transition (EMT), we sought to determine whether miR-93 is involved in this process. Here, we report that a previously unidentified target of miR-93, neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L), is able to mediate TGF-ß-mediated EMT in lung cancer cells. miR-93 binds directly to the 3'-UTR of the NEDD4L messenger RNA (mRNA), leading to a downregulation of NEDD4L expression at the protein level. We next demonstrated that the downregulation of NEDD4L enhanced, while overexpression of NEDD4L reduced TGF-ß signaling, reflected by increased phosphorylation of SMAD2 in the lung cancer cell line after TGF-ß treatment. Furthermore, overexpression of miR-93 in lung cancer cells promoted TGF-ß-induced EMT through downregulation of NEDD4L. The analysis of publicly available gene expression array datasets indicates that low NEDD4L expression correlates with poor outcomes among patients with lung cancer, further supporting the oncogenic role of miR-93 in lung tumorigenesis and metastasis.

DDB2 increases radioresistance of NSCLC cells by enhancing DNA damage responses.

Radiotherapy resistance is one of the major factors limiting the efficacy of radiotherapy in lung cancer patients. The extensive investigations indicate the diversity in the mechanisms underlying radioresistance. Here, we revealed that DNA damage binding protein 2 (DDB2) is a potential regulator in the radiosensitivity of non-small cell lung cancer (NSCLC) cells. DDB2, originally identified as a DNA damage recognition factor in the nucleotide excision repair, promotes the survival and inhibits the apoptosis of NSCLC cell lines upon ionizing radiation (IR). Mechanistic investigations demonstrated that DDB2 is able to facilitate IR-induced phosphorylation of Chk1, which plays a critical role in the cell cycle arrest and DNA repair in response to IR-induced DNA double-strand breaks (DSBs). Indeed, knockdown of DDB2 compromised the G2 arrest in the p53-proficient A549 cell line and reduced the efficiency of homologous recombination (HR) repair. Taken together, our data indicate that the expression of DDB2 in NSCLC could be used as a biomarker to predict radiosensitivity of the patients. Targeting Chk1 can be used to increase the efficacy of radiotherapy in patients of NSCLC possessing high levels of DDB2.

Toxicological proteomic responses of halophyte Suaeda salsa to lead and zinc.

The long term (30 days) toxicological effects of environmentally relevant concentrations of Pb2+ (20µg/L) and Zn2+ (100µg/L) were characterized in Suaeda salsa using proteomics techniques. The responsive proteins were related to metabolism (Krebs cycle and Calvin cycle), protein biosynthesis, stress and defense, energy, signaling pathway and photosynthesis in Pb2+, Zn2+ and Pb2++ Zn2+ exposed groups in S. salsa after exposures for 30 days. The proteomic profiles also showed differential responses in S. salsa to metal exposures. In Pb2+-treated group, the proteins were categorized into cystein metabolism and pentose phosphate pathway. The responsive proteins were basically involved in glutathione metabolism, glycolysis, cystein and methane metabolism, and voltage-dependent anion channel in Zn2+-treated group. In Pb2++ Zn2+-treated group, the proecular mechanism at protein level remtein responses were devided into tyrosine metabolism and glycolysis. Our results showed that the two typical heavy metals, lead and zinc, could induce toxicological effects in halophyte S. salsa at protein level.

The interactive effects of mercury and selenium on metabolic profiles, gene expression and antioxidant enzymes in halophyte Suaeda salsa.

Suaeda salsa is the pioneer halophyte in the Yellow River Delta and was consumed as a popular vegetable. Mercury has become a highly risky contaminant in the sediment of intertidal zones of the Yellow River Delta. In this work, we investigated the interactive effects of mercury and selenium in S. salsa on the basis of metabolic profiling, antioxidant enzyme activities and gene expression quantification. Our results showed that mercury exposure (20 µg L(-1)) inhibited plant growth of S. salsa and induced significant metabolic responses and altered expression levels of INPS, CMO, and MDH in S. salsa samples, together with the increased activities of antioxidant enzymes including SOD and POD. Overall, these results indicated osmotic and oxidative stresses, disturbed protein degradation and energy metabolism change in S. salsa after mercury exposures. Additionally, the addition of selenium could induce both antagonistic and synergistic effects including alleviating protein degradation and aggravating osmotic stress caused by mercury.

Discovery of a new series of potent prostacyclin receptor agonists with in vivo activity in rat.

The design and synthesis of two closely related series of prostacyclin receptor agonist compounds that showed excellent human IP receptor potency and efficacy is described. Compounds from this series showed in vivo activity after SC dosing in the monocrotaline model of PAH in rat.

Assessing urban park equity in Chaoyang District, Beijing using online review data.

Urban parks are essential components of urban ecosystems, providing vital ecological resources for city residents. However, the rapid expansion of high-density urban areas has led to an unequal distribution of park resources, raising growing concerns about spatial equity. To address these challenges, we employed an improved Gaussian two-step floating catchment area (2SFCA) method, considering park quality variations and integrating sentiment scores from park reviews to calculate a comprehensive park accessibility index, accounting for both supply and demand dynamics among park users. The results demonstrate the significance of park management, as users prioritise convenience and cleanliness of public facilities. Recreational quality significantly influences park distribution equity, with areas near Beijing's initial greenbelt zone showing improved accessibility (IA). Nonetheless, our analysis exposes disparities in urban park resource allocation within the Chaoyang District, indicating relative inequity. Spatial supply and demand mismatches, especially in the northwest and southeast, are evident. To enhance park layout equity, we recommend strategies like identifying and repurposing underused spaces, establishing pocket parks and micro-green areas, and improving recreational facilities. It is crucial to address the needs of vulnerable groups such as older residents and children. These insights stress the importance of ensuring fair urban park access to enhance the well-being of all city residents.

Assessing the Quality of ChatGPT Responses to Dementia Caregivers' Questions: Qualitative Analysis.

Background: Artificial intelligence (AI) such as ChatGPT by OpenAI holds great promise to improve the quality of life of patients with dementia and their caregivers by providing high-quality responses to their questions about typical dementia behaviors. So far, however, evidence on the quality of such ChatGPT responses is limited. A few recent publications have investigated the quality of ChatGPT responses in other health conditions. Our study is the first to assess ChatGPT using real-world questions asked by dementia caregivers themselves. objectives: This pilot study examines the potential of ChatGPT-3.5 to provide high-quality information that may enhance dementia care and patient-caregiver education. Methods: Our interprofessional team used a formal rating scale (scoring range: 0-5; the higher the score, the better the quality) to evaluate ChatGPT responses to real-world questions posed by dementia caregivers. We selected 60 posts by dementia caregivers from Reddit, a popular social media platform. These posts were verified by 3 interdisciplinary dementia clinicians as representing dementia caregivers' desire for information in the areas of memory loss and confusion, aggression, and driving. Word count for posts in the memory loss and confusion category ranged from 71 to 531 (mean 218; median 188), aggression posts ranged from 58 to 602 words (mean 254; median 200), and driving posts ranged from 93 to 550 words (mean 272; median 276). Results: ChatGPT's response quality scores ranged from 3 to 5. Of the 60 responses, 26 (43%) received 5 points, 21 (35%) received 4 points, and 13 (22%) received 3 points, suggesting high quality. ChatGPT obtained consistently high scores in synthesizing information to provide follow-up recommendations (n=58, 96%), with the lowest scores in the area of comprehensiveness (n=38, 63%). Conclusions: ChatGPT provided high-quality responses to complex questions posted by dementia caregivers, but it did have limitations. ChatGPT was unable to anticipate future problems that a human professional might recognize and address in a clinical encounter. At other times, ChatGPT recommended a strategy that the caregiver had already explicitly tried. This pilot study indicates the potential of AI to provide high-quality information to enhance dementia care and patient-caregiver education in tandem with information provided by licensed health care professionals. Evaluating the quality of responses is necessary to ensure that caregivers can make informed decisions. ChatGPT has the potential to transform health care practice by shaping how caregivers receive health information.

Caffeine improves mitochondrial dysfunction in the white matter of neonatal rats with hypoxia-ischemia through deacetylation: a proteomic analysis of lysine acetylation.

Aims: White matter damage (WMD) is linked to both cerebral palsy and cognitive deficits in infants born prematurely. The focus of this study was to examine how caffeine influences the acetylation of proteins within the neonatal white matter and to evaluate its effectiveness in treating white matter damage caused by hypoxia-ischemia. Main methods: We employed a method combining affinity enrichment with advanced liquid chromatography and mass spectrometry to profile acetylation in proteins from the white matter of neonatal rats grouped into control (Sham), hypoxic-ischemic (HI), and caffeine-treated (Caffeine) groups. Key findings: Our findings included 1,999 sites of lysine acetylation across 1,123 proteins, with quantifiable changes noted in 1,342 sites within 689 proteins. Analysis of these patterns identified recurring sequences adjacent to the acetylation sites, notably YKacN, FkacN, and G * * * GkacS. Investigation into the biological roles of these proteins through Gene Ontology analysis indicated their involvement in a variety of cellular processes, predominantly within mitochondrial locations. Further analysis indicated that the acetylation of tau (Mapt), a protein associated with microtubules, was elevated in the HI condition; however, caffeine treatment appeared to mitigate this over-modification, thus potentially aiding in reducing oxidative stress, inflammation in the nervous system, and improving mitochondrial health. Caffeine inhibited acetylated Mapt through sirtuin 2 (SITR2), promoted Mapt nuclear translocation, and improved mitochondrial dysfunction, which was subsequently weakened by the SIRT2 inhibitor, AK-7. Significance: Caffeine-induced changes in lysine acetylation may play a key role in improving mitochondrial dysfunction and inhibiting oxidative stress and neuroinflammation.

Cuproptosis facilitates immune activation but promotes immune escape, and a machine learning-based cuproptosis-related signature is identified for predicting prognosis and immunotherapy response of gliomas.

AIMS: Cell death, except for cuproptosis, in gliomas has been extensively studied, providing novel targets for immunotherapy by reshaping the tumor immune microenvironment through multiple mechanisms. This study aimed to explore the effect of cuproptosis on the immune microenvironment and its predictive power in prognosis and immunotherapy response. METHODS: Eight glioma cohorts were included in this study. We employed the unsupervised clustering algorithm to identify novel cuproptosis clusters and described their immune microenvironmental characteristics, mutation landscape, and altered signaling pathways. We verified the correlation among FDX1, SLC31A1, and macrophage infiltration in 56 glioma tissues. Next, based on multicenter cohorts and 10 machine learning algorithms, we constructed an artificial intelligence-driven cuproptosis-related signature named CuproScore. RESULTS: Our findings suggested that glioma patients with high levels of cuproptosis had a worse prognosis owing to immunosuppression caused by unique immune escape mechanisms. Meanwhile, we experimentally validated the positive association between cuproptosis and macrophages and its tumor-promoting mechanism in vitro. Furthermore, our CuproScore exhibited powerful and robust prognostic predictive ability. It was also capable of predicting response to immunotherapy and chemotherapy drug sensitivity. CONCLUSIONS: Cuproptosis facilitates immune activation but promotes immune escape. The CuproScore could predict prognosis and immunotherapy response in gliomas.