Exercise attenuates the perioperative neurocognitive disorder induced by hyperhomocysteinemia in mice.

The perioperative neurocognitive disorder (PND) is a severe complication that affects millions of surgical patients each year. Homocysteine (Hcy) is known to increase the risk of developing PND in both young and elderly mice. However, whether Hcy alone can induce cognitive deficits in middle-aged mice (12-month-old), whether exercise can attenuate Hcy-induced hippocampus-related cognitive deficits after surgery through suppressing neuroinflammation, synaptic elimination, and the level of Hcy remains unknown. The present study aimed to answer these questions through testing the possibility of establishing a PND model using 12-month-old mice which received homocysteine injections before exploratory laparotomy and the therapeutic mechanism of exercise. In the present study, it was found that levels of serum homocysteine were age-dependently increased in mice with a significant difference between that of 18-month-old mice and 6-week, 6-month, and 12-month-old mice. PND occurred in 18-month but not in 12-month-old mice after exploratory laparotomy under isoflurane anesthesia. Intraperitoneal injection of Hcy for 3 consecutive days before surgery rendered 12-month-old mice to develop PND after abdominal laparotomy under isoflurane anesthesia at a minimal dosage of 20 mg/kg. Neuroinflammation and synaptic elimination was present in 12-month-old preoperative Hcy-injected mice. Preoperative voluntary wheel exercise could prevent PND in 12-month-old mice that have received Hcy injection before surgery, which might be related to the decreased level of serum Hcy. Activation of glial cells, proinflammatory phenotype markers and synaptic elimination were attenuated in the hippocampus of 12-month-old preoperative Hcy-injected mice by this exercise. These results provide direct evidence that hyperhomocysteinemia can induce postoperative cognitive deficits in middle-aged mice. Pre-surgery exercise can effectively prevent Hcy-precipitated postoperative cognitive dysfunction.

Genomic gain/methylation modification/hsa-miR-132-3p increases RRS1 overexpression in liver hepatocellular carcinoma.

This study aimed to determine the upstream regulatory factors affecting ribosome biogenesis regulator 1 homolog (RRS1) expression and the development and prognosis of liver hepatocellular carcinoma (LIHC). The expression profiles of RRS1 were evaluated in pan-cancer tissues and liver tumor cell lines. The associations of RRS1 with pan-cancer survival, immune infiltrations, immune checkpoints, and drug sensitivity were identified. We explored the potential upstream regulatory mechanisms of RRS1 expression. Hsa-miR-132-3p knockdown, CCK-8 assays, transwell, and wound healing assays were performed to validate the regulatory effect of hsa-miR-132-3p on RRS1 expression and the development of LIHC. Our findings demonstrated that RRS1 was significantly elevated in 27 types of cancers. RRS1 predicts a poor outcome of LIHC, lung adenocarcinoma, head and neck cancer, and kidney papillary cell carcinoma. RRS1 expression showed a significant association with immune cell infiltrates and the expression of immune checkpoints-related genes in LIHC tissues. Increased RRS1 expression may have a negative effect on these anticancer drugs of LIHC. Low methylation of the RRS1 promoter and its genomic gain may elevate RRS1 expression and predict poor prognosis for LIHC. Increased hsa-miR-132-3p expression may elevate RRS1 expression and result in poor prognosis for LIHC. Hsa-miR-132-3p inhibition can decrease RRS1 expression and the development of liver tumor cell lines. Low methylation of the RRS1 promoter, RRS1 genomic gain, and hsa-miR-132-3p upregulation in LIHC may promote RRS1 upregulation and thus lead to the development and poor prognosis for LIHC. RRS1 is a promising therapeutic target for LIHC.

Integration of ATAC-Seq and RNA-Seq identifies key genes and pathways involved in the neuroprotection of S-adenosylmethionine against perioperative neurocognitive disorder.

The gene-regulatory landscape is highly dynamic in healthy and diseased brains. DNA methylation is a well-known epigenetic modification that regulates gene expression, and our previous study demonstrated that S-adenosylmethionine (SAM), a methylome modulator, was a neuroprotectant against perioperative neurocognitive disorder (PND). However, the underlying mechanism remains to be elucidated. Here, we integrated an assay for transposase-accessible chromatin by sequencing (ATAC-seq) and RNA sequencing (RNA-seq) to identify the key genes and pathways involved in the neuroprotection of SAM against PND. Our RNA-seq data demonstrated that genes involved in biological processes such as Wnt signaling, inflammatory response, transcription and long-term potentiation likely mediate the neuroprotection of SAM. Our ATAC-seq data provided comprehensive maps of chromatin accessibility changes induced by laparotomy and laparotomy + SAM treatment, and functional annotation of the regions with high variations in chromatin accessibility highlighted the role of the Wnt signaling pathway in PND pathogenesis and SAM treatment. Further motif analysis identified key transcription factors (e.g., CTCF, TFDP1, TCFL5, KLF15, ZBTB14, TFAP2E) that may participate in the neuroprotection of SAM. In conclusion, the current study provides an epigenomic perspective to understand the pathogenesis of PND and its treatment by SAM.

A decrease in NR2B expression mediated by DNA hypermethylation induces perioperative neurocognitive disorder in aged mice.

AIMS: This study was designed to investigate the role of NR2B and the contribution of DNA methylation to NR2B expression in the pathogenesis of PND. METHODS: Eighteen-month-old C57BL/6J mice were subjected to experimental laparotomy under 1.4% isoflurane anesthesia. Hippocampus-dependent learning and memory were evaluated by using the Barnes maze and contextual fear conditioning tests. The protein and mRNA expression levels of NR2B were evaluated by western blotting and qRT-PCR respectively, and the methylation of the NR2B gene was examined by using targeted bisulfite sequencing. Long-term synaptic plasticity (LTP) was measured by electrophysiology. RESULTS: Mice that underwent laparotomy exhibited hippocampus-dependent cognitive deficits accompanied by decreased NR2B expressions and LTP deficiency. The overexpression of NR2B in the dorsal hippocampus could improve learning and memory in mice subjected to laparotomy. In particular, the decreased NR2B expressions induced by laparotomy was attributed to the NR2B gene hypermethylation. Preoperative administration of S-adenosylmethionine (SAM) could hypomethylate the NR2B gene, upregulate NR2B expression and improve LTP, exerting a dose-dependent therapeutic effect against PND. Moreover, inhibiting NR2B abrogated the benefits of SAM pretreatment. CONCLUSIONS: Laparotomy cause hippocampus-dependent cognitive decline by hypermethylating the NR2B gene, allowing us to understand the pathogenesis of PND in an epigenetic landscape.

A modified mouse model of perioperative neurocognitive disorders exacerbated by sleep fragmentation.

Aging is one of the greatest risk factors for postoperative cognitive dysfunction (POCD), also known as perioperative neurocognitive disorder (PND). Animal models of PND are usually induced in mice over 18 months of age, which imposes expensive economic and time costs for PND-related studies. Sleep disorders, including sleep fragmentation, are reported to aggravate memory impairment in neurocognitive-related diseases such as Alzheimer's disease (AD). Therefore, the aim of the present study was to explore whether a PND model could be constructed in younger mice with the help of fragmented sleep. We found that fragmented sleep followed by laparotomy under isoflurane anesthesia could stably induce PND in 15-month-old mice. To determine whether the neurocognitive decline in this model could be salvaged by clinical treatments, we administered repetitive transcranial magnetic stimulation (rTMS) to the model mice before anesthesia and surgery. We found that 10 days of high-frequency rTMS (HF-rTMS) could improve spatial learning and memory deficits in this modified PND model. We are the first to successfully construct a PND model in younger mice,which is more economical, that can be used as an alternative model for future PND studies.

Targeting neuroinflammation as a preventive and therapeutic approach for perioperative neurocognitive disorders.

Perioperative neurocognitive disorders (PND) is a common postoperative complication associated with regional or general anesthesia and surgery. Growing evidence in both patient and animal models of PND suggested that neuroinflammation plays a critical role in the development and progression of this problem, therefore, mounting efforts have been made to develop novel therapeutic approaches for PND by targeting specific factors or steps alongside the neuroinflammation. Multiple studies have shown that perioperative anti-neuroinflammatory strategies via administering pharmacologic agents or performing nonpharmacologic approaches exert benefits in the prevention and management of PND, although more clinical evidence is urgently needed to testify or confirm these results. Furthermore, long-term effects and outcomes with respect to cognitive functions and side effects are needed to be observed. In this review, we discuss recent preclinical and clinical studies published within a decade as potential preventive and therapeutic approaches targeting neuroinflammation for PND.

Xiaoxuming Decoction: A Traditional Herbal Recipe for Stroke With Emerging Therapeutic Mechanisms.

Xiaoxuming decoction (XXMD) has been traditionally used to manage stroke though debates on its clinical efficacy were present in the history. Till nowadays, it is still one of the most commonly used herbal recipes for stroke. One of the reasons is that a decent proportion of ischemic stroke patients still have residue symptoms even after thrombolysis with rt-PA or endovascular thrombectomy. Numerous clinical studies have shown that XXMD is an effective alternative therapy not only at the acute stage, but also at the chronic sequelae stage of ischemic stroke. Modern techniques have isolated groups of compounds from XXMD which have shown therapeutic effects, such as dilating blood vessels, inhibiting thrombosis, suppressing oxidative stress, attenuating nitric oxide induced damage, protecting the blood brain barrier and the neurovascular unit. However, which of the active compounds is responsible for its therapeutic effects is still unknown. Emerging studies have screened and tested these active compounds aiming to find individual compounds that can be used as drugs to treat stroke. The present study summarized both clinical evidence of XXMD in managing stroke and experimental evidence on its molecular mechanisms that have been reported recently using advanced techniques. A new perspective has also been discussed with an aim to provide new targets that can be used for screening active compounds from XXMD.

Identification of the Role and Clinical Prognostic Value of Target Genes of m6A RNA Methylation Regulators in Glioma.

m6A RNA methylation regulators can regulate the growth, progression, and invasion of glioma cells by regulating their target genes, which provides a reliable support for the m6A regulator-target axes as the novel therapeutic targets and clinical prognostic signature in glioma. This study aimed to explore the role and prognostic value of m6A RNA methylation regulators and their targets. Expression profiles and clinicopathological data were obtained from the Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Clinical Proteome Tumor Analysis Consortium (CPTAC) datasets. Differential expression and correlation analyses were performed between normal and glioma tissues at mRNA and protein levels. Univariate Cox regression, survival, and Lasso Cox regression analyses were conducted to identify and establish the prognostic gene signature. Kaplan-Meier curve, multivariate Cox regression analysis, and ROC were utilized to evaluate the prognostic capacity of the prognostic gene signature. The correlation analysis, systematic bioinformatics analysis, and cell experiment were performed to further understand the potential underlying molecular mechanisms and drug sensitivity. Our results suggested that IGF2BP2, KIAA1429, METTL16, and METTL3, as well as 208 targets are involved in the occurrence of glioma, GBM, and LGG. YTHDF1 and 78 targets involved the occurrence of glioma and GBM, not LGG, among which 181 genes were associated with overall survival. From other findings and our cell experiment results, we demonstrated that METTL3 can activate Notch pathway and facilitate glioma occurrence through regulating its direct targets NOTCH3, DLL3, and HES1, and Notch pathway genes may serve as the potential treatment targets for glioma. Our study established and validated a seven-gene signature comprising METTL3, COL18A1, NASP, PHLPP2, TIMP1, U2AF2, and VEGFA, with a good capability for predicting glioma survival, which may guide therapeutic customization and clinical decision-making. These genes were identified to influence 81 anticancer drug responses, which further contributes to the early phase clinical trials of drug development.

Identification of Hub Genes and Pathways Associated With Idiopathic Pulmonary Fibrosis via Bioinformatics Analysis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease whose etiology remains unknown. The purpose of this study was to explore hub genes and pathways related to IPF development and prognosis. Multiple gene expression datasets were downloaded from the Gene Expression Omnibus database. Weighted correlation network analysis (WGCNA) was performed and differentially expressed genes (DEGs) identified to investigate Hub modules and genes correlated with IPF. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein-protein interaction (PPI) network analysis were performed on selected key genes. In the PPI network and cytoHubba plugin, 11 hub genes were identified, including ASPN, CDH2, COL1A1, COL1A2, COL3A1, COL14A1, CTSK, MMP1, MMP7, POSTN, and SPP1. Correlation between hub genes was displayed and validated. Expression levels of hub genes were verified using quantitative real-time PCR (qRT-PCR). Dysregulated expression of these genes and their crosstalk might impact the development of IPF through modulating IPF-related biological processes and signaling pathways. Among these genes, expression levels of COL1A1, COL3A1, CTSK, MMP1, MMP7, POSTN, and SPP1 were positively correlated with IPF prognosis. The present study provides further insights into individualized treatment and prognosis for IPF.

Restoring VTA DA neurons excitability accelerates emergence from sevoflurane general anesthesia of anxiety state.

Preoperative anxiety is common and often comes with a higher probability of worse recovery. However, the neurological mechanism of the effect of preoperative anxiety on general anesthesia and subsequent awakening remains unknown. In this study, we report an anxious state results in delayed awakening in anxiety model mice from sevoflurane general anesthesia. More profound inhibition of DA neurons in the VTA contributes to delayed awakening. Optogenetic stimulation of VTA DA neurons can reverse the delay. The results indicate that VTA DA neurons may be involved in the delay in awakening from general anesthesia caused by anxiety.

The Potential Mechanism of Cancer Patients Appearing More Vulnerable to SARS-CoV-2 and Poor Outcomes: A Pan-Cancer Bioinformatics Analysis.

To explore the potential mechanism of cancer patients appearing more vulnerable to SARS-CoV-2 infection and poor COVID-19 outcomes, we conducted an integrative bioinformatics analysis for SARS-CoV-2-required genes and host genes and variants related to SARS-CoV-2 susceptibility and COVID-19 severity. BLCA, HNSC, KIRC, KIRP, LGG, PCPG, PRAD, TGCT, and THCA patients carrying rs10774671-A (OAS1) genotype may be more likely to have poor COVID-19 outcomes relative to those who carry rs10774671-G, because individuals carrying rs10774671-A will have lower expression of OAS1, which serves as a protective factor against SARS-CoV-2 processes and poor COVID-19 outcomes. SARS-CoV-2-required genes were correlated with TME, immune infiltration, overall survival, and anti-cancer drug sensitivity. CHOL patients may have a higher risk of SARS-CoV-2 infection than healthy subjects. SARS-CoV-2-induced ACE2 and NPC1 elevation may have a negative influence on the immune responses of LUSC and CD8+T infiltration of LUAD, and negatively affect the sensitivity of anti-lung cancer drugs. LUSC and LUAD patients may have a varying degree of adverse outcomes if they are infected with SARS-CoV-2. miR-760 may target and inhibit ACE2 expression. Cancer patients appearing vulnerable to SARS-CoV-2 infection and having poor COVID-19 outcomes may be partly due to host genetic factors and dysregulation of SARS-CoV-2-required genes. OAS1, ACE2, and miR-760 could serve as the treatment and intervention targets for SARS-CoV-2.