CircAKT3 alleviates postoperative cognitive dysfunction by stabilizing the feedback cycle of miR-106a-5p/HDAC4/MEF2C axis in hippocampi of aged mice.

Circular RNAs (circRNAs) have garnered significant attention in the field of neurodegenerative diseases including Alzheimer's diseases due to their covalently closed loop structure. However, the involvement of circRNAs in postoperative cognitive dysfunction (POCD) is still largely unexplored. To identify the genes differentially expressed between non-POCD (NPOCD) and POCD mice, we conducted the whole transcriptome sequencing initially in this study. According to the expression profiles, we observed that circAKT3 was associated with hippocampal neuronal apoptosis in POCD mice. Moreover, we found that circAKT3 overexpression reduced apoptosis of hippocampal neurons and alleviated POCD. Subsequently, through bioinformatics analysis, our data showed that circAKT3 overexpression in vitro and in vivo elevated the abundance of miR-106a-5p significantly, resulting in a decrease of HDAC4 protein and an increase of MEF2C protein. Additionally, this effect of circAKT3 was blocked by miR-106a-5p inhibitor. Interestingly, MEF2C could activate the transcription of miR-106a-5p promoter and form a positive feedback loop. Therefore, our findings revealed more potential modulation ways between circRNA-miRNA and miRNA-mRNA, providing different directions and targets for preclinical studies of POCD.

Inorganic-Ligand Quantum Dots Meet Inorganic-Ligand Semiconductor Nanoplatelets: A Promising Fusion to Construct All-Inorganic Assembly.

By the reaction of inorganic-ligand CdS/Cd2+ quantum dots (QDs) with inorganic-ligand CdSe/CdS/S2- nanoplatelets (NPLs), semiconductor CdS QDs were fused with CdSe/CdS NPLs to yield all-inorganic assemblies, accompanied by great photoluminescence-enhancement. These all-inorganic assemblies facilitate charge transport between each other and open up interesting prospects with electronic and optoelectronic nanodevices.

Postoperative cognitive dysfunction in the aged: the collision of neuroinflammaging with perioperative neuroinflammation.

The aging population is burgeoning globally and this trend presents great challenges to the current healthcare system as the growing number of aged individuals receives procedures of surgery and anesthesia. Postoperative cognitive dysfunction (POCD) is a severe postoperative neurological sequela. Advanced age is considered as an independent risk factor of POCD. Mounting evidence have shown that neuroinflammation plays an essential role in POCD. However, it remains debatable why this complication occurs highly in the aged individuals. As known, aging itself is the major common high-risk factor for age-associated disorders including diabetes, cardiovascular disease, cancer, and neurodegenerative diseases. Chronic low-grade neuroinflammation (dubbed neuroinflammaging in the present paper) is a hallmark alternation and contributes to age-related cognitive decline in the normal aging. Interestingly, several lines of findings show that the neuroinflammatory pathogenesis of POCD is age-dependent. It suggests that age-related changes, especially the neuroinflammaging, are possibly associated with the postoperative cognitive impairment. Understanding the role of neuroinflammaging in POCD is crucial to elucidate the mechanism of POCD and develop strategies to prevent or treat POCD. Here the focus of this review is on the potential role of neuroinflammaging in the mechanism of POCD. Lastly, we briefly review promising interventions for this neurological sequela.

METTL14 contributes to acute lung injury by stabilizing NLRP3 expression in an IGF2BP2-dependent manner.

Acute lung injury (ALI) as well as its more severe form, acute respiratory distress syndrome (ARDS), frequently leads to an uncontrolled inflammatory response. N6-methyladenosine (m6A) modification was associated with the progression of several inflammatory diseases. However, the role of methyltransferase-like 14 (METTL14)-mediated m6A methylation in ALI/ARDS remains unclear. Here, we reported an increase in overall expression levels of m6A and METTL14 in circulating monocyte-derived macrophages recruited to the lung following ALI, which is correlated with the severity of lung injury. We further demonstrated the critical function of METTL14 in activating NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome in vitro and in mouse models of ALI/ARDS, and validated NLRP3 as the downstream target of METTL14 by the m6A RNA immunoprecipitation (MeRIP) and RIP assays. Mechanistically, METTL14-methylated NLRP3 transcripts were subsequently recognized by insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), an m6A reader, which stabilized NLRP3 mRNA. Furthermore, we observed that IGF2BP2 knockdown diminished LPS-induced ALI in mice by downregulating NLRP3 expression. In summation, our study revealed that the molecular mechanism underlying the pathogenesis of ALI/ARDS involves METTL14-mediated activation of NLRP3 inflammasome in an IGF2BP2 dependent manner, thereby demonstrating the potential of METTL14 and IGF2BP2 as promising biomarkers and therapeutic targets for ALI/ARDS treatment.

Innovation, advertising, personal selling, and sustainability in the industries massively benefited from major public health emergencies: paradoxical evidence from China.

Background: While major public health emergencies have severe socio-economic impacts, they may also present many opportunities for certain industries. For these industries that have benefited significantly (e.g., China' s healthcare industry), the traditional emphasis on improving business performance through increased investment in innovation, marketing and sustainability may face contextual applicability challenges. Methods: We used the data of healthcare industry in China during Covid-19 and the methods of hierarchical regression, moderating effect test to analyze the impact of innovation, advertising, personal selling, and sustainability on healthcare firms' profitability. Three kinds of robust test including increasing the measurement range of variables, changing the data source and parameter estimation method, and Quantile regression are used. Results: This paper finds that innovation, advertising, and environmental sustainability have significant negative impacts on profitability, while personal selling, social sustainability, and governance sustainability have significant positive impacts on profitability in the industries massively benefited from major public health emergencies. Besides, social sustainability can significantly moderate the relationship between innovation and profitability. Conclusion: On one hand, for companies in industries that have benefited greatly from major public health emergencies, a shift in resource allocation from innovation, advertising, and environmental sustainability to personal selling, social sustainability, and governance sustainability may be more conducive to improving their profitability. On the other hand, for public health regulatory authorities, it is necessary to strengthen the supervision of sales representatives of health care enterprises, hospitals, public health organizations, etc., and appropriately subsidize the innovation of enterprises to enhance their innovation motivation.

Transcriptome Profiling of miRNA-mRNA Interactions and Associated Mechanisms in Chemotherapy-Induced Neuropathic Pain.

Chemotherapy-induced neuropathic pain (CINP) is a dose-limiting adverse event affecting 40% of chemotherapy patients. MiRNA-mRNA interaction plays an important role in various processes. However, detailed profiling of miRNA-mRNA interactions in CINP remains unclear. Here, a rat-based CINP model was established using paclitaxel, followed by nociceptive behavioral tests related to mechanical allodynia, thermal hyperalgesia, and cold allodynia. The landscape of miRNA-mRNA interaction in the spinal dorsal horn was investigated through mRNA transcriptomics and small RNA sequencing. Under CINP condition, 86 differentially expressed mRNAs and 56 miRNAs were identified. Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated the activity of Odorant binding, postsynaptic specialization and synaptic density, extracellular matrix, mitochondrial matrix, retrograde endocannabinoid signaling, and GTPase activity. Protein-protein interaction (PPI), networks of circRNA-miRNA-mRNA, lncRNA-miRNA-mRNA, and TF-genes were demonstrated. We next explored the immune infiltration microenvironment and found a higher infiltration abundance of Th17 and a lower abundance of MDSC in CINP. RT-qPCR and dual-luciferase assays were used to verify the sequencing results, and single-cell analysis based on the SekSeeq database was conducted. Combined with bioinformatics analyses and experimental validations, Mpz, a protein-coding gene specifically expressed in Schwann cells, was found critical in maintaining CINP under miRNA regulation. Therefore, these data highlight the expression patterns of miRNA-mRNA, and the underlying mechanism in the spinal dorsal horn under CINP condition, and Mpz may serve as a promising therapeutic target for patients with CINP.

Sirtuins functions in central nervous system cells under neurological disorders.

The sirtuins (SIRTs), a class of NAD+ -dependent deacylases, contain seven SIRT family members in mammals, from SIRT1 to SIRT7. Extensive studies have revealed that SIRT proteins regulate virous cell functions. Central nervous system (CNS) decline resulted in progressive cognitive impairment, social and physical abilities dysfunction. Therefore, it is of vital importance to have a better understanding of potential target to promote homeostasis of CNS. SIRTs have merged as the underlying regulating factors of the process of neurological disorders. In this review, we profile multiple functions of SIRT proteins in different cells during brain function and under CNS injury.

The Role of Perioperative Sleep Disturbance in Postoperative Neurocognitive Disorders.

Postoperative neurocognitive disorder (PND) increases the length of hospital stay, mortality, and risk of long-term cognitive impairment. Perioperative sleep disturbance is prevalent and commonly ignored and may increase the risk of PND. However, the role of perioperative sleep disturbances in PND remains unclear. Nocturnal sleep plays an indispensable role in learning, memory, and maintenance of cerebral microenvironmental homeostasis. Hospitalized sleep disturbances also increase the incidence of postoperative delirium and cognitive dysfunction. This review summarizes the role of perioperative sleep disturbances in PND and elucidates the potential mechanisms underlying sleep-deprivation-mediated PND. Activated neuroinflammation and oxidative stress; impaired function of the blood-brain barrier and glymphatic pathway; decreased hippocampal brain-derived neurotrophic factor, adult neurogenesis, and sirtuin1 expression; and accumulated amyloid-beta proteins are associated with PND in individuals with perioperative sleep disorders. These findings suggest that the improvement of perioperative sleep might reduce the incidence of postoperative delirium and postoperative cognitive dysfunction. Future studies should further investigate the role of perioperative sleep disturbance in PND.

NR2B receptor- and calpain-mediated KCC2 cleavage resulted in cognitive deficiency exposure to isoflurane.

BACKGROUND: During brain development, volatile anesthetic can rapidly interfere with physiologic patterns of dendritic development and synaptogenesis and impair the formation of precise neuronal circuits. KCC2 plays vital roles in spine development and synaptogenesis through its Cl- transport function and structural interactions with the spine cytoskeleton protein 4.1 N. The aim of this study was to dissect the mechanism of volatile anesthetics, which impair dendritic development and synaptogenesis via mediation of KCC2 cleavage. METHODS: Westernblotting was employed to assess the expression change of NR2B, NR2A, calpain-1, calpain-2, KCC2, and 4.1 N protein of rat (PND 5). Co-immunoprecipitation was applied to demonstrate the interaction between KCC2 and 4.1 N protein. Long-term cognitive deficiency was assessed by MWM. Lentivirus-calpain-2 was administered by hippocampus stereotaxic injection. RESULTS: There was a significant increase in the level of NR2B instead of NR2A exposure to isoflurane. Calpain-2 was excessively activated via NR2B after 6 h of isoflurane exposure. The expression of plasmalemmal KCC2 and 4.1 N protein was significantly decreased treated with isoflurane. The isoflurane group showed longer traveled distance, prolonged escape latency, less time spent in the target quadrant, and decreased platform crossings. Pretreatment with ifenprodil and downregulated calpain-2 expression significantly alleviated these neurotoxicity responses and cognitive deficiency after isoflurane exposure. CONCLUSIONS: A significant increase in NR2B, excessive activation of calpain-2 and increased cleavage of plasmalemmal KCC2, are involved in isoflurane-induced neurotoxicity and long-term cognitive deficiency. Blocking NR2B and calpain-2 activity significantly attenuated these responses. The KCC2 cleavage mediated by NR2B and calpain-2 is a major determinant of isoflurane-induced long-term cognitive deficiency.

General Anesthetic-Induced Neurotoxicity in the Immature Brain: Reevaluating the Confounding Factors in the Preclinical Studies.

General anesthetic (GA) is used clinically to millions of young children each year to facilitate surgical procedures, relieve perioperative stress, and provide analgesia and amnesia. During recent years, there is a growing concern regarding a causal association between early life GA exposure and subsequently long-term neurocognitive abnormalities. To address the increasing concern, mounting preclinical studies and clinical trials have been undergoing. Until now, nearly all of the preclinical findings show that neonatal exposure to GA causally leads to acute neural cell injury and delayed cognitive impairment. Unexpectedly, several influential clinical findings suggest that early life GA exposure, especially brief and single exposure, does not cause adverse neurodevelopmental outcome, which is not fully in line with the experimental findings and data from several previous cohort trials. As the clinical data have been critically discussed in previous reviews, in the present review, we try to analyze the potential factors of the experimental studies that may overestimate the adverse effect of GA on the developing brain. Meanwhile, we briefly summarized the advance in experimental research. Generally, our purpose is to provide some useful suggestions for forthcoming preclinical studies and strengthen the powerfulness of preclinical data.

Resveratrol Mitigates Hippocampal Tau Acetylation and Cognitive Deficit by Activation SIRT1 in Aged Rats following Anesthesia and Surgery.

Postoperative cognitive dysfunction (POCD) is a sever postsurgical neurological complication in the elderly population. As the global acceleration of population ageing, POCD is proved to be a great challenge to the present labor market and healthcare system. In the present study, our findings showed that tau acetylation mediated by SIRT1 deficiency resulted in tau hyperphosphorylation in the hippocampus of the aged POCD model and consequently contributed to cognitive impairment. Interestingly, pretreatment with resveratrol almost restored the expression of SIRT1, reduced the levels of acetylated tau and hyperphosphorylated tau in the hippocampus, and improved the cognitive performance in the behavioral tests. What is more, we observed that microglia-derived neuroinflammation resulting from SIRT1 inhibition in microglia probably aggravated the tau acetylation in cultured neurons in vitro. Our findings supported the notion that activation SIRT1 provided dually beneficial effect in the aged POCD model. Taken together, our findings provided the initial evidence that tau acetylation was associated with cognitive impairment in the aged POCD model and paved a promising avenue to prevent POCD by inhibiting tau acetylation in a SIRT1-dependent manner.

Resveratrol Mitigates Sevoflurane-Induced Neurotoxicity by the SIRT1-Dependent Regulation of BDNF Expression in Developing Mice.

Various lines of evidence suggest that neonatal exposure to general anesthetics, especially repeatedly, results in neuropathological brain changes and long-term cognitive impairment. Although progress has been made in experimental models, the exact mechanism of GA-induced neurotoxicity in the developing brain remains to be clarified. Sirtuin 1 (SIRT1) plays an important role in synaptic plasticity and cognitive performance, and its abnormal reduction is associated with cognitive dysfunction in neurodegenerative diseases. However, the role of SIRT1 in GA-induced neurotoxicity is unclear to date. In this study, we found that the protein level of SIRT1 was inhibited in the hippocampi of developing mice exposed to sevoflurane. Furthermore, the SIRT1 inhibition in hippocampi was associated with brain-derived neurotrophic factor (BDNF) downregulation modulated by methyl-cytosine-phosphate-guanine-binding protein 2 (MeCP2) and cAMP response element-binding protein (CREB). Pretreatment of neonatal mice with resveratrol nearly reversed the reduction in hippocampal SIRT1 expression, which increased the expression of BDNF in developing mice exposed to sevoflurane. Moreover, changes in the levels of CREB and MeCP2, which were considered to interact with BDNF promoter IV, were also rescued by resveratrol. Furthermore, resveratrol improved the cognitive performance in the Morris water maze test of the adult mice with exposure to sevoflurane in the neonatal stage, without changing motor function in the open field test. Taken together, our findings suggested that SIRT1 deficiency regulated BDNF signaling via regulation of the epigenetic activity of MeCP2 and CREB, and resveratrol might be a promising agent for mitigating sevoflurane-induced neurotoxicity in developing mice.

The role of SIRT1 in neuroinflammation and cognitive dysfunction in aged rats after anesthesia and surgery.

Postoperative cognitive dysfunction (POCD) is a neurological sequela of surgery and anesthesia. It occurs with high incidence in the aged population. Neuroinflammation is considered one of the least controversial culprits contributing to this postsurgical cognitive impairment, although it is a matter of debate as to why this complication occurs frequently in geriatric individuals. It is unclear how neuroinflammation is activated in aged populations following exposure to anesthesia and surgical procedures. In this study, we investigated the role of sirtuin 1 (SIRT1) in neuroinflammatory priming and cognitive deficits in aged rats after anesthesia and surgery. Our findings demonstrated that the hippocampal expression of SIRT1 decreased with age. The trend of declining SIRT1 expression further deteriorated in aged rats after exposure to anesthesia and surgery. Furthermore, we found that decreased SIRT1 was associated with downregulated expression of DNA methyltransferase 1 (DNMT1) and upregulated acetylated-nuclear factor kappa B (ac-NF-κB) expression, resulting in microglial activation and increased proinflammatory cytokines in the hippocampus of aged rats. Interestingly, our results showed that pretreatment with resveratrol, a SIRT1 agonist, mitigated the neuroinflammatory response and microglial activation and improved cognitive performance in the context fear-conditioning test and Morris water maze. Taken together, our findings suggest that anesthesia and surgery-induced inhibition of hippocampal SIRT1 expression is involved in the activation of neuroinflammation and cognitive impairment in aged rats and that activating SIRT1 might paved a promising path to preventing this postsurgical sequela.

Mdivi-1 pretreatment mitigates isoflurane-induced cognitive deficits in developmental rats.

Accumulating evidence indicates that general anesthetics can cause acute neuroapoptosis and long-term cognitive deficit in models exposed to anesthetics during the brain growth-spurt period. Anesthetics-induced imbalance of mitochondrial fusion and fission preceded and contributed to developmental neuroapoptosis. Accordingly, the imbalance was accompanied by activation of dynamin-related protein (Drp)1 which was closely associated with synaptic degeneration in neurodegenerative diseases. Based on the neuroprotective role of mitochondrial division inhibitor-1 (mdivi-1) in neurodegeneration and stroke, we set out to examine whether mdivi-1 can mitigate developmental neurotoxicity induced by isoflurane. In the present study, we showed that 2% isoflurane exposure for 2 h triggered Drp1 dephosphorylation at serine 656 and increased translocation of Drp1 and Bax from cytosol to mitochondria, concomitant with cytochrome C leakage into the cytosol. Remarkably, pretreatment with mdivi-1 not only alleviated isoflurane-induced disturbed mitochondrial translocation of Drp1 and Bax and almost restored morphological changes, but also inhibited cytochrome C release, caspase9 and caspase3 activation in hippocampi. Furthermore, mdivi-1 mitigated the loss of synaptic proteins and long-lasting cognitive deficit in later life of rats neonatally exposed to isoflurane. Taken together, isoflurane-induced Drp1 activation and translocation led to excessive mitochondrial fission and subsequently contributed to the synaptic injury and long-term cognitive impairment. However, mdivi-1 pretreatment prevented Drp1-dependent excessive mitochondrial fission and mitigated neuro-apoptosis and synaptic injury, and improved the long-term cognitive function. Thus mdivi-1 holds far-reaching insight for prophylaxis of developmental neurotoxicity induced by isoflurane.