Mild therapeutic hypothermia upregulates the O-GlcNAcylation level of COX10 to alleviate mitochondrial damage induced by myocardial ischemia-reperfusion injury.

OBJECTIVE: Mild therapeutic hypothermia (MTH) is an important method for perioperative prevention and treatment of myocardial ischemia-reperfusion injury (MIRI). Modifying mitochondrial proteins after protein translation to regulate mitochondrial function is one of the mechanisms for improving myocardial ischemia-reperfusion injury. This study investigated the relationship between shallow hypothermia treatment improving myocardial ischemia-reperfusion injury and the O-GlcNAcylation level of COX10. METHODS: We used in vivo Langendorff model and in vitro hypoxia/reoxygenation (H/R) cell model to investigate the effects of MTH on myocardial ischemia-reperfusion injury. Histological changes, myocardial enzymes, oxidative stress, and mitochondrial structure/function were assessed. Mechanistic studies involved various molecular biology methods such as ELISA, immunoprecipitation (IP), WB, and immunofluorescence. RESULTS: Our research results indicate that MTH upregulates the O-GlcNACylation level of COX10, improves mitochondrial function, and inhibits the expression of ROS to improve myocardial ischemia-reperfusion injury. In vivo, MTH effectively alleviates ischemia-reperfusion induced cardiac dysfunction, myocardial injury, mitochondrial damage, and redox imbalance. In vitro, the OGT inhibitor ALX inhibits the OGT mediated O-GlcNA acylation signaling pathway, downregulates the O-Glc acylation level of COX10, promotes ROS release, and counteracts the protective effect of MTH. On the contrary, the OGA inhibitor ThG showed opposite effects to ALX, further confirming that MTH activated the OGT mediated O-GlcNAcylation signaling pathway to exert cardioprotective effects. CONCLUSIONS: In summary, MTH activates OGT mediated O-glycosylation modified COX10 to regulate mitochondrial function and improve myocardial ischemia-reperfusion injury, which provides important theoretical basis for the clinical application of MTH.

Targeting CB2R in astrocytes for Parkinson's disease therapy: unraveling the Foxg1-mediated neuroprotective mechanism through autophagy-mediated NLRP3 degradation.

BACKGROUND: Inflammasomes in astrocytes have been shown to play a crucial role in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Cannabinoid Receptor 2(CB2R), a G protein-coupled receptor (GPCR), is considered a promising therapeutic target in inflammation-related disorders. This study aims to explore the role of CB2R in regulating NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated neuroinflammation in astrocytes. METHODS: In an in vivo animal model, specific targeting of astrocytic CB2R was achieved by injecting CB2R-specific adenovirus (or fork head box g1(foxg1) adenovirus) to knock down CB2R or administering CB2R agonists, inhibitors, etc., in the substantia nigra pars compacta (SNc) of mice. A PD mouse model was established using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induction. Animal behavioral tests, western blot, immunofluorescence, and other experiments were performed to assess the loss of midbrain tyrosine hydroxylase (TH) neurons, activation of astrocytes, and activation of the NLRP3 pathway. Primary astrocytes were cultured in vitro, and NLRP3 inflammasomes were activated using 1-methyl-4-phenylpyridinium (MPP+) or lipopolysaccharide (LPS) and adenosine triphosphate (ATP). Western blot and ELISA experiments were conducted to assess the release of inflammatory factors. Transcriptomic sequencing and CUT&RUN techniques were employed to study the CB2R regulation of the foxg1 binding site on the autophagy molecule microtubule-associated protein 1 light chain 3 beta (MAP1LC3B). RESULTS: Astrocytic CB2R knockdown impaired the motor abilities of MPTP-induced mice, exacerbated the loss of TH neurons, and induced activation of the NLRP3/Caspase-1/interleukin 1 (IL-1ß) pathway. Activation of CB2R significantly alleviated motor impairments in mice while reducing NLRP3 deposition on astrocytes. In vitro cell experiments showed that CB2R activation attenuated the activation of the NLRP3/Caspase-1/IL-1ß pathway induced by LPS + ATP or MPP+. Additionally, it inhibited the binding of foxg1 to MAP1LC3B, increased astrocytic autophagy levels, and facilitated NLRP3 degradation through the autophagy-lysosome pathway. CONCLUSION: Activation of CB2R on astrocytes effectively mitigates NLRP3-mediated neuroinflammation and ameliorates the disease characteristics of PD in mice. CB2R represents a potential therapeutic target for treating PD.

ß-arrestin1 regulates astrocytic reactivity via Drp1-dependent mitochondrial fission: implications in postoperative delirium.

Postoperative delirium (POD) is a frequent and debilitating complication, especially amongst high risk procedures, such as orthopedic surgery. This kind of neurocognitive disorder negatively affects cognitive domains, such as memory, awareness, attention, and concentration after surgery; however, its pathophysiology remains unknown. Multiple lines of evidence supporting the occurrence of inflammatory events have come forward from studies in human patients' brain and bio-fluids (CSF and serum), as well as in animal models for POD. ß-arrestins are downstream molecules of guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). As versatile proteins, they regulate numerous pathophysiological processes of inflammatory diseases by scaffolding with inflammation-linked partners. Here we report that ß-arrestin1, one type of ß-arrestins, decreases significantly in the reactive astrocytes of a mouse model for POD. Using ß-arrestin1 knockout (KO) mice, we find aggravating effect of ß-arrestin1 deficiency on the cognitive dysfunctions and inflammatory phenotype of astrocytes in POD model mice. We conduct the in vitro experiments to investigate the regulatory roles of ß-arrestin1 and demonstrate that ß-arrestin1 in astrocytes interacts with the dynamin-related protein 1 (Drp1) to regulate mitochondrial fusion/fission process. ß-arrestin1 deletion cancels the combination of ß-arrestin1 and cellular Drp1, thus promoting the translocation of Drp1 to mitochondrial membrane to provoke the mitochondrial fragments and the subsequent mitochondrial malfunctions. Using ß-arrestin1-biased agonist, cognitive dysfunctions of POD mice and pathogenic activation of astrocytes in the POD-linked brain region are reduced. We, therefore, conclude that ß-arrestin1 is a promising target for the understanding of POD pathology and development of POD therapeutics.

Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging.

MOTS-c is a peptide encoded by the short open reading frame of the mitochondrial 12S rRNA gene. It is significantly expressed in response to stress or exercise and translocated to the nucleus, where it regulates the expression of stress adaptation-related genes with antioxidant response elements (ARE). MOTS-c mainly acts through the Folate-AICAR-AMPK pathway, thereby influencing energy metabolism, insulin resistance, inflammatory response, exercise, aging and aging-related pathologies. Because of the potential role of MOTS-c in maintaining energy and stress homeostasis to promote healthy aging, especially in view of the increasing aging of the global population, it is highly pertinent to summarize the relevant studies. This review summarizes the retrograde signaling of MOTS-c toward the nucleus, the regulation of energy metabolism, stress homeostasis, and aging-related pathological processes, as well as the underlying molecular mechanisms.

Dual roles of interleukin-33 in cognitive function by regulating central nervous system inflammation.

With the advent of an aging society, the incidence of dementia is increasing, resulting in a vast burden on society. It is increasingly acknowledged that neuroinflammation is implicated in various neurological diseases with cognitive dysfunction such as Alzheimer's disease, multiple sclerosis, ischemic stroke, traumatic brain injury, and central nervous system infections. As an important neuroinflammatory factor, interleukin-33 (IL-33) is highly expressed in various tissues and cells in the mammalian brain, where it plays a role in the pathogenesis of a number of central nervous system conditions. Reams of previous studies have shown that IL-33 has both pro- and anti-inflammatory effects, playing dual roles in the progression of diseases linked to cognitive impairment by regulating the activation and polarization of immune cells, apoptosis, and synaptic plasticity. This article will summarize the current findings on the effects IL-33 exerts on cognitive function by regulating neuroinflammation, and attempt to explore possible therapeutic strategies for cognitive disorders based on the adverse and protective mechanisms of IL-33.

Roles of neuroligins in central nervous system development: focus on glial neuroligins and neuron neuroligins.

Neuroligins are postsynaptic cell adhesion molecules that are relevant to many neurodevelopmental disorders. They are differentially enriched at the postsynapse and interact with their presynaptic ligands, neurexins, whose differential binding to neuroligins has been shown to regulate synaptogenesis, transmission, and other synaptic properties. The proper functioning of functional networks in the brain depends on the proper connection between neuronal synapses. Impaired synaptogenesis or synaptic transmission results in synaptic dysfunction, and these synaptic pathologies are the basis for many neurodevelopmental disorders. Deletions or mutations in the neuroligins genes have been found in patients with both autism and schizophrenia. It is because of the important role of neuroligins in synaptic connectivity and synaptic dysfunction that studies on neuroligins in the past have mainly focused on their expression in neurons. As studies on the expression of genes specific to various cells of the central nervous system deepened, neuroligins were found to be expressed in non-neuronal cells as well. In the central nervous system, glial cells are the most representative non-neuronal cells, which can also express neuroligins in large amounts, especially astrocytes and oligodendrocytes, and they are involved in the regulation of synaptic function, as are neuronal neuroligins. This review examines the mechanisms of neuron neuroligins and non-neuronal neuroligins in the central nervous system and also discusses the important role of neuroligins in the development of the central nervous system and neurodevelopmental disorders from the perspective of neuronal neuroligins and glial neuroligins.

The correlation of intraoperative hypotension and postoperative cognitive impairment: a meta-analysis of randomized controlled trials.

BACKGROUND: There is no consensus on whether intraoperative hypotension is associated with postoperative cognitive impairment. Hence, we performed a meta-analysis to evaluate the correlation of intraoperative hypotension and the incidence of postoperative delirium (POD) or postoperative cognitive dysfunction (POCD). METHODS: We searched PubMed, Embase, and Cochrane Library databases to find randomized controlled trials (RCTs) in which reported the relationship between intraoperative hypotension and POD or POCD. The retrieval time is up to January 2020, without language restrictions. Quality assessment of the eligible studies was conducted by two researchers independently with the Cochrane evaluation system. RESULTS: We analyzed five eligible RCTs. Based on the relative mean arterial pressure (MAP), participants were divided into low-target and high-target groups. For the incidence of POD, there were two studies with 99 participants in the low-target group and 94 participants in the high-target pressure group. For the incidence of POCD, there were four studies involved 360 participants in the low-target group and 341 participants in the high-target group, with a study assessed both POD and POCD. No significant difference between the low-target and the high-target group was observed in the incidence of POD (RR = 3.30, 95% CI 0.80 to 13.54, P = 0.10), or POCD (RR = 1.26, 95% CI 0.76 to 2.08, P = 0.37). Furthermore, it also demonstrates that intraoperative hypotension prolonged the length of ICU stay, but did not increased the mortality, the length of hospital stay, and mechanical ventilation (MV) time. CONCLUSIONS: There is no significant correlation between intraoperative hypotension and the incidence of POD or POCD.

Alpha-Lipoic Acid Preconditioning and Ischaemic Postconditioning Synergistically Protect Rats from Cerebral Injury Induced by Ischemia and Reperfusion Partly via Inhibition TLR4/MyD88/ NF-κB Signaling Pathway.

BACKGROUND/AIMS: A combination of alpha-lipoic acid preconditioning (ALAP) and ischaemic preconditioning (IPC) has not been tested in an in vivo rat cerebral ischaemia/reperfusion injury (I/RI) model, and the potential protective mechanisms have not been well elucidated. The aim of this study was to investigate the role of the TLR4/ MyD88/ NF-κB signaling pathway in the synergistically neuroprotective and anti-inflammatory effects of ALAP and IPC. METHODS: One hundred and fifty male Sprague-Dawley rats, weighing 180-230 g, were randomly divided into the following 5 groups: 1) sham-operated control; 2) I/R; 3) I/R+ALAP; 4) I/R+IPC; 5) I/R+IPC+ALAP. After 2 h of reperfusion, the infarct size, neurological deficit scores, brain oedema, oxidative stress, and inflammatory and apoptotic biomarkers were assessed. In addition, reactive oxygen species (ROS) and cell apoptosis were detected by DHE staining and TUNEL staining, respectively. RESULTS: Both ALAP and IPC treatment attenuated the I/RI-induced neuronal injury, reflected by reductions in the infarct size, neurological deficit scores, brain oedema, lactate dehydrogenase (LDH) release and the inflammatory response, as well as decreased HMGB1, TLR4, MyD88, p65, C-Caspase 3 and Bax expression and increased IKB-α, HO-1, SOD-2 and Bcl-2 expression compared to that in the I/R group. Furthermore, the combination of the two strategies had synergistic anti-inflammatory effects and antioxidant benefits, ultimately limiting neuronal apoptosis. CONCLUSION: The 'cocktail' strategy exhibited a significant neuroprotection against I/RI by attenuating neuroinflammation via inhibition of the TLR4/MyD88/NF-κB signaling pathway.

To clarify features of photoplethysmography in monitoring balanced anesthesia, compared with Cerebral State Index.

BACKGROUND: Although photoplethysmography and cerebral state index (CSI) have been used as indices in monitoring vital signs perioperatively, there are only a few reports comparing the performance of photoplethysmography with CSI in monitoring anaesthesia depth. The aim of the present study was to clarify features of photoplethysmography in monitoring balanced general anesthesia compared with CSI. MATERIAL AND METHODS: Forty-five patients undergoing elective operation under general anaesthesia were enrolled in this study. Anaesthesia was induced with target-controlled infusion propofol. The photoplethysmogram, CSI, Modified Observer's Assessment of Alertness/Sedation Scale (MOAAS), and mean arterial pressure (MAP) were continuously monitored and recorded. Finger photoplethysmogram amplitude (PPGA) and pulse beat interval (PBI) were calculated off-line. RESULTS: For the period of time from pre-induction to pre-intubation, the coefficient of correlation between MOAAS and CSI was higher than those between MOAAS and PPGA, PBI, and MAP. CSI showed higher prediction probabilities (Pk) to differentiate the levels of MOAAS than did PPGA, PBI, and MAP. PPGA, PBI, and MAP values showed significant differences between before and after intubation, as well as pre- and post-incision (P<0.05), but no significant changes in cerebral state index (P>0.05). CONCLUSIONS: The present study shows that photoplethysmography-derived parameters appear to be more suitable in monitoring the nociceptive component of balanced general anesthesia, while CSI performs well in detecting the sedation or hypnotic component of balanced general anesthesia.

Efficacy and safety of flurbiprofen axetil in the prevention of pain on propofol injection: a systematic review and meta-analysis.

BACKGROUND: Pain on injection is an acknowledged adverse effect (AE) of propofol administration for the induction of general anesthesia. Flurbiprofen axetil has been reported to reduce the pain of injection. However, results of published papers on the efficacy of flurbiprofen axetil in managing pain on injection of propofol are inconsistent. MATERIAL/METHODS: We conducted a comprehensive meta-analysis of studies to appraise the efficacy and safety of flurbiprofen axetil for controlling pain induced by propofol injection. The pooled risk ratio (RR) with corresponding 95% confidence intervals (CI) was calculated employing fixed- or random-effects models, depending upon the heterogeneity of the included trials. RESULTS: Compared with the placebo group, flurbiprofen axetil allows more patients to have no pain (RR 3.51, 95% CI 2.22-5.55, p=0.000), and decreases the cumulative number of patients with mild, moderate, and severe pain on injecting propofol (RR 0.70, 95% CI 0.58-0.86, p=0.000; RR 0.59, 95% CI 0.46-0.75, p=0.000; RR 0.25, 95% CI 0.16-0.38, p=0.000, respectively). In the stratified analysis by the doses, flurbiprofen axetil at a dose of over 50 mg was found to be effective in reducing propofol-induced pain on injection; however, there were no significant differences in relieving pain between treatment and placebo groups with flurbiprofen axetil at a dose of 25 mg. In terms of drug safety, there were no adverse effects (AEs) reported between flurbiprofen axetil-based regimens and placebo regimens. CONCLUSIONS: Flurbiprofen axetil, an injectable prodrug of flurbiprofen, can significantly prevent or relieve the pain induced by propofol injection. More studies are required to assess its adverse effects.

Dexmedetomidine enhances Mitophagy via PINK1 to alleviate hippocampal neuronal Pyroptosis and improve postoperative cognitive dysfunction in elderly rat.

Postoperative cognitive dysfunction (POCD) is a common complication in elderly surgical patients, significantly affecting their quality of life. Dexmedetomidine (Dex), an anesthetic, has shown promise in alleviating POCD, but its underlying mechanism remains unclear. This study aims to explore how Dex improves POCD in aged rats by targeting the PINK1-mediated mitochondrial autophagy pathway, reducing caspase-1/11-GSDMD-induced hippocampal neuronal pyroptosis. Transcriptome sequencing identified 300 differentially expressed genes enriched in the mitochondrial autophagy pathway in Dex-treated POCD rat hippocampal tissue, with Pink1 as a key candidate. In a POCD rat model, Dex treatment upregulated hippocampal PINK1 expression. In vitro experiments using H19-7 rat hippocampal neurons revealed that Dex enhanced mitochondrial autophagy and suppressed neuronal pyroptosis by upregulating PINK1. Further mechanistic validation demonstrated that Dex activated PINK1-mediated mitochondrial autophagy, inhibiting caspase-1/11-GSDMD-induced neuronal pyroptosis. In vivo experiments confirmed Dex's ability to reduce caspase-1/11-GSDMD-dependent hippocampal neuronal pyroptosis and improve postoperative cognitive function in aged rats. Dexmedetomidine improves postoperative cognitive dysfunction in elderly rats by enhancing mitochondrial autophagy via PINK1 upregulation, mitigating caspase-1/11-GSDMD-induced neuronal pyroptosis.

The anti-inflammatory and haemodynamic effects of levosimendan on advanced heart failure patients: a meta-analysis of published studies.

OBJECTIVE: Increasing evidence from randomized controlled trials shows the anti-inflammatory and haemodynamic effects of levosimendan in advanced heart failure (AdHF), however, conflicting results have been reported in some studies. The aim of this study was to estimate the anti-inflammatory and haemodynamic effects of levosimendan on AdHF (registration number: INPLASY202250097). METHODS: The MEDLINE, PubMed, ClinicalTrials.com and Cochrane Library databases were systematically searched for studies published in English up to April 2019. Data were extracted from applicable articles. Meta-analyses were performed to assess interleukin (IL)-6, cardiac index, pulmonary artery pressure (PAP) and New York Heart Association (NYHA) functional class efficacy outcomes, following PRISMA 2020 guidelines. RESULTS: A total of 11 studies were included (211 patients who received levosimendan and 193 controls). Meta-analyses showed that the levosimendan group displayed significantly reduced IL-6 (standardized mean difference [SMD] -1.05; 95% confidence interval [CI] -1.44, -0.66; I2 = 50.9%), improved cardiac index (SMD 0.59; 95% CI 0.29, 0.88; I2 = 0.0%); reduced PAP (SMD -1.22; 95% CI -1.91, -0.53; I2 = 89.7%) and improved NYHA functional class (SMD -1.66; 95% CI -2.27, -1.04; I2 = 74.6%) versus controls. CONCLUSIONS: Levosimendan infusion was beneficial in patients with AdHF, displayed by anti-inflammatory and improved haemodynamic effects, and improved NYHA functional class.

Melatonin-Driven NLRP3 Inflammation Inhibition Via Regulation of NF-κB Nucleocytoplasmic Transport: Implications for Postoperative Cognitive Dysfunction.

The aseptic inflammatory response of the central nervous system is one of the important causes of neurodegenerative diseases in individuals and is also recognized in postoperative cognitive dysfunction (POCD). Inflammasome is thought to be closely related to brain homeostasis. However, there are few drugs targeting the inflammasome to suppress inflammation in clinical practice. Here, we showed that the neuroinflammatory response mediated by the NLRP3 (NLR family, pyrin domain containing 3) inflammasome was involved in the pathological process of POCD. Melatonin protected mice from nerve damage by inhibiting activation of the NLRP3-caspase-1-interleukin 1 beta (IL-ß) pathway and thus reduced the secretion of IL-1ß inflammatory factors in microglia. Further research found that melatonin has a potential binding effect with NLRP3 protein, and at the same time could reduce the phosphorylation of nuclear factor kappa-B (NF-κB) and inhibit its nuclear translocation. The underlying mechanism was that melatonin inhibited the expression of acetylation of histone H3 and melatonin attenuated the binding of NF-κb to the NLRP3 promoter region 1-200 bp, where there are two potential binding target sites of NF-κb and NLRP3, namely the sequences 5'-GGGAACCCCC-3' and 5'-GGAAATCCA -3'. Therefore, we confirmed a novel mechanism of action of melatonin in the prevention and treatment of POCD.

Association between human blood metabolome and the risk of delirium: a Mendelian Randomization study.

Background: Delirium significantly contributes to both mortality and morbidity among hospitalized older adults. Furthermore, delirium leads to escalated healthcare expenditures, extended hospital stays, and enduring cognitive deterioration, all of which are acknowledged detrimental outcomes. Nonetheless, the current strategies for predicting and managing delirium remain constrained. Our aim was to employ Mendelian randomization (MR) to investigate the potential causal relationship between metabolites and delirium, as well as to identify potential therapeutic targets. Methods: We identified 129 distinct blood metabolites from three genome-wide association studies (GWASs) conducted on the metabolome, involving a total of 147,827 participants of European descent. Genetic information pertaining to delirium was sourced from the ninth iteration of the Finngen Biobank, encompassing 359,699 individuals of Finnish ancestry. We conducted MR analyses to evaluate the connections between blood metabolites and delirium. Additionally, we extended our analysis to encompass the entire phenome using MR, aiming to uncover potential on-target consequences resulting from metabolite interventions. Results: In our investigation, we discovered three metabolites serving as causal mediators in the context of delirium: clinical low density lipoprotein cholesterol (LDL-C) (odds ratio [OR]: 1.47, 95% confidence interval [CI]: 1.25-1.73, p = 3.92 x 10-6), sphingomyelin (OR: 1.47, 95% CI: 1.25-1.74, p = 5.97 x 10-6), and X-11593-O-methylascorbate (OR: 0.21, 95% CI: 0.10-0.43, p = 1.86 x 10-5). Furthermore, utilizing phenome-wide MR analysis, we discerned that clinical LDL-C, sphingomyelin, and O-methylascorbate not only mediate delirium susceptibility but also impact the risk of diverse ailments. Limitations: (1) Limited representation of the complete blood metabolome, (2) reliance on the PheCode system based on hospital diagnoses may underrepresent conditions with infrequent hospital admissions, and (3) limited to European ancestry. Conclusion: The genetic prediction of heightened O-methylascorbate levels seems to correspond to a diminished risk of delirium, in contrast to the association of elevated clinical LDL-C and sphingomyelin levels with an amplified risk. A comprehensive analysis of side-effect profiles has been undertaken to facilitate the prioritization of drug targets. Notably, O-methylascorbate emerges as a potentially auspicious target for mitigating and treating delirium, offering the advantage of lacking predicted adverse side effects.

DNA damage response and GATA4 signaling in cellular senescence and aging-related pathology.

Aging is the continuous degradation of biological function and structure with time, and cellular senescence lies at its core. DNA damage response (DDR) can activate Ataxia telangiectasia-mutated serine/threonine kinase (ATM) and Rad3-related serine/threonine kinase (ATR), after which p53 activates p21, stopping the cell cycle and inducing cell senescence. GATA4 is a transcription factor that plays an important role in the development of many organs, such as the heart, testis, ovary, foregut, liver, and ventral pancreas. Studies have shown that GATA4 can also contribute to the DDR, leading to aging. Consistently, there is also evidence that the GATA4 signaling pathway is associated with aging-related diseases, including atherosclerosis and heart failure. This paper reviews the relationship between GATA4, DDR, and cellular senescence, as well as its effect on aging-related diseases.

Lipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases.

The importance of neuroglia in maintaining normal brain function under physiological and pathological conditions has been supported by growing evidence in recent years. The most important issues regarding glial metabolism and function include the cooperation between glial populations and neurons, morphological and functional changes in pathological states, and the role in the onset and progression of neurodegenerative diseases. Although lipid accumulation and further lipid droplet production in neurodegenerative disease brain models have been observed for a long time, the dynamic development of brain lipid droplet research in recent years suggests its role in the development and progression of neurodegenerative diseases was previously underestimated. First recognized as organelles of lipid storage, lipid droplets (LDs) have emerged as an important organelle in metabolic diseases, inflammation, and host defense. Dynamic changes in lipid metabolism within neurons and glial cells resulting in lipid accumulation and lipid droplet formation are present in brain models of various neurodegenerative diseases, yet their role in the brain remains largely unexplored. This paper first reviews the metabolism and accumulation of several major lipids in the brain and discusses the regulation of lipid accumulation in different types of brain cells. We explore the potential role of intracellular lipid accumulation in the pathogenesis of neurodegeneration, starting from lipid metabolism and LDs biogenesis in glial cells, and discuss several pathological factors that promote lipid droplet formation, mainly focusing on oxidative stress, energy metabolism and glial cell-neuron coupling, which are closely related to the etiology and progression of neurodegenerative diseases. Finally, the directions and challenges of intracellular lipid metabolism in glial cells in neurodegeneration are discussed.

CB2R Activation Regulates TFEB-Mediated Autophagy and Affects Lipid Metabolism and Inflammation of Astrocytes in POCD.

Evidence suggests that the accumulation of lipid drots (LDs) accelerates damage to mitochondria and increases the release of inflammatory factors. These have been implicated as a mechanism underlying neurodegenerative diseases or tumors and aging-related diseases such as postoperative cognitive dysfunction (POCD), nevertheless, accumulation of lipid droplets has not been extensively studied in the central nervous system (CNS). Here, we found that after surgery, there was activation of astrocytes and lipid accumulation in the hippocampus. However, cannabinoid receptor type II (CB2R) activation significantly reduced lipid accumulation in astrocytes and change the expression of genes related to lipid metabolism. CB2R reduces the release of the inflammatory factors interleukin-1 beta (IL-1ß) and interleukin 6 (IL-6) in peripheral serum and simultaneously improves cognitive ability in mice with POCD. Further research on mechanisms indicates that CB2R activation promotes the nuclear entry of the bHLH-leucine zipper transcription factor, the transcription factor EB (TFEB), and which is a master transcription factor of the autophagy-lysosomal pathway, also reduces TFEB-S211 phosphorylation. When CB2R promotes TFEB into the nucleus, TFEB binds at two sites within promoter region of PGC1α, promoting PGC1α transcription and accelerating downstream lipid metabolism. The aforementioned process leads to autophagy activation and decreases cellular lipid content. This study uncovers a new mechanism allowing CB2R to regulate lipid metabolism and inflammation in POCD.

Rapamycin inhibits LOC102553434-mediated pyroptosis to improve lung injury induced by limb ischemia-reperfusion.

Limb ischemia reperfusion (I/R) triggers local or systemic injury, and whether the process is mediated by pyroptosis remains unclear, we aimed to explore whether pyroptosis was involved in the process of rapamycin alleviating lung injury induced by I/R and investigate the molecular mechanisms. The histopathology of lung injury induced by I/R was confirmed by hematoxylin-eosin (HE) staining, and malondialdehyde (MDA), superoxide dismutase (SOD), and the expression of pyroptosis related molecules were detected. RNA sequencing was used to mine key long non-coding RNAs (lncRNAs). The model of lipopolysaccharide (LPS)-induced L2 cell damage was also used to explore the effect and mechanism of rapamycin on lncRNA. Rapamycin treatment alleviated I/R-induced lung histopathologically injury and increased the concentration of MDA while decreased activity of SOD and expression of NLRP3, Caspase-1, interleukin-1ß (IL-1ß), and IL-18 in rat. A total of 63 differentially expressed lncRNAs (DElncRNAs) were identified from IR + Rap group compared with IR group, and these DElncRNAs were mainly involved in cell adhesion molecules (CAMs) and endocytosis pathway. The lncRNA LOC102553434 and its target gene MMP9 were most significantly up-regulated in I/R-injured rat. In vitro experiments showed that LPS induction caused a significant increase in LOC102553434, MMP9, IL-1ß, and IL-18 in L2 cells, but rapamycin treatment significantly reversed the effects. After interfering with the expression of LOC102553434 in the LPS-injured cells pretreated with rapamycin, cell proliferation significantly increased, and the expression of MMP, NLRP3 and caspase-1 were significantly decreased. Rapamycin protects the lung from limb I/R injury by regulating LOC102553434 expression and inhibiting pyroptosis pathway. LOC102553434 plays a role in promoting pyroptosis and thus provides a target for clinical treatment of I/R-induced lung injury. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-02708-9.

Long Non-coding RNAs and Circular RNAs: Insights Into Microglia and Astrocyte Mediated Neurological Diseases.

Microglia and astrocytes maintain tissue homeostasis in the nervous system. Both microglia and astrocytes have pro-inflammatory phenotype and anti-inflammatory phenotype. Activated microglia and activated astrocytes can contribute to several neurological diseases. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), two groups of non-coding RNAs (ncRNAs), can function as competing endogenous RNAs (ceRNAs) to impair the microRNA (miRNA) inhibition on targeted messenger RNAs (mRNAs). LncRNAs and circRNAs are involved in various neurological disorders. In this review, we summarized that lncRNAs and circRNAs participate in microglia dysfunction, astrocyte dysfunction, neuron damage, and inflammation. Thereby, lncRNAs and circRNAs can positively or negatively regulate neurological diseases, including spinal cord injury (SCI), traumatic brain injury (TBI), ischemia-reperfusion injury (IRI), stroke, neuropathic pain, epilepsy, Parkinson's disease (PD), multiple sclerosis (MS), and Alzheimer's disease (AD). Besides, we also found a lncRNA/circRNA-miRNA-mRNA regulatory network in microglia and astrocyte mediated neurological diseases. Through this review, we hope to cast light on the regulatory mechanisms of lncRNAs and circRNAs in microglia and astrocyte mediated neurological diseases and provide new insights for neurological disease treatment.

The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies.

Aberrant Notch signaling profoundly affects cancer progression. Especially the Notch3 receptor was found to be dysregulated in cancer, where its expression is correlated with worse clinicopathological features and poor prognosis. The activation of Notch3 signaling is closely related to the activation of cancer stem cells (CSCs), a small subpopulation in cancer that is responsible for cancer progression. In addition, Notch3 signaling also contributes to tumor chemoresistance against several drugs, including doxorubicin, platinum, taxane, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and gemcitabine, through complex mechanisms. In this review, we mainly focus on discussing the molecular mechanisms by which Notch3 modulates cancer stemness and chemoresistance, as well as other cancer behaviors including metastasis and angiogenesis. What's more, we propose potential treatment strategies to block Notch3 signaling, such as non-coding RNAs, antibodies and antibody-drug conjugates, providing a comprehensive reference for research on precise targeted cancer therapy.