Background and PurposeMyocardial infarction leads to heart failure. Autophagy is excessively activated in myocardial ischemia/reperfusion (I/R) in rats. The aim of this study is to investigate whether the protection of sevoflurane postconditioning (SPC) in myocardial I/R is through restored impaired autophagic flux.MethodsExcept for the sham control (SHAM) group, each rat underwent 30 min occlusion of the left anterior descending coronary (LAD) followed by 2 h reperfusion. Cardiac infarction was determined by 2,3,5-triphenyltetrazolium chloride triazole (TTC) staining. Cardiac function was examined by hemodynamics and echocardiography. The activation of autophagy was evaluated by autophagosome accumulation, LC3 conversion and p62 degradation. Potential molecular mechanisms were investigated by immunoblotting, real-time PCR and immunofluorescence staining.ResultsSPC improved the hemodynamic parameters, cardiac dysfunction, histopathological and ultrastructural damages, and decreased myocardial infarction size after myocardial I/R injury (P < 0.05 vs. I/R group). Compared with the cases in I/R group, myocardial ATP and NAD+ content, mitochondrial function related genes and proteins, and the expressions of SOD2 and HO-1 were increased, while the expressions of ROS and Vimentin were decreased in the SPC group (P < 0.05 vs. I/R group). SPC significantly activated Akt/mTOR signaling, and inhibited the formation of Vps34/Beclin1 complex via increasing expression of Bcl2 protein (P < 0.05 vs. I/R group). SPC suppressed elevated expressions of LC3 II/I ratio, Beclin1, Atg5 and Atg7 in I/R rat, which indicated that SPC inhibited over-activation of autophagy, and promoted autophagosome clearance. Meanwhile, SPC significantly suppressed the decline of Opa1 and increases of Drp1 and Parkin induced by I/R injury (P < 0.05 vs. I/R group). Moreover, SPC maintained the contents of ATP by reducing impaired mitochondria.ConclusionSPC protects rat hearts against I/R injury via ameliorating mitochondrial impairment, oxidative stress and rescuing autophagic clearance.

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.

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.

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-1β) 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.

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 hightarget 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.

Background: Surgery and anesthesia-induced perioperative neurocognitive disorder (PND) are closely related to NOD-like receptors (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome microglia inflammatory response. Inhibiting the occurrence of neuroinflammation is an important treatment method to improve postoperative delirium. Fewer NLRP3-targeting molecules are currently available in the clinic to reduce the incidence of postoperative delirium. Dexmedetomidine (DEX), an α2 adrenergic receptor agonist has been shown to have antioxidant and anti-inflammatory activities. The present study showed that DEX reduced the production of cleaved caspase1 (CASP1) and destroyed the NLRP3–PYD And CARD Domain Containing (PYCARD)–CASP1 complex assembly, thereby reducing the secretion of IL-1β interleukin beta (IL-1β). DEX promoted the autophagy process of microglia and reduced NLRP3 expression. More interestingly, it promoted the ubiquitination and degradation of NLRP3. Thus, this study demonstrated that DEX reduced NLRP3-mediated inflammation through the activation of the ubiquitin-autophagy pathway. This study provided a new mechanism for treating PND using DEX.Methods: C57BL/6 mice were pre-administered DEX 3 days in advance, and an abdominal exploration model was used to establish a perioperative neurocognitive disorder model. The anti-inflammatory effect of DEX was explored in vivo by detecting NLRP3-CASP1/IL-1β protein expression and behavioral testing. Primary microglia were stimulated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP) in vitro, the expression of CASP1 and IL-1β was detected in the supernatant of cells, and the expression of autophagy-related proteins microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) and sequestosome 1 (SQSTM1) was examined in the cytoplasm. Meanwhile, Co-immunoprecipitation (Co-IP) was used to detect NLRP3 protein ubiquitination so as to clarify the new mechanism underlying the anti-inflammatory effect of DEX.Results: Pre-administration of DEX reduced the protein expression of NLRP3, CASP1, and IL-1β in the hippocampus of mice induced by surgery and also improved the impairment of learning and memory ability. At the same time, DEX also effectively relieved the decrease in spine density of the hippocampal brain induced by surgery. DEX decreased the cleaved CASP1 expression, blocked the assembly of NLRP3–PYCARD–CASP1 complex, and also reduced the secretion of mature IL-1β in vitro. Mechanically, it accelerated the degradation of NLRP3 inflammasome via the autophagy–ubiquitin pathway and reduced the green fluorescent protein/red fluorescent protein MAP1LC3B ratio, which was comparable to the effect when using the autophagy activator rapamycin (Rapa). Furthermore, it increased the ubiquitination of NLRP3 after LPS plus ATP stimulated microglia.Conclusion: DEX attenuated the hippocampal brain inflammation by promoting NLRP3 inflammasome degradation via the autophagy–ubiquitin pathway, thus improving cognitive impairment in mice.

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.

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.