Microglial EPOR Contribute to Sevoflurane-induced Developmental Fine Motor Deficits Through Synaptic Pruning in Mice.

Clinical researches including the Mayo Anesthesia Safety in Kids (MASK) study have found that children undergoing multiple anesthesia may have a higher risk of fine motor control difficulties. However, the underlying mechanisms remain elusive. Here, we report that erythropoietin receptor (EPOR), a microglial receptor associated with phagocytic activity, was significantly downregulated in the medial prefrontal cortex of young mice after multiple sevoflurane anesthesia exposure. Importantly, we found that the inhibited erythropoietin (EPO)/EPOR signaling axis led to microglial polarization, excessive excitatory synaptic pruning, and abnormal fine motor control skills in mice with multiple anesthesia exposure, and those above-mentioned situations were fully reversed by supplementing EPO-derived peptide ARA290 by intraperitoneal injection. Together, the microglial EPOR was identified as a key mediator regulating early synaptic development in this study, which impacted sevoflurane-induced fine motor dysfunction. Moreover, ARA290 might serve as a new treatment against neurotoxicity induced by general anesthesia in clinical practice by targeting the EPO/EPOR signaling pathway.

Electromagnetic pulse induced blood-brain barrier breakdown through tight junction opening in rats.

The blood-brain barrier (BBB) is the main obstacle to hydrophilic and large molecules to enter the brain, maintaining the stability of the central nervous system (CNS). But many environmental factors may affect the permeability and structure of the BBB. Electromagnetic pulses (EMP) irradiation has been proven to enhance the permeability of the BBB, but the specific mechanism is still unclear. To explore the potential mechanism of EMP-induced BBB opening, this study investigated the permeability, fine structure and the proteins expression of the tight junction (TJ) of the BBB in the rats exposed to EMP. Using the leakage of fluorescein isothiocyanate-labeled dextran with different molecular mass under different field intensity of EMP exposure, we found that the tracer passing through the BBB is size-dependent in the rat exposed to EMP as field intensity increased. Transmission electron microscopy showed TJ of the endothelial cells in the EMP-exposed group was open, compared with the sham-irradiated group. But the levels of TJ proteins including ZO-1, claudin-5, or occludin were not changed as indicated by western blot. These data suggest that EMP induce BBB opening in a field intensity-dependent manner and probably through dysfunction of TJ proteins instead of their expression. Our findings increase the understanding of the mechanism for EMP working on the brain and are helpful for CNS protection against EMP.

First-principles study of the structures and superconductivity of H-S-La systems under high pressure.

Recent experimental and theoretical studies have shown that a La-H system displays remarkable superconducting properties, and it is also possible to improve the superconducting state by introducing other elements into this system. In this study, we systematically investigated the crystal structures and physical properties of an H-S-La system by using first-principles calculations combined with the CALYPSO structure exploration technique. We predicted four stable stoichiometries containing H2SLa, H3SLa, H4Sla, and H6SLa. These compounds undergo a series of phase transitions under 50-300 GPa. The bonding characters and electronic properties were calculated. It was found that Cm-H2SLa, C2/c-H2SLa, and Cmcm-H6SLa exhibit good metallic nature, which stimulates us to further study their superconducting properties. The calculated superconducting transition temperatures (Tc) of Cm-H2SLa, C2/c-H2Sla, and Cmcm-H6SLa are 15.0 K at 200 GPa, 6.9 K at 300 GPa, and 23.6 K at 300 GPa, respectively.

Simulated weightlessness induces hippocampal insulin resistance and cognitive impairment.

Growing evidence highlights the potential consequences of long-term spaceflight, including gray matter volume reduction and cognitive dysfunction with subclinical manifestations of diabetes mellitus among astronauts, but the underlying mechanisms remain unknown. In this study, we found that long-term simulated weightlessness induced hippocampal insulin resistance and subsequent neuronal damage and cognitive impairment in rats. Rats subjected to 4-week tail suspension exhibited peripheral insulin resistance, evidenced by increased fasting blood glucose and abnormal glucose tolerance and insulin tolerance, alongside reduced spontaneous activity and impaired recognition memory. In addition, 4 weeks of simulated weightlessness induced neuronal apoptosis and degeneration in the hippocampus, as evidenced by increased TUNEL and Fluoro-Jade B staining-positive neurons. Mechanistically, insulin-stimulated hippocampal Akt phosphorylation was decreased, while PTEN, the negative regulator of insulin signaling, was increased in the hippocampus in tail-suspended rats. Interestingly, treatment with berberine, an insulin sensitizer, partly reversed the above-mentioned effects induced by simulated weightlessness. These data suggest that long-term simulated weightlessness induces cognitive impairment as well as neuronal apoptosis and neural degeneration, partially through hippocampal insulin resistance via PTEN up-regulation. Berberine treatment attenuates hippocampal insulin resistance and improves cognitive function.

Myeloid-specific blockade of notch signaling alleviates dopaminergic neurodegeneration in Parkinson's disease by dominantly regulating resident microglia activation through NF-κB signaling.

Yolk sac-derived microglia and peripheral monocyte-derived macrophages play a key role during Parkinson's disease (PD) progression. However, the regulatory mechanism of microglia/macrophage activation and function in PD pathogenesis remains unclear. Recombination signal-binding protein Jκ (RBP-J)-mediated Notch signaling regulates macrophage development and activation. In this study, with an 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) hydrochloride-induced acute murine PD model, we found that Notch signaling was activated in amoeboid microglia accompanied by a decrease in tyrosine hydroxylase (TH)-positive neurons. Furthermore, using myeloid-specific RBP-J knockout (RBP-JcKO) mice combined with a PD model, our results showed that myeloid-specific disruption of RBP-J alleviated dopaminergic neurodegeneration and improved locomotor activity. Fluorescence-activated cell sorting (FACS) analysis showed that the number of infiltrated inflammatory macrophages and activated major histocompatibility complex (MHC) II+ microglia decreased in RBP-JcKO mice compared with control mice. Moreover, to block monocyte recruitment by using chemokine (C-C motif) receptor 2 (CCR2) knockout mice, the effect of RBP-J deficiency on dopaminergic neurodegeneration was not affected, indicating that Notch signaling might regulate neuroinflammation independent of CCR2+ monocyte infiltration. Notably, when microglia were depleted with the PLX5622 formulated diet, we found that myeloid-specific RBP-J knockout resulted in more TH+ neurons and fewer activated microglia. Ex vitro experiments demonstrated that RBP-J deficiency in microglia might reduce inflammatory factor secretion, TH+ neuron apoptosis, and p65 nuclear translocation. Collectively, our study first revealed that RBP-J-mediated Notch signaling might participate in PD progression by mainly regulating microglia activation through nuclear factor kappa-B (NF-κB) signaling.

PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons.

Ischemic stroke is a neurological disorder caused by vascular stenosis or occlusion, accounting for approximately 87% of strokes. Clinically, the most effective therapy for ischemic stroke is vascular recanalization, which aims to rescue neurons undergoing ischemic insults. Although reperfusion therapy is the most effective treatment for ischemic stroke, it still has limited benefits for many patients, and ischemia-reperfusion (I/R) injury is a widely recognized cause of poor prognosis. Here, we aim to investigate the mechanism of protein phosphatase Mg2+/Mn2+ dependent 1 K (PPM1K) mediates metabolic disorder of branched-chain amino acids (BCAA) by promoting fatty acid oxidation led to ferroptosis after cerebral I/R injury. We established the I/R model in mice and used BT2, a highly specific BCAA dehydrogenase (BCKD) kinase inhibitor to promote BCAA metabolism. It was further verified by lentivirus knocking down PPM1K in neurons. We found that BCAA levels were elevated after I/R injury due to dysfunctional oxidative degradation caused by phosphorylated BCKD E1α subunit (BCKDHA). Additionally, the level of phosphorylated BCKDHA was determined by decreased PPM1K in neurons. We next demonstrated that BCAA could induce oxidative stress, lipid peroxidation, and ferroptosis in primary cultured cortical neurons in vitro. Our results further showed that BT2 could reduce neuronal ferroptosis by enhancing BCAA oxidation through inhibition of BCKDHA phosphorylation. We further found that defective BCAA catabolism could induce neuronal ferroptosis by PPM1K knockdown. Furthermore, BT2 was found to alleviate neurological behavior disorders after I/R injury in mice, and the effect was similar to ferroptosis inhibitor ferrostatin-1. Our findings reveal a novel role of BCAA in neuronal ferroptosis after cerebral ischemia and provide a new potential target for the treatment of ischemic stroke.

Spatial Distribution of Parvalbumin-Positive Fibers in the Mouse Brain and Their Alterations in Mouse Models of Temporal Lobe Epilepsy and Parkinson's Disease.

Parvalbumin interneurons belong to the major types of GABAergic interneurons. Although the distribution and pathological alterations of parvalbumin interneuron somata have been widely studied, the distribution and vulnerability of the neurites and fibers extending from parvalbumin interneurons have not been detailly interrogated. Through the Cre recombinase-reporter system, we visualized parvalbumin-positive fibers and thoroughly investigated their spatial distribution in the mouse brain. We found that parvalbumin fibers are widely distributed in the brain with specific morphological characteristics in different regions, among which the cortex and thalamus exhibited the most intense parvalbumin signals. In regions such as the striatum and optic tract, even long-range thick parvalbumin projections were detected. Furthermore, in mouse models of temporal lobe epilepsy and Parkinson's disease, parvalbumin fibers suffered both massive and subtle morphological alterations. Our study provides an overview of parvalbumin fibers in the brain and emphasizes the potential pathological implications of parvalbumin fiber alterations.

TLR4-MyD88 signaling is involved in the spinal neurons during the full length of recovery from transection of the motor branch of the femoral nerve in mice.

This study was designed to see the expression of toll-like receptor 4 (TLR4) and downstream molecules including myeloid differentiation factor 88 (MyD88) and interleukin 1-ß (IL-1ß) in the spinal cord as peripheral nerve injury recovered in mice. We established a model of femoral nerve injury (FNI) in C57BL/6 mice by transection of the motor branch of the femoral nerve, followed by retrograde labeling to show the according motor neurons in the anterior horn of the spinal cord pars lumbar. We observed the motor function recovery of the injured hind limbs using behavioral tests. The expression of TLR4, MyD88, and IL-1ß was examined by immunofluorescent staining and western blot. According to the behavior test, the FNI animals fully recovered within 6-8 weeks. TLR4, MyD88, and IL-1ß were expressed in the ventral horn of the spinal cord both at 72 h till 6 weeks after the femoral nerve transection surgery, and these proteins were mostly co-localized with neurons. IL-1ß also tended to rise in the same surgery groups, but more intimate with microglia surrounding nearby retrograde labeled neurons. And western blot results were consistent with histological findings. The results indicate that peripheral nerve injury may induce innate immune reactions of the central neurons and critical signaling like TLR4/MyD88 in the spinal cord may reflect the recovery of the injury. These findings suggest that peripheral nerve injury triggered the TLR4/MyD88 signal in the soma of spinal neurons may be involved in function and nerve restoration through neuron-glia crosstalk.

Ioversol Induced Microglia Proinflammatory Activation and Oxidative Stress in Rats.

Contrast-induced encephalopathy (CIE) following angiography, though not often and reversible, can in some cases lead to permanent neurological dysfunction. To identify how neuroinflammation is involved in CIE, we investigated microglia responses to a bolus injection of ioversol in the internal carotid artery (ICA) in rats. MicroCT scanning indicated that the injected ioversol was cleared from the rat's brain within 25 min. However, proinflammatory activated and significantly increased microglia were found in the rat occipital cortex at 1 day, and the number of blood vessel-associated microglia was still significantly higher at 3-day post-injection, compared with sham- and PBS-treated rats. Moreover, significantly upregulated malondialdehyde (MDA), downregulated superoxide dismutase (SOD) levels, and elevated proinflammatory cytokines were observed in the brain of rats treated with ioversol. Ioversol administration decreased cell viability of primarily cultured microglia and induced significant proinflammatory activation. Furthermore, ioversol remarkably upregulated astrocytic aquaporin (AQP) 4 expression in the rats brain, and transwell cultures showed significantly enhanced microglia migrating to ioversol-treated endothelial cells. Immediate injection of edaravone dexborneol, a novel antioxidative drug, after ioversol injection effectively rescued ioversol-induced neuroinflammation. Together, these findings suggest that ioversol induced neuroinflammation and oxidative stress in the brain via microglia activation in a direct and indirect manner, which might contribute to the pathogenesis of CIE.

Effect of Ligand Structures on Ligand-Protected Gold Clusters: [Au-(p-/m-/o-MBT)]1-8 Clusters.

The controllable preparation of ligand-protected clusters is still an unresolved problem, which may be due to that their formation mechanism is unclear. We propose that the ligand is the key to solve the above problems. Here, by using p-, m-, and o-methylbenzenethiol ligand protected gold clusters as examples, we try to explore the effect of ligand structures on ligand-protected gold clusters. The geometrical structures, relative stabilities and surface properties of small-sized ligand-protected gold clusters [Au-SR]1-8 (SR = p-/m-/o-MBT) have been systematically studied based on the density functional theory. The results show that the ground state structures of [Au-SR]1-8 clusters tend to form closed rings except for [Au-SR]1,2. The different structures of ligand have significant effect on the structures and stabilities of ligand-protected clusters. By analyzing their surface properties and possible growth patterns, it is found that [Au-SR]1,2 clusters serve as the basic building blocks, and the larger clusters can be regarded as the combinations of them. This study provides some insights into the effect of ligands on ligand-protected clusters, which is useful for understanding the formation mechanism of ligand-protected clusters.

Quercetin ameliorates memory impairment by inhibiting abnormal microglial activation in a mouse model of paradoxical sleep deprivation.

Paradoxical sleep deprivation (PSD) is prevalent in modern society, and impaired memory is one of its serious consequences. The pathogenic mechanism is still unclear, and the therapeutic strategies for PSD are limited. Here, we found that quercetin treatment ameliorated memory impairments caused by PSD in a dose-dependent manner in an animal model. Quercetin could restore the dynamic changes of the gamma band while the animals performed novel object recognition (NOR) tasks as determined by electroencephalogram analysis. Morphological analysis showed that quercetin, by targeting the hippocampal CA1 region, strikingly ameliorated the overactivation of microglia induced by PSD. Mechanistically, quercetin inhibited the toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa-b (NF-κB) cascade, which is critical for abnormal microglial activation following PSD stress. Our results provided experimental evidence for the therapeutic effects of quercetin on PSD-related memory impairments by suppressing TLR4/MyD88/NF-κB signaling that mediated abnormal microglia activation in the hippocampus.

Monolayer SnI2: An Excellent p-Type Thermoelectric Material with Ultralow Lattice Thermal Conductivity.

Using density functional theory and semiclassical Boltzmann transport equation, the lattice thermal conductivity and electronic transport performance of monolayer SnI2 were systematically investigated. The results show that its room temperature lattice thermal conductivities along the zigzag and armchair directions are as low as 0.33 and 0.19 W/mK, respectively. This is attributed to the strong anharmonicity, softened acoustic modes, and weak bonding interactions. Such values of the lattice thermal conductivity are lower than those of other famous two-dimensional thermoelectric materials such as MoO3, SnSe, and KAgSe. The two quasi-degenerate band valleys for the valence band maximum make it a p-type thermoelectric material. Due to its ultralow lattice thermal conductivities, coupled with an ultrahigh Seebeck coefficient, monolayer SnI2 possesses an ultrahigh figure of merits at 800 K, approaching 4.01 and 3.34 along the armchair and zigzag directions, respectively. The results indicate that monolayer SnI2 is a promising low-dimensional thermoelectric system, and would stimulate further theoretical and experimental investigations of metal halides as thermoelectric materials.

Successful combinatorial therapy of sirolimus and neuraminidase inhibitors in a patient with highly pathogenic avian influenza A (H5N6) virus: a case report.

Background: Highly pathogenic avian influenza A (H5N6) virus poses a continuous threat to human health since 2014. Although neuraminidase inhibitors (NAIs) are prescribed in most patients infected with the H5N6 virus, the fatality remains high, indicating the need for an improved treatment regimen. Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), has been reported to reduce viral replication and improve clinical outcomes in severe H1N1 infections when combined with oseltamivir. Here, we report the first case of severe H5N6 pneumonia successfully treated by sirolimus and NAIs. Case Description: A 22-year-old man developed high fever and chills on September 24, 2018 (Day-0) and was hospitalized on Day-3. Influenza A (H5N6) was identified on Day-6 from a throat swab specimen. Despite the administration of NAIs and other supportive measures, the patient's clinical conditions and lung images showed continued deterioration, accompanied by persistently high viral titers. Consequently, sirolimus administration (rapamycin; 2 mg per day for 14 days) was started on Day-12. His PaO2/FiO2 values and Sequential Organ Failure Assessment (SOFA) score gradually improved, and imaging outcomes revealed the resolution of bilateral lung infiltrations. The viral titer gradually decreased and turned negative on Day-25. Sirolimus and NAIs were stopped on the same day. The patient was discharged on Day-65. Based on observations from a 2-year follow-up, the patient was found to be in a good condition without complications. Conclusions: In conclusion, sirolimus might be a novel and practical therapeutic approach to severe H5N6-associated pneumonia in humans.

Cost-Effectiveness Analysis of Camrelizumab Immunotherapy versus Docetaxel or Irinotecan Chemotherapy as Second-Line Therapy for Advanced or Metastatic Esophageal Squamous Cell Carcinoma.

PURPOSE: The aim of this study was to assess the cost-effectiveness of camrelizumab immunotherapy versus docetaxel or irinotecan chemotherapy as second-line therapy for advanced esophageal squamous cell carcinoma (ESCC), which was evaluated in the ESCORT trial. MATERIALS AND METHODS: A partitioned survival model was developed to reflect the costs and effectiveness of the ESCORT trial. The clinical efficacy data, safety data, and health-related costs and utilities were derived from published data from clinical trials or health administration departments in China. Adverse event-related costs, drug administration, and other expenses were derived from a single center of Fujian Medical University Cancer Hospital in 2021. All survival analyses were performed with SPSS software. Overall survival was estimated with the Kaplan-Meier method, and progression-free survival was estimated with the life table method. Sensitivity analyses were conducted to assess the uncertainty of the model. Incremental cost, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) were calculated. RESULTS: Camrelizumab therapy had 0.232 QALYs at an incremental cost of USD$9959.44 compared with the chemotherapy group with 0.158 QALYs at an incremental cost of USD$8601.67. The ICER was USD$18393.12/QALY. Probabilistic sensitivity analyses showed that when the willingness-to-pay threshold reached USD$31200/QALY, which is nearly three times the Chinese gross domestic product per capita, camrelizumab had an 80% possibility of being cost-effective versus docetaxel or irinotecan chemotherapy. CONCLUSION: Camrelizumab is a cost-effective option compared with docetaxel or irinotecan chemotherapy in patients with advanced ESCC as second-line therapy in China.

Gender Differences in Associated and Predictive Factors of Anxiety and Depression in People With Epilepsy.

PURPOSE: Comorbid anxiety and depression in people with epilepsy (PWE) are highly prevalent and contribute to low quality of life (QOL) and may even lead to poor outcomes of epilepsy. Among the various factors that affect these negative emotional comorbidities, possible gender differences remain poorly understood and are often neglected. This research aimed to determine whether there are discrepancies in the incidence and influence factors of anxiety and depression between men and women with epilepsy in a hospital in northwest China. METHODS: A total of 158 adult PWE (female: N = 65; 41.1%) completed self-report questionnaires, including the Self-rating Anxiety Scale (SAS), the Self-rating Depression Scale (SDS), the Chinese version of the Quality of Life in Epilepsy-31 (QOLIE-31) inventory and the Pittsburgh Sleep Quality Inventory (PSQI). The comparison between male and female PWE was made by regression analysis. RESULTS: For the prevalence of anxiety and depression in PWE, no gender difference was found in this study. However, the moderating factors of psychiatric comorbidities were significantly different between men and women: male PWE with comorbid anxiety were more likely to be affected by sleep quality, while anxiety symptoms in female PWE were closely associated with the frequency of seizures. Education years and QOL social function were significant indicators of depression in male PWE but not in female PWE. The important and common predictor for anxiety and depressive symptoms in PWE was QOL energy/fatigue, with male patients being more affected. CONCLUSION: For the PWE included in this study, the incidence of comorbid anxiety and depression in PWE was similar for men and women, but the moderating factors affecting comorbid anxiety and depressive disorders differed between genders: male PWE were more likely to be affected by psychosocial factors, while female PWE were more influenced by epilepsy itself. This exploration suggests that gender-specific health care should be considered in epilepsy therapy to improve the psychiatric condition and QOL of PWE, and different treatments should be conducted for male and female PWE to prevent negative emotional comorbidities.

Aromatic compounds from Endocomia macrocoma.

Twenty-seven compounds, including a new diarypropane and two new lignans were isolated from the twigs and leaves of Endocomia macrocoma. Their structures were elucidated by spectroscopic analysis. Cytotoxicity evaluation of the new compounds against five human tumor lines showed no inhibitory effects.[Formula: see text].

Etomidate affects the anti-oxidant pathway to protect retinal ganglion cells after optic nerve transection.

Our previous studies revealed that etomidate, a non-barbiturate intravenous anesthetic agent, has protective effects on retinal ganglion cells within 7 days after optic nerve transection. Whether this process is related to anti-oxidative stress is not clear. To reveal its mechanism, we established the optic nerve transection injury model by transecting 1 mm behind the left eyeball of adult male Sprague-Dawley rats. The rats received an intraperitoneal injection of etomidate (4 mg/kg) once per day for 7 days. The results showed that etomidate significantly enhanced the number of retinal ganglion cells retrogradely labeled with Fluorogold at 7 days after optic nerve transection. Etomidate also significantly reduced the levels of nitric oxide and malonaldehyde in the retina and increased the level of glutathione at 12 hours after optic nerve transection. Thus, etomidate can protect retinal ganglion cells after optic nerve transection in adult rats by activating an anti-oxidative stress response. The study was approved by the Animal Ethics Committee at Air Force Medical University, China (approval No. 20180305) on March 5, 2018.

Horisfieldones A and B, Two Aromatic Ring-Contracted Dimeric Diarylpropanes with Human DOPA Decarboxylase Inhibitory Activity from Horsfieldia kingii.

Horisfieldones A (1) and B (2), two dimeric diarylpropanes featuring an unprecedentedly aromatic ring-contracted framework, were isolated from Horsfieldia kingii. Their structures and absolute configurations were determined by the inspection of extensive spectroscopic data and electronic circular dichroism calculations. Molecular modeling analysis, in vitro enzyme-based bioassays, and structure-activity relationship analysis of these isolates revealed that (+)-1 (IC50 = 35.1 ± 3.9 µM, SI > 11.4) could present a new class of human DOPA decarboxylase inhibitor.

Moderate prenatal alcohol exposure suppresses the TLR4-mediated innate immune response in the hippocampus of young rats.

Prenatal alcohol exposure (PAE) could lead to developmental disorders of the central nervous system (CNS) and mental retardation. Toll-like receptor (TLR) 4 plays an important role in PAE-induced neurodevelopmental defects. However, how PAE affects TLR4 response in the brain remains controversial. Using a moderate PAE model by feeding pregnant rats with liquid ethanol diet, we investigated the TLR4-mediated response to intraventricular injection of lipopolysaccharide (LPS) in the hippocampus of PEA rats at postnatal day (PND) 30. The results showed that PAE significantly up-regulated the expression of Toll-Interleukin-1 Receptor (TIR)-domain-containing adaptor protein inducing interferon (IFN)-ß (TRIF), TNF-α, and IL-1ß in the rat hippocampus in the absence of LPS, indicated by western blot assay. LPS treatment dramatically up-regulated the expressions of TLR4 and its downstream molecules in the hippocampus of paired-food and control groups. But no such significant changes of those molecules were found in the hippocampus of PAE animals. Moreover, the LPS stimulation even down-regulated the levels of TLR4 and TRIF in the PAE group. These data suggest that the relatively moderate level of PAE may lead to a mild neuroinflammation and a suppression of TLR4-mediated response to LPS in the hippocampus of young rats. As innate immunity plays crucial roles in CNS development, moderate PAE-induced suppression of TLR4-mediated response may serve as a new candidate mechanism of CNS developmental defects.