Unconventional Superconducting Diode Effects via Antisymmetry and Antisymmetry Breaking.

Symmetry breaking plays a pivotal role in unlocking intriguing properties and functionalities in material systems. For example, the breaking of spatial and temporal symmetries leads to a fascinating phenomenon: the superconducting diode effect. However, generating and precisely controlling the superconducting diode effect pose significant challenges. Here, we take a novel route with the deliberate manipulation of magnetic charge potentials to realize unconventional superconducting flux-quantum diode effects. We achieve this through suitably tailored nanoengineered arrays of nanobar magnets on top of a superconducting thin film. We demonstrate the vital roles of inversion antisymmetry and its breaking in evoking unconventional superconducting effects, namely a magnetically symmetric diode effect and an odd-parity magnetotransport effect. These effects are nonvolatilely controllable through in situ magnetization switching of the nanobar magnets. Our findings promote the use of antisymmetry (breaking) for initiating unconventional superconducting properties, paving the way for exciting prospects and innovative functionalities in superconducting electronics.

Correlation Analysis of Macrophage Distribution and Pathological Features of Carotid Atherosclerotic Plaque.

BACKGROUND: Macrophages play an important role in maintaining the chronic inflammatory of atherosclerosis (AS) and are hallmark of atherosclerotic plaques. They differentiate into different subpopulations under the influence of oxidized lipids and cytokines and play different roles in the formation and development of plaque. To explore the differences in the amount and distribution of different macrophage subpopulations around different carotid plaque pathological features in human AS, and based on these results, to explore the correlation between some macrophage subpopulations and AS pathological features. METHODS: First, we analyzed the single cells RNA-sequence data from the Gene Expression Omnibus DataSets (GSE159677). Second, we investigated the distribution difference of macrophage subpopulations in 61 surgically resected AS plaques by markers staining include CD68, inducible nitric oxide synthase, Arg-1, CD163 and HO-1. RESULTS: The result of single cells RNA-Sequence analysis showed that there were a large number of macrophages infiltrated in AS and they can be categorized into different subpopulations with different transcriptional features and functions; moreover in different part of AS (calcified AS core versus proximal adjacent), the total number and subpopulation ratios were all different. The result of staining analysis showed that macrophages mainly distributed in some pathological lesions such as necrosis, fibrous tissue degeneration, cholesterol crystallization etc., and different subpopulations were distributed differently in these lesions. CONCLUSIONS: This study confirmed that macrophages were heavily infiltrated in atherosclerotic plaques, and there existed subtype variability in different pathological lesions; meanwhile, these results suggested that different macrophage subpopulations may contribute differently in different pathological lesions.

Intracranial penetrating injury by clothes fork in an infant: case report and review of the literature.

Nonmissile intracranial penetrating injury (IPI) in pediatric population is rare. Here, we report the exceedingly rare case of a 5-month-old infant sustained by a metallic clothes fork penetrating into his left forehead. The little baby was identified to carry a traumatic hemorrhagic shock, and a multidisciplinary team (MDT) was immediately established response for whole-course evaluation and decision-making. Computed tomography revealed that the clothes fork had impaled into the left frontal bone and brain parenchyma with about 3.2 cm inside the cranial vault. The infant underwent emergency surgery, and the clothes fork was removed jointly by MDT members under general anesthesia in the retrograde direction. His recovery was uneventful and was followed up 2 years without growth and developmental abnormality. As an extremely rare entity with distinct age-related characteristics, a MDT approach is a best choice and effective strategy to manage infant nonmissile IPI, including preoperative management, surgical treatment, and even following rehabilitation.

Enhancer-driven transcription of MCM8 by E2F4 promotes ATR pathway activation and glioma stem cell characteristics.

BACKGROUND: Glioma stem cells (GSCs) are responsible for glioma recurrence and drug resistance, yet the mechanisms underlying their maintenance remains unclear. This study aimed to identify enhancer-controlled genes involved in GSCs maintenance and elucidate the mechanisms underlying their regulation. METHODS: We analyzed RNA-seq data and H3K27ac ChIP-seq data from GSE119776 to identify differentially expressed genes and enhancers, respectively. Gene Ontology analysis was performed for functional enrichment. Transcription factors were predicted using the Toolkit for Cistrome Data Browser. Prognostic analysis and gene expression correlation was conducted using the Chinese Glioma Genome Atlas (CGGA) data. Two GSC cell lines, GSC-A172 and GSC-U138MG, were isolated from A172 and U138MG cell lines. qRT-PCR was used to detect gene transcription levels. ChIP-qPCR was used to detect H3K27ac of enhancers, and binding of E2F4 to target gene enhancers. Western blot was used to analyze protein levels of p-ATR and γH2AX. Sphere formation, limiting dilution and cell growth assays were used to analyze GSCs growth and self-renewal. RESULTS: We found that upregulated genes in GSCs were associated with ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) pathway activation, and that seven enhancer-controlled genes related to ATR pathway activation (LIN9, MCM8, CEP72, POLA1, DBF4, NDE1, and CDKN2C) were identified. Expression of these genes corresponded to poor prognosis in glioma patients. E2F4 was identified as a transcription factor that regulates enhancer-controlled genes related to the ATR pathway activation, with MCM8 having the highest hazard ratio among genes positively correlated with E2F4 expression. E2F4 bound to MCM8 enhancers to promote its transcription. Overexpression of MCM8 partially restored the inhibition of GSCs self-renewal, cell growth, and the ATR pathway activation caused by E2F4 knockdown. CONCLUSION: Our study demonstrated that E2F4-mediated enhancer activation of MCM8 promotes the ATR pathway activation and GSCs characteristics. These findings offer promising targets for the development of new therapies for gliomas.

A novel multiplex qPCR method for assessing the comparative lengths of telomeres.

BACKGROUND: The comparative length of telomeres is considered to be related to diseases such as cancer, aging, and cardiovascular diseases. qPCR is currently one of the main methods for detecting telomere length. However, due to the unique sequence of telomeres (highly repetitive six-base sequence), it is difficult to design primers and probes to expand and detect telomere and to put internal reference gene and telomere into the same tube for detection to reduce the possible inter-pore errors and improve amplification efficiency. Besides, the stability and accuracy of the test results are greatly affected by the difference between reference genes and telomere copy number. METHODS: In this study, the single-copy genes were replaced with high-copy genes (300 copies) as the internal control to reduce the copy number difference of the internal genes and telomere. In addition, a multiplex qPCR system was constructed to detect the telomeres and an internal reference gene product. We also detected the lengths of telomeres in the genomic DNA in immortalized cells (293T and Hela) from different generations of cells. RESULTS: We detected the comparative telomere lengths of 1500 random Chinese volunteers of different ages with the multiplex qPCR method; the result shows that the comparative length of telomeres is negatively related to age. In addition, we compared our qPCR detection method with a terminal restriction fragmentation (TRF) method. Both of them were highly consistent, indicating that the qPCR method was reliable. CONCLUSIONS: In conclusion, we developed a stable, convenient, and accurate comparative telomere length detection method.

PTPRM methylation induced by FN1 promotes the development of glioblastoma by activating STAT3 signalling.

CONTEXT: The phosphorylation of signal transducer and activator of transcription protein 3 (STAT3) is up-regulated in glioblastoma (GBM) cells and is regulated by protein tyrosine phosphatase receptor type M (PTPRM). Fibronectin-1 (FN1) is also reported to be up-regulated in GBM. OBJECTIVE: We explored the role of FN1-induced PTPRM methylation in GBM. MATERIALS AND METHODS: The lentivirus particles of oe-PTPRM, sh-PTPRM, oe-FN1, sh-FN1, or their negative controls (NSCs) were transfected into GBM cells with or without stattic (0.5 µM, 24 h) or 5-aza (1 µM, 0, 2, 4 h) treatments. Methylation-specific PCR was performed to detect PTPRM methylation levels. RESULTS: PTPRM was down-regulated (0.373 ± 0.124- and 0.455 ± 0.109-fold), FN1 and p-STAT3 were up-regulated (p < 0.001) in A172 and U87 MG cells as compared to NSCs. Overexpressing PTPRM inhibited STAT3 phosphorylation. Interfering with PTPRM increased colony numbers in A172 and U-87 MG cells (2.253 ± 0.111- and 2.043 ± 0.19-fold), and stattic reduced them. Cell viability was reduced after treatment with 5-aza in A172 and U-87 MG cells (p < 0.05). P-STAT3 was down-regulated after 5-aza treatment. Overexpressing FN1 decreased PTPRM levels (p < 0.001), knockdown of FN1 decreased PTPRM methylation and inhibited STAT3 phosphorylation. Overexpressing FN1 increased cell viability (1.497 ± 0.114- and 1.460 ± 0.151-fold), and stattic or 5-aza reversed such effects (p < 0.05). DISCUSSION AND CONCLUSIONS: The up-regulation of FN1 reduced PTPRM by increasing its methylation, resulting in an increase of STAT3 phosphorylation and promoting GBM cell proliferation. Interfering with FN1 may be a potential therapeutic target for GBM.

Effects of Edaravone on Neurological Function and Tumor Necrosis Factor Alpha and Interleukin 8 Levels in Patients with Cerebral Infarction.

OBJECTIVE: The present study aimed to explore the effects of edaravone on neurological function, tumor necrosis factor α (TNF-α), and interleukin (IL)-8 levels in patients with cerebral infarction. METHODS: A total of 96 patients with cerebral -infarction who were admitted to the department of neurology in our hospital were enrolled in the present study, and they were randomly assigned to Group A (n = 48) and Group B (n = 48). Group A was treated with conventional therapy plus edaravone for 2 weeks and Group B with conventional therapy alone for 2 weeks. Enzyme-linked immunosorbent assay was used to determine serum TNF-α and IL-8 levels before and after treatment, and Pearson correlation analysis was conducted to analyze the correlation between serum TNF-α and IL-8 levels as well as National Institutes of Health Stroke Scale (NIHSS) score. RESULTS: After treatment, Group A had a lower NIHSS score and serum TNF-α and IL-8 levels as well as higher activities of daily living score than Group B (all p < 0.05). In addition, after treatment, no significant differences were observed between the 2 groups in terms of the presence of adverse reactions (p > 0.05). Pearson correlation analysis revealed a significant positive correlation between serum TNF-α and IL-8 levels as well as NIHSS score (r = -0.567 and r = -0.556, both p < 0.05). CONCLUSION: Edaravone can improve the neurological function of patients without causing evident adverse reactions, thereby improving quality of life, which may be correlated to decreased serum TNF-α and IL-8 levels.

Exosomal miR-221 targets DNM3 to induce tumor progression and temozolomide resistance in glioma.

MicroRNA is an important regulator of glioblastoma. This study aims at validating microRNA-221 (miR-221) as a biomarker for glioblastoma, and understanding how miR-221 regulates glioblastoma progression. Using clinical samples, miR-221 expression was analyzed by quantitative reverse-transcriptase PCR (qPCR). SHG-44 cells were treated with anti-miR-221 or U87MG-derived exosomes followed by monitoring changes in cell viability, migration and temozolomide (TMZ) resistance. Bioinformatics approach was used to identify targets of miR-221. The interaction between miR-221 and its target, DNM3 gene, was studied with dual-luciferase reporter assay, Spearman's correlation analysis, and western blotting. To verify that RELA regulates miR-221 expression, RELA-expressing vector or shRNA was introduced into SHG-44 cells and its effect on miR-221 expression was monitored. Both tissue-level and exosomal miR-221 expression increased with glioma grades. In SHG-44 cells, downregulating miR-221 expression inhibited cell proliferation, migration, and TMZ resistance, whereas incubation with U87MG-derived exosomes exerted tumor-promoting effects. DNM3 gene is a target of miR-221. RELA induced miR-221 expression. In glioma, elevated miR-221 expression is a biomarker for glioma. DNM3 is a target of miR-221 and RELA regulates miR-221 expression. The RELA/miR-221 axis is a target for glioma diagnosis and therapy.

Impaired autophagic flux in the human brain after traumatic brain injury.

Emerging evidence indicates that dysfunctional autophagic flux significantly contributes to the pathology of experimental traumatic brain injury (TBI). The current study aims to clarify its role post-TBI using brain tissues from TBI patients. Histological examinations, including hematoxylin and eosin, Nissl staining, and brain water content analysis, were employed to monitor brain damage progression. Electron microscopy was used to visualize autophagic vesicles. Western blotting and immunohistochemistry were performed to analyze the levels of important autophagic flux-related proteins such as Beclin1, autophagy-related protein 5, lipidated microtubule-associated protein light-chain 3 (LC3-II), autophagic substrate sequestosome 1 (SQSTM1/p62), and cathepsin D (CTSD), a lysosomal enzyme. Immunofluorescence assays evaluated LC3 colocalization with NeuN, P62, or CTSD, and correlation analysis linked autophagy-related protein levels with brain water content and Nissl bodies. Early-stage TBI results showed increased autophagic vesicles and LC3-positive neurons, suggesting autophagosome accumulation due to enhanced initiation and reduced clearance. As TBI progressed, LC3-II and P62 levels increased, while CTSD levels decreased. This indicates autophagosome overload from impaired degradation rather than increased initiation. The study reveals a potential association between worsening brain damage and impaired autophagic flux post-TBI, positioning improved autophagic flux as a viable therapeutic target for TBI.

Activation of NFE2L2 Alleviates Endoplasmic Reticulum Stress-Mediated Pyroptosis in Murine Hippocampus: A Bioinformatics Analysis and Experimental Validation.

Pyroptosis has been implicated in many pathologic processes, including endoplasmic reticulum stress (ERS). However, the underlying mechanisms and molecular targets of ERS affecting pyroptosis still need further exploration. We obtained gene sets associated with ERS and pyroptosis, and the common genes were regarded as crosstalk genes linking ERS and pyroptosis. Protein-protein interaction (PPI) network was constructed, and the hub genes were obtained via Cytoscape. Moreover, to validate the efficacy of the therapeutic target, neurological tests, brain water content measurements, Nissl staining, Western blot, ELISA, TUNEL analyses, and transmission electron microscopy were performed in a mouse model. A total of 13 crosstalk genes were acquired, and enrichment analysis revealed that these genes were mainly enriched in stress-associated cellular processes and pathways, including KEAP1-NFE2L2 pathway. The hub gene, NFE2L2, was identified by Cytoscape, and tert-butylhydroquinone (tBHQ) was screened as candidate drug to activate NFE2L2. Western blot and ELISA results showed that activation of NFE2L2 could attenuate the expression of ERS and pyroptosis-related proteins by promoting nuclear translocation of Nrf2 (encoded by NFE2L2). Pathological evaluation by Nissl staining and TUNEL assay reflected a similar trend. Furthermore, activation of NFE2L2 ameliorated neurological deficits and reduced brain edema. In conclusion, our bioinformatic analysis results established the theoretical foundation of NFE2L2 as a promising therapeutic target. Moreover, in the mouse model, tBHQ pretreatment further confirmed the effectiveness of this target. We hypothesized NFE2L2 may play a key role in the progression of ERS-mediated pyroptosis. These findings may inspire new ideas to treat neurological disorders.

Nrf2 functions as a pyroptosis-related mediator in traumatic brain injury and is correlated with cytokines and disease severity: a bioinformatics analysis and retrospective clinical study.

Background: Traumatic brain injury (TBI) is a serious hazard to human health. Evidence has accumulated that pyroptosis plays an important role in brain trauma. The aim of this study is to screen potential key molecules between TBI and pyroptosis, and further explore their relationships with disease severity and cytokines. Methods: To acquire differentially expressed genes (DEGs) before and after brain injury, the GSE89866 dataset was downloaded from the Gene Expression Omnibus (GEO) database. Meanwhile, pyroptosis-related genes were obtained from the GeneCards database, and the intersected genes were identified as differentially expressed pyroptosis-related genes (DEPGs). Moreover, the hub genes were screened via four algorithms (namely Maximum Clique Centrality, Edge Percolated Component, BottleNeck and EcCentricity) in Cytoscape software. Blood levels of Nrf2 were measured by ELISA using a commercially available kit. Finally, we further investigated the correlation between Nrf2 levels and medical indicators in TBI such as clinical characteristics, inflammatory cytokines, and severity. Results: Altogether, we found 1,795 DEGs in GSE89866 and 98 pyroptosis-related genes in the GeneCards database. Subsequently, four hub genes were obtained, and NFE2L2 was adopted for further clinical study. By using Kruskal-Wallis test and Spearman correlation test, we found that the serum Nrf2 levels in severe TBI patients were negatively correlated with GCS scores. On the contrary, there was a positive correlation between serum Nrf2 levels and pupil parameters, Helsinki CT scores, IL-1 ß and IL-18. Conclusions: In summary, bioinformatic analyses showed NFE2L2 plays a significant role in the pathology of TBI. The clinical research indicated the increase in serum Nrf2 levels was closely related to the severity of trauma and cytokines. We speculate that serum Nrf2 may serve as a promising biochemical marker for the assessment of TBI in clinical practice.

Identification of Lower Grade Glioma Antigens Based on Ferroptosis Status for mRNA Vaccine Development.

Purpose: mRNA vaccines represent a promising and innovative strategy within the realm of cancer immunotherapy. However, their efficacy in treating lower-grade glioma (LGG) requires evaluation. Ferroptosis exhibits close associations with the initiation, evolution, and suppression of cancer. In this study, we explored the landscape of the ferroptosis-associated tumor microenvironment to facilitate the development of mRNA vaccines for LGG patients. Patients and Methods: Genomic and clinical data of the LGG patients was obtained from the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Ferroptosis-related tumor antigens were identified based on differential expression, mutation status, correlation with antigen-presenting cells, and prognosis, relevance to immunogenic cell death (ICD). Antigen expression levels in LGG specimens and cell lines were validated using real time-polymerase chain reaction (RT-PCR). Consensus clustering was employed for patient classification. The immune landscapes of ferroptosis subtypes were further characterized, including immune responses, prognostic ability, tumor microenvironment, and tumor-related signatures. Results: Five tumor antigens, namely, HOTAIR, IDO1, KIF20A, NR5A2, and RRM2 were identified in LGG. RT-PCR demonstrated higher expression of these genes in LGG compared to the control. Twelve gene modules and four ferroptosis subtypes (FS1-FS4) of LGG were defined. FS2 and FS4, characterized as "cold" tumors due to their decreased tumor mutation burden (TMB) and immune checkpoint proteins (ICPs), were deemed appropriate candidates for the mRNA vaccine. Conclusion: HOTAIR, IDO1, KIF20A, NR5A2, and RRM2 were identified as promising candidate antigens for the development of an LGG mRNA vaccine, particularly offering potential benefits to FS2 and FS4 patients.

Astragaloside IV ameliorated neuroinflammation and improved neurological functions in mice exposed to traumatic brain injury by modulating the PERK-eIF2α-ATF4 signaling pathway.

Increasing evidence suggests that endoplasmic reticulum stress (ER stress) and neuroinflammation are involved in the complex pathological process of traumatic brain injury (TBI). However, the pathological mechanisms of their interactions in TBI remain incompletely elucidated. Therefore, investigating and ameliorating neuroinflammation and ER stress post-TBI may represent effective strategies for treating secondary brain injury. Astragaloside IV (AS-IV) has been reported as a potential neuroprotective and anti-inflammatory agent in neurological diseases. This study utilized a mouse TBI model to investigate the pathological mechanisms and crosstalk of ER stress, neuroinflammation, and microglial cell morphology in TBI, as well as the mechanisms and potential of AS-IV in improving TBI. The research revealed that post-TBI, inflammatory factors IL-6, IL-1ß, and TNF-α increased, microglial cells were activated, and the specific inhibitor of PERK phosphorylation, GSK2656157, intervened to alleviate neuroinflammation and inhibit microglial cell activation. Post-TBI, levels of ER stress-related proteins (p-PERK, p-eIF2a, ATF4, ATF6, and p-IRE1a) increased. Following AS-IV treatment, neurological dysfunction in TBI mice improved. Levels of p-PERK, p-eIF2a, and ATF4 decreased, along with reductions in inflammatory factors IL-6, IL-1ß, and TNF-α. Changes in microglial/macrophage M1/M2 polarization were observed. Additionally, the PERK activator CCT020312 intervention eliminated the impact of AS-IV on post-TBI inflammation and ER stress-related proteins p-PERK, p-eIF2a, and ATF4. These results indicate that AS-IV alleviates neuroinflammation and brain damage post-TBI through the PERK pathway, offering new directions and theoretical insights for TBI treatment.

Exosomes in Glioma: Unraveling Their Roles in Progression, Diagnosis, and Therapy.

Gliomas, the most prevalent primary malignant brain tumors, present a challenging prognosis even after undergoing surgery, radiation, and chemotherapy. Exosomes, nano-sized extracellular vesicles secreted by various cells, play a pivotal role in glioma progression and contribute to resistance against chemotherapy and radiotherapy by facilitating the transportation of biological molecules and promoting intercellular communication within the tumor microenvironment. Moreover, exosomes exhibit the remarkable ability to traverse the blood-brain barrier, positioning them as potent carriers for therapeutic delivery. These attributes hold promise for enhancing glioma diagnosis, prognosis, and treatment. Recent years have witnessed significant advancements in exosome research within the realm of tumors. In this article, we primarily focus on elucidating the role of exosomes in glioma development, highlighting the latest breakthroughs in therapeutic and diagnostic approaches, and outlining prospective directions for future research.

Integrated and DC-powered superconducting microcomb.

Frequency combs, specialized laser sources emitting multiple equidistant frequency lines, have revolutionized science and technology with unprecedented precision and versatility. Recently, integrated frequency combs are emerging as scalable solutions for on-chip photonics. Here, we demonstrate a fully integrated superconducting microcomb that is easy to manufacture, simple to operate, and consumes ultra-low power. Our turnkey apparatus comprises a basic nonlinear superconducting device, a Josephson junction, directly coupled to a superconducting microstrip resonator. We showcase coherent comb generation through self-started mode-locking. Therefore, comb emission is initiated solely by activating a DC bias source, with power consumption as low as tens of picowatts. The resulting comb spectrum resides in the microwave domain and spans multiple octaves. The linewidths of all comb lines can be narrowed down to 1 Hz through a unique coherent injection-locking technique. Our work represents a critical step towards fully integrated microwave photonics and offers the potential for integrated quantum processors.

TAK-242, a toll-like receptor 4 antagonist, against brain injury by alleviates autophagy and inflammation in rats.

Inhibition of Toll-like receptor 4 (TLR4)-mediated inflammatory pathways exerts a critical effect on neuronal death; therefore, it is a possible new therapeutic approach for traumatic brain injury (TBI). Resatorvid (TAK-242) is a novel small-molecule compound widely used to inhibit TLR4-mediated pathways, but the protective mechanism of TAK-242 in TBI remains unclear. Herein, we analyzed the neuroprotective effects of TAK-242 in rats after TBI. The rat model of brain injury was established using a modified Free-fall device, and the rats were injected with TAK-242 (0.5 mg/kg) through the caudal vein before TBI. The rats were allocated into four groups: a sham group, a TBI group, a TBI + vehicle group, and a TBI + TAK-242 group. The brain tissue was extracted for histology and determination of the expression of autophagy-related proteins and inflammatory mediators. TAK-242 pretreatment significantly reduced the damage to hippocampal neurons. Neuronal autophagy increased after brain injury, whereas TAK-242 significantly reduced autophagy marker protein LC3-II in the hippocampus. In addition, TAK-242 pretreatment significantly downregulated NF-κB p65, TNF-α, and IL-1ß in the hippocampus. In conclusion, TAK-242 significantly reduced hippocampal neuronal damage by inhibiting autophagy and neuroinflammatory activity, possibly via the NF-κB signaling pathway.

Atorvastatin prevents endoplasmic reticulum stress-mediated apoptosis via the Nrf2/HO-1 signaling pathway in TBI mice.

BACKGROUND: Our present study evaluated the neuroprotection effects of atorvastatin by inhibiting TBI-induced ER stress, as well as the potential role of the Nrf2/HO-1 pathway in experimental TBI. METHODS: First, the mice were divided into four groups:sham, TBI, TBI+Vehicle and TBI+atorvastatin groups. The mice received atorvastatin (10 mg/kg/day) through intragastric gavage once a day for 3 days before TBI. In addition, Nrf2 WT and Nrf2 knockout mice were randomly divided into four groups: Nrf2+/+ TBI, Nrf2+/+ TBI+atorvastatin, Nrf2-/- TBI, and Nrf2-/- TBI+atorvastatin groups. Several neurobehavioral parameters were assessed post-TBI using mNSS, brain edema and the rotarod test, and the brain was isolated for molecular and biochemical analysis conducted through TUNEL staining and western blotting. . RESULTS: The results showed that atorvastatin treatment significantly improved neurological deficits, alleviated brain edema, and apoptosis caused by TBI. Western blotting analysis showed that atorvastatin significantly suppressed ER stress and its related apoptotic pathway after TBI, which may be associated with the further activation of the Nrf2/HO-1 pathway. However, compared with the Nrf2+/+ TBI+Vehicle group, Nrf2 deficiency further aggravated neurological deficits and promoted ER stress-mediated apoptosis induced by TBI. Interestingly, atorvastatin failed to improve neurological deficits but reversed apoptosis, and the loss of the beneficial properties of anti-ER stress in the Nrf2-/- TBI mice. . CONCLUSIONS: The results indicated that atorvastatin improves the neurologic functions and protects the brain from injury in the Nrf2+/+ TBI mice, primarily by counteracting ER stress-mediated apoptosis, which may be achieved through the activation of the Nrf2/HO-1 signaling pathway.

Nrf2 loss of function exacerbates endoplasmic reticulum stress-induced apoptosis in TBI mice.

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays an important role in neuroprotection and recover. Our studies have showed that endoplasmic reticulum (ER) stress-induced apoptosis aggravates secondary damage following traumatic brain injury (TBI). Whether Nrf2 involved in ER stress and ER stress-mediated apoptosis is not clearly investigated. This present study explored the effect of Nrf2 knockout on ER stress and ER stress-induced apoptosis in TBI mice. A lateral fluid percussion injury (FPI)model of TBI was built based on Nrf2 knockout (Nrf2(-/-)) mice and wild-type (Nrf2(+/+)) mice, and the expressions of marker proteins of ER stress and ER stress-induced apoptosis were checked at 24 h following TBI. We found that Nrf2(-/-) mice presented more severe neurological deficit, brain edema and neuronal cell apoptosis compared with Nrf2(+/+) mice. And, the TBI Nrf2(-/-) mice were significantly increased expression of marker proteins of ER stress and ER stress-induced apoptotic pathway including glucose regulated protein (GRP78), protein kinase RNA-like ER kinase (PERK), inositol requiring enzyme (IRE1), activating transcription factor 6 (ATF6), C/EBP homologous protein (CHOP), caspase-12 and caspase-3, compared with that in WT mice. These results suggest that Nrf2 could ameliorate TBI-induced second brain injury partly through ER stress signal pathway.

Resveratrol attenuates autophagy and inflammation after traumatic brain injury by activation of PI3K/Akt/mTOR pathway in rats.

AIM OF THE STUDY: Accumulating studies have demonstrated that neuronal autophagy and inflammation are crucial for hippocampus development in rats subjected to traumatic brain injury (TBI). Therefore, we have investigated whether resveratrol is protective against brain damage through the attenuation of neuronal autophagy and inflammation, and explored underlying mechanisms. MATERIAL AND METHODS: Rats were injected with resveratrol (50 mg/kg, i.p.), following controlled cortical impact (CCI) injury. Brain water content, behavioral studies, and mNSS score were measured to assess the effects of resveratrol treatment. Autophagy-related proteins and inflammatory cytokines in the hippocampus were detected by Western blotting at 12, 24, and 48 hours after TBI. In addition, spatial distribution of LC3 was evaluated with immunofluorescence analysis 24 hours after injury. Finally, factors related to PI3K/Akt/mTOR signaling pathway were assessed at the same time in the hippocampus. RESULTS: Our results depicted that resveratrol could reduce the cerebral edema caused by TBI and improve the recovery of functional deficits in rats. Resveratrol was also able to remarkably reduce the expression of LC3 II and Beclin-1, while increased the expression levels of P62 in the hippocampus. Moreover, we found that interleukin b (IL-1b) and tumor necrosis factor a (TNF-a) were significantly decreased in resveratrol-treated rats. Indeed, we observed an activation of the PI3K/Akt/mTOR pathway after TBI, which may be related to the neuro-protective effect of resveratrol. CONCLUSIONS: Data presented herein support that resveratrol is a potential treatment against TBI through the inhibition of neuronal autophagy and inflammation by activation of PI3K/Akt/mTOR pathway.

A Model for Predicting Clinical Prognosis in Patients with WHO Grade 2 Glioma.

Objectives: Although patients with grade 2 glioma have a relatively better prognosis and longer survival than those with high-grade glioma, there are still a number of patients with disappointing outcomes. In order to accurately predict the prognosis of patients, relevant risk factors were included in the analysis to establish a clinical prediction model so as to provide a basis for clinically individualized treatment. Methods: A retrospective study was conducted in patients diagnosed with grade 2 glioma. Data including clinical features, pathological type, molecular classification, neuroimaging examination, treatment, and survival were collected. The data sets were randomly assigned, with 80% of the data used for model building and 20% for validation. Cox proportional hazard regression analysis was used to construct the model using important risk factors and present it in the form of a nomogram. The nomogram was evaluated a using C-index and calibration chart. Results: A total of 160 patients were enrolled in this analysis, including 128 in the training group and 32 in the validation group. In the training group, eight important risk factors including preoperative KPS, the first presenting symptom, the extent of resection, the gross tumor size, 1p19q, IDH, radiotherapy, and chemotherapy were identified to construct the model. The C-index of the training group and the validation group was 0.832 and 0.801, respectively, indicating that the model had good prediction ability. The calibration charts of the two groups were drawn respectively, which showed that the calibration line and the standard line had a good consistency, which suggested that the model-predicted risk had a good consistency with the actual risk. Conclusions: Based on the data of our center, a nomogram prediction model with eight variables has been established as an off-the-rack tool and verified its accuracy, which can guide clinical work and provide consultation for patients.