PDMS Film-Based Flexible Pressure Sensor Array with Surface Protruding Structure for Human Motion Detection and Wrist Posture Recognition.

Flexible pressure sensors have been widely concerned because of their great application potential in the fields of electronic skin, human-computer interaction, health detection, and so on. In this paper, a flexible pressure sensor is designed, with polydimethylsiloxane (PDMS) films with protruding structure as elastic substrate and poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate) (PEDOT:PSS)/cellulose nanocrystals (CNC) as conductive-sensitive material. The flexible pressure sensor has a wide linear detection range (0-100 kPa), outstanding sensitivity (2.32 kPa-1), and stability of more than 2000 cycles. The sensor has been proven to be able to detect a wide range of human movements (finger bending, elbow bending, etc.) and small movements (breathing, pulse, etc.). In addition, the pressure sensor array can detect the pressure distribution and judge the shape of the object. A smart wristband equipped with four flexible pressure sensors is designed. Among them, the k-nearest neighbor (KNN) algorithm is used to classify sensor data to achieve high accuracy (99.52%) recognition of seven kinds of wrist posture. This work provides a new opportunity to fabricate simple, flexible pressure sensors with potential applications in the next-generation electronic skin, health detection, and intelligent robotics.

Neuroprotective effect of the traditional decoction Tian-Si-Yin against Alzheimer's disease via suppression of neuroinflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease among old adults. As a traditional Chinese medicine, the herbal decoction Tian-Si-Yin consists of Morinda officinalis How. and Cuscuta chinensis Lam., which has been widely used to nourish kidney. Interestingly, Tian-Si-Yin has also been used to treat dementia, depression and other neurological conditions. However, its therapeutic potential for neurodegenerative diseases such as AD and the underlying mechanisms remain unclear. AIM OF THE STUDY: To evaluate the therapeutic effect of the herbal formula Tian-Si-Yin against AD and to explore the underlying mechanisms. MATERIALS AND METHODS: The N2a cells treated with amyloid ß (Aß) peptide or overexpressing amyloid precursor protein (APP) were used to establish cellular models of AD. The in vivo anti-AD effects were evaluated by using Caenorhabditis elegans and 3 × Tg-AD mouse models. Tian-Si-Yin was orally administered to the mice for 8 weeks at a dose of 10, 15 or 20 mg/kg/day, respectively. Its protective role on memory deficits of mice was examined using the Morris water maze and fear conditioning tests. Network pharmacology, proteomic analysis and ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UHPLC-MS/MS) were used to explore the underlying molecular mechanisms, which were further investigated by Western blotting and immunohistochemistry. RESULTS: Tian-Si-Yin was shown to improve cell viability of Aß-treated N2a cells and APP-expressing N2a-APP cells. Tian-Si-Yin was also found to reduce ROS level and extend lifespan of transgenic AD-like C. elegans model. Oral administration of Tian-Si-Yin at medium dose was able to effectively rescue memory impairment in 3 × Tg mice. Tian-Si-Yin was further shown to suppress neuroinflammation by inhibition of glia cell activation and downregulation of inflammatory cytokines, diminishing tau phosphoralytion and Aß deposition in the mice. Using UHPLC-MS/MS and network pharmacology technologies, 17 phytochemicals from 68 components of Tian-Si-Yin were identified as potential anti-AD components. MAPK1, BRAF, TTR and Fyn were identified as anti-AD targets of Tian-Si-Yin from network pharmacology and mass spectrum. CONCLUSIONS: This study has established the protective effect of Tian-Si-Yin against AD and demonstrates that Tian-Si-Yin is capable of improving Aß level, tau pathology and synaptic disorder by regulating inflammatory response.

Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer's disease mice.

Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of Alzheimer's disease (AD) cases without any family history. Although genome-wide association studies have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus (DG)-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which, in turn, further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a highly vascularized malignant cancer of the central nervous system, and the presence of vasculogenic mimicry (VM) severely limits the effectiveness of anti-vascular therapy. In this study, we identified downregulated circHECTD1, which acted as a key VM-suppressed factor in GBM. circHECTD1 elevation significantly inhibited cell proliferation, migration, invasion and tube-like structure formation in GBM. RIP assay was used to demonstrate that the flanking intron sequence of circHECTD1 can be specifically bound by RBMS3, thereby inducing circHECTD1 formation to regulate VM formation in GBM. circHECTD1 was confirmed to possess a strong protein-encoding capacity and the encoded functional peptide 463aa was identified by LC-MS/MS. Both circHECTD1 and 463aa significantly inhibited GBM VM formation in vivo and in vitro. Analysis of the 463aa protein sequence revealed that it contained a ubiquitination-related domain and promoted NR2F1 degradation by regulating the ubiquitination of the NR2F1 at K396. ChIP assay verified that NR2F1 could directly bind to the promoter region of MMP2, MMP9 and VE-cadherin, transcriptionally promoting the expression of VM-related proteins, which in turn enhanced VM formation in GBM. In summary, we clarified a novel pathway for RBMS3-induced circHECTD1 encoding functional peptide 463aa to mediate the ubiquitination of NR2F1, which inhibited VM formation in GBM. This study aimed to reveal new mechanisms of GBM progression in order to provide novel approaches and strategies for the anti-vascular therapy of GBM. The schematic illustration showed the inhibitory effect of circHECTD1-463aa in the VM formation in GBM.

Pseudogene MAPK6P4-encoded functional peptide promotes glioblastoma vasculogenic mimicry development.

Glioma is the most common primary malignancy of the central nervous system. Glioblastoma (GBM) has the highest degree of malignancy among the gliomas and the strongest resistance to chemotherapy and radiotherapy. Vasculogenic mimicry (VM) provides tumor cells with a blood supply independent of endothelial cells and greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. Vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial cadherin (VE-cadherin) are currently recognized molecular markers of VM in tumors. In the present study, we show that pseudogene MAPK6P4 deficiency represses VEGFR2 and VE-cadherin protein expression levels, as well as inhibits the proliferation, migration, invasion, and VM development of GBM cells. The MAPK6P4-encoded functional peptide P4-135aa phosphorylates KLF15 at the S238 site, promoting KLF15 protein stability and nuclear entry to promote GBM VM formation. KLF15 was further confirmed as a transcriptional activator of LDHA, where LDHA binds and promotes VEGFR2 and VE-cadherin lactylation, thereby increasing their protein expression. Finally, we used orthotopic and subcutaneous xenografted nude mouse models of GBM to verify the inhibitory effect of the above factors on GBM VM development. In summary, this study may represent new targets for the comprehensive treatment of glioma.

Age differentially modulates the cortical tracking of the lower and higher level linguistic structures during speech comprehension.

Speech comprehension requires listeners to rapidly parse continuous speech into hierarchically-organized linguistic structures (i.e. syllable, word, phrase, and sentence) and entrain the neural activities to the rhythm of different linguistic levels. Aging is accompanied by changes in speech processing, but it remains unclear how aging affects different levels of linguistic representation. Here, we recorded magnetoencephalography signals in older and younger groups when subjects actively and passively listened to the continuous speech in which hierarchical linguistic structures of word, phrase, and sentence were tagged at 4, 2, and 1 Hz, respectively. A newly-developed parameterization algorithm was applied to separate the periodically linguistic tracking from the aperiodic component. We found enhanced lower-level (word-level) tracking, reduced higher-level (phrasal- and sentential-level) tracking, and reduced aperiodic offset in older compared with younger adults. Furthermore, we observed the attentional modulation on the sentential-level tracking being larger for younger than for older ones. Notably, the neuro-behavior analyses showed that subjects' behavioral accuracy was positively correlated with the higher-level linguistic tracking, reversely correlated with the lower-level linguistic tracking. Overall, these results suggest that the enhanced lower-level linguistic tracking, reduced higher-level linguistic tracking and less flexibility of attentional modulation may underpin aging-related decline in speech comprehension.

U3 snoRNA-mediated degradation of ZBTB7A regulates aerobic glycolysis in isocitrate dehydrogenase 1 wild-type glioblastoma cells.

AIMS: The isocitrate dehydrogenase (IDH) phenotype is associated with reprogrammed energy metabolism in glioblastoma (GBM) cells. Small nucleolar RNAs (snoRNAs) are known to exert an important regulatory role in the energy metabolism of tumor cells. The purpose of this study was to investigate the role of C/D box snoRNA U3 and transcription factor zinc finger and BTB domain-containing 7A (ZBTB7A) in the regulation of aerobic glycolysis and the proliferative capacity of IDH1 wild-type (IDH1WT ) GBM cells. METHODS: Quantitative reverse transcription PCR and western blot assays were utilized to detect snoRNA U3 and ZBTB7A expression. U3 promoter methylation status was analyzed via bisulfite sequencing and methylation-specific PCR. Seahorse XF glycolysis stress assays, lactate production and glucose consumption measurement assays, and cell viability assays were utilized to detect glycolysis and proliferation of IDH1WT GBM cells. RESULTS: We found that hypomethylation of the CpG island in the promoter region of U3 led to the upregulation of U3 expression in IDH1WT GBM cells, and the knockdown of U3 suppressed aerobic glycolysis and the proliferation ability of IDH1WT GBM cells. We found that small nucleolar-derived RNA (sdRNA) U3-miR, a small fragment produced by U3, was able to bind to the ZBTB4 3'UTR region and reduce ZBTB7A mRNA stability, thereby downregulating ZBTB7A protein expression. Furthermore, ZBTB7A transcriptionally inhibited the expression of hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA), which are key enzymes of aerobic glycolysis, by directly binding to the HK2 and LDHA promoter regions, thereby forming the U3/ZBTB7A/HK2 LDHA pathway that regulates aerobic glycolysis and proliferation of IDH1WT GBM cells. CONCLUSION: U3 enhances aerobic glycolysis and proliferation in IDH1WT GBM cells via the U3/ZBTB7A/HK2 LDHA axis.

Brain structure and cortical activity changes of new daily persistent headache: multimodal evidence from MEG/sMRI.

BACKGROUND: New daily persistent headache (NDPH) is a rare but debilitating primary headache disorder that poses a significant burden on individuals and society. Despite its clinical importance, the underlying pathophysiological mechanisms of NDPH remain unclear. In this study, we aimed to investigate the brain structural changes and neural activity patterns in patients with NDPH using multimodal brain imaging analysis of structural magnetic resonance imaging (sMRI) combined with magnetoencephalography (MEG). METHODS: Twenty-eight patients with NDPH and 37 healthy controls (HCs) were recruited for this study, and their structural and resting-state data were collected by 3.0 Tesla MRI and MEG. We analyzed the brain morphology using voxel-based morphometry and source-based morphometry. In each brain region, MEG sensor signals from 1 to 200 Hz were analyzed using an adapted version of Welch's method. MEG source localization was conducted using the dynamic statistical parametric mapping, and the difference of source distribution between patients with NDPH and HCs was examined. RESULTS: Our results revealed significant differences in the regional grey matter volume, cortical thickness, and cortical surface area between the two groups. Specifically, compared with HCs, patients with NDPH showed a significant decrease in cortical thickness of the left rostral cortex in the middle frontal gyrus, decreased cortical surface area of the left fusiform gyrus, decreased grey matter volume of the left superior frontal gyrus and the left middle frontal gyrus, and increased grey matter volume of the left calcarine. Furthermore, the power of the whole brain, bilateral frontal lobes, and right temporal lobe in the NDPH group were higher than that in HCs in the ripple frequency band (80-200 Hz). Functional and structural analysis suggested that there were structural changes and abnormal high frequency cortical activity in both frontal and temporal lobes in patients with NDPH. CONCLUSION: Our findings indicated that patients with NDPH have abnormalities in brain morphology, such as cortical area, cortical thickness, and grey matter volume, accompanied by abnormal cortical neural activity. Brain structural changes in the frontotemporal cortex and abnormalities in cortical ripple activity may be involved in the pathogenesis of NDPH.

Prognostic value of NOX2 as a potential biomarker for lung adenocarcinoma using TCGA and clinical validation.

Lung adenocarcinoma (LUAD) is associated with high morbidity and mortality; therefore, effective biomarkers are essential. In recent years, a rapid increase in the efficiency of high­throughput sequencing technologies and the continuous improvement of comprehensive online databases have facilitated the study of the genomic changes that affect tumor progression, including the identification of tumor biomarkers. Therefore, the identification of genes that may affect the progression and prognosis of LUAD is necessary. In the present study, the CIBERSORT and ESTIMATE bioinformatics packages were used to evaluate data from The Cancer Genome Atlas, including assessment of the proportion of tumor­infiltrating immune cells in the tumor microenvironment, Cox regression analysis of differentially expressed genes and cross analysis of protein­protein interaction networks. Myeloid cell NADPH oxidase isoform 2 (NOX2), an indispensable gene in the immune system, was demonstrated to serve a vital role in LUAD pathogenesis. Western blotting and immunohistochemistry confirmed that, at the protein level, NOX2 expression was increased in normal cells compared with cancer cells. Furthermore, reverse transcription­quantitative PCR results at the mRNA level were consistent with these results, which confirmed that the abundance of NOX2 was significantly reduced in LUAD patients. NOX2 may be used as a novel marker and an independent prognostic indicator of LUAD. Its potential function was enriched in tumor immune and metabolic signaling pathways, which could provide clues for the study of the signaling pathways and molecular networks related to the disease progression of LUAD, which would be helpful for the assessment of prognosis in the clinical setting.

In Situ Polymerized MXene/Polypyrrole/Hydroxyethyl Cellulose-Based Flexible Strain Sensor Enabled by Machine Learning for Handwriting Recognition.

Flexible strain sensors have significant progress in the fields of human-computer interaction, medical monitoring, and handwriting recognition, but they also face many challenges such as the capture of weak signals, comprehensive acquisition of the information, and accurate recognition. Flexible strain sensors can sense externally applied deformations, accurately measure human motion and physiological signals, and record signal characteristics of handwritten text. Herein, we prepare a sandwich-structured flexible strain sensor based on an MXene/polypyrrole/hydroxyethyl cellulose (MXene/PPy/HEC) conductive material and a PDMS flexible substrate. The sensor features a wide linear strain detection range (0-94%), high sensitivity (gauge factor 357.5), reliable repeatability (>1300 cycles), ultrafast response-recovery time (300 ms), and other excellent sensing properties. The MXene/PPy/HEC sensor can detect human physiological activities, exhibiting excellent performance in measuring external strain changes and real-time motion detection. In addition, the signals of English words, Arabic numerals, and Chinese characters handwritten by volunteers measured by the MXene/PPy/HEC sensor have unique characteristics. Through machine learning technology, different handwritten characters are successfully identified, and the recognition accuracy is higher than 96%. The results show that the MXene/PPy/HEC sensor has a significant impact in the fields of human motion detection, medical and health monitoring, and handwriting recognition.

Flexible Pressure Sensors Based on Molybdenum Disulfide/Hydroxyethyl Cellulose/Polyurethane Sponge for Motion Detection and Speech Recognition Using Machine Learning.

Flexible pressure sensors with excellent performance have broad application potential in wearable devices, motion monitoring, and human-computer interaction. In this paper, a flexible pressure sensor with a porous structure is proposed by coating molybdenum disulfide (MoS2) and hydroxyethyl cellulose (HEC) on a polyurethane (PU) sponge skeleton. The obtained sensor has excellent sensitivity (0.746 kPa-1), a wide detection range (250 kPa), fast response (120 ms), and outstanding repeatability over 2000 cycles. It is proven that the sensor can realize human motion detection and distinguish the touch of varying strength. In addition, a pressure sensing array was fabricated to reflect the pressure distribution and recognize the writing of Arabic numerals. Finally, the sensor performs speech detection through throat muscle movements, and high-accuracy (97.14%) speech recognition for seven words was achieved by a machine learning algorithm based on the support vector machine (SVM). This work provides an opportunity to fabricate simple flexible pressure sensors with potential applications in next-generation electronic skin, health detection, and intelligent robotics.

The mechanism of BUD13 m6A methylation mediated MBNL1-phosphorylation by CDK12 regulating the vasculogenic mimicry in glioblastoma cells.

Vasculogenic mimicry (VM) is an endothelium-independent tumor microcirculation that provides adequate blood supply for tumor growth. The presence of VM greatly hinders the treatment of glioblastoma (GBM) with anti-angiogenic drugs. Therefore, targeting VM formation may be a feasible therapeutic strategy for GBM. The research aimed to evaluate the roles of BUD13, CDK12, MBNL1 in regulating VM formation of GBM. BUD13 and CDK12 were upregulated and MBNL1 was downregulated in GBM tissues and cells. Knockdown of BUD13, CDK12, or overexpression of MBNL1 inhibited GBM VM formation. METTL3 enhanced the stability of BUD13 mRNA and upregulated its expression through m6A methylation. BUD13 enhanced the stability of CDK12 mRNA and upregulated its expression. CDK12 phosphorylated MBNL1, thereby regulating VM formation of GBM. The simultaneous knockdown of BUD13, CDK12, and overexpression of MBNL1 reduced the volume of subcutaneously transplanted tumors in nude mice and prolonged the survival period. Thus, the BUD13/CDK12/MBNL1 axis plays a crucial role in regulating VM formation of GBM and provides a potential target for GBM therapy.

Self-Powered Nitrogen Dioxide Sensor Based on Pd-Decorated ZnO/MoSe2 Nanocomposite Driven by Triboelectric Nanogenerator.

This paper introduces a high-performance self-powered nitrogen dioxide gas sensor based on Pd-modified ZnO/MoSe2 nanocomposites. Poly(vinyl alcohol) (PVA) nanofibers were prepared by high-voltage electrospinning and tribological nanogenerators (TENGs) were designed. The output voltage of TENG and the performance of the generator at different frequencies were measured. The absolute value of the maximum positive and negative voltage exceeds 200 V. Then, the output voltage of a single ZnO thin-film sensor, Pd@ZnO thin-film sensor and Pd@ZnO/MoSe2 thin-film sensor was tested by using the energy generated by TENG at 5 Hz, when the thin-film sensor was exposed to 1-50 ppm NO2 gas. The experimental results showed that the sensing response of the Pd@ZnO/MoSe2 thin-film sensor was higher than that of the single ZnO film sensor and Pd@ZnO thin-film sensor. The TENG-driven response rate of the Pd@ZnO/MoSe2 sensor on exposure to 50 ppm NO2 gas was 13.8. At the same time, the sensor had good repeatability and selectivity. The synthetic Pd@ZnO/MoSe2 ternary nanocomposite was an ideal material for the NO2 sensor, with excellent structure and performance.

CPEB2 m6A methylation regulates blood-tumor barrier permeability by regulating splicing factor SRSF5 stability.

The blood-tumor barrier (BTB) contributes to poor therapeutic efficacy by limiting drug uptake; therefore, elevating BTB permeability is essential for glioma treatment. Here, we prepared astrocyte microvascular endothelial cells (ECs) and glioma microvascular ECs (GECs) as in vitro blood-brain barrier (BBB) and BTB models. Upregulation of METTL3 and IGF2BP3 in GECs increased the stability of CPEB2 mRNA through its m6A methylation. CPEB2 bound to and increased SRSF5 mRNA stability, which promoted the ETS1 exon inclusion. P51-ETS1 promoted the expression of ZO-1, occludin, and claudin-5 transcriptionally, thus regulating BTB permeability. Subsequent in vivo knockdown of these molecules in glioblastoma xenograft mice elevated BTB permeability, promoted doxorubicin penetration, and improved glioma-specific chemotherapeutic effects. These results provide a theoretical and experimental basis for epigenetic regulation of the BTB, as well as insight into comprehensive glioma treatment.

The MBNL1/circNTRK2/PAX5 pathway regulates aerobic glycolysis in glioblastoma cells by encoding a novel protein NTRK2-243aa.

Glioblastoma multiforme (GBM) is the most common tumor of the human central nervous system. Aerobic glycolysis has been strongly related to tumor development and malignant behavior. In this study, we found that MBNL1, circNTRK2, and NTRK2-243aa were markedly downregulated and inhibited glycolysis in GBM, whereas PAX5 was upregulated and promoted glycolysis. Functionally, MBNL1 promoted the expression of circNTRK2 by binding to NTRK2 pre-mRNA, as validated using RNA pull-down and nascent RNA immunoprecipitation assays. Mass spectrometry, western blotting, and immunofluorescence staining methods were used to detect the expression of NTRK2-243aa. NTRK2-243aa-encoded by circNTRK2-phosphorylated PAX5 at Y102, leading to the attenuation of the half-life of PAX5, as validated by in vitro kinase and MG132 rescue assays. Besides, PAX5 transcriptionally facilitated the expression of PKM2 and HK2 by binding to their promoter regions, as verified by luciferase reporter and chromatin immunoprecipitation assays. Finally, overexpression of MBNL1 and circNTRK2 combined with PAX5 knockdown effectively inhibited the formation of GBM xenograft tumors and significantly prolonged the survival of orthotopic nude mice. We have delineated that the MBNL1/circNTRK2/PAX5 pathway plays a crucial role in regulating GBM glycolysis and could provide potential targets and alternative strategies for the treatment of GBM.

Guar Gum/Ethyl Cellulose-Polyvinyl Pyrrolidone Composite-Based Quartz Crystal Microbalance Humidity Sensor for Human Respiration Monitoring.

In this work, the guar gum (GG) and the electrospinned ethyl cellulose-polyvinyl pyrrolidone (EC-PVP) nanofibers were used as humidity-sensitive materials for fabricating a quartz crystal microbalance (QCM) sensor. Fourier transform infrared spectroscopy, scanning electron microscopy, water contact angle test, and X-ray photoelectron spectra were used to characterize the synthesized GG/EC-PVP composite material, confirming its successful preparation and good hydrophilicity. The humidity sensitivity experiments were performed at room temperature. The GG/EC-PVP-coated QCM sensor has high sensitivity (55.72 Hz/%RH) and low hysteresis (2.8% RH) in a wide relative humidity range (0-97% RH), short response/recovery time (26/2 s), excellent selectivity, good repeatability, and stability. The combined action of hydrophilic groups and porous structure enhances the humidity sensitivity. The GG/EC-PVP sensor can be used to capture and measure typical breathing patterns in different human basic emotions due to its good performance. Furthermore, a lie-detector system was also designed for judging the lying through detecting the emotional breathing pattern of the subjects.

Social isolation reinforces aging-related behavioral inflexibility by promoting neuronal necroptosis in basolateral amygdala.

Aging is characterized with a progressive decline in many cognitive functions, including behavioral flexibility, an important ability to respond appropriately to changing environmental contingencies. However, the underlying mechanisms of impaired behavioral flexibility in aging are not clear. In this study, we reported that necroptosis-induced reduction of neuronal activity in the basolateral amygdala (BLA) plays an important role in behavioral inflexibility in 5-month-old mice of the senescence-accelerated mice prone-8 (SAMP8) line, a well-established model with age-related phenotypes. Application of Nec-1s, a specific inhibitor of necroptosis, reversed the impairment of behavioral flexibility in SAMP8 mice. We further observed that the loss of glycogen synthase kinase 3α (GSK-3α) was strongly correlated with necroptosis in the BLA of aged mice and the amygdala of aged cynomolgus monkeys (Macaca fascicularis). Moreover, genetic deletion or knockdown of GSK-3α led to the activation of necroptosis and impaired behavioral flexibility in wild-type mice, while the restoration of GSK-3α expression in the BLA arrested necroptosis and behavioral inflexibility in aged mice. We further observed that GSK-3α loss resulted in the activation of mTORC1 signaling to promote RIPK3-dependent necroptosis. Importantly, we discovered that social isolation, a prevalent phenomenon in aged people, facilitated necroptosis and behavioral inflexibility in 4-month-old SAMP8 mice. Overall, our study not only revealed the molecular mechanisms of the dysfunction of behavioral flexibility in aged people but also identified a critical lifestyle risk factor and a possible intervention strategy.

A novel protein encoded by ZCRB1-induced circHEATR5B suppresses aerobic glycolysis of GBM through phosphorylation of JMJD5.

BACKGROUND: RNA-binding proteins (RBPs) and circular RNAs (circRNAs) play important roles in glioblastoma multiforme (GBM). Aerobic glycolysis is a metabolic characteristic of GBM. However, the roles of RBPs and circRNAs in aerobic glycolysis in GBM remain unclear. The aim of this study is to explore the mechanisms by which RBPs and circRNAs regulate aerobic glycolysis in GBM cells. METHODS: RNA sequencing and circRNA microarray analysis were performed to identify RBPs and circRNAs for further study. Mass spectrometry validated the encoded protein and its interacting proteins. Quantitative reverse transcription PCR and western blot assays were used to determine the mRNA and protein expression, respectively. Furthermore, immunofluorescence and fluorescence in situ hybridization assays were used to determine the protein and RNA localization, respectively. Glucose and lactate measurement assays, Seahorse XF glycolysis stress assays and cell viability assays were conducted to investigate the effects on glycolysis and proliferation in GBM cells. RESULTS: We selected zinc finger CCHC-type and RNA-binding motif 1 (ZCRB1) and circRNA HEAT repeat containing 5B (circHEATR5B) as candidates for this study. These genes were expressed at low levels in GBM tissues and cells. Both ZCRB1 and circHEATR5B overexpression suppressed aerobic glycolysis and proliferation in GBM cells. ZCRB1 overexpression promoted the Alu element-mediated formation of circHEATR5B. In addition, circHEATR5B encoded a novel protein HEATR5B-881aa which interacted directly with Jumonji C-domain-containing 5 (JMJD5) and reduced its stability by phosphorylating S361. JMJD5 knockdown increased pyruvate kinase M2 (PKM2) enzymatic activity and suppressed glycolysis and proliferation in GBM cells. Finally, ZCRB1, circHEATR5B and HEATR5B-881aa overexpression inhibited GBM xenograft growth and prolonged the survival time of nude mice. CONCLUSIONS: This study reveals a novel mechanism of regulating aerobic glycolysis and proliferation in GBM cells through the ZCRB1/circHEATR5B/HEATR5B-881aa/JMJD5/PKM2 pathway, which can provide novel strategies and potential targets for GBM therapy.

Ghrelin alleviates 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells.

Ghrelin is a neuropeptide that has various physiological functions and has been demonstrated to be neuroprotective in a number of neurological disease models. However, the underlying mechanisms of ghrelin in Parkinson's disease remain largely unexplored. The current study aimed to study the effects of ghrelin in a 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease model and evaluate the potential underlying mechanisms. In the present study, we treated an SH-SY5Y cell model with 6-OHDA, and observed that pretreatment with different concentrations of ghrelin (1, 10, and 100 nM) for 30 minutes relieved the neurotoxic effects of 6-OHDA, as revealed by Cell Counting Kit-8 and Annexin V/propidium iodide (PI) apoptosis assays. Reverse transcription quantitative polymerase chain reaction and western blot assay results demonstrated that 6-OHDA treatment upregulated α-synuclein and lincRNA-p21 and downregulated TG-interacting factor 1 (TGIF1), which was predicted as a potential transcription regulator of the gene encoding α-synuclein (SNCA). Ghrelin pretreatment was able to reverse the trends caused by 6-OHDA. The Annexin V/PI apoptosis assay results revealed that inhibiting either α-synuclein or lincRNA-p21 expression with small interfering RNA (siRNA) relieved 6-OHDA-induced cell apoptosis. Furthermore, inhibiting lincRNA-p21 also partially upregulated TGIF1. By retrieving information from a bioinformatics database and performing both double luciferase and RNA immunoprecipitation assays, we found that lincRNA-p21 and TGIF1 were able to form a double-stranded RNA-binding protein Staufen homolog 1 (STAU1) binding site and further activate the STAU1-mediated mRNA decay pathway. In addition, TGIF1 was able to transcriptionally regulate α-synuclein expression by binding to the promoter of SNCA. The Annexin V/PI apoptosis assay results showed that either knockdown of TGIF1 or overexpression of lincRNA-p21 notably abolished the neuroprotective effects of ghrelin against 6-OHDA-induced neurotoxicity. Collectively, these findings suggest that ghrelin exerts neuroprotective effects against 6-OHDA-induced neurotoxicity via the lincRNA-p21/TGIF1/α-synuclein pathway.

Pseudogene RPL32P3 regulates the blood-tumor barrier permeability via the YBX2/HNF4G axis.

The existence of the blood-tumor barrier (BTB) severely hinders the transport of anti-tumor drugs to brain tumor tissues. Selectively opening BTB is of great significance to improve the chemotherapy effect of glioma. Pseudogenes have been recognized as important regulators in various biologic processes. In this study, we identified that ribosomal protein L32 pseudogene 3 (RPL32P3) was highly expressed in glioma-exposed endothelial cells (GECs). Knockdown of RPL32P3 decreased the expression of tight junction-related proteins (TJPs) and increased BTB permeability. Subsequent analysis of the underlying mechanism indicated that RPL32P3 recruited lysine methyltransferase 2 A (KMT2A) to the Y-box binding protein 2 (YBX2) promoter region and mediated H3K4me3 to promote YBX2 transcription. Highly expressed YBX2 bound and stabilized hepatocyte nuclear factor 4 gamma (HNF4G) mRNA. Highly expressed HNF4G directly bound to the promoters of TJPs ZO-1, occludin and claudin-5 to promote their transcriptional activities and regulated BTB permeability. The simultaneous knockdown of RPL32P3, YBX2, and HNF4G combined with doxorubicin (DOX) increased the apoptosis of glioma cells. In conclusion, the current study indicated that RPL32P3 knockdown increased BTB permeability through the YBX2/HNF4G pathway. These findings may provide new targets for the comprehensive treatment of glioma.