Enhancing intraneural revascularization following peripheral nerve injury through hypoxic Schwann-cell-derived exosomes: an insight into endothelial glycolysis.

BACKGROUND: Endothelial cell (EC)-driven intraneural revascularization (INRV) and Schwann cells-derived exosomes (SCs-Exos) both play crucial roles in peripheral nerve injury (PNI). However, the interplay between them remains unclear. We aimed to elucidate the effects and underlying mechanisms of SCs-Exos on INRV following PNI. RESULTS: We found that GW4869 inhibited INRV, as well as that normoxic SCs-Exos (N-SCs-Exos) exhibited significant pro-INRV effects in vivo and in vitro that were potentiated by hypoxic SCs-Exos (H-SCs-Exos). Upregulation of glycolysis emerged as a pivotal factor for INRV after PNI, as evidenced by the observation that 3PO administration, a glycolytic inhibitor, inhibited the INRV process in vivo and in vitro. H-SCs-Exos more significantly enhanced extracellular acidification rate/oxygen consumption rate ratio, lactate production, and glycolytic gene expression while simultaneously suppressing acetyl-CoA production and pyruvate dehydrogenase E1 subunit alpha (PDH-E1α) expression than N-SCs-Exos both in vivo and in vitro. Furthermore, we determined that H-SCs-Exos were more enriched with miR-21-5p than N-SCs-Exos. Knockdown of miR-21-5p significantly attenuated the pro-glycolysis and pro-INRV effects of H-SCs-Exos. Mechanistically, miR-21-5p orchestrated EC metabolism in favor of glycolysis by targeting von Hippel-Lindau/hypoxia-inducible factor-1α and PDH-E1α, thereby enhancing hypoxia-inducible factor-1α-mediated glycolysis and inhibiting PDH-E1α-mediated oxidative phosphorylation. CONCLUSION: This study unveiled a novel intrinsic mechanism of pro-INRV after PNI, providing a promising therapeutic target for post-injury peripheral nerve regeneration and repair.

Molecular mechanism of microRNA-21 promoting Schwann cell proliferation and axon regeneration during injured nerve repair.

At present, the functional recovery after nerve injury is not satisfactory in clinical practice. The aim of this study was to explore the molecular mechanism of miR-21 promoting Schwann cells (SC) proliferation and axon regeneration after peripheral nerve injury, providing a theoretical basis for injured nerve repair. Nerve injury models were constructed to determine the expression of miR-21 in the injured nerve by Quantitative Real-Time PCR (qRT-PCR). After miR-21 over-expression SC (mimic-miR-21) group, control SC (control-miR-21) group and blank SC (RSC96) group were constructed, SC proliferation was determined by CCK-8, cell cycle was analysed by flow cytometry, dorsal root ganglion neuron (DRGn) axon regeneration was observed after DRGn was cultured with SCs for 7 days, the expressions of TGFßI, TIMP3, EPHA4 as well as apoptosis-related proteins caspase-3 and caspase-9 were detected by qRT-PCR and Western blot in the three groups, respectively. Target genes were confirmed by dual-luciferase reporter gene assay. The expressions of TGFßI, TIMP3 and EPHA4 were assessed by immunofluorescence in vivo. qRT-PCR indicated that miR-21 expression was significantly higher in the model group than in the sham operation and blank groups. SC proliferation index (PI) was significantly higher, the apoptosis rate was significantly lower, the axon was significantly longer, and mRNA and protein expressions of TGFßI, TIMP3, EPHA4 as well as apoptosis-related proteins caspase-3 and caspase-9 were significantly lower in the mimic-miR-21 group than in the control-miR-21 and RSC96 groups. The double luciferase assay confirmed that TGFßI, TIMP3 and EPHA4 were potential target genes of miR-21. In vivo immunofluorescence also indicated that expressions of TGFßI, TIMP3, EPHA4 were lower in the mimic-miR-21 group than in the control-miR-21 and RSC96 groups. We conclude that during injured peripheral nerve repair, miRNA-21 plays an important role in promoting SC proliferation and axon regeneration by regulating TGFßI, TIMP3 and EPHA4 target genes.

[Diagnostic Value of Combining Permeability with T1 Perfusion Parameters in Quantitative Dynamic Contrast-enhanced Magnetic Resonance Imaging for Glioma Grading].

UNLABELLED: OBJECTIVE To investigate the diagnostic value of combining permeability with T1 perfusion parameters in quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in glioma grading. METHODS: Magnetic resonance imaging was performed in 16 patients with high grade gliomas (HGG) and 12 patients with low grade gliomas(LGG) confirmed by pathology. The permeability was quantitatively analyzed and the T1 perfusion parameters of the tumor were calculated by the pharmacokinetic model,including volume transfer constant (K(trans)),volume fraction of extravascular extracellular space (ve),reflux constant (kep),fractional plasma volume (vp),cerebral blood flow (CBF),cerebral blood volume (CBV),and mean transit time (MTT). A t-test was used to calculate the statistical significance of quantitative analysis parameters between HGG and LGG. The receiver operating characteristic curve analysis was also performed for evaluating the sensitivity,specificity,and area under curve (AUC) of the permeability parameters and perfusion parameters and the combination of these parameters. RESULTS: The differences of the K(trans),ve,CBF,and CBV values [(0.276<0.164)/min vs. (0.084<0.044)/min;0.486<0.191 vs. 0.274<0.132;(1.755<1.164)ml/(g·min) vs. (0.761<0.625) ml/(g·min);(0.204<0.101) ml/g vs. (0.115<0.097)ml/g] were statistically significant (t=3.934,3.293,2.672,2.338,P<0.05) between HGG and LGG. The differences of the kep,vp, and MTT value [(1.632<1.204)/min vs. (1.537<1.194)/min;0.114<0.107 vs. 0.055<0.039;(0.128<0.070)min vs. (0.145<0.066)min] were not statistically significant (t=0.208,1.823,0.688,P>0.05). When the K(trans) value was 0.105/min,the AUC was the largest (0.919) by the single parameter in glioma grading,and meanwhile the sensitivity and specificity were 87.5% and 83.3%,respectively. When the ve-CBF value was 0.631,the AUC was the largest (0.974) by the multiple parameter,and meanwhile the sensitivity and specificity were 93.7% and 100.0%,respectively. CONCLUSION: Combining permeability with perfusion parameters in quantitative DCE-MRI can improve the accuracy of the glioma grading.

Survival prediction using apparent diffusion coefficient values in recurrent glioblastoma under bevacizumab treatment: an updated systematic review and meta-analysis

Bevacizumab is a common strategy for the treatment of recurrent glioblastoma. Survival status is a crucial issue for patients with recurrent glioblastoma, and the apparent diffusion coefficient (ADC) values of the lower Gaussian curve have been reported to have the potential to predict prognosis in recurrent glioblastoma. In the present study, we aimed to clarify the survival prediction of ADC values in patients with recurrent glioblastoma receiving bevacizumab treatment through a systematic review and meta-analysis of randomized clinical trials, comparing ADC values higher than the cut-off values with those lower than the cut-off values to determine which type of ADC values can be associated with significant survival benefits. Different survival indicators were analyzed, including overall survival (OS) and progression-free survival (PFS). Ten studies with a total of 782 patients with recurrent glioblastoma were included. The focused outcomes were OS and PFS. Our results showed that ADC values lower than the cut-off values were associated with significant benefits for OS status compared with ADC values higher than the cut-off values. Similar significant benefits were observed for PFS. The meta-analysis results suggest that ADC values lower than the cut-off values might be associated with significant benefits for OS and PFS when compared with ADC values higher than the cut-off values. However, bias in relation to the different stages of recurrent glioblastoma and different types, doses, and regimens of bevacizumab should not be ignored.

Proteomic and metabolomic analyses illustrate the mechanisms of expression of the O6 -methylguanine-DNA methyltransferase gene in glioblastoma.

AIM: Glioblastoma (GBM) has been reported to be the most common high-grade primary malignant brain tumor in clinical practice and has a poor prognosis. O6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation has been related to prolonged overall survival (OS) in GBM patients after temozolomide treatment. METHODS: Proteomics and metabolomics were combined to explore the dysregulated metabolites and possible protein expression alterations in white matter (control group), MGMT promoter unmethylated GBM (GBM group) or MGMT promoter methylation positive GBM (MGMT group). RESULTS: In total, 2745 upregulated and 969 downregulated proteins were identified in the GBM group compared to the control group, and 131 upregulated and 299 downregulated proteins were identified in the MGMT group compared to the GBM group. Furthermore, 131 upregulated and 299 downregulated metabolites were identified in the GBM group compared to the control group, and 187 upregulated and 147 downregulated metabolites were identified in the MGMT group compared to the GBM group. The results showed that 94 upregulated and 19 downregulated proteins and 20 upregulated and 16 downregulated metabolites in the MGMT group were associated with DNA repair. KEGG pathway enrichment analysis illustrated that the dysregulated proteins and metabolites were involved in multiple metabolic pathways, including the synthesis and degradation of ketone bodies, amino sugar and nucleotide sugar metabolism. Moreover, integrated metabolomics and proteomics analysis was performed, and six key proteins were identified in the MGMT group and GBM group. Three key pathways were recognized as potential biomarkers for recognizing MGMT promoter unmethylated GBM and MGMT promoter methylation positive GBM from GBM patient samples, with areas under the curve of 0.7895, 0.7326 and 0.7026, respectively. CONCLUSION: This study provides novel mechanisms to understand methylation in GBM and identifies some biomarkers for the prognosis of two different GBM types, MGMT promoter unmethylated or methylated GBM, by using metabolomics and proteomics analyses.

Hematoma Enlargement After Intracerebral Hemorrhage: A Bibliometric Analysis.

OBJECTIVE: To conduct a quantitative analysis of published studies on hematoma enlargement after intracerebral hemorrhage. METHODS: Studies on hematoma enlargement after cerebral hemorrhage were retrieved from the Web of Science database on June 30, 2023. Microsoft Excel, VOSviewer, and CiteSpace software were used for bibliometric analysis and visualization, focusing on the quantitative characteristics of the literature. RESULTS: A total of 444 articles were published in 161 journals, with 2161 authors from 41 countries and 717 institutions. The most published authors, countries, and institutions were Goldstein, the USA, and Massachusetts General Hospital. Stroke published the most studies, but the average citation number per year of Lancet Neurology far exceeded that of other journals. The research field of hematoma enlargement is mainly divided into 3 focuses, including mechanisms, identification (computed tomography signs, predictive models), and treatment (hemostasis, antihypertensive therapy). Most bursts in publication number have been since 2010, where the highest burst was from research on spot signs, and the latest burst focused on tranexamic acid. Treatment using tranexamic acid based on different computed tomography signs is a focus of current research, but the effectiveness still requires further exploration. CONCLUSIONS: This bibliometric analysis analyzed the research framework and hotspots on hematoma enlargement after cerebral hemorrhage, which can help researchers better understand this field and provide potential suggestions for collaborations and research.

Impact of premorbid hypertension and renin-angiotensin-aldosterone system inhibitors on the severity of aneurysmal subarachnoid haemorrhage: a multicentre study.

BACKGROUND: Hypertension is widely acknowledged as a significant contributory factor to the heightened risk of intracranial aneurysm rupture. Nevertheless, the impact of hypertension management on the outcomes subsequent to aneurysmal subarachnoid haemorrhage (aSAH), particularly concerning the severity of aSAH, remains an underexplored area. METHODS: We conducted a retrospective analysis using data from a prospectively multicentre cohort of 4545 patients with aSAH in China. Premorbid hypertension status and the utilisation of antihypertensive medications prior to admission were set as key exposure factors. The primary outcomes encompassed unfavourable clinical grading scales observed on admission. Employing multivariable logistic regression, we explored the association between premorbid hypertension status, preadmission use of renin-angiotensin-aldosterone system (RAAS) inhibitors and unfavourable clinical grading scales. RESULTS: In comparison to patients with normal blood pressure, only uncontrolled hypertension demonstrated a significant and independent association with an elevated risk of poor outcomes on the Hunt-Hess scale (OR=1.799, 95% CI 1.413 to 2.291, p<0.001) and the World Federation of Neurological Surgeons (WFNS) scale (OR=1.721, 95% CI 1.425 to 2.079, p<0.001). Furthermore, the antecedent use of RAAS inhibitors before admission was markedly and independently linked to a diminished risk of adverse outcomes on the Hunt-Hess scale (OR=0.653, 95% CI 0.430 to 0.992, p=0.046) and the WFNS scale (OR=0.656, 95% CI 0.469 to 0.918, p=0.014). CONCLUSIONS: Uncontrolled hypertension markedly elevates the risk of adverse clinical outcomes following an aSAH. Conversely, the preadmission utilisation of RAAS inhibitors demonstrates a noteworthy association with a favourable clinical outcome after aSAH.

Oral Curcumin-Thioketal-Inulin Conjugate Micelles against Radiation-Induced Enteritis.

Radiation-induced enteritis is an unavoidable complication associated with pelvic tumor radiotherapy, significantly influencing the prognosis of cancer patients. The limited availability of commercial gastrointestinal radioprotectors in clinical settings poses a substantial challenge in preventing radiation enteritis. Despite the inherent radioprotective characteristics of Cur in vitro, its poor solubility in water, instability, and low bioavailability lead to inferior therapeutic effects in vivo. Herein, we developed novel ROS-responsive micelles (CTI) from inulin and curcumin, aimed at mitigating radiation enteritis. CTI micelles had excellent solubility and stability. Importantly, CTI improved the cytotoxicity and bioavailability of curcumin, thereby showing enhanced effectiveness in neutralizing ROS induced by radiation, safeguarding against DNA damage, and reducing radiation-induced cellular mortality. Moreover, in a radiation enteritis mice model, CTI not only alleviated severe radiation-induced intestinal injury but also improved redox-related indicators and reduced inflammatory cytokine expression. Furthermore, CTI effectively increased gut microbiota abundance and maintained gut homeostasis. In conclusion, CTI could be a promising candidate for the clinical management of radiation enteritis. Our study provides a new perspective for radioprotection using natural antioxidants.

Mechanism of Jizhi syrup's prevention and treatment of acute bronchitis based on LPS-iNOS inflammatory mediators' signalling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Jizhi syrup (JZTJ) is composed of eight medicinal herbs, including Houttuynia cordata, Fagopyrum dibotrys, Ilex chinensis, Ephedra sinica, Aster tataricus, Peucedanum praeruptorum, Citrus aurantium and Glycyrrhiza uralensis. It is mainly used for coughing caused by exogenous wind heat. Symptoms include fever, aversion to cold, chest and diaphragm tightness, cough and sore throat; and acute bronchitis and acute exacerbation of chronic bronchitis with the above symptoms. PURPOSE: This study aimed to preliminary analyse the chemical components in the liposoluble part of JZTJ, evaluate the anti-inflammatory effect of JZTJ by using six animal and cell models and predict the target and mechanism of acute bronchitis prevention and treatment with JZTJ. METHODS: The chemical components in the liposoluble fraction of JZTJ (extracted by cyclohexane) were quantitatively analysed using gas chromatography-mass spectrometry (GC-MS). Classic non-specific inflammation models and acute bronchitis models were established to systematically evaluate the anti-inflammatory effect of JZTJ. The anti-inflammatory intensity and characteristics of three doses of JZTJ were comprehensively compared on the basis of principal component analysis method at the cellular and overall animal levels. By using lipopolysaccharides (LPSs) as modelling factors, a RAW264.7 macrophage inflammatory response model and a rat acute bronchitis model were created to study the effect of JZTJ on the in-vitro and - vivo LPS-iNOS-inflammatory mediators' inflammatory signalling pathway to reveal the mechanism of acute bronchitis prevention and treatment by JZTJ at the levels of genes, proteins, and inflammatory mediators. RESULTS: Seventeen alkane and ester compounds were preliminarily qualitatively identified from the lipid soluble fraction of JZTJ: dibutyl phthalate, tetradecane, ridecane, n-hexadecanoic acid, pentadecane, n-decanoic acid, 2,6,10,14,18,22-tetracosahexaene, 2,6,10,15,19,23-hexamethyl-(all-E)-; phenol, 2,2'-methylenebis[6-(1,1-dimethylethyl)-4-methyl-; hexadecane. JZTJ has a significant inhibitory effect on acute non-specific inflammation, specifically inhibiting 'xylene-induced ear swelling in mice', 'acetic acid-induced increased permeability of abdominal capillaries in mice' and 'egg white-induced foot swelling in rats'. The above effects are most evident in high doses, followed by medium doses, whereas low doses have poorer or no effects. JZTJ can prevent and treat acute bronchitis induced by LPS in mice and rats, significantly improve the pathological changes in patchy interstitial and alveolar bleeding with excessive neutrophil infiltration and inhibit the release of inflammatory mediators by LPS-induced RAW264.7 macrophages. Its mechanism of action may be by downregulating the phosphorylation level of p-ERK1/2 protein, thereby inhibiting inducible nitric oxide synthase (iNOS) mRNA, tumour necrosis factor (TNF)-α MRNA and IL-1ß. The expression levels of genes, such as mRNA and IL-6 mRNA, thereby reducing iNOS, TNF-α and IL-1ß. The expression of proteins in the cytoplasm of lung and bronchial tissue cells reduced the release of downstream inflammatory mediators NO and IL-6. CONCLUSION: Preliminary analysis of the chemical components in the lipid soluble fraction of JZTJ can lay the foundation for subsequent research on its effective components. Evaluating the anti-inflammatory effect of JZTJ is helpful for further research on its mechanism of action. The anti-inflammatory effects are exerted by regulating the inflammatory signalling pathway of LPS-iNOS inflammatory mediators, providing a scientific basis for their clinical application.

Improving the diagnostic performance of computed tomography angiography for intracranial large arterial stenosis by a novel super-resolution algorithm based on multi-scale residual denoising generative adversarial network.

BACKGROUND: Computed tomography angiography (CTA) is very popular because it is characterized by rapidity and accessibility. However, CTA is inferior to digital subtraction angiography (DSA) in the diagnosis of intracranial artery stenosis or occlusion. DSA is an invasive examination, so we optimized the quality of cephalic CTA images. METHODS: We used 5000 CTA images to train multi-scale residual denoising generative adversarial network (MRDGAN). And then 71 CTA images with intracranial large arterial stenosis were treated by Super-Resolution based on Generative Adversarial Network (SRGAN), Enhanced Super-Resolution based on Generative Adversarial Network (ESRGAN) and post-trained MRDGAN, respectively. Peak signal-to-noise ratio (PSNR) and structural similarity index measurement (SSIM) of the SRGAN, ESRGAN, MRDGAN and original CTA images were measured respectively. The qualities of MRDGAN and original images were visually assessed using a 4-point scale. The diagnostic coherence of digital subtraction angiography (DSA) with MRDGAN and original images was analyzed. RESULTS: The PSNR was significantly higher in the MRDGAN CTA images (35.96 ± 1.51) than in the original (31.51 ± 1.43), SRGAN (25.75 ± 1.18) and ESRGAN (30.36 ± 1.05) CTA images (all P < 0.001). The SSIM was significantly higher in the MRDGAN CTA images (0.95 ± 0.02) than in the SRGAN (0.88 ± 0.03) and ESRGAN (0.90 ± 0.02) CTA images (all P < 0.01). The visual assessment was significantly higher in the MRDGAN CTA images (3.52 ± 0.58) than in the original CTA images (2.39 ± 0.69) (P < 0.05). The diagnostic coherence between MRDGAN and DSA (κ = 0.89) was superior to that between original images and DSA (κ = 0.62). CONCLUSION: Our MRDGAN can effectively optimize original CTA images and improve its clinical diagnostic value for intracranial large artery stenosis.

Down-regulation miR-146a-5p in Schwann cell-derived exosomes induced macrophage M1 polarization by impairing the inhibition on TRAF6/NF-κB pathway after peripheral nerve injury.

BACKGROUND: Both Schwann cell-derived exosomes (SC-Exos) and macrophagic sub-phenotypes are closely related to the regeneration and repair after peripheral nerve injury (PNI). However, the crosstalk between them is less clear. OBJECTIVE: We aim to investigate the roles and underlying mechanisms of exosomes from normoxia-condition Schwann cell (Nor-SC-Exos) and from post-injury oxygen-glucose-deprivation-condition Schwann cell in regulating macrophagic sub-phenotypes and peripheral nerve injury repair. METHOD: Both Nor-SC-Exos and OGD-SC-Exos were extracted through ultracentrifugation, identified by transmission electron microscopy (TEM), Nanosight tracking analysis (NTA) and western blotting. High-throughput sequencing was performed to explore the differential expression of microRNAs in both SC-Exos. In vitro, RAW264.7 macrophage was treated with two types of SC-Exos, M1 macrophagic markers (IL-10, Arg-1, TGF-ß1) and M2 macrophagic markers (IL-6, IL-1ß, TNF-α) were detected by enzyme-linked Immunosorbent Assay (ELISA) or qRT-PCR, and the expression of CD206, iNOS were detected via cellular immunofluorescence (IF) to judge macrophage sub-phenotypes. Dorsal root ganglion neurons (DRGns) were co-cultured with RAW264.7 cells treated with Nor-SC-Exos and OGD-SC-Exos, respectively, to explore their effect on neuron growth. In vivo, we established a sciatic nerve crush injury rat model. Nor-SC-Exos and OGD-SC-Exos were locally injected into the injury site. The mRNA expression of M1 macrophagic markers (IL-10, Arg-1, TGF-ß1) and M2 macrophagic markers (IL-6, IL-1ß, TNF-α) were detected by qRT-PCR to determine the sub-phenotype of macrophages in the injury site. IF was used to detect the expression of MBP and NF200, reflecting the myelin sheath and axon regeneration, and sciatic nerve function index (SFI) was measured to evaluate function repair. RESULT: In vitro, Nor-SC-Exos promoted macrophage M2 polarization, increased anti-inflammation factors secretion, and facilitated axon elongation of DRGns. OGD-SC-Exos promoted M1 polarization, increased pro-inflammation factors secretion, and restrained axon elongation of DRGns. High-throughput sequencing and qRT-PCR results found that compared with Nor-SC-Exos, a shift from anti-inflammatory (pro-M2) to pro-inflammatory (pro-M1) of OGD-SC-Exos was closely related to the down-regulation of miR-146a-5p and its decreasing inhibition on TRAF6/NF-κB pathway after OGD injury. In vivo, we found Nor-SC-Exos and miR-146a-5p mimic promoted regeneration of myelin sheath and axon, and facilitated sciatic function repair via targeting TRAF6, while OGD-SC-Exos and miR-146a-5p inhibitor restrained them. CONCLUSION: Our study confirmed that miR-146a-5p was significantly decreased in SC-Exos under the ischemia-hypoxic microenvironment of the injury site after PNI, which mediated its shift from promoting macrophage M2 polarization (anti-inflammation) to promoting M1 polarization (pro-inflammation), thereby limiting axonal regeneration and functional recovery.

The CDK inhibitor AT7519 inhibits human glioblastoma cell growth by inducing apoptosis, pyroptosis and cell cycle arrest.

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor with a poor median survival of less than 15 months. However, clinical strategies and effective therapies are limited. Here, we found that the second-generation small molecule multi-CDK inhibitor AT7519 is a potential drug for GBM treatment according to high-throughput screening via the Approved Drug Library and Clinical Compound Library (2718 compounds). We found that AT7519 significantly inhibited the cell viability and proliferation of U87MG, U251, and patient-derived primary GBM cells in a dose-dependent manner. Furthermore, AT7519 also inhibited the phosphorylation of CDK1/2 and arrested the cell cycle at the G1-S and G2-M phases. More importantly, AT7519 induced intrinsic apoptosis and pyroptosis via caspase-3-mediated cleavage of gasdermin E (GSDME). In the glioblastoma intracranial and subcutaneous xenograft assays, tumor volume was significantly reduced after treatment with AT7519. In summary, AT7519 induces cell death through multiple pathways and inhibits glioblastoma growth, indicating that AT7519 is a potential chemical available for GBM treatment.

Knockdown of BATF3 Inhibits Gastric Cancer Cell Growth and Radioresistance via S1PR1/STAT3 Pathway.

OBJECTIVE: Gastric cancer is one of the most common and deadly cancers worldwide. Basic leucine zipper transcription factor ATF-like 3 (BATF3) plays a key role in tumor immunity. However, the function of BATF3 in gastric cancer remains unclear. Here, we demonstrated BATF3 positively regulated proliferation and radioresistance of gastric cancer cells by regulating S1PR1/STAT3 pathway. METHODS: The RNA-seq analyzed the gene expression by UALCAN web portal and Tumor Immune Estimation Resource. RT-qPCR and western blot was performed to verify BATF3 expression in gastric cancer cells. The assays of CCK-8, EdU incorporation and colony formation were used to analyze cell proliferation, and radioresistance in AGS and MKN45 cells. Flow cytometry was used to detect the cell apoptosis of AGS and MKN45 in treatment with si-BATF3 or radiation. Finally, western blot was performed to measure the expression of cell apoptosis-related modules including Bax, cleaved-caspase3, cleaved-PARP and assess the regulation of S1PR1/STAT3 pathway. RESULTS: BATF3 expression was upregulated in gastric cancer cells. Knockdown of BATF3 suppressed proliferation, radioresistance but promoted the radiation-induced apoptosis of gastric cancer cells through positively regulating S1PR1 expression and STAT3 phosphorylation. CONCLUSIONS: Knockdown of BATF3 inhibits gastric cancer cell growth and radioresistance via S1PR1/STAT3 pathway. BATF3 would become a potential diagnostic indicator for gastric cancer and target of therapeutic treatment.

Identification of ubiquitin-specific protease 32 as an oncogene in glioblastoma and the underlying mechanisms.

Glioblastoma (GBM) patients present poor prognosis. Deubiquitination by deubiquitinating enzymes (DUBs) is a critical process in cancer progression. Ubiquitin-specific proteases (USPs) constitute the largest sub-family of DUBs. Evaluate the role of USP32 in GBM progression and provide a potential target for GBM treatment. Clinical significance of USP32 was investigated using Gene Expression Omnibus databases. Effects of USP32 on cell growth and metastasis were studied in vitro and in vivo. Differentially expressive genes between USP32-knockdown U-87 MG cells and negative control cells were detected using RNA sequencing and used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomic pathway enrichment analyses. Finally, RT-qPCR was used to validate the divergent expression of genes involved in the enriched pathways. USP32 was upregulated in GBM patients, being correlated to poor prognosis. USP32 downregulation inhibited cell growth and metastasis in vitro. Furthermore, USP32 knockdown inhibited tumorigenesis in vivo. In addition, UPS32 was identified as a crucial regulator in different pathways including cell cycle, cellular senescence, DNA replication, base excision repair, and mismatch repair pathways. USP32 acts as an oncogene in GBM through regulating several biological processes/pathways. It could be a potential target for GBM treatment.

Effect of Renin-Angiotensin-Aldosterone System Inhibitors on the Rupture Risk Among Hypertensive Patients With Intracranial Aneurysms.

BACKGROUND: Mounting experimental evidence supports the concept that the RAAS (renin-angiotensin-aldosterone system) is involved in the pathogenesis of intracranial aneurysm rupture. However, whether RAAS inhibitors could reduce the rupture risk of intracranial aneurysms remains unclear. METHODS: We performed a chart review of a multicenter, prospectively maintained database of 3044 hypertensive patients with intracranial aneurysms from 20 medical centers in China. The patients were separated into ruptured and unruptured groups. Univariable and multivariable logistical regression analyses were performed to determine the association between the use of RAAS inhibitors and the rupture risk. Sensitivity analyses and subgroup analyses were performed to verify the robustness of the results. RESULTS: In multivariable analyses, female sex, passive smoking, uncontrolled, or unmonitored hypertension, use of over 2 antihypertensive medications, RAAS inhibitors use, antihyperglycemic agents use, hyperlipidemia, ischemic stroke, and aneurysmal location were independently associated with the rupture risk. The use of RAAS inhibitors was significantly associated with a reduced rupture risk compared with the use of non-RAAS inhibitors (odds ratio, 0.490 [95% CI, 0.402-0.597]; P=0.000). Compared with the use of non-RAAS inhibitors, the use of ACE (angiotensin-converting enzyme) inhibitors (odds ratio, 0.559 [95% CI, 0.442-0.709]; P=0.000) and use of ARBs (angiotensin receptor blockers; odds ratio, 0.414 [95% CI, 0.315-0.542]; P=0.000) were both significantly associated with a reduced rupture risk. The negative association of the rupture risk with RAAS inhibitors was consistent across 3 analyzed data and the predefined subgroups (including controlled hypertension). CONCLUSIONS: The use of RAAS inhibitors was significantly associated with a decreased rupture risk independent of blood pressure control among hypertensive patients with intracranial aneurysms.

Multi-Source and Multi-Representation Adaptation for Cross-Domain Electroencephalography Emotion Recognition.

Due to the non-invasiveness and high precision of electroencephalography (EEG), the combination of EEG and artificial intelligence (AI) is often used for emotion recognition. However, the internal differences in EEG data have become an obstacle to classification accuracy. To solve this problem, considering labeled data from similar nature but different domains, domain adaptation usually provides an attractive option. Most of the existing researches aggregate the EEG data from different subjects and sessions as a source domain, which ignores the assumption that the source has a certain marginal distribution. Moreover, existing methods often only align the representation distributions extracted from a single structure, and may only contain partial information. Therefore, we propose the multi-source and multi-representation adaptation (MSMRA) for cross-domain EEG emotion recognition, which divides the EEG data from different subjects and sessions into multiple domains and aligns the distribution of multiple representations extracted from a hybrid structure. Two datasets, i.e., SEED and SEED IV, are used to validate the proposed method in cross-session and cross-subject transfer scenarios, experimental results demonstrate the superior performance of our model to state-of-the-art models in most settings.

Postoperative neovascularization, cerebral hemodynamics, and clinical prognosis between combined and indirect bypass revascularization procedures in hemorrhagic moyamoya disease.

OBJECTIVE: We evaluated what few studies emphasized the postoperative collateral formation and cerebral hemodynamics of hemorrhagic moyamoya disease (MMD). METHODS: Hemorrhagic MMD patients treated surgically were retrospectively collected and dichotomized into combined bypass (CB) and indirect bypass (IB) groups. CB used superficial temporal artery-to-middle cerebral artery anastomosis combined with encephaloduroarteriomyosynangiosis (STA-MCA+EDAMS), and IB used encephaloduroarteriomyosynangiosis (EDAMS) for revascularization. Postoperative complications and clinical prognosis, as well as pre- and post-operative Modified Rankin Scale (mRS), collateral circulation status, and cerebral hemodynamics were observed and compared between the CB and IB groups. RESULTS: A total of 37 patients with hemorrhagic MMD were identified. Of the 68 cerebral hemispheres, 47(69.1%) were combined revascularization, and the rest were indirect. During an average follow-up of 16.5 ± 8.7 months, the recurrent stroke events were significantly lower, as well as having a postoperative mRS scores≤ 2. A satisfactory postoperative collateral formation, and an improved dilation or extension of the anterior choroidal/posterior communication artery (AchA/PcoA) were significantly higher in the CB group than in the IB group (all P < .05). Compared with preoperative cerebral hemodynamics, relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), mean transit time (MTT), and relative time to peak (rTTP) in the CB group; rCBF, rCBV, and MTT in the IB group were significantly improved (all P < .001). The CB group's postoperative rCBF was significantly improved compared with the IB group (P < .001). CONCLUSIONS: STA-MCA bypass combined with EDAMS can obtain better postoperative collateral formation, cerebral hemodynamics, and clinical prognosis than EDAMS alone.

Superficial Temporal Artery-Posterior Cerebral Artery Bypass for the Treatment of Chronic Basilar Artery Occlusion.

OBJECTIVE: To investigate the effect of superficial temporal artery-posterior cerebral artery (STA-PCA) bypass on chronic basilar artery occlusion (CBAO). METHODS: A total of 4 patients who underwent STA-PCA bypass between January 2018 and October 2019 were enrolled in this study. Cerebral blood perfusion, ischemic events, STA diameter and blood flow changes, modified Rankin scale score (mRS), and National Institutes of Health Stroke Scale (NIHSS) score changes were recorded before and after bypass surgery. RESULTS: The average time from basilar artery occlusion (confirmed by cerebral angiography or computed tomography angiography) to operation was 76 ± 38.89 days (range: 30-120 days). Average scores on the NIHSS were 6.8 ± 1.26 (5-8) and 5.2 ± 2.06 (3-7) before and after treatment, respectively. mRS scores averaged 1.8 ± 0.5 (1-2) and 1.5 ± 0.58 (1-2) points, respectively. There were no obvious complications or further stroke during the follow-up. The STA diameter and flow rate were significantly increased at 12 months after operation (P < 0.05). CONCLUSIONS: STA-PCA bypass can improve cerebral blood flow perfusion in CBAO patients. The diameter and flow of the superficial temporal artery can be increased to meet the demand of blood supply.

Downregulation of phosphoglycerate mutase 5 improves microglial inflammasome activation after traumatic brain injury.

Traumatic brain injury (TBI) is considered as the most common cause of disability and death, and therefore an effective intervention of cascade pathology of secondary brain injury promptly can be a potential therapeutic direction for TBI prognosis. Further study of the physiological mechanism of TBI is urgent and important. Phosphoglycerate mutase 5 (Pgam5), a mitochondrial protein, mediate mitochondrial homeostasis, cellular senescence, and necroptosis. This study evaluated the effects of Pgam5 on neurological deficits and neuroinflammation of controlled cortical impact-induced TBI mouse model in vivo and LPS + ATP-induced microglia model in vitro. Pgam5 was overexpressed post-TBI. Pgam5 depletion reduced pyroptosis-related molecules and improved microglia activation, neuron damage, tissue lesion, and neurological dysfunctions in TBI mice. RNA-seq analysis and molecular biology experiments demonstrated that Pgam5 might regulate inflammatory responses by affecting the post-translational modification and protein expression of related genes, including Nlrp3, caspase1, Gsdmd, and Il-1ß. In microglia, Pgam5-sh abrogated LPS + ATP-induced Il-1ß secretion through Asc oligomerization-mediated caspase-1 activation, which was independent of Rip3. The data demonstrate the critical role Pgam5 plays in nerve injury in the progression of TBI, which regulates Asc polymerization and subsequently caspase1 activation, and thus reveals a fundamental mechanism linking microglial inflammasome activation to Asc/caspase1-generated Il-1ß-mediated neuroinflammation. Thus, our data indicate Pgam5 worsens physiological and neurological outcomes post-TBI, which may be a potential therapeutic target to improve neuroinflammation after TBI.

Association Between Body Mass Index and Intracranial Aneurysm Rupture: A Multicenter Retrospective Study.

Background and Aims: It has recently emerged the concept of "obesity paradox," a term used to describe an inverse association between obesity and clinical outcomes in cardiovascular diseases and stroke. The purpose of this study was to investigate the association between body mass index (BMI) and the risk of intracranial aneurysm rupture. Methods: In this study, we conducted a retrospective analysis of a prospectively maintained database of patients with intracranial aneurysms from 21 medical centers in China. A total of 3,965 patients with 4,632 saccular intracranial aneurysms were enrolled. Patients were separated into unruptured (n = 1,977) and ruptured groups (n = 1,988). Univariable and multivariable logistic regression analyses were performed to determine the association between BMI and intracranial aneurysm rupture. Results: Compared to the patients with normal BMI (18.5 to < 24.0 kg/m2), the odds of intracranial aneurysm rupture were significantly lower in patients with BMI 24.0 to < 28.0 kg/m2 (OR = 0.745, 95% CI = 0.638-0.868, P = 0.000) and patients with BMI ≥ 28.0 kg/m2 (OR = 0.628, 95% CI = 0.443-0.890, P = 0.009). Low BMI (<18.0 kg/m2) was not associated with intracranial aneurysm rupture (OR = 0.894, 95% CI = 0.483-1.657, P = 0.505). For males, both the BMI 24.0 to < 28.0 kg/m2 (OR = 0.606, 95% CI = 0.469-0.784, P = 0.000) and the BMI ≥ 28.0 kg/m2 (OR = 0.384, 95% CI = 0.224-0.658, P = 0.001) were associated with a lower rupture risk, whereas the inverse association was not observed in females. Both the BMI 24.0 to < 28.0 kg/m2 (OR = 0.722 for aged 50-60y, 95% CI = 0.554-0.938, P = 0.015; OR = 0.737 for aged >60y, 95% CI = 0.586-0.928, P = 0.009) and the BMI ≥ 28.0 kg/m2 (OR = 0.517 for aged 50-60y, 95% CI = 0.281-0.950, P = 0.0034; OR = 0.535 for aged >60y, 95% CI = 0.318-0.899, P = 0.0018) was associated with a lower rupture risk in patients aged ≥50 years, whereas the association was not significant in patients aged <50 years. Conclusions: Increased BMI is significantly and inversely associated with saccular intracranial aneurysm rupture in males and patients aged ≥50 years.