Association of gender and age at onset with glucocerebrosidase associated Parkinson's disease: a systematic review and meta-analysis.

Glucocerebrosidase (GBA) gene has been proved to be a risk factor for the development of Parkinson's disease (PD). However, the gender effect in the prevalence of GBA-associated PD (GBA-PD) is still controversial. And there is no conclusion whether the age at onset (AAO) of PD is different between carriers and non-carriers of GBA. To clarify the association between gender and AAO in GBA-PD, we conducted a systematic review and meta-analysis. PubMed, Web of Science, and Embase were retrieved to obtain potentially related studies. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine the association between gender and GBA-PD. And the weighted mean difference (WMD) with 95% CIs was employed to assess the difference of AAO between carriers and non-carriers of GBA. A total of twenty-eight studies involving 16,488 PD patients were included in this meta-analysis. The results showed the prevalence of female patients was higher in GBA-PD [OR: 1.19, (95% CI, 1.07-1.32), P = 0.001]. Meanwhile, GBA carriers had younger age at PD onset than GBA non-carriers [WMD: 2.87, (95% CI, 2.48-3.27), P < 0.001]. Results of subgroup analysis showed the prevalence of women in GBA-PD was higher than men in North American and European PD patients, while the gender difference was not significant in other areas around the world, suggesting an ethnic specificity of gender effect for GBA-PD. Our results indicate the higher female prevalence with ethnic specificity and younger AAO of GBA carriers in GBA-PD.

A novel circular RNA, hsa_circ_0046701, promotes carcinogenesis by increasing the expression of miR-142-3p target ITGB8 in glioma.

In the present study, we identified a novel circular RNA (circRNA), hsa_circ_0046701, in glioma cells. We measured the expression of hsa_circ_0046701 using qRT-PCR in glioma tissues and cell lines, and explored its functions using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation, and Transwell assays. Luciferase reporter assays were performed to validate the correlation between microRNA miR-142-3p and hsa_circ_0046701 or integrin subunit beta 8 (ITGB8). The results showed that hsa_circ_0046701 was significantly upregulated in glioma tissues and cell lines, and knockdown of hsa_circ_0046701 inhibited cell proliferation and invasion. Luciferase reporter assays indicated that hsa_circ_0046701 functions as a sponge for miR-142-3p and regulates the expression of ITGB8. Subsequently, functional assays revealed that silencing of hsa_circ_0046701 could upregulate miR-142-3p, resulting in downregulation of ITGB8. The results demonstrated that the hsa_circ_0046701/miR-142-3p/ITGB8 axis might play critical regulatory roles in the pathogenesis and development of glioma.

Targeted suppression of chaperone-mediated autophagy by miR-320a promotes α-synuclein aggregation.

Chaperone-mediated autophagy (CMA) is involved in wild-type α-synuclein degradation in Parkinson's disease (PD), and LAMP2A and Hsc 70 have recently been indicated to be deregulated by microRNAs. To recognize the regularory role of miR-320a in CMA and the possible role in α-synuclein degradation, in the present study, we examined the targeting and regulating role of miR-320 in Hsc 70 expression. We first constructed an α-synuclein-overexpressed human neuroblastoma cell line, SH-SY5Y-Syn(+), stably over-expressing wild-type α-synuclein and sensitive to an autophagy inhibitor, which exerted no effect on the expression of LAMP2A and Hsc 70. Then we evaluated the influence on the CMA by miR-320a in the SH-SY5Y-Syn(+) cells. It was shown that miR-320a mimics transfection of specifically targeted Hsc 70 and reduced its expression at both mRNA and protein levels, however, the other key CMA molecule, LAMP2A was not regulated by miR-320a. Further, the reduced Hsc 70 attenuated the α-synuclein degradation in the SH-SY5Y-Syn(+) cells, and induced a significantly high level of α-synuclein accumulation. In conclusion, we demonstrate that miR-320a specifically targeted the 3' UTR of Hsc 70, decreased Hsc 70 expression at both protein and mRNA levels in α-synuclein-over-expressed SH-SY5Y cells, and resulted in significant α-synuclein intracellular accumulation. These results imply that miR-320a might be implicated in the α-synuclein aggravation in PD.

Dynamic Cross-Linking, Self-Healing, Antibacterial Hydrogel for Regenerating Irregular Cranial Bone Defects.

Given the widespread clinical demand, addressing irregular cranial bone defects poses a significant challenge following surgical procedures and traumatic events. In situ-formed injectable hydrogels are attractive for irregular bone defects due to their ease of administration and the ability to incorporate ceramics, ions, and proteins into the hydrogel. In this study, a multifunctional hydrogel composed of oxidized sodium alginate (OSA)-grafted dopamine (DO), carboxymethyl chitosan (CMCS), calcium ions (Ca2+), nanohydroxyapatite (nHA), and magnesium oxide (MgO) (DOCMCHM) was prepared to address irregular cranial bone defects via dynamic Schiff base and chelation reactions. DOCMCHM hydrogel exhibits strong adhesion to wet tissues, self-healing properties, and antibacterial characteristics. Biological evaluations indicate that DOCMCHM hydrogel has good biocompatibility, in vivo degradability, and the ability to promote cell proliferation. Importantly, DOCMCHM hydrogel, containing MgO, promotes the expression of osteogenic protein markers COL-1, OCN, and RUNX2, and stimulates the formation of new blood vessels by upregulating CD31. This study could provide meaningful insights into ion therapy for the repair of cranial bone defects.

Development and validation of radiomics models for the prediction of diagnosis of classic trigeminal neuralgia.

The study aims to develop a magnetic resonance imaging (MRI)-based radiomics model for the diagnosis of classic trigeminal neuralgia (cTN). This study involved 350 patients with cTN and 100 control participants. MRI data were collected retrospectively for all the enrolled subjects. The symptomatic side trigeminal nerve regions of patients and both sides of the trigeminal nerve regions of control participants were manually labeled on MRI images. Radiomics features of the areas labeled were extracted. Principle component analysis (PCA) and least absolute shrinkage and selection operator (LASSO) regression were utilized as the preliminary feature reduction methods to decrease the high dimensionality of radiomics features. Machine learning methods were established, including LASSO logistic regression, support vector machine (SVM), and Adaboost methods, evaluating each model's diagnostic abilities using 10-fold cross-validation. All the models showed excellent diagnostic ability in predicting trigeminal neuralgia. A prospective study was conducted, 20 cTN patients and 20 control subjects were enrolled to validate the clinical utility of all models. Results showed that the radiomics models based on MRI can predict trigeminal neuralgia with high accuracy, which could be used as a diagnostic tool for this disorder.

LncRNA SNHG25 Promotes Glioma Progression Through Activating MAPK Signaling.

Numerous studies indicated that long non-coding RNAs (lncRNAs) play critical roles in glioma initiation and progression. SNHG25 is a newly identified lncRNA. And the functional role and molecular mechanism of SNHG25 in glioma cells have not been investigated. In this study, we found that SNHG25 was upregulated in glioma cells and tissues. CCK-8, EDU, and colony formation assays demonstrated that SNHG25 knockdown markedly inhibited glioma cell proliferation. In vivo studies showed that SNHG25 knockdown significantly inhibited tumor growth. Further studies indicated that SNHG25 positively regulated MAP2K2 through sponging miR-579-5p. High expression of SNHG25 activated MAPK signaling through MAP2K2. These data suggest that SNHG25 is a potential target and biomarker for glioma.

HOTTIP downregulation reduces neuronal damage and microglial activation in Parkinson's disease cell and mouse models.

HOXA transcript at the distal tip (HOTTIP), a newly identified long noncoding RNA, has been shown to exhibit anti-inflammatory effects and inhibit oxygen-glucose deprivation-induced neuronal apoptosis. However, its role in Parkinson's disease (PD) remains unclear. 1-Methyl-4-phenylpyridium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were used to establish PD models in SH-SY5Y and BV2 cells and in C57BL/6 male mice, respectively. In vitro, after HOTTIP knockdown by sh-HOTTIP transfection, HOTTIP and FOXO1 overexpression promoted SH-SY5Y apoptosis, BV2 microglial activation, proinflammatory cytokine expression, and nuclear factor kappa-B and NACHT, LRR and PYD domains-containing protein 3 inflammasome activation. Overexpression of miR-615-3p inhibited MPP+-induced neuronal apoptosis and microglial inflammation and ameliorated HOTTIP- and FOXO1-mediated nerve injury and inflammation. In vivo, HOTTIP knockdown alleviated motor dysfunction in PD mice and reduced neuronal apoptosis and microglial activation in the substantia nigra. These findings suggest that inhibition of HOTTIP mitigates neuronal apoptosis and microglial activation in PD models by modulating miR-615-3p/FOXO1. This study was approved by the Ethics Review Committee of the Affiliated Hospital of Qingdao University, China (approval No. UDX-2018-042) in June 2018.

Association analysis of risk genes identified by SCHEMA with schizophrenia in the Chinese Han population.

BACKGROUND: Schizophrenia is a chronic brain disorder. Previously, the Schizophrenia Exome Sequencing Meta-analysis consortium identified 10 highest risk genes related to schizophrenia. This study aimed to analyze the relationship between the 10 highest risk genes identified by the SCHEMA and schizophrenia in a Chinese population. METHODS: A total of 225 variants in 10 genes were screened in a Chinese population of 6836 using a customized array. All variants were annotated through the Variant Effect Predictor tool, and the functional impacts of missense variants were assessed based on sorting intolerant from tolerant and PolyPhen-2 scores. The SHEsisPlus tool was used to analyze the association between risk genes and schizophrenia at the locus and gene levels. RESULTS: At the locus level, no missense variants significantly related to schizophrenia were found, but we detected three missense variants that appeared only in cases, including TRIO p. Arg1185Gln, RB1CC1 p. Arg1514Cys, and HERC1 p. Val4517Leu. At the gene level, five genes (TRIO, RB1CC1, HERC1, GRIN2A, and CACAN1G) with more than one variant analyzed were kept for the gene-level association analysis. Only the association between RB1CC1 and schizophrenia reached a significant level (OR = 1.634; 95% CI, 1.062-2.516; P = 0.025). CONCLUSION: In this study, we determined that RB1CC1 might be a risk gene for schizophrenia in the Chinese population. Our results provide new evidence for recognizing the correlation of these risk genes with the Chinese schizophrenia population.

Curcumin Inhibits HGF-Induced EMT by Regulating c-MET-Dependent PI3K/Akt/mTOR Signaling Pathways in Meningioma.

Meningiomas, which are the most common primary intracranial tumors, have highly aggressive cells in malignant cases. Due to its extensive antitumor effects, curcumin is widely used in experimental and clinical studies. However, the role of curcumin during the epithelial-mesenchymal transition (EMT) in meningioma has not been established. We found that curcumin blocks hepatocyte growth factor- (HGF-) induced proliferation, migration, invasion, and EMT of human malignant meningioma cells by regulating the PI3K/Akt/mTOR signaling pathway. In addition, treatment of human malignant meningioma cells with the tyrosine protein kinase (c-MET) inhibitor (SU11274) or the phosphoinositide 3-kinase (PI3K) inhibitor (LY294002) suppressed HGF-induced migration and EMT. Furthermore, we found that curcumin inhibited tumor growth and HGF-induced EMT in mice subjected to subcutaneous xenotransplantation. These findings indicate that HGF regulates EMT in human malignant meningioma cells through c-MET/PI3K/Akt/mTOR modulation. In conclusion, curcumin inhibits HGF-induced EMT by targeting c-MET and subsequently blocking the PI3K/Akt/mTOR pathway.

Profiles of immune infiltration and its relevance to survival outcome in meningiomas.

Tumor-infiltrating immune cells play a decisive part in prognosis and survival. Until now, previous researches have not made clear about the diversity of cell types involved in the immune response. The objective of this work was to confirm the composition of tumor-infiltrating immune cells and their correlation with prognosis in meningiomas based on a metagene approach (known as CIBERSORT) and online databases. A total of 22 tumor-infiltrating immune cells were detected to determine the relationship between the immune infiltration pattern and survival. The proportion of M2 macrophages was more abundant in 68 samples, reaching more than 36%. Univariate Cox regression analysis displayed that the proportion of dendritic cells was obviously related to prognosis. Hierarchical clustering analysis identified two clusters by the method of within sum of squares errors, which exhibited different infiltrating immune cell composition and survival. To summarize, our results indicated that proportions of tumor-infiltrating immune cells as well as cluster patterns were associated with the prognosis, which offered clinical significance for research of meningiomas.

An 85-Gene Coexpression Module for Progression of Hypertension-Induced Spontaneous Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) represents the most lethal form of stroke. We sought to identify potential genes that might contribute to progression of hypertension-induced spontaneous ICH (HIS-ICH). RNA-sequencing data set of cerebral vessel samples from HIS-ICH mice and normal mice was obtained from the Gene Expression Omnibus. Differential expression genes in HIS-ICH samples were obtained compared with normal samples followed by functional enrichment analysis. What is more, we explored the potential gene coexpression module (GCM) for HIS-ICH progression by using weighted gene coexpression network analysis. We further conducted protein-protein interaction network analysis for genes contained in GCM that was closely correlated with HIS-ICH to disclose their biological interactions. As a result, 554 genes were found to aberrantly express in HIS-ICH mice compared with normal mice, which were mainly associated with cancer-related pathways in addition to some well-known ICH-related pathways. A total of 28 GCMs were obtained, and darkturquoise module that contained 85 genes, which were closely associated with mitochondrion and hydrolase activity, was significantly correlated with HIS-ICH progression. Besides, we identified dense biological interactions among some genes in darkturquoise, such as Psma gene family and Hsp90a gene family. This study should shed new light on HIS-ICH progression and its treatment.

Kalirin-7 plays a neuroprotective role in Neuro-2A cells injured by oxygen-glucose deprivation and reperfusion through Rac1 activation.

OBJECTIVES: The study explored the neuroprotective role of Kalirin-7 (Kal-7) in Neuro-2A cells after oxygen-glucose deprivation and reperfusion (OGD/R) treatment. MATERIALS AND METHODS: The study used an OGD/R model of mouse Neuro-2A neuroblastoma cells in vitro. Cells were transfected with pCAGGS-Kal-7 to up-regulating kal-7. Then cell proliferation and apoptosis were respectively analyzed by Trypan blue exclusion method and flow cytometry. To examine the involvement of Rac1, cells were treated with Rac1-GTP inhibitor NSC23766 before treatment with OGD/R. Expressions of Bax, Bcl-2, Rac1, and down-stream targets of Rac1 were analyzed by Western blot. RESULTS: Kal-7 significantly decreased OGD/R induced cell apoptosis (P<0.01), but no significant effects were observed on cell proliferation. Kal-7 increased the expressions of apoptosis-related protein of Bcl-2 and Rac1, but decreased the expression of Bax in Neuro-2A cells stimulated to OGD/R. Rac1 was activated by Kal-7 due to the increased levels of its down-stream targets, p-p38 and p-PAK1. NSC23766 reduced the anti-apoptotic effect of Kal-7 as the enhanced apoptotic cell rate and increased Bax/Bcl-2 ratio. CONCLUSION: These findings suggest that the protective effects of Kal-7 against OGD/R injury in Neuro-2A cells were dependent in a Rac1 activation signaling.