LOC554202 contributes to chordoma progression by sponging miR-377-3p and up-regulating SMAD3.

Chordoma is a rare malignant bone tumor originating from the remnants of the notochord. Here, the role of long noncoding LOC554202 in chordoma progression and its associated mechanism were explored. Cell proliferation was analyzed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide and colony formation assays. Flow cytometry was conducted to analyze cell apoptosis rate. The migration and invasion of chordoma cells were analyzed by transwell migration and invasion assays and wound healing assays. A xenograft tumor model was established in nude mice to explore the role of LOC554202 in regulating tumor growth in vivo . The interaction between microRNA-377-3p (miR-377-3p) and LOC554202 or sekelsky mothers against d PP (SMAD) family member 3 (SMAD3) was verified by dual-luciferase reporter and RNA immunoprecipitation assays. The glycolytic rate of chordoma cells was analyzed using glucose assay kit, lactic acid kit and ApoSENSOR ADP/ATP ratio assay kit. LOC554202 expression was upregulated in chordoma tissues and cell lines. LOC554202 silencing suppressed the proliferation, migration and invasion and induced the apoptosis of chordoma cells. LOC554202 knockdown restrained xenograft tumor growth in vivo . miR-377-3p was confirmed as a target of LOC554202, and miR-377-3p silencing largely overturned LOC554202 knockdown-mediated anti-tumor effects in chordoma cells. miR-377-3p interacted with the 3' untranslated region (3'UTR) of SMAD3 and miR-377-3p overexpression-mediated antitumor effects in chordoma cells were largely attenuated by SMAD3 overexpression. LOC554202 could positively regulate SMAD3 expression by sponging miR-377-3p in chordoma cells. LOC554202 contributed to the glycolysis of chordoma cells by targeting binding to miR-377-3p/SMAD3 axis. LOC554202 facilitated the proliferation, migration, invasion and glycolysis and inhibited the apoptosis of chordoma cells by mediating miR-377-3p/SMAD3 axis.

Autophagy-deficiency in bone marrow mononuclear cells from patients with myasthenia gravis: a possible mechanism of pathogenesis.

Myasthenia gravis (MG) is a chronic autoimmune disorder resulting from autoantibodies against neuromuscular junction components. Research shows that this disease might be a primary bone marrow (BM) stem cell disorder. Autophagy protects the dynamics and homeostasis of the host cells by removing damaged mitochondria, protein aggregates and other intercellular materials. Dysfunctional autophagy is associated with autoimmune diseases. However, the autophagy activity and mechanisms in BM stem cell from MG patients remain largely uncharacterized. We evaluated the autophagy activity in bone marrow mononuclear cells (BM-MNCs) and the effects of autophagy on cell survival from patients with MG and healthy controls. Our results revealed that autophagy was significantly decreased in patients with MG before immunomodulation treatment compared with that in age-/sex-matched controls, and was lower in generalized MG (GMG) patients than in ocular MG (OMG) patients. Immunomodulatory treatment partially increased autophagy activity of BM-MNCs in MG patients and improved the symptoms. Furthermore, defective BM-MNCs differentiation, proliferation and apoptosis were observed due to dysfunctional autophagy. These findings suggest for the first time that BM-MNCs autophagy is impaired in patients with MG before immunomodulation therapy, and that autophagy is indispensable for the survival of BM-MNCs, implicating autophagy might be a potential pathogenic mechanism of MG and a novel therapeutic strategy for MG treatment.

DanHong injection dose-dependently varies amino acid metabolites and metabolic pathways in the treatment of rats with cerebral ischemia.

AIM: To determine how the relative amino acid contents and metabolic pathways regulate the pharmacological phenotypes in rats with cerebral ischemia after treatment with varying doses of DanHong injection (DHI). METHODS: Adult male rats underwent middle cerebral artery occlusion (MCAO), and were injected with DHI (DH-1: 1 mL/kg; DH-2: 2.5 mL/kg; DH-3: 5 mL/kg, and DH-4: 10 mL/kg, iv) daily for 3 d. The neurological deficit score, body weights and infarct volume were assessed. Serum levels of 20 free amino acids were determined using HPLC, and the values were transformed through the quantitative analysis of the amino acids in the serum metabolic spectrum. Multivariate statistical analysis methods (PCA and PLS-DA) and web-based metabolomics tools (MetPa and MetaboAnalyst) were used to analyze the biological data sets for the amino acids. RESULTS: Administration of DHI dose-dependently decreased cerebral infarct volume, and ameliorated neurological deficits. A total of 5, 6, 7 and 7 non-overlapping metabolites were identified in the DH-1, DH-2, DH-3, and DH-4 groups, respectively. Eight metabolites were shared between the DHI groups and the vehicle group. In addition, the serum levels of glutamic acid, aspartic acid and serine increased with increasing DHI dose. A total of 3, 2, 2 and 5 non-overlapping metabolic pathways were identified in the DH-1, DH-2, DH-3 and DH-4 groups, respectively, and glycine, serine, threonine and histidine metabolism were identified as overlapping pathways among the 4 dose groups. CONCLUSION: Overlapping and non-overlapping amino acid metabolites and metabolic pathways are associated with the dose-dependent neuroprotective effect of DHI.

Chronic Stress Exacerbates Cerebral Amyloid Angiopathy Through Promoting Neutrophil Extracellular Traps Formation.

Cerebral amyloid angiopathy (CAA) is the leading cause of vascular dementia among the elderly. Neuropsychiatric symptoms are commonly manifested in cerebral amyloid angiopathy patients but are usually considered as consequences of cerebral amyloid angiopathy pathology. Here, it is reported that chronic stress promotes cerebral amyloid angiopathy progression, which enhances deposition of amyloid protein beta (Aß) in brain blood vessels and exacerbates subsequent brain injury. Mechanistically, neutrophil is implicated in cerebral amyloid angiopathy development. Aß that accumulates in brain vasculature induces neutrophil extracellular traps (NETs) by activating STAT6 signaling, which inhibits neutrophil apoptosis and switches the programmed cell death toward NETosis. During chronic stress, circulatory Norepinephrine (NE) strengthens STAT6 activation in neutrophil and promotes NET formation, thus exacerbates the NET-dependent angiopathy. It is demonstrated that inhibiting neutrophil chemotaxis towards brain or suppressing NET formation both ameliorate cerebral amyloid angiopathy severity in the context of chronic stress. Therefore, it is proposed that stress-associated psychological disorders and NETs are promising therapeutic targets in cerebral amyloid angiopathy.

Agomelatine promotes differentiation of oligodendrocyte precursor cells and preserves white matter integrity after cerebral ischemic stroke.

White matter injury contributes to neurological disorders after acute ischemic stroke (AIS). The repair of white matter injury is dependent on the re-myelination by oligodendrocytes. Both melatonin and serotonin antagonist have been proved to protect against post-stroke white matter injury. Agomelatine (AGM) is a multi-functional treatment which is both a melatonin receptor agonist and selective serotonin receptor antagonist. Whether AGM protects against white matter injury after stroke and the underlying mechanisms remain elusive. Here, using the transient middle cerebral artery occlusion (tMCAO) model, we evaluated the therapeutic effects of AGM in stroke mice. Sensorimotor and cognitive functions, white matter integrity, oligodendroglial regeneration and re-myelination in stroke hemisphere after AGM treatment were analyzed. We found that AGM efficiently preserved white matter integrity, reduced brain tissue loss, attenuated long-term sensorimotor and cognitive deficits in tMCAO models. AGM treatment promoted OPC differentiation and enhanced re-myelination both in vitro, ex vivo and in vivo, although OPC proliferation was unaffected. Mechanistically, AGM activated low density lipoprotein receptor related protein 1 (LRP1), peroxisome proliferator-activated receptor γ (PPARγ) signaling thus promoted OPC differentiation and re-myelination after stroke. Inhibition of PPARγ or knock-down of LRP1 in OPCs reversed the beneficial effects of AGM. Altogether, our data indicate that AGM represents a novel therapy against white matter injury after cerebral ischemia.

Bone marrow-derived mesenchymal stem cell ameliorates post-stroke enterobacterial translocation through liver-gut axis.

BACKGROUND: Enterobacterial translocation is a leading contributor to fatal infection among patients with acute ischaemic stroke (AIS). Accumulative evidence suggests that mesenchymal stem cell (MSC) effectively ameliorates stroke outcomes. Whether MSC could inhibit post-stroke enterobacterial translocation remains elusive. METHODS: Patients with AIS and healthy individuals were enrolled in the study. Mice subjected to transient middle cerebral artery occlusion were treated with bone marrow-derived MSC (BM-MSC) right after reperfusion. Enterobacterial translocation was evaluated with Stroke Dysbiosis Index and circulating endotoxin. Thickness of mucus was assessed with Alcian blue staining. Hepatic glucocorticoid (GC) metabolism was analysed with expression of HSD11B2, HSD11B1 and SRD5A1. RESULTS: We report that the gut mucus layer was attenuated after the stroke leading to pronounced enterobacterial translocation. The attenuation of the gut mucus was attributed to diminished mucin production by goblet cells in response to the elevated systemic GC after cerebral ischaemia. Transferred-BM-MSC restored the mucus thickness, thus preserving gut microbiota homeostasis and preventing enterobacterial invasion. Mechanistically, the transferred-BM-MSC stationed in the liver and enhanced peroxisome proliferator-activated receptor γ signalling in hepatocytes. Consequently, expression of HSD11B2 and SRD5A1 was increased while HSD11B1 expression was downregulated which promoted GC catabolism and subsequently restored mucin production. CONCLUSIONS: Our findings reveal that MSC transfer improves post-stroke gut barrier integrity and inhibits enterobacterial translocation by enhancing the hepatic GC metabolism thus representing a protective modulator of the liver-gut-brain axis in AIS.

Intra-cisterna-magna bevacizumab injection (ICM-BI) reproduces pathological alterations of cerebral small vessel diseases.

General modeling strategies for sporadic cerebral small blood vessel diseases (CSVDs) include limiting blood stream in large blood vessels and inducing systemic hypertension, in which small blood vessel deficit is either a secondary or concomitant pathology. In the current study, we introduce that intra-cisterna-magna Bevacizumab injection (ICM-BI) directly causes cerebral small blood vessel injury by neutralizing VEGF-A, the indispensable growth factor for angiogenesis. ICM-BI reproduces neuro-functional impairment, tight junction loss, cerebral micro-bleeds (CMBs), amyloid peptide accumulation, neuronal injury, white matter loss, and glial cell activation, which are common manifestations of sporadic CSVDs. Compared with existing CSVD models, small blood vessel injury is more prominent in the ICM-BI brain. Moreover, no significant alteration in large blood vessels or peripheral organs after ICM-BI is recorded. We thus propose that ICM-BI is a neat, economic and applicable methodology to establish murine sporadic CSVD model.

Bone Marrow Mesenchymal Stem Cell-Derived Dermcidin-Containing Migrasomes enhance LC3-Associated Phagocytosis of Pulmonary Macrophages and Protect against Post-Stroke Pneumonia.

Pneumonia is one of the leading causes of death in patients with acute ischemic stroke (AIS). Antibiotics fail to improve prognosis of patients with post-stroke pneumonia, albeit suppressing infection, due to adverse impacts on the immune system. The current study reports that bone marrow mesenchymal stem cells (BM-MSC) downregulate bacterial load in the lungs of stroke mice models. RNA-sequencing of the lung from BM-MSC-treated stroke models indicates that BM-MSC modulates pulmonary macrophage activities after cerebral ischemia. Mechanistically, BM-MSC promotes the bacterial phagocytosis of pulmonary macrophages through releasing migrasomes, which are migration-dependent extracellular vesicles. With liquid chromatography-tandem mass spectrometry (LC-MS/MS), the result shows that BM-MSC are found to load the antibacterial peptide dermcidin (DCD) in migrasomes upon bacterial stimulation. Besides the antibiotic effect, DCD enhances LC3-associated phagocytosis (LAP) of macrophages, facilitating their bacterial clearance. The data demonstrate that BM-MSC is a promising therapeutic candidate against post-stroke pneumonia, with dual functions of anti-infection and immunol modulation, which is more than a match for antibiotics treatment.

KCNN4 is a Potential Biomarker for Predicting Cancer Prognosis and an Essential Molecule that Remodels Various Components in the Tumor Microenvironment: A Pan-Cancer Study.

Objectives: Potassium Calcium-Activated Channel Subfamily N Member 4 (KCNN4) is a member of the KCNN family. Studies have revealed that KCNN4 is implicated in various physiological processes as well as promotes the malignant phenotypes of cancer cells. However, little is known about its associations with survival outcomes across varying cancer types. Methods: Herein, we systematically explored the prognostic value of KCNN4 in the pan-cancer dataset retrieved from multiple databases. Next, we performed correlation analysis of KCNN4 expression with tumor mutational burden (TMB) and microsatellite instability (MSI), and immune checkpoint genes (ICGs) to assess its potential as a predictor of immunotherapy efficacy. Afterwards, patients were divided into increased-risk group and decreased-risk group based on the contrasting survival outcomes in various cancer types. Furthermore, the underlying mechanisms of the distinctive effects were analyzed using ESTIMATE, CIBERSORT algorithms, and Gene Set Enrichment Analysis (GSEA) analysis. Results: KCNN4 expression levels were aberrant in transcriptomic and proteomic levels between cancer and normal control tissues in pan-cancer datasets, further survival analysis elucidated that KCNN4 expression was correlated to multiple survival data, and clinical annotations. Besides, KCNN4 expression was correlated to TMB and MSI levels in 14 types and 12 types of pan-cancers, respectively. Meanwhile, different types of cancer have specific tumor-infiltrating immune cell (TICs) profiles. Conclusions: Our results revealed that KCNN4 could be an essential biomarker for remodeling components in the tumor microenvironment (TME), and a robust indicator for predicting prognosis as well as immunotherapy response in pan-cancer patients.

Analysis of the Curative Effect and Prognostic Factors of Anterior Cervical Surgery for Spinal Cord Injury without Radiographic Abnormalities.

Objective: The study aimed to investigate the effect of anterior cervical surgery in the treatment of spinal cord injury without radiographic abnormalities (SCIWORAs) and analyze the related factors affecting the prognosis of patients. Methods: A total of 86 patients with SCIWORA who were admitted to our hospital from June 2018 to March 2021 were selected as the research subjects. According to the different treatment methods selected by the patients, they were divided into the control group (n = 38) and the observation group (n = 48). The control group was treated with conservative therapy, and the observation group was treated with anterior cervical total laminectomy decompression, internal fixation, and bone graft fusion. The efficacy of the treatment was assessed preoperatively and 6 months after surgery using the Japanese Orthopedics Association (JOA) functional evaluation criteria for cervical spinal cord injury. The improvement rate of the JOA score at the last follow-up visit was calculated according to the Hirabayashi formula to evaluate the prognosis of patients. Results: The JOA score of the observation group six months after surgery was (14.98 ± 2.75) that was higher than that of the control group (12.16 ± 2.54) (P < 0.05). After surgery, the improvement rate of the JOA score in the observation group was higher than that in the control group (P < 0.05). After surgery, the scores of health condition, physiological function, and role physical in the observation group were (23.18 ± 1.09), (22.75 ± 1.54), and (22.64 ± 1.46), which were higher than those in the control groups (20.94 ± 1.65), (20.26 ± 1.78), and (19.56 ± 1.82) (P < 0.05). The results of univariate analysis showed that the ASIA classification of cervical spinal cord injury, the type of MRI cervical spinal cord injury, the scope of cervical spinal cord injury, lumbar disc herniation, and the time from injury to treatment were all related to the prognosis of the patients (P < 0.05). Multivariate analysis showed that the ASIA classification of cervical spinal cord injury, the type of MRI cervical spinal cord injury, the scope of cervical spinal cord injury, and the time from injury to treatment were the independent factors affecting the prognosis of patients (P < 0.05). Conclusion: For patients with SCIWORA, anterior total lamina decompression and internal fixation with bone grafting and fusion can effectively promote the recovery of cervical spinal cord function and improve the prognosis and quality of life of patients. The ASIA classification of cervical spinal cord injury, the type of MRI cervical spinal cord injury, the scope of cervical spinal cord injury, and the time from injury to treatment were the independent prognostic factors for patients.

Study on the Prognostic Values of Dynactin Genes in Low-Grade Glioma.

OBJECTIVE: This present study aims to investigate the potential prognostic values of dynactin genes (DCTN) for predicting the overall survival (OS) in low-grade glioma (LGG) patients. METHODS: The DCTN mRNA expression data were downloaded from The Cancer Genome Atlas database containing 518 patients with LGG. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses for DCTN genes were performed by using Database for Annotation, Visualization, and Integrated Discovery platform, and their enrichment results were verified by using the Biological Networks Gene Ontology tool. Next, the correlations between DCTN genes and LGG were identified by Pearson correlation coefficient analysis. The OS was estimated by Kaplan-Meier survival analysis. The cBio Cancer Genomics Portal was used to analyze the mutations of DCTN genes and their effects on the prognosis of LGG. The correlation between the abundance of immune infiltration and tumor purity of DCTN genes were predicted by The Tumor Immune Estimation Resource. RESULTS: Our research showed that the mRNA expression of DCTN4 in tumor tissues was much higher (P < 0.01) than that in normal tissues. Meanwhile, there was a certain correlation between the DCTN genes. Survival analysis showed that the high expression of DCTN1, DCTN3, DCTN4, DCTN6, and their co-expression were significantly correlated with favorable OS in LGG patients (P < 0.05). In DCTN2, a high mutation rate was observed. Further research showed that the genetic alteration in DCTN genes was related to a poor OS and progression-free survival of LGG patients. The expression of DCTN genes had a certain correlation with immune infiltrating cells. CONCLUSION: Our study showed that the high expressions of DCTN1, DCTN3, DCTN4, and DCTN6 were associated with a favorable OS of LGG patients, indicating that these DCTN genes are potential biomarkers for evaluating the prognosis of LGG patients.

Study on the Inhibitory Effect of Curcumin on GBM and Its Potential Mechanism.

BACKGROUND: Glioblastoma (GBM) is the most prevalent malignant tumor of the central nervous system (CNS). However, current GBM treatments are ineffective, signifying the great importance of exploring new therapeutic targets. Curcumin has been found to be a natural compound with an anticancer potential. However, its targets and mechanisms in GBM are still unclear. METHODS: Differentially expressed genes (DEGs) were screened from the GBM dataset in the GEO database and intersected with the target genes of curcumin to select potential target genes. Subsequently, survival analysis was performed with the GEPIA database to confirm the effect of target genes on the prognosis of GBM, and functional enrichment analysis was performed using the DAVID database. In vitro, CCK-8 assay was used to screen the appropriate concentration of curcumin; scratch and transwell invasion assays were used to evaluate the effect of curcumin on the migration and invasion abilities of GBM cells. Furthermore, RT-qPCR and Western blotting were used to detect changes in target genes and flow cytometry was used to assess the apoptosis level. RESULTS: A total of 16 target genes of curcumin and GBM were obtained, among which ENO1, MMP2, and PRKD2 significantly affected the prognosis (P < 0.05). We further selected ENO1 for functional enrichment analysis and found that it was enriched in the glycolytic pathway. Meanwhile, in vitro experiments showed that curcumin could inhibit the migration and invasion of U251 cells and promote apoptosis (P < 0.05). CONCLUSION: ENO1 could be a possible target for curcumin in the suppression of GBM cells.

KCNN4 is a potential prognostic marker and critical factor affecting the immune status of the tumor microenvironment in kidney renal clear cell carcinoma.

BACKGROUND: The tumor microenvironment (TME) has emerged as a crucial factor in cancer development and progression. Recent findings have indicated that tumor-infiltrating immune cells (TICs) in the TME may predict cancer prognosis and response to treatment. Herein, we sought to identify critical modulators of the kidney renal clear cell carcinoma (KIRC) TME. METHODS: KIRC datasets from The Cancer Genome Atlas (TCGA) were analyzed using the ESTIMATE algorithm to determine the ImmuneScore and StromalScore. By profiling the differentially expressed genes (DEGs) in the ImmuneScore and StromalScore, we finally identified the immune- and stromal-related DEGs of the cases, through which we then performed intersection analysis to determine the immune-related genes (IRGs). Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were used to identify critical IRGs and construct a prognostic model. The CIBERSORT algorithm was used to calculate the relative content of 22 immune cell types. Finally, the datasets from the Gene Expression Omnibus (GEO) database were analyzed to validate results from the above analyses. Experimental validation was used on KIRC tissues by quantitative polymerase chain reaction (qPCR) and western blot. RESULTS: We found that the ImmuneScore was negatively correlated with patients' prognosis. Intersection analysis of the ImmuneScore and StromalScore identified 118 IRGs that were enriched in immune-related functions. Following IRGs screening by Cox and LASSO regression analyses, six genes were identified and used to construct a KIRC prognostic model. Intersection analysis of these six genes and protein-protein interaction (PPI) were performed and obtained the most critical gene: Potassium Calcium-Activated Channel Subfamily N Member 4 (KCNN4). Further analysis showed that KCNN4 expression was higher in tumor samples relative to normal controls, and was negatively correlated with prognosis. CIBERSORT analysis revealed significant correlation between KCNN4 expression and multiple types of TICs, demonstrating that KCNN4 may affect KIRC prognosis by influencing the TME immune status. Ultimately, the GEO datasets and validation experiments confirmed that KCNN4 was highly expressed in tumor tissues compared to the corresponding normal tissues. CONCLUSIONS: Our study demonstrated that KCNN4 might be a potential prognostic marker in KIRC, offering a novel therapeutic avenue.

MiR-582-3p alleviates osteoarthritis progression by targeting YAP1.

Osteoarthritis (OA) is a widespread degenerative joint disease that affects more than 350 million people worldwide. Although YAP1 has been proved to play a key role in OA, the biological function and mechanism of YAP1 in OA still need further investigation. In the present study, we demonstrated that YAP1 was highly expressed in OA rat chondrocytes. Recently, growing microRNAs (miRNAs) have been reported to play important roles in OA development. Among them, miR-582-3p is one of the few significantly downregulated miRNAs and attracted our attention. Functional investigations indicated that miR-582-3p inhibited chondrocyte apoptosis, reduced the proinflammatory cytokine production and suppressed extracellular matrix (ECM) degradation. Subsequently, molecular mechanism exploration implied that YAP1 is a downstream target of miR-582-3p. Furthermore, rescue assays revealed that YAP1 amplification can reverse miR-582-3p mimic-mediated effects on chondrocyte apoptosis, inflammatory response, and ECM degradation. Moreover, the OA rat model was established to explore the function of miR-582-3p/YAP1 axis in vivo. The results showed that YAP1 overexpression can recover the effects induced by injection of AAV-miR-582-3p mimic on OA progression. To sum up, these findings implied a crucial role of miR-582-3p/YAP1 axis in OA, which may provide a promising therapeutic strategy for OA.

Inflammatory response and oxidative stress attenuated by sulfiredoxin­1 in neuron­like cells depends on nuclear factor erythroid­2­related factor 2.

Sulfiredoxin­1 (SRX1) is a conserved endogenous antioxidative protein, which is involved in the response to cellular damage caused by oxidative stress. Oxidative stress and inflammation are the primary pathological changes in spinal cord injuries (SCI). The aim of present study was to explore the roles of SRX1 in SCI. Using reverse transcription­quantitative PCR and western blotting, the present study discovered that the expression levels of SRX1 were downregulated in the spinal cord tissues of SCI model rats. Massive irregular cavities and decreased Nissl bodies were observed in the model group compared with the sham group. Thus, to determine the underlying mechanisms, neuron­like PC12 cells were cultured in vitro. Western blotting analysis indicated that SRX1 expression levels were downregulated following the exposure of cells to lipopolysaccharide (LPS). Following the transfection with the SRX1 overexpression plasmid and stimulation with LPS, the results of the Cell Counting Kit­8 assay indicated that the cell viability was increased compared with LPS stimulation alone. Furthermore, the expression levels of proinflammatory cytokines secreted by LPS­treated PC12 cells were downregulated following SRX1 overexpression. Increased malondialdehyde content, decreased superoxide dismutase activity and reactive oxygen species production were also identified in PC12 cells treated with LPS using commercial detection kits, whereas the overexpression of SRX1 partially reversed the effects caused by LPS stimulation. The aforementioned results were further verified by determining the expression levels of antioxidative proteins using western blotting analysis. In addition, nuclear factor erythroid­2­related factor 2 (NRF2), a transcription factor known to regulate SRX1, was indicated to participate in the protective effect of SRX1 against oxidative stress. Inhibition of NRF2 further downregulated the expression levels of SRX1, NAD(P)H dehydrogenase quinone 1 and heme oxygenase­1 in the presence of LPS, while activation of NRF2 reversed the effects of LPS on the expression levels of these proteins. In conclusion, the results of the present study indicated that the anti­inflammatory and antioxidative effects of SRX1 may depend on NRF2, providing evidence that SRX1 may serve as a novel molecular target to exert a neuroprotective effect in SCI.

17ß-Estradiol Prevents Extracellular Matrix Degradation by Downregulating MMP3 Expression via PI3K/Akt/FOXO3 Pathway.

STUDY DESIGN: In vitro studies of the role of 17ß-estradiol (E2) and its possible targets in intervertebral disc degeneration (IDD). OBJECTIVE: To define the regulatory role of E2 in IDD and the potential mechanisms. SUMMARY OF BACKGROUND DATA: IDD has intricate etiology that is influenced by multiple risk factors. However, the underlying molecular mechanisms of occurrence and progression of IDD are not well elucidated. The degradation of extracellular matrix (ECM) has been extensively observed in IDD. E2 was found to inhibit ECM degradation in human nuleus pulposus cells (HNPCs), but the molecular mechanism remained to be determined. METHODS: Western blot and qPCR was performed to quantify the expression of target proteins in HNPCs. Luciferase reporter gene assay was applied to detect the effects of E2 and forkhead box O-3 (FOXO3) on matrix metalloproteinases (MMP)-3 promoter activity. Chromatin immunoprecipitation assay analyzed the binding of FOXO3 to MMP-3 and the effect of E2 on this process. RESULTS: We identified the upregulation of collagen II and aggrecan by E2 independent of time and concentration. And E2 downregulated MMP-3 expression in human nucleus pulposus cells. The phosphorylation of FOXO3 led to the reduction of MMP-3 promoter activity. Furthermore, 17ß-estradiol-induced the activation of PI3K/Akt pathway is required for FOXO3 phosphorylated. CONCLUSION: E2 prevents the degradation of ECM by upregulating collagen II and aggrecan expression via reducing MMP-3 expression in HNPCs, and PI3K/Akt/FOXO3 pathway is dispensable for MMP-3 downregulated. Therefore, E2 protects against IDD by preventing ECM degradation. LEVEL OF EVIDENCE: 3.

Comprehensive analysis of glutathione peroxidase-1 (GPX1) expression and prognostic value in three different types of renal cell carcinoma.

BACKGROUND: Glutathione peroxidase-1 (GPX1) is generally expressed in tissues with high oxygen tension such as the kidneys and lungs, and its main function is to degrade reactive oxygen species (ROS) and protect cells from oxidative stress. Studies have shown that GPX1 is upregulated in many tumor tissues and is closely related to tumor progression and metastasis. This study aimed to explore the possibility of GPX1 as a biomarker for kidney chromophobe cell carcinoma (KICH), kidney renal papillary cell carcinoma (KIRP), and kidney renal clear cell carcinoma (KIRC). METHODS: The Oncomine and GEPIA databases were used to analyze the GPX1 expression differences between tumor and normal tissues, and the UALCAN, GEPIA and DriverDBv3 databases were used to perform the survival analyses. The GeneMANIA interactive tool was then used to find the GPX1-related protein-protein interaction (PPI). Following this, the LinkedOmics database was used for the enrichment analysis of GPX1, and the Timer database was used to estimate the abundance of immune infiltration. Finally, quantitative polymerase chain reaction (qPCR) was performed on patient specimens collected in the clinic to confirm the database findings. RESULTS: In our study, we found that the expression of GPX1 in three types of renal cell carcinoma (RCC) were upregulated, and the high expression of GXP1 was related to the poor prognosis of patients with KICH and KIRC. On the contrary, KIRP patients with a high expression of GPX1 had a better prognosis. In addition, GPX1 was related to the abundance of immune cell infiltration. The results of the qPCR analysis confirmed that the expression of GPX1 in RCC was increased compared with the control group (P<0.05). CONCLUSIONS: Our results indicate that the expression of GPX1 is related to the prognosis of three types of RCC. As such, GPX1 expression could be a reliable diagnostic and prognostic biomarker for RCC and, more importantly, may provide a new direction for therapeutic strategies.

Effect of osteoprotegerin gene polymorphisms on the risk of cervical spondylotic myelopathy in a Chinese population.

OBJECTIVE: Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord dysfunction. Our study aims to explore the correlation of osteoprotegerin (OPG) gene polymorphisms and the risk factors and severity of CSM. PATIENTS AND METHODS: The peripheral blood samples from 494 CSM patients and 515 healthy individuals were collected for detecting the 950T/C, 1181G/C and 163A/G genotypes and genetic equilibrium of OPG in the CSM and control groups and analyzing the genotype distribution and allele frequency. The severity of CSM and the impaired segments were evaluated by the Japanese Orthopedic Association (JOA) scoring combined with cervical magnetic resonance imaging (MRI), in order to investigate the relations between the three genotypes of OPG promoter gene loci (950T/C, 163A/G and 1181G/C) and occurrence as well as severity of CSM. RESULTS: The risk rate of TC genotype carrier suffered from CSM was 0.46, of TT genotype carrier was 0.27. The risk rate of T allele carrier suffered from CSM was 0.37. In 950T/C single nucleotide polymorphism (SNP), patients with TC, TT and T genotypes had lower risk to suffer from CSM. CONCLUSION: Taken together, OPG 950T/C SNP protects against CSM, and it is correlated with the severity of CSM, providing a new idea for the prevention and treatment of CSM.

Investigating shape representation using sensitivity to part- and axis-based transformations.

Part- and axis-based approaches organize shape representations in terms of simple parts and their spatial relationships. Shape transformations that alter qualitative part structure have been shown to be more detectable than those that preserve it. We compared sensitivity to various transformations that change quantitative properties of parts and their spatial relationships, while preserving qualitative part structure. Shape transformations involving changes in length, width, curvature, orientation and location were applied to a small part attached to a larger base of a two-part shape. Increment thresholds were estimated for each transformation using a 2IFC procedure. Thresholds were converted into common units of shape difference to enable comparisons across transformations. Higher sensitivity was consistently found for transformations involving a parameter of a single part (length, width, curvature) than those involving spatial relations between two parts (relative orientation and location), suggesting a single-part superiority effect. Moreover, sensitivity to shifts in part location - a biomechanically implausible shape transformation - was consistently poorest. The influence of region-based geometry was investigated via stereoscopic manipulation of figure and ground. Sensitivity was compared across positive parts (protrusions) and negative parts (indentations) for transformations involving a change in orientation or location. For changes in part orientation (biomechanically plausible), sensitivity was better for positive than negative parts; whereas for changes in part location (biomechanically implausible), no systematic difference was observed.