Revealing Novel Genes Related to Parkinson's Disease Pathogenesis and Establishing an associated Model.

Parkinson's disease (PD) represents a multifaceted neurological disorder whose genetic underpinnings warrant comprehensive investigation. This study focuses on identifying genes integral to PD pathogenesis and evaluating their diagnostic potential. Initially, we screened for differentially expressed genes (DEGs) between PD and control brain tissues within a dataset comprising larger number of specimens. Subsequently, these DEGs were subjected to weighted gene co-expression network analysis (WGCNA) to discern relevant gene modules. Notably, the yellow module exhibited a significant correlation with PD pathogenesis. Hence, we conducted a detailed examination of the yellow module genes using a cytoscope-based approach to construct a protein-protein interaction (PPI) network, which facilitated the identification of central hub genes implicated in PD pathogenesis. Employing two machine learning techniques, including XGBoost and LASSO algorithms, along with logistic regression analysis, we refined our search to three pertinent hub genes: FOXO3, HIST2H2BE, and HDAC1, all of which demonstrated a substantial association with PD pathogenesis. To corroborate our findings, we analyzed two PD blood datasets and clinical plasma samples, confirming the elevated expression levels of these genes in PD patients. The association of the genes with PD, as reflected by the area under the curve (AUC) values for FOXO3, HIST2H2BE, and HDAC1, were moderate for each gene. Collectively, this research substantiates the heightened expression of FOXO3, HIST2H2BE, and HDAC1 in both PD brain and blood samples, underscoring their pivotal contribution to the pathogenesis of PD.

N-telopeptide as a potential diagnostic and prognostic marker for bone metastasis in human cancers: A meta-analysis.

Purpose: Whether N-telopeptide of type I collagen (NTx) can be applied for diagnosis and prognostic prediction of bone metastasis in human cancers is still conflicting. This study aimed to investigate the diagnostic and prognostic value of NTx for cancer patients with bone metastasis. Methods: Embase, PubMed, Chinese National Knowledge Infrastructure and Wanfang databases were retrieved to collect related publications. In diagnostic meta-analysis, the sensitivity (SEN) and specificity (SPE) were calculated. Hazard ratio (HR) with 95% confidence interval (95% CI) was used in the prognostic meta-analysis. Sensitivity and publication analyses were conducted for potential heterogeneity sources. Results: The pooled SEN and SPE were 77% (72-81%) and 80% (75-84%) for 45 diagnostic studies. A higher diagnostic efficacy was obtained from NTx combining with other markers (AUC: 0.94 (0.92-0.96)) for bone metastasis of human cancers, especially for lung cancer (AUC: 0.87 (0.84-0.90)), breast cancer (AUC: 0.83 (0.79-0.86)) and prostate cancer (AUC: 0.88 (0.85-0.90)) in Asian people (AUC: 0.86 (0.83-0.89)). For the value of NTx on prognosis of human cancers with bone metastasis, the pooled HR was 2.12 (1.74-2.58) for high versus low NTx level, indicating high NTx level would increase the risk of poor overall survival. Conclusion: Our results indicated serum NTx combining with other markers can become a feasible biomarker for the diagnosis and prognosis prediction for bone metastasis of different cancers, including lung cancer, breast cancer and prostate cancer in Asian people.

Superenhancer-transcription factor regulatory network in malignant tumors.

OBJECTIVE: This study aims to identify superenhancer (SE)-transcriptional factor (TF) regulatory network related to eight common malignant tumors based on ChIP-seq data modified by histone H3K27ac in the enhancer region of the SRA database. METHODS: H3K27ac ChIP-seq data of eight common malignant tumor samples were downloaded from the SRA database and subjected to comparison with the human reference genome hg19. TFs regulated by SEs were screened with HOMER software. Core regulatory circuitry (CRC) in malignant tumor samples was defined through CRCmapper software and validated by RNA-seq data in TCGA. The findings were substantiated in bladder cancer cell experiments. RESULTS: Different malignant tumors could be distinguished through the H3K27ac signal. After SE identification in eight common malignant tumor samples, 35 SE-regulated genes were defined as malignant tumor-specific. SE-regulated specific TFs effectively distinguished the types of malignant tumors. Finally, we obtained 60 CRC TFs, and SMAD3 exhibited a strong H3K27ac signal in eight common malignant tumor samples. In vitro experimental data verified the presence of a SE-TF regulatory network in bladder cancer, and SE-TF regulatory network enhanced the malignant phenotype of bladder cancer cells. CONCLUSION: The SE-TF regulatory network with SMAD3 as the core TF may participate in the carcinogenesis of malignant tumors.

lncRNA OXCT1-AS1 Promotes Metastasis in Non-Small-Cell Lung Cancer by Stabilizing LEF1, In Vitro and In Vivo.

Long noncoding RNAs (lncRNAs) play nonnegligible roles in the metastasis of non-small-cell lung cancer (NSCLC). This study is aimed at investigating the biological role of lncRNA OXCT1-AS1 in NSCLC metastasis and the underlying regulatory mechanisms. The expression profiles of lncRNA OXCT1-AS1 in different NSCLC cell lines were examined. Then, the biological function of lncRNA OXCT1-AS1 in NSCLC metastasis was explored by loss-of-function assays in vitro and in vivo. Further, the protective effect of lncRNA OXCT1-AS1 on lymphoid enhancer factor 1 (LEF1) was examined using RNA pull-down and RNA immunoprecipitation assays. Additionally, the role of LEF1 in NSCLC metastasis was investigated. Results indicated that lncRNA OXCT1-AS1 expression was significantly increased in NSCLC cell lines. Functional analysis revealed that knockdown of lncRNA OXCT1-AS1 impaired invasion and migration in vitro. Additionally, the ability of lncRNA OXCT1-AS1 to promote NSCLC metastasis was also confirmed in vivo. Mechanistically, through direct interaction, lncRNA OXCT1-AS1 maintained LEF1 stability by blocking NARF-mediated ubiquitination. Furthermore, LEF1 knockdown impaired invasion and migration of NSCLC in vitro and in vivo. Collectively, these data highlight the ability of lncRNA OXCT1-AS1 to promote NSCLC metastasis by stabilizing LEF1 and suggest that lncRNA OXCT1-AS1 represents a novel therapeutic target in NSCLC.

IL-27 Protects the Brain from Ischemia-Reperfusion Injury via the gp130/STAT3 Signaling Pathway.

The occurrence of ischemia-reperfusion (I/R) injury leads to dysfunction as well as high rates of morbidity and mortality in stroke, and new effective therapeutic strategies for I/R are still needed. We investigated the effect of IL-27 on I/R injury-induced neurological function impairment, cerebral infarction volume and variation in levels of inflammatory factors in mice with middle cerebral artery occlusion (MCAO), as well as concentration of LDH and neuronal apoptosis in a neuron oxygen-glucose deprivation and reperfusion (OGD/R) model mediated by gp130/STAT3 signaling in vitro. Our results indicated that IL-27 could bind to its receptor of gp130 to attenuate the I/R injury-induced impairment function and cerebral infarction volume, and decrease inflammatory cytokines TNF-α, IL-1ß and MCP-1 but increase anti-inflammatory factors IL-10 and TGF-ß in vivo, while inhibiting LDH leakage and neuronal apoptosis through activation of STAT3 to antagonize I/R induction. Our results suggest that IL-27 may protect the brain from I/R injury through the gp130/STAT3 signaling pathway.

Echinacea polysaccharide alleviates LPS-induced lung injury via inhibiting inflammation, apoptosis and activation of the TLR4/NF-κB signal pathway.

Lung injury is a common critical life-threatening syndrome. Inflammation is a key factor in the pathogenesis of lung injury. It is reported that Echinacea Polysaccharides (EP) has anti-inflammatory activity. However, the effect of EP on lung injury remains unclear. In our study, murine model of lung injury was induced with 2.5 mg/kg LPS before administration of 5 mg/kg or 10 mg/kg EP. EP ameliorated LPS-induced lung pathological damage, along with reduction in lung wet/dry weight ratio and myeloperoxidase activity. EP decreased the number of leukocytes, eosinophils, neutrophils, lymphocytes and macrophages in bronchoalveolar lavage fluid, and the release of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in LPS-treated lung. EP suppressed LPS-induced apoptosis along with down-regulation of Bcl2-associated X (Bax) and cleaved caspase-3 (CC3), and elevated B-cell lymphoma-2 (Bcl-2). Besides, RAW 264.7 cells were treated with EP 100 µg/ml for 1 h and then incubated with 1 µg/ml LPS for 24 h. TNF-α, IL-6 and IL-1ß levels were lowered by treatment of EP in LPS-treated RAW 264.7 cells. Moreover, EP down-regulated the expression of toll-like receptor 4 (TLR4), myeloid differentiating factor 88 (MyD88), p-IκBα, nuclear factor kappa-B (NF-κB), p-NF-κB, and up-regulated the inhibitor of NF-κB (IκBα) in vivo and in vitro following LPS induction, which is consistent with the effect of TAK-242. In conclusion, EP may alleviate LPS-induced lung injury via inhibiting inflammation, apoptosis and activation of TLR4/NF-κB signal pathway.

Baicalein Promotes Neuronal and Behavioral Recovery After Intracerebral Hemorrhage Via Suppressing Apoptosis, Oxidative Stress and Neuroinflammation.

Intracerebral hemorrhage (ICH) is an important public health problem in neurology, which is not only associated with high mortality but also leading to disability. Yet no satisfactory treatment has been developed. The secondary injury that resulted from a number of self-destructive processes such as neuroinflammation, apoptosis and oxidative stress, is the key factor contributing to ICH-induced brain damage. Baicalein has been proved to improve neuronal functional recovery in rat model of subarachnoid hemorrhage and ischemic brain damage. To investigate the effect of baicalein on ICH and its underlying mechanism, a collagenase-induced ICH rat model was performed. Baicalein treatment significantly decreased neurological severity score at day 1 and 3 after ICH injury. Our results showed that the lesion volume, the brain water content, the expression levels of four pro-inflammatory cytokines (IL-1ß, IL-4 and IL-6 and TNF-α) and the numbers of apoptotic cells were reduced significantly in ICH rats receiving baicalein treatment, especially in 50 mg/kg baicalein-treated group. Moreover, baicalein increased SOD and GSH-Px activities and down-regulated MDA level of brain tissues in rats. These results suggested that the therapeutic efficacy of baicalein on repairing brain damage is probably caused by suppressing apoptosis, oxidative stress and neuroinflammation. Baicalein could be developed into a novel drug for clinical treatment of ICH and ICH-related brain injuries.

Association between glutathione S-transferase T1 null genotype and risk of lung cancer: a meta-analysis of 55 studies.

The relationship between glutathione S-transferase T1 (GSTT1) gene polymorphism and the risk of lung cancer from the published reports are still conflicting. This study was conducted to evaluate the relationship between GSTT1 polymorphism and the risk of lung cancer. A comprehensive research was conducted through the databases, and 55 studies were recruited into this meta-analysis for the association of null genotype of GSTT1 with lung cancer susceptibility, consisting of 15,140 patients with lung cancer and 16,662 controls. There was a significant association between GSTT1 null genotype and lung cancer risk in the overall populations (OR = 1.138, 95% CI = 1.032-1.255, P heterogeneity = 0.000, P = 0.009). Furthermore, GSTT1 null genotype was associated with the lung cancer risk in Asians (OR = 1.469, 95% CI = 1.228-1.757, P heterogeneity = 0.000, P = 0.000). However, GSTT1 null genotype was not associated with the risk of lung cancer in Caucasians and Africans. In conclusion, GSTT1 null genotype is associated with the lung cancer in overall populations and in Asians.