The accumulation of the amyloid-β peptide (Aβ) into amyloid plaques, an essential event in Alzheimer's disease (AD) pathogenesis, has caused researchers to seek compounds that physiologically bind Aβ and modulate its aggregation and neurotoxicity. In order to develop new Aβ-specific peptides for AD, a randomized 12-mer peptide library with Aβ1-10 as the target was used to identify peptides in the present study. After three rounds of selection, specific phages were screened, and their binding affinities to Aβ1-10 were found to be highly specific. Finally, a special peptide was synthesized according to the sequences of the selected phages. In addition, the effects of the special peptide on Aβ aggregation and Aβ-mediated neurotoxicity in vitro and in vivo were assessed. The results show that the special peptide not only inhibited the aggregation of Aβ into plaques, but it also alleviated Aβ-induced PC12 cell viability and apoptosis at appropriate concentrations as assessed by the cell counting kit-8 assay and propidium iodide staining. Moreover, the special peptide exhibited a protective effect against Aβ-induced learning and memory deficits in rats, as determined by the Morris water maze task. In conclusion, we selected a peptide that specifically binds Aβ1-10 and can modulate Aβ aggregation and Aβ-induced neuronal damage. This opens up possibilities for the development of a novel therapeutic approach for the treatment of AD.
Di(2-ethylhexyl) phthalate (DEHP) is a common environmental pollutant with renal and reproductive toxicity. Lycium barbarum glycopeptide (LbGp) is the main active component of Lycium barbarum, which can protect the kidney and promote reproduction. Autophagy and apoptosis are the regulatory mechanisms of cell adaptation to external stress. This study investigated whether DEHP and LbGp affect kidney and testis by regulating autophagy and apoptosis. DEHP induced apoptosis in human embryonic kidney-293 (HEK-293) cells and human kidney-2 (HK-2) cells, as well as glomerular enlargement, enhanced renal autophagy and inflammation, decreased testicular germ cells, and enhanced testicular autophagy. LbGp reduced apoptosis in HEK-293 cells and HK-2 cells, reduced glomerular enlargement and renal inflammation, enhanced renal autophagy, increased testicular germ cells, and alleviated testicular autophagy. These results suggested that DEHP induced inflammation to cause kidney injury, mildly enhanced renal autophagy, and also induced excessive autophagy, leading to testicular injury. LbGp reduced inflammation and appropriately enhanced autophagy to alleviate renal injury and also reduced excessive autophagy to alleviate testicular injury. Silent information regulator 1 (SIRT1)/forkhead box O3a (FoxO3a)-mediated autophagy and p38 mitogen-activated protein kinase (p38 MAPK)-mediated inflammation played important roles.
Pancreatic cancer (PCa) is a highly lethal and aggressive disease, characterized by high mortality rates. Although necroptosis plays a vital role in tumor progression, cancer metastasis, prognosis of cancer patients, necroptosis-related gene (NRG) sets have rarely been analyzed in PCa. Therefore, definition of novel necroptosis-related prognostic markers for PCa patients is urgently needed. Here, we screened 159 NRGs and identified 132 differentially expressed NRGs in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) cohorts. Next, we employed univariate and multivariate Cox proportional regression models to establish a prognostic-related NRG signature comprising five NRGs that could stratify patients into high-risk and low-risk groups. Results from survival analysis showed that patients in the high-risk had dramatically shorter overall survival (OS) rates compared with their low-risk counterparts. Results from univariate and multivariate Cox regression analysis further confirmed the independent prognostic value of the established necroptosis-related signature, and the area under receiver (AUC) of the operating curve (ROC) for 1-, 3-, 5-years was 0.72, 0.74, and 0.75, respectively. Finally, we validated the signature efficacy using an independent cohort from the Gene Expression Omnibus (GEO) database. The ROC curve confirmed the predictive capacity of the five-gene signature. Furthermore, we validated expression of the signature proteins using the Human Protein Atlas (HPA) database. In conclusion, we successfully constructed a novel necroptosis-related signature for prognosis of patients with pancreatic cancer.
Background: Extensive evidence has shown that immune cell infiltration is associated with the pathogenesis of Crohn’s disease (CD). In the present study, we explored the potential mechanism underlying the pathogenesis biomarkers for CD.Methods: The GSE179285 dataset containing sequence data for intestinal mucosal was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in the intestinal mucosa of CD patients and healthy individuals were then identified. The infiltration pattern of 22 immune cell types was assessed using the CIBERSORT algorithm. The DEGs and 22 immune cell types were combined to find the key gene network using weighted gene co-expression network analysis (WGCNA), and pathway enrichment analyzes were performed on the hub module in the WGCNA. A linear regression model for the relationship between the expression of the hub genes in CD patients and infiltration of immune cells were also developed. The utility and accuracy of the hub genes for CD diagnosis were assessed using receiver operating characteristic (ROC) analysis. The accuracy of the model was validated using GSE20881 dataset. Results: There were 1135 DEGs between the intestinal mucosal tissue of CD patients and healthy individuals. Of these DEGs, 711 genes were upregulated, whereas 424 of them were downregulated. There was also a significant difference in the infiltration of immune cells to the intestinal mucosal between the CD patients and healthy individuals. WGCNA revealed that the turquoise module genes were strongly correlated with the infiltration of M1 macrophages (cor=0.68, p=10-16). Pathway enrichment analysis further showed the genes in the turquoise module mainly regulated the secretion of interferon-gamma and other immune effector molecules. Finally, the expression of GBP4, the identified hub gene, strongly correlated with the infiltration of M1 macrophages (adjusted r-squared=0.661, p<2x10-16), and is a relatively good marker for CD diagnostic prediction (AUC=0.736). The relationship between GBP4 expression and infiltration of M1 macrophages (adjusted r-squared=0.435, p<2x10-16) and prognostic value of the gene (AUC=0.702) were verified using the GSE20881 validation dataset.Conclusion: GBP4 is a potential biomarker for accurate CD diagnosis. The expression of GBP4 promotes the infiltration of M1 macrophages to the intestinal mucosa of CD patients.
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