Bioinformatic identification of differentially expressed genes regulated by DNA-methylation in glioblastoma.

DNA methylation-driven differentially expressed genes (DEGs) play potentially important roles in glioblastoma (GBM). In the present study, we applied bioinformatic analyses to identify key methylation-regulated DEGs (MeDEGs) in glioblastoma and elucidate their functions. Gene expression and methylation profile data from glioblastoma samples along with clinical information were obtained from GEO and TCGA databases. A total of 65 genes were identified as MeDEGs from the aforementioned data. Subsequently, gene ontology and kyoto encyclopaedia of genes and genomes enrichment analyses of these MeDEGs exhibited that MeDEGs were mostly enriched in several tumour-related terms such as 'activation of cysteine-type endopeptidase activity involved in apoptotic process' and 'phospholipid scrambling'. Kaplan-Meier survival analysis demonstrated significant correlation of CASP1, CFH and TTLL7 hyper-methylation with patient prognosis. Finally, CASP1 protein could indirectly interact with CFH protein, but interaction of TTLL7 protein with CASP1 or CFH protein was not evident. Based on gene set enrichment analysis, hyper-methylation of CASP1, CFH and TTLL7 were found enriched in tumour-related KEGG terms, such as 'RNA degradation', 'apyruvate metabolism' and 'nitrogen metabolism'. Methylation levels of CASP1, CFH and TTLL7 were addressed to negatively correlate with their mRNA levels in GBM cell lines. In sum, the present identification of MeDEGs associated with overall survival put forth potential molecular targets for translation towards improved diagnosis and treatment of GBM, and specifically, methylation levels of CASP1, CFH and TTLL7 genes could serve as key prognostic biomarkers in GBM.

Liver Cell Mitophagy in Metabolic Dysfunction-Associated Steatotic Liver Disease and Liver Fibrosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of the global population. MASLD and its advanced-stage liver fibrosis and cirrhosis are the leading causes of liver failure and liver-related death worldwide. Mitochondria are crucial organelles in liver cells for energy generation and the oxidative metabolism of fatty acids and carbohydrates. Recently, mitochondrial dysfunction in liver cells has been shown to play a vital role in the pathogenesis of MASLD and liver fibrosis. Mitophagy, a selective form of autophagy, removes and recycles impaired mitochondria. Although significant advances have been made in understanding mitophagy in liver diseases, adequate summaries concerning the contribution of liver cell mitophagy to MASLD and liver fibrosis are lacking. This review will clarify the mechanism of liver cell mitophagy in the development of MASLD and liver fibrosis, including in hepatocytes, macrophages, hepatic stellate cells, and liver sinusoidal endothelial cells. In addition, therapeutic strategies or compounds related to hepatic mitophagy are also summarized. In conclusion, mitophagy-related therapeutic strategies or compounds might be translational for the clinical treatment of MASLD and liver fibrosis.

Identification of novel therapeutic target and prognostic biomarker in matrix metalloproteinase gene family in pancreatic cancer.

Matrix metalloproteinases (MMPs) play an essential role in various physiological events. Recent studies have revealed its carcinogenic effect in malignancies. However, the different expression patterns, prognostic value, and immunological value of MMPs in pancreatic ductal adenocarcinoma (PDAC) are yet to be comprehensively explored. We utilized Gene Expression Profiling Interactive Analysis (GEPIA) and Gene Expression Omnibus databases to explore the abnormal expression of MMPs in PDAC. Then, Kaplan-Meier survival curve and Cox regression analysis were performed to assess the prognostic value of MMPs. Association between MMPs expression and clinicopathological features was analyzed through UALCAN website. Functional annotations and GSEA analysis were performed to excavate the possible signaling pathways involving prognostic-related MMP. TIMER and TISCH database were used to performed immune infiltration analysis. The expression of prognostic-related MMP in pancreatic cancer cell lines and normal pancreatic cells was detected by Real time quantitative PCR. We observed that 10 MMP genes were consistently up-regulated in GEPIA and GSE62452 dataset. Among them, five highly expressed MMPs (MMP1, MMP3, MMP11, MMP14, MMP28) were closely related to poor clinical outcomes of PDAC patients. Cox regression analysis indicated MMP28 was a risk factor influencing the overall survival of patients. In the clinicopathological analysis, up-regulated MMP28 was significantly associated with higher tumor grade and the mutation status of TP53. GSEA analysis demonstrated that high expression of MMP28 was involved in "interferon_alpha_response" and "P53_pathway". Immune infiltration analysis showed that there was no correlation between MMP28 expression and immune cell infiltration. Single-cell sequencing analysis showed MMP28 has strong correlations with malignant cells and stromal cells infiltration in the tumor microenvironment. And MMP28 was highly expressed in various pancreatic cancer cell lines. In conclusion, MMP28 may represent a potential prognosis biomarker and novel therapeutic molecular targets for PDAC.

Exploration and validation of metastasis-associated genes for skin cutaneous melanoma.

Skin cutaneous melanoma is a malignant and highly metastatic skin tumor, and its morbidity and mortality are still rising worldwide. However, the molecular mechanisms that promote melanoma metastasis are unclear. Two datasets (GSE15605 and GSE46517) were retrieved to identify the differentially expressed genes (DEGs), including 23 normal skin tissues (N), 77 primary melanoma tissues (T) and 85 metastatic melanoma tissues (M). Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to explore the functions of the DEGs. We constructed protein-protein interaction network using the STRING database and Cytoscape software. Using the cytoHubba plugin of Cytoscape, we identified the most significant hub genes by five analytical methods (Degree, Bottleneck, MCC, MNC, and EPC). Hub gene expression was validated using the UALCAN website. Clinical relevance was investigated using The Cancer Genome Atlas resources. Finally, we explored the association between metastasis-associated genes and immune infiltrates through the Tumor Immune Estimation Resource (TIMER) database and performed drug-gene interaction analysis using the Drug-Gene Interaction database. A total of 294 specific genes were related to melanoma metastasis and were mainly involved in the positive regulation of locomotion, mitotic cell cycle process, and epithelial cell differentiation. Four hub genes (CDK1, FOXM1, KIF11, and RFC4) were identified from the cytoHubba plugin of Cytoscape. CDK1 was significantly upregulated in metastatic melanoma compared with primary melanoma, and high CDK1 expression was positively correlated with worse overall survival. Immune infiltration analysis revealed that CDK1 expression negatively correlated with macrophage infiltration (Rho = - 0.164, P = 2.02e-03) and positively correlated with neutrophil cells (Rho = 0.269, P = 2.72e-07) in SKCM metastasis. In addition, we identified that CDK1 had a close interaction with 10 antitumor drugs. CDK1 was identified as a hub gene involved in the progression of melanoma metastasis and may be regarded as a therapeutic target for melanoma patients to improve prognosis and prevent metastasis in the future.

Role of mitochondria on UV-induced skin damage and molecular mechanisms of active chemical compounds targeting mitochondria.

Mitochondria are the principal place of energy metabolism and ROS production, leading to mtDNA being especially sensitive to the impacts of oxidative stress. Our review aims to elucidate and update the mechanisms of mitochondria in UV-induced skin damage. The mitochondrial deteriorative response to UV manifests morphological and functional alterations, including mitochondrial fusion and fission, mitochondrial biogenesis, mitochondrial energy metabolism and mitophagy. Additionally, we conclude the effect and molecular mechanisms of active chemical components to protect skin from UV-induced damage via mitochondrial protection which have been described in the last five years, showing prospective prospects in cosmetics as new therapeutic targets.