Identification of sequence polymorphisms in the mitochondrial deoxyribonucleic acid displacement-loop region as risk factors for systemic lupus erythematosus.

OBJECTIVES: This study aims to evaluate the relationship between sequence polymorphisms (SNPs) in the displacement-loop (D-loop) region of mitochondrial deoxyribonucleic acid (mtDNA) and systemic lupus erythematosus (SLE) in Chinese female patients. PATIENTS AND METHODS: This cross-sectional study was conducted between May 2017 and October 2017. The mtDNA was extracted from the peripheral blood of 97 female SLE patients (mean age 40.8 years; range, 20 to 79 years) and 108 age-matched healthy controls (mean age 48.7 years; range, 22 to 78 years). The SNPs of mtDNA D-loop were verified by polymerase chain reaction amplification and sequence analysis. The allele frequencies of D-loop region were compared by the Chi-square test between SLE and control groups. RESULTS: The SNP accumulation in SLE patients was significantly higher than that in the controls (p=0.027, 95% confidence interval [CI]: 0.075, 1.210). The frequencies of the major alleles of the nucleotides 73G/A (p<0.001, odds ratio [OR]=1.241) and 195T/C (p=0.047, OR=4.318) as well as the minor allele of nucleotide 199T/C (p=0.048, OR=0.279) were significantly higher in the SLE patients than in the controls, which indicated that 73G, 195T and 199C allele in the D-loop of mtDNA were associated with the risk of SLE. Further analysis indicated that the reactive oxygen species level in the SLE patients was significantly higher than that of controls (mean fluorescence intensity ± standard deviation: 3054.333±256.099 vs. 2099.167±599.662, p=0.009, 95% CI: 321.243, 1589.091). CONCLUSION: This study indicated the SNPs in the mtDNA may associated with the risk of SLE. Analysis of SNPs in the mitochondrial D-loop may help identify individuals who are at high risk of developing SLE.

Hydrazinocurcumin Induces Apoptosis of Hepatocellular Carcinoma Cells Through the p38 MAPK Pathway.

Hydrazinocurcumin (HZC), a synthetic derivative of curcumin (CUR), has been documented to show anticancer potential in impeding tumor growth in several cancers, including hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms remain unclear. This study aimed to explore the function and underlying mechanisms of HZC on HCC cells, which may involve the p38 mitogen activated protein kinase (MAPK) pathway. HZC was first purified and identified. HepG2 cells were then subjected to treatment with HZC or CUR of different concentrations and p38 MAPK signaling inhibitor (SB203580) to verify their effects on HCC cell apoptosis and proliferation. Furthermore, the functional relevance between HZC and the p38 MAPK pathway in HCC was examined. It was observed that 40 µM HZC exhibited the best pro-apoptosis effect in HCC cells. HZC was found to inhibit HCC cell proliferation and promote apoptosis, the effect of which was stronger than 5-fluorouracil (5-FU). More importantly, the anti-oncogenic effect of HZC and 5-FU was implicated with activation of the p38 MAPK pathway. In vivo experimental results showed that HZC inhibited tumor growth more effectively than 5-FU through the p38 MAPK pathway. These results provide evidence that HZC exerted anti-oncogenic and pro-apoptosis effects in HCC cells through activation of the p38 MAPK pathway.

Downregulation of histone methyltransferase SET8 inhibits progression of hepatocellular carcinoma.

The expression of lysine methyltransferase SET8, which is involved in carcinogenesis of many types of human cancers through monomethylation of histone H4 lysine 20 (H4K20), is associated with the prognosis of hepatocellular carcinoma (HCC). We performed a functional analysis for SET8 to assess its effect on HCC progression. SET8 knockdown inhibited proliferation, migration and invasion of HCC cells. SET8 knockdown also inhibited tumour growth in a human xenograft mouse model. Overexpression of SET8 displayed the reverse effect, while treatment with the SET8 inhibitor UNC0379 produced an effect similar to SET8 knockdown. In addition, drug sensitivity testing in SET8-siRNA transfected HCC cells indicated that docetaxel inhibited cell growth dramatically, as demonstrated by the Cell Counting Kit-8 (CCK-8) assay. Furthermore, gene expression microarray analysis showed that genes altered after SET8 knockdown were clustered in pathways related to tumorigenesis and metastasis. Our data suggests that targeting SET8 for HCC therapy can inhibit the proliferation and invasion of HCC cells as well as increase their sensitivity to chemotherapy.

Development of a Prognostic Signature Based on Single-Cell RNA Sequencing Data of Immune Cells in Intrahepatic Cholangiocarcinoma.

Analysis of single-cell RNA sequencing (scRNA-seq) data of immune cells from the tumor microenvironment (TME) may identify tumor progression biomarkers. This study was designed to investigate the prognostic value of differentially expressed genes (DEGs) in intrahepatic cholangiocarcinoma (ICC) using scRNA-seq. We downloaded the scRNA-seq data of 33,991 cell samples, including 17,090 ICC cell samples and 16,901 ICC adjacent tissue cell samples regarded as normal cells. scRNA-seq data were processed and classified into 20 clusters. The immune cell clusters were extracted and processed again in the same way, and each type of immune cells was divided into several subclusters. In total, 337 marker genes of macrophages and 427 marker genes of B cells were identified by comparing ICC subclusters with normal subclusters. Finally, 659 DEGs were obtained by merging B cell and macrophage marker genes. ICC sample clinical information and gene expression data were downloaded. A nine-prognosis-related-gene (PRG) signature was established by analyzing the correlation between DEGs and overall survival in ICC. The robustness and validity of the signature were verified. Functional enrichment analysis revealed that the nine PRGs were mainly involved in tumor immune mechanisms. In conclusion, we established a PRG signature based on scRNA-seq data from immune cells of patients with ICC. This PRG signature not only reflects the TME immune status but also provides new biomarkers for ICC prognosis.