Mycobacterium tuberculosis Rv2653 Protein Promotes Inflammation Response by Enhancing Glycolysis.

Mycobacterium tuberculosis (M.tb) infection causes the communicable disease tuberculosis (TB), a major disease and one of the leading causes of death worldwide. The protein encoded by the region of deletion (RD) in M.tb mediates the pathogenic properties of M.tb by inducing an inflammatory response or disrupting host cell metabolism. We cloned and purified the Rv2653 protein from RD13 to explore its regulatory effects on host macrophages. We found that Rv2653 promoted glycolysis and upregulated the expression of key glycolytic enzymes, namely, hexokinase 2 (HK2) and lactate dehydrogenase-A (LDHA) in human leukemia monocytic (THP1) cells. Furthermore, the induction of glycolysis by Rv2653 contributes to the activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome. Rv2653 activated the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, and the mTORC1 inhibitor NR1 blocked Rv2653-induced HK2, LDHA, and NLRP3 expression. siRNA interfering with HK2 or LDHA significantly inhibited the activation of NLRP3 inflammasome by Rv2653, blocked Rv2653-triggered inflammatory factors interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, reactive oxygen species (ROS), and nitric oxide (NO), and promoted the survival of Bacillus Calmette-Guerin (BCG) in THP1 cells. Overall, Rv2653 promoted glycolysis by activating the mTORC1 signaling pathway, activating the NLRP3 inflammasome, and releasing inflammatory factors, ultimately inhibiting the intracellular survival of BCG in THP1 cells. Therefore, we revealed that anti-M.tb immune mechanisms induced by Rv2653 contribute to the development of new anti-TB strategies.

Role of high-mobility group box 1 in cancer. / 高迁移率族蛋白B1在肿瘤中的作用.

High-mobility group box 1 (HMGB1) is a non-histone nuclear protein in most eukaryocytes. Inside the nucleus, HMGB1 plays an important role in several DNA events such as DNA repair, transcription, telomere maintenance, and genome stability. While outside the nucleus, it fulfils more complicated functions, including promoting cell proliferation, inflammation, angiogenesis, immune tolerance and immune escape, which may play a pro-tumoral role.Meanwhile, HMGB1 acts as an anti-tumoral protein by regulating immune cell recruitment and inducing immunogenic cell death (ICD) during the carcinogenesis process. Therefore, abnormal expression of HMGB1 is associated with oncogenesis, development, and metastasis of cancer, which may play a dual role of pro-tumor and anti-tumor.

CYP2J2-produced epoxyeicosatrienoic acids contribute to the ferroptosis resistance of pancreatic ductal adenocarcinoma in a PPARγ-dependent manner. / CYP2J2介导生成的EETs通过PPARÎ³ä¿ƒè¿›èƒ°è ºå¯¼ç®¡è ºç™Œé“æ­»äº¡æŠµæŠ—.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant digestive tract tumors with a poor prognosis and high recurrence rate. Recently, ferroptosis resistance has been found in PDAC. However, the underlying mechanism of ferroptosis resistance has not been fully elucidated. Cytochrome P450 2J2 (CYP2J2) is the main enzyme which mediates arachidonic acid to produce epoxyeicosatrienoic acids (EETs) in human tissues. It has been reported that EETs involve in the development of cancer, while the roles of EETs in PDAC and ferroptosis remain unclear.This study aims to explore the effect of CYP2J2/EETs on ferroptosis of human pancreatic ductal adenocarcinoma cells PANC-1 cells and the underlying mechanisms. METHODS: The tumor tissues and para-carcinoma tissues of 9 patients with PDAC were collected and the expression of CYP2J2 was detected with real-time PCR and Western blotting. Enzyme-linked immunosorbent assay (ELISA) was used to detect the level of 8,9-dihydroxyeicosatrienoic acid (8,9-DHET), and the degradation product of 8,9-epoxyeicosa-trienoic acid (8,9-EET). PANC-1 cells were used in this study. The ferroptosis inducer erastin was used to induce ferroptosis. The intracellular long-chain acyl-CoA synthetase 4 (ACSL4) protein level, lactate dehydrogenase (LDH) activity, malondialdehyde (MDA) content, Fe2+ concentration, and cell survival were detected. The 8,9-EET was pretreated to observe its effect on erastin-induced ferroptosis in PANC-1 cells. Lentivirus was used to construct a CYP2J2 knockdown cell line to observe its effect on the ferroptosis of PANC-1 cells induced by erastin. A peroxisome proliferation-activated receptor γ (PPARγ) blocker was used to observe the effect of 8,9-EET on erastin-induced glutathione peroxidase 4 (GPX4) and MDA content in PANC-1 cells. RESULTS: High expression of CYP2J2 was found in PDAC, accompanied by an increased level of 8,9-DHET. The 8,9-EET pretreatment significantly attenuated the PANC-1 cell death induced by erastin. The 8,9-EET reduced the Fe2+ concentration, LDH activity and MDA content, and ACSL4 protein expression in erastin-treated PANC-1 cells. The 8,9-EET also restored the ferroportin (FPN) and ferroptosis suppressor protein 1 (FSP1) mRNA expressions in erastin-treated PANC-1 cells. But CYP2J2 knockdown exacerbated the erastin-induced ferroptosis in PANC-1 cells. Besides, CYP2J2 knockdown furtherly down-regulated the gene expression of FPN and FSP1. The 8,9-EET increased the expression of GPX4 in the erastin-treated PANC-1 cells, which was eliminated by a PPARγ blocker GW9662. And GW9662 abolished the anti-ferroptosis effects of 8,9-EET. CONCLUSIONS: CYP2J2/EETs are highly expressed in PDAC tissues. EETs inhibit the ferroptosis via up-regulation of GPX4 in a PPARγ-dependent manner, which contributes to the ferroptosis resistance of PDAC.

Association of Polymorphism rs1045411 in the HMGB1 Gene with Cancer Risk: Evidence from a Meta-analysis.

The high-mobility group box protein 1 (HMGB1) rs1045411 polymorphism has been demonstrated to be associated with cancer risk in some studies. However, the results regarding this topic are inconsistent. A meta-analysis was applied to elucidate the association between the HMGB1 rs1045411 polymorphism and cancer risk. Ten relevant studies were subjected to our analysis, and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. In total, of 3,918 cases and 5,296 controls were included in this study. The pooled ORs were calculated using a random-effects or fixed-effects model according to the heterogeneity. The pooled results revealed that TT genotype was significantly related to increased cancer risk in the comparisons of TT vs. CC+TC (OR=1.35; 95% CI: 1.09-1.67; p=0.005). Though no statistical significance was achieved between HMGB1 rs1045411 polymorphism and cancer risk in other four genetic models (T vs. C: OR=1.08, 95% CI 0.90-1.30; TC vs. CC: OR=1.01, 95% CI 0.82-1.24; CC vs. TC+TT: OR=0.95, 95% CI 0.77-1.18; TT vs. CC: OR=1.42; 95% CI 0.98-2.05), a trend of increased risk could be drawn. In the subgroup analysis by type of malignancy and ethnicity, no obvious difference was found in the tumour risk regarding the HMGB1 rs1045411 polymorphism amongst the cancer types except for breast cancer (OR=1.94; 95% CI: 1.05-3.59; p=0.03) and hepatocellular carcinoma (OR=1.82; 95% CI: 1.15-2.88; p=0.01), while rs1045411 polymorphism was positively associated with risks of cancer amongst Hans (OR=1.37; 95% CI: 1.11-1.69; p=0.004) rather than Caucasians (OR=0.89; 95% CI: 0.26-3.02; p=0.01). These results suggest that the HMGB1 rs1045411 polymorphism might be associated with increased cancer risk.