p53 contributes to cardiovascular diseases via mitochondria dysfunction: A new paradigm.

Cardiovascular diseases (CVDs) are leading causes of global mortality; however, their underlying mechanisms remain unclear. The tumor suppressor factor p53 has been extensively studied for its role in cancer and is also known to play an important role in regulating CVDs. Abnormal p53 expression levels and modifications contribute to the occurrence and development of CVDs. Additionally, mounting evidence underscores the critical involvement of mitochondrial dysfunction in CVDs. Notably, studies indicate that p53 abnormalities directly correlate with mitochondrial dysfunction and may even interact with each other. Encouragingly, small molecule inhibitors targeting p53 have exhibited remarkable effects in animal models of CVDs. Moreover, therapeutic strategies aimed at mitochondrial-related molecules and mitochondrial replacement therapy have demonstrated their advantageous potential. Therefore, targeting p53 or mitochondria holds immense promise as a pioneering therapeutic approach for combating CVDs. In this comprehensive review, we delve into the mechanisms how p53 influences mitochondrial dysfunction, including energy metabolism, mitochondrial oxidative stress, mitochondria-induced apoptosis, mitochondrial autophagy, and mitochondrial dynamics, in various CVDs. Furthermore, we summarize and discuss the potential significance of targeting p53 or mitochondria in the treatment of CVDs.

Untargeted metabolomic analysis of ischemic injury in human umbilical vein endothelial cells reveals the involvement of arginine metabolism.

OBJECTIVE: In this study, differentially expressed metabolites of vascular endothelial cells were examined to further understand the metabolic regulation of ischemic injury by untargeted metabolomics. METHOD: Human umbilical vein endothelial cells (HUVECs) were selected to construct an ischemia model using oxygen-glucose deprivation (OGD) and 0, 3, 6, and 9 h of treatment. After that, cell survival levels were determined by CCK8 detection. Flow cytometry, ROS detection, JC-1 detection, and western blotting were used to measure apoptosis and oxidative stress in cells. Then, combined with UPLC Orbitrap/MS, we verified the impacted metabolism pathways by western blotting and RT‒PCR. RESULTS: CCK8 assays showed that the survival of HUVECs was decreased with OGD treatment. Flow cytometry and the expression of cleaved caspase 3 showed that the apoptosis levels of HUVECs increased following OGD treatment. The ROS and JC-1 results further suggested that oxidative stress injury was aggravated. Then, combined with the heatmap, KEGG and IPA, we found that arginine metabolism was differentially altered during different periods of OGD treatment. Furthermore, the expression of four arginine metabolism-related proteins, ASS1, ARG2, ODC1 and SAT1, was found to change during treatment. CONCLUSION: Arginine metabolism pathway-related proteins were significantly altered by OGD treatment, which suggests that they may have a potential role in ischemic injury.

LncRNA UCA1 promoted cisplatin resistance in lung adenocarcinoma with HO1 targets NRF2/HO1 pathway.

PURPOSE: Our previous experiments have demonstrated that lncRNA UCA1 (UCA1) promoted cisplatin resistance in lung adenocarcinoma (LUAD). This study aimed to explore the potential downstream target genes regulated by UCA1 and how this downstream gene promotes cisplatin resistance in LUAD. METHODS: Here, we measured the expression level of Heme oxygenase1 (HO1) in LUAD cell lines by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) based on UCA1 overexpression cell lines and UCA1 knockdown cell lines. HO1 was knocked down in the UCA1 overexpression cell line, and HO1 was overexpressed in the UCA1 knockdown cell line, and the half maximal inhibitory concentration (IC50) trends were observed by adding cisplatin containing a certain concentration gradient. Cell functional assays were performed to observe the changes in the biological behavior of HO1 after overexpression and knockdown, and the tumorigenic assay in nude mice was performed to verify the effect of UCA1 in regulating the growth and cisplatin resistance of HO1 on LUAD cells in vivo. RESULTS: The results showed that HO1 and UCA1 expression were both upregulated in LUAD tissues and LUAD cisplatin-resistant cell lines, and there was a significant positive correlation between the expression of HO1 and UCA1. In vitro experiments showed that HO1 overexpression could reverse the reduced sensitivity to cisplatin caused by UCA1 knockdown in A549/DDP cells, and HO1 knockdown could reduce cisplatin resistance in A549 UCA1 overexpressing cells. Tumorigenic assays in nude mice further confirmed the role of HO1 in the regulation of UCA1 by activating the NRF2/HO1 pathway against LUAD cisplatin resistance. CONCLUSION: Our findings suggested that UCA1 regulates HO1 targets the UCA1/NRF2-HO1 pathway to exert cisplatin resistance in LUAD.

circ_0086296 induced atherosclerotic lesions via the IFIT1/STAT1 feedback loop by sponging miR-576-3p.

Extensive inflammation of endothelial cells (ECs) facilitates atherosclerotic lesion formation. Circular RNA (circRNA) participates in atherosclerosis (AS)-related inflammation responses; however, whether and how circ_0086296 regulates atherosclerotic inflammation and lesions have not been investigated. Microarray analysis, quantitative real-time polymerase chain reaction, and fluorescence in situ hybridization assay were performed to detect the expression and location of hsa_circ_0086296 in human carotid artery plaques, aorta of atherosclerotic mice, and human umbilical vein endothelial cells (HUVECs). Sanger sequencing was used to verify the loop structure of circ_0086296. The relationship among circ_0086296, miR-576-3p, IFIT1, STAT1, and EIF4A3 was validated using bioinformatics, luciferase assay, RNA pull-down assay, and RNA immunoprecipitation. The atherosclerosis mouse model was used to evaluate the function of circ_0086296 in vivo. circ_0086296 expression was significantly upregulated in human carotid artery plaques, oxidized low-density lipoprotein (ox-LDL)-treated HUVECs, and the aorta of atherosclerotic mice. Functional analysis indicated that circ_0086296 promotes ECs injury in vitro and atherosclerosis progression in vivo. The mechanism analysis indicated that circ_0086296 sponged miR-576-3p to promote IFIT1-STAT1 expression. Moreover, STAT1 upregulated circ_0086296 expression, forming the circ_0086296/miR-576-3p/IFIT1/STAT1 feedback loop. Notably, inhibition of the circ_0086296/miR-576-3p/IFIT1 axis could block atherosclerotic lesion formation both in vivo and in vitro. Finally, circ_0086296 was overexpressed in exosomes of patients with atherosclerosis and exosomes of ox-LDL-treated ECs. Therefore, the circ_0086296/miR-576-3p/IFIT1/STAT1 feedback loop participates in atherosclerosis progression and contributes to the high circ_0086296 expression observed in the exosomes of serum of patients with atherosclerosis. This study sought to provide a deep understanding of the mechanisms underlying the aberrant EC phenotype in AS.

Super enhancer-LncRNA SENCR promoted cisplatin resistance and growth of NSCLC through upregulating FLI1.

BACKGROUND: Super enhancer-lncRNA smooth muscle and endothelial cell-enriched migration/differentiation-associated lncRNA (SENCR) were highly overexpressed in cisplatin-resistant A549/DDP cells, while the mechanism was unclear. METHODS: SE-lncRNA SENCR and FLI1 mRNA expression in A549/DDP cell, LAD tissues were detected. SENCR knockdown of A549/DDP cell and SENCR overexpression of cisplatin-sensitive A549 cell were constructed. Experiments of cell-confirmed function of SENCR and the correlation between SENCR and FLI1 were validated. RESULTS: The expression of SENCR and FLI1 mRNA in A549/DDP cell were both upregulated and mainly localized in the nucleus. Compared with DDP-sensitive tissues with disease relief, SENCR expression was higher in DDP-resistant tissues with disease progression from LAD. Knockdown of SENCR in A549/DDP reduced proliferation ability and cisplatin resistance, consistent with the decreased levels of proteins PCNA, MDMX, and P-gp. Besides, whatever without cisplatin or with 2 µg/ml cisplatin, knockdown of SENCR reduced the migration, invasion, and colony formation abilities of A549/DDP cell and promoted apoptosis. However, when SENCR was overexpressed in A549 cell, all above results were reversed. Mechanistically, FLI1 expression was reduced after knocking down SENCR, while overexpressing SENCR increased FLI1 expression. CONCLUSION: SE-LncRNA SENCR was upregulated in A549/DDP, which could promote cisplatin resistance and growth of NSCLC cell through upregulating FLI1 expression.

Inhibition of Phospholipase D1 mRNA Expression Slows Down the Proliferation Rate of Prostate Cancer Cells That Have Transited to Androgen Independence.

To explore the role of phospholipase D1 (PLD1) mRNA in transition of prostate cancer (PCa) cells to androgen independence, we used Arraystar Human LncRNA Microarray V3.0 to detect and compare the differential expression of PLD1 and its signaling pathway-related gene in standard androgen dependence prostate cancer (ADPC) cell line LNCaP before and after the occurrence of androgen independence prostate cancer (AIPC) transition. In addition, we used the shRNA lentiviral vector to inhibit the PLD1 mRNA expression and observed its effect on LNCaP cell proliferation after AIPC transition by using MTS method. The results showed that the expression level of PLD1 mRNA was increased by 373-fold after AIPC transition (P<0.05); the PI3K/AKT signaling pathway-related gene expression was also elevated (P<0.05); the growth rate of LNCaP cells that had transited to androgen independence was reduced by about 30% when the PLD1 mRNA expression was inhibited by the shRNA lentivirus as compared with the negative control group (P<0.05). All these results suggest that PLD1 mRNA and the related PI3K/AKT signaling pathway may play an important role in AIPC. Down-regulating the expression of PLD1 mRNA could to some extent inhibit the proliferation rate of PCa cells after AIPC transition.

Identification of the differential expression of serum microRNA in type 2 diabetes.

The identification of disease-specific alterations in miRNA expression and the ability to detect miRNAs in serum furnish the basis for identified potential research value. This study was aimed to characterize the expression of miRNAs in the serum samples from people with type 2 diabetes mellitus (T2DM) and healthy individuals in order to detect the differential expression of miRNAs in T2DM. In total, 582 participants were recruited. Microarray-based miRNA expression profiles were screened in pooled serum samples from two groups (T2DM and healthy control). The candidates' miRNAs were validated by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). Five significantly different serum miRNAs were identified in T2DM patients (hsa-miR-320d, hsa-miR-4534, hsa-miR-3960, hsa-miR-451a, and hsa-miR-572) compared to those in the serum of healthy controls. This study provided evidence that serum miRNAs had differential expressions between healthy controls and T2DM patients. These five differential expression miRNAs might be of help for subsequent study in T2DM.

The clinical diagnostic significance of cerebrospinal fluid D-lactate for bacterial meningitis.

BACKGROUND: To study the clinical and laboratory significance of D­lactate in the diagnosis of bacterial meningitis (BM). METHODS: The levels of D­lactate, L­lactate, IL-6, IL-8, and other biochemical markers were determined in 83 CSF samples from different types of meningitis and the controls. RESULTS: The CSF values of D­lactate, L­lactate, IL-6, IL-8, erythrocytes, leukocytes, and protein were higher in patients with BM than those in the controls and patients with viral meningitis. The levels of D­lactate, L­lactate, IL-6, and erythrocytes in the BM group were higher than those in the tuberculous meningitis group. At the cutoff 12.8 µmol/l, D­lactate showed the diagnostic sensitivity of 94.7%. D­lactate gave the area under the curve (AUC) 0.905, which was higher than those of other markers. Using multiple marker detection, the AUC reached 0.956, which was the highest among all the parameters. Pearson correlation analysis revealed that D­lactate was positively correlated to IL-6 and L­lactate (r=0.727, 0.789 and P=0.000, 0.000, respectively). CONCLUSIONS: THE CSF concentrations of D­lactate are significantly increased in the presence of BM. Measurement of D­lactate provides a rapid diagnosis and differential diagnosis for BM. Combination of D­lactate with other biochemical markers improves the specificity.