SP1-SYNE1-AS1-miR-525-5p feedback loop regulates Ang-II-induced cardiac hypertrophy.

Cardiac hypertrophy (CH) has become a huge threat to human health. Recent years, long noncoding RNAs (lncRNAs) have been studied in human diseases, including CH. According to bioinformatics analysis, 10 lncRNAs possibly involved in the progression of CH were screened out. Among which, lncRNA SYNE1 antisense RNA 1 (SYNE1-AS1) could be upregulated by Angiotensin II (Ang-II) in cardiomyocytes. Thus, we chose SYNE1-AS1 to do further study. To identify the biological function of SYNE1-AS1 in CH, SYNE1-AS1 was silenced in Ang-II-induced cardiomyocytes. Results of immunofluorescence staining demonstrated that increased cell surface area in Ang-II-induced cardiomyocytes was reduced by SYNE1-AS1 knockdown. Moreover, the hypertrophic responses were attenuated by SYNE1-AS1 knockdown. Mechanically, SYNE1-AS1 positively regulated Sp1 transcription factor (SP1) by sponging microRNA-525-5p (miR-525-5p). On the basis of previous reports, SP1 can transcriptionally activate lncRNAs. Therefore, we investigated the interaction between SP1 and SYNE1-AS1 promoter. Intriguingly, SYNE1-AS1 was activated by SP1. At last, rescue assays demonstrated the function of SP1-SYNE1-AS1 axis in CH. In conclusion, SP1-induced upregulation of lncRNA SYNE1-AS1 promoted CH via miR-525-5p/SP1 axis.

Silencing MFHAS1 Induces Pyroptosis via the JNK-activated NF-κB/Caspase1/ GSDMD Signal Axis in Breast Cancer.

INTRODUCTION: Breast cancer has emerged as the most widespread cancer globally surpassing lung cancer, and has become a primary cause of mortality among women. While MFHAS1 has been implicated in the pathophysiology of various diseases, its precise involvement in breast cancer remains unclear. METHODS: This study endeavors to elucidate the regulatory function of MFHAS1 in breast cancer cell pyroptosis and the associated molecular mechanisms. Our findings indicate that the inhibition of MFHAS1 can impede the proliferation and invasion of breast cancer cells, while also inducing cell pyroptosis via caspase1-dependent activation of GSDMD. RESULTS: This process results in the cleavage of cell membranes, leading to the release of inflammatory factors and LDH. Subsequent investigations revealed that the silencing of MFHAS1 can promote JNK phosphorylation, thereby activating the JNK signaling cascade. Notably, this effect can be counteracted by the JNK-specific inhibitor sp600125. Ultimately, our investigation substantiated the identical function of MFHAS1 in breast cancer tissue derived from animal models. CONCLUSION: To summarize, our findings demonstrate that the inhibition of MFHAS1 elicits pyroptosis in human breast cancer cells through the facilitation of JNK phosphorylation and the activation of the downstream NF-κB/caspase-1/GSDMD signaling cascade, thereby proposing the prospect of MFHAS1 as a viable therapeutic target for breast cancer.

The Mechanism Actions of Astragaloside IV Prevents the Progression of Hypertensive Heart Disease Based on Network Pharmacology and Experimental Pharmacology.

Astragaloside IV (AS-IV) has been used to treat cardiovascular disease. However, whether AS-IV exerts a protective effect against hypertensive heart disease has not been investigated. This study aimed to investigate the antihypertensive and cardioprotective effects of AS-IV on L-NAME-induced hypertensive rats via network pharmacology and experimental pharmacology. The network pharmacology and bioinformatics analyses were performed to obtain the potential targets of AS-IV and hypertensive heart disease. The rat hypertension model was established by administrated 50 mg/kg/day of L-NAME for 5 weeks. Meanwhile, hypertension rats were intragastrically administrated with vehicle or AS-IV or fosinopril for 5 weeks. Cardiovascular parameters (systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rates, and body weight), cardiac function parameters (LVEDd, LVEDs, and fractional shortening), cardiac marker enzymes (creatine kinase, CK-MB, and lactate dehydrogenase), cardiac hypertrophy markers (atrial natriuretic peptide and brain natriuretic peptide), endothelial function biomarkers (nitric oxide and eNOS), inflammation biomarkers (IL-6 and TNF-α) and oxidative stress biomarkers (SOD, MDA, and GSH) were measured and cardiac tissue histology performed. Network pharmacological analysis screened the top 20 key genes in the treatment of hypertensive heart disease treated with AS-IV. Besides, AS-IV exerted a beneficial effect on cardiovascular and cardiac function parameters. Moreover, AS-IV alleviated cardiac hypertrophy via down-regulating the expression of ANP and BNP and improved histopathology changes of cardiac tissue. AS-IV improved endothelial function via the up-regulation of eNOS expression, alleviated oxidative stress via increasing antioxidant enzymes activities, and inhibited cardiac inflammation via down-regulating IL-6 and TNF-α expression. Our findings suggested that AS-IV is a potential therapeutic drug to improve L-NAME-induced hypertensive heart disease partly mediated via modulation of eNOS and oxidative stress.

Suppression of miR-708 inhibits the Wnt/ß-catenin signaling pathway by activating DKK3 in adult B-all.

Inactivation of Dickkopf-3 (DKK3) is closely associated with a poor prognosis in various solid tumor and hematologic malignancies. Promoter hypermethylation is one potential cause of DKK3 inactivation. However, whether other mechanisms lead to DKK3 inactivation and the subsequent effects of these inactivations on cell proliferation and the Wnt signaling pathway in adult B acute lymphoblastic leukemia (B-ALL) remain unclear. In the present study, we found that low DKK3 expression levels were associated with high miR-708 expression and promoter hypermethylation in adult B-ALL. miR-708 was confirmed to directly decrease DKK3 expression in Nalm-6 and BALL-1 cells. Additionally, a miR-708 inhibitor decreased cell proliferation mainly through apoptosis and cell cycle arrest at the G1 phase, and these effects were eliminated by DKK3 siRNA treatment. Moreover, the demethylating agent 5-aza-2'-deoxycytidine (5-aza) decreased the methylation state of the DKK3 promoter based on methylation-specific PCR (MSP) and bisulfite genomic sequencing PCR (BSP), although this demethylation effect was not enhanced by the miR-708 inhibitor. The miR-708 inhibitor or 5-aza significantly increased DKK3 expression and decreased p-GSK3ß, cyclin D1 and nuclear and cytoplasmic ß-catenin protein expression, indicating that the Wnt/ß-catenin signaling pathway was inhibited. These effects became more pronounced when the miR-708 inhibitor and 5-aza were used simultaneously. These findings provide greater insights into the mechanisms that increase DKK3 expression and suggest that a miR-708 inhibitor and 5-aza might be useful as targeted therapies for adult B-ALL.

Rapamycin restores p14, p15 and p57 expression and inhibits the mTOR/p70S6K pathway in acute lymphoblastic leukemia cells.

The aim of the present study was to investigate the effects of rapamycin and its underlying mechanisms on acute lymphoblastic leukemia (ALL) cells. We found that the p14, p15, and p57 genes were not expressed in ALL cell lines (Molt-4 and Nalm-6) and adult ALL patients, whereas mTOR, 4E-BP1, and p70S6K were highly expressed. In Molt-4 and Nalm-6 cells exposed to rapamycin, cell viability decreased and the cell cycle was arrested at the G1/S phase. Rapamycin restored p14, p15, and p57 gene expression through demethylation of the promoters of these genes. As expected, rapamycin also increased p14 and p15 protein expression in both Molt-4 and Nalm-6 cells, as well as p57 protein expression in Nalm-6 cells. Rapamycin additionally decreased mTOR and p70S6K mRNA levels, as well as p70S6K and p-p70S6K protein levels. However, depletion of mTOR by siRNA did not alter the expression and promoter methylation states of p14, p15, and p57. These results indicate that the inhibitory effect of rapamycin may be due mainly to increased p14, p15, and p57 expression via promoter demethylation and decreased mTOR and p70S6K expression in ALL cell lines. These results suggest a potential role for rapamycin in the treatment of adult ALL.