Dual roles of demethylation in cancer treatment and cardio-function recovery.

There are no effective therapeutic targets or strategies that simultaneously inhibit tumour growth and promote cardiac function recovery. Here, we analyzed targets for cancer treatments and cardiac repair, with demethylation emerging as a common factor in these candidate lists. As DNA methyltransferase 1 (DNMT1) majorly responds to methylation, a natural compound library is screened, identifying dioscin as a novel agent targeted at DNMT1, widely used for heart diseases. Dioscin was found to reduce DNMT activities and inhibits growth in breast cancer cells. Combined with analyses of RNA-seq and MeDIP-seq, the promoters of antioxidant genes were demethylated after dioscin, recruiting NRF2 and elevating their expression. In Nrf2 knockout mice, the cardiac protection role of dioscin was blocked by Nrf2-loss. Furthermore, in tumour-bearing mice with hypertrophy, dioscin was observed to inhibit tumour growth and alleviate cardiac injury simultaneously. This study is the first to identify dioscin as a novel demethylation agent with dual functions of anti-cancer and cardio-protection.

Dioscin Alleviates Cardiac Dysfunction in Acute Myocardial Infarction via Rescuing Mitochondrial Malfunction.

Myocardial infarction is one of the most severe heart diseases, leading to sudden death. Currently, angiography and stenting are widely performed in clinics, yet more effective treatment is still needed. Herein, we presented that dioscin, a natural product, showed protective effect on infarcted hearts via mitochondrial maintenance. Upon dioscin treatment, cardiac dysfunction was alleviated, and remodeling is prevented. Mechanistically, disocin maintains mitochondria function through the maintenance of Kreb's cycle, and suppresion of ROS accumulation. In this way, by targeting mitochondrial dysfunction, dioscin is a potential drug for infarcted hearts.

Dioscin Attenuates Myocardial Ischemic/Reperfusion-Induced Cardiac Dysfunction through Suppression of Reactive Oxygen Species.

Myocardial ischemic/reperfusion (MI/R) is a leading cause of cardiovascular disease with high morbidity and mortality. However, the mechanisms underlying pathological reperfusion remain obscure. In this study, we found that dioscin, a natural product, could be a potential candidate for treating MI/R through modulating cardiac dysfunction. Mechanistically, our work revealed that dioscin could suppress the production of reactive oxygen species (ROS) via repressing the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2) and enhancing the expression of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx). These findings indicate that dioscin may be a potential candidate for therapeutic interventions in MI/R injury.

Dioscin elevates lncRNA MANTIS in therapeutic angiogenesis for heart diseases.

Dioscin has been widely used in clinics for coronary artery disease (CAD) treatment for years in China. However, the underlying mechanism for Dioscin-mediated cardioprotective effect has not been elucidated. Here, we showed that Dioscin significantly rescues the cardiac function in mouse model of myocardial infarction (MI), accompanied by the reduction of cardiac fibrosis and apoptosis, resulting from elevated angiogenesis. Mechanistically, Dioscin promotes the proliferation and migration of hypoxic endothelial cells via the up-regulation of lncRNA MANTIS, which serves as a scaffolding lncRNA within a chromatin remodeling complex. Meanwhile, it enables pol II binding to the transcription start sites, which leads to induced expression of angiogenesis-related genes, including SOX18, SMAD6, and COUP-TFII. Conversely, IncRNA MANTIS silencing prevents Dioscin-induced migration and angiogenesis in hypoxic endothelial cells. Taken together, these data provide new insights that clarifies the cardioprotective effects of Dioscin against myocardial infarcted injury and confirms the effect on angiogenic activity of endothelial cells. This will build a solid theoretical basis for clinical therapeutic strategies.

Diabetic nephropathy execrates epithelial-to-mesenchymal transition (EMT) via miR-2467-3p/Twist1 pathway.

Although diabetic nephropathy (DN) is induced by a complicate interplay of multiple factors, the underlying mechanisms remain poorly characterized, even the treatment. Herein, we show that both of DN patients and STZ-induced type 1 diabetic rat exhibit the reduction both of urinary and circulating miR-2467-3p. We identify a negative correlation between miR-2467-3p levels and renal dysfunction. Administration of miR-2467-3p prevents diabetes-induced renal dysfunction and represses renal fibrosis in STZ-induced type 1 diabetic rats. Conversely, anti-miR-2467 overexpression exacerbates renal dysfunction and fibrosis in STZ-induced rats. In diabetic condition, the reduction of miR-2467-3p promotes expression of Twist1, inducing epithelial-to-mesenchymal transition (EMT), resulting in renal fibrosis and kidney dysfunction. Together, our study presents miR-2467/Twist1/EMT as a regulatory axis of renal dysfunction in DN.

The 3' Untranslated Region Protects the Heart from Angiotensin II-Induced Cardiac Dysfunction via AGGF1 Expression.

The messenger RNA (mRNA) 3' untranslated regions (3' UTRs), as cis-regulated elements bound by microRNAs (miRNAs), affect their gene translation. However, the role of the trans-regulation of 3' UTRs during heart dysfunction remains elusive. Compared with administration of angiogenic factor with G-patch and forkhead-associate domains 1 (Aggf1), ectopic expression of Aggf1 with its 3' UTR significantly suppressed cardiac dysfunction in angiotensin II-infused mice, with upregulated expression of both Aggf1 and myeloid cell leukemia 1 (Mcl1). Along their 3' UTRs, Mcl1 and Aggf1 mRNAs share binding sites for the same miRNAs, including miR-105, miR-101, and miR-93. We demonstrated that the protein-coding Mcl1 and Aggf1 mRNAs communicate and co-regulate each other's expression through competition for these three miRNAs that target both transcripts via their 3' UTRs. Our results indicate that Aggf1 3' UTR, as a trans-regulatory element, accelerates the cardioprotective role of Aggf1 in response to hypertensive conditions by elevating Mcl1 expression. Our work broadens the scope of gene therapy targets and provides a new insight into gene therapy strategies involving 3' UTRs.

The Anti-apoptotic Role of 3'-Untranslational Region in Response to Angiotensin II via Mcl1 Expression.

Myeloid cell leukemia 1 (Mcl1), an abundant protein in the myocardium, plays an essential role in fibrosis and anti-inflammation in cardiomyocytes to prevent heart failure. However, whether Mcl1 3'-untranslated regions (3'-UTR) has the cardio-protecting function remains unclear. Down-regulation of Mcl1 was observed in adult mice heart tissues after Angiotensin II (Ang II) treatment. Consistent with in vivo results, the reduction of Mcl1 expression was identified in Ang II-treated neonatal cardiomyocytes. Mechanistically, Mcl1 3'-UTR prevented Ang II-induced cardiac apoptosis via up-regulation of Mcl1 and an angiogenic factor with a G-patch domain and a forkhead-associated domain 1 (Aggf1), which plays cardiac-protective role. Our work broadens the scope of gene therapy targets and provides a new insight into gene therapy strategies involving mRNAs' 3'-UTRs application.