Ononin alleviates endoplasmic reticulum stress in doxorubicin-induced cardiotoxicity by activating SIRT3.

Doxorubicin (DOX) is a potent anthracycline antineoplastic drug. However, its dose-dependent cardiotoxicity limits its clinical application. Ononin is a natural isoflavone glycoside that is crucial in modulating apoptosis-related signaling pathways. In this study, we assessed the possible cardioprotective effects of ononin in DOX-induced cardiotoxicity and elucidated the underlying molecular mechanisms. In vitro and in vivo assessments were performed using DOX-treated H9C2 cells and rats, respectively. First, DOX was injected into the tail veins of Wistar rats to induce cardiomyopathy. Next, rats in the DOX + Ononin30 and DOX + Ononin60 groups were intragastrically administered ononin two weeks before DOX treatment. H9C2 cells were treated with vehicle or DOX with or without ononin. Next, 3-TYP was used to determine the relationship between endoplasmic reticulum (ER) stress and sirtuin 3 (SIRT3) expression. Ononin treatment ameliorated DOX-induced myocardial injury as determined by echocardiography. Furthermore, ononin partially restored DOX-induced cardiac dysfunction; the left ventricular ejection fraction (LVEF) and left ventricular systolic fractional shortening (LVFS) increased after pre-treatment with ononin. Further, ononin suppressed DOX-induced ER stress and apoptosis in rat cardiomyocytes and H9C2 cells. The Bax/Bcl-2 ratio and 78-kD glucose-regulated protein (GRP78) and CCAAT enhancer-binding protein (CHOP) expression levels were higher in the DOX-treated group than in the control group but ononin treatment improved these parameters. These effects are associated with SIRT3 activity. Moreover, 3-TYP blocked the ononin-mediated protective effects. Hence, ononin positively affected DOX-induced cardiotoxicity by inhibiting ER stress and apoptosis, possibly mediated by stimulation of the SIRT3 pathway.

LncRNA GHET1 from bone mesenchymal stem cell-derived exosomes improves doxorubicin-induced pyroptosis of cardiomyocytes by mediating NLRP3.

Doxorubicin (DOX) is an important chemotherapeutic agent for the treatment of hematologic tumors and breast carcinoma. However, its clinical application is limited owing to severe cardiotoxicity. Pyroptosis is a form of programmed cell death linked to DOX-induced cardiotoxicity. Bone mesenchymal stem cell-derived exosomes (BMSC-Exos) and endothelial progenitor cells-derived exosomes (EPC-Exos) have a protective role in the myocardium. Here we found that BMSC-Exos could improve DOX-induced cardiotoxicity by inhibiting pyroptosis, but EPC-Exos couldn't. Compared with EPCs-Exo, BMSC-Exo-overexpressing lncRNA GHET1 more effectively suppressed pyroptosis, protecting against DOX-induced cardiotoxicity. Further studies showed that lncRNA GHET1 effectively decreased the expression of Nod-like receptor protein 3 (NLRP3), which plays a vital role in pyroptosis by binding to IGF2 mRNA-binding protein 1 (IGF2BP1), a non-catalytic posttranscriptional enhancer of NLRP3 mRNA. In summary, lncRNA GHET1 released by BMSC-Exo ameliorated DOX-induced pyroptosis by targeting IGF2BP1 to reduce posttranscriptional stabilization of NLRP3.

METTL14 suppresses pyroptosis and diabetic cardiomyopathy by downregulating TINCR lncRNA.

N6-methyladenosine (m6A) is one of the most important epigenetic regulation of RNAs, such as lncRNAs. However, the underlying regulatory mechanism of m6A in diabetic cardiomyopathy (DCM) is very limited. In this study, we sought to define the role of METTL14-mediated m6A modification in pyroptosis and DCM progression. DCM rat model was established and qRT-PCR, western blot, and immunohistochemistry (IHC) were used to detect the expression of METTL14 and TINCR. Gain-and-loss functional experiments were performed to define the role of METTL14-TINCR-NLRP3 axis in pyroptosis and DCM. RNA pulldown and RNA immunoprecipitation (RIP) assays were carried out to verify the underlying interaction. Our results showed that pyroptosis was tightly involved in DCM progression. METTL14 was downregulated in cardiomyocytes and hear tissues of DCM rat tissues. Functionally, METTL14 suppressed pyroptosis and DCM via downregulating lncRNA TINCR, which further decreased the expression of key pyroptosis-related protein, NLRP3. Mechanistically, METTL14 increased m6A methylation level of TINCR gene, resulting in its downregulation. Moreover, the m6A reader protein YTHDF2 was essential for m6A methylation and mediated the degradation of TINCR. Finally, TINCR positively regulated NLRP3 by increasing its mRNA stability. To conclude, our work revealed the novel role of METTL14-mediated m6A methylation and lncRNA regulation in pyroptosis and DCM, which could help extend our understanding the epigenetic regulation of pyroptosis in DCM progression.

Machine learning algorithms identifying the risk of new-onset ACS in patients with type 2 diabetes mellitus: A retrospective cohort study.

Background: In recent years, the prevalence of type 2 diabetes mellitus (T2DM) has increased annually. The major complication of T2DM is cardiovascular disease (CVD). CVD is the main cause of death in T2DM patients, particularly those with comorbid acute coronary syndrome (ACS). Although risk prediction models using multivariate logistic regression are available to assess the probability of new-onset ACS development in T2DM patients, none have been established using machine learning (ML). Methods: Between January 2019 and January 2020, we enrolled 521 T2DM patients with new-onset ACS or no ACS from our institution's medical information recording system and divided them into a training dataset and a testing dataset. Seven ML algorithms were used to establish models to assess the probability of ACS coupled with 5-cross validation. Results: We established a nomogram to assess the probability of newly diagnosed ACS in T2DM patients with an area under the curve (AUC) of 0.80 in the testing dataset and identified some key features: family history of CVD, history of smoking and drinking, aspartate aminotransferase level, age, neutrophil count, and Killip grade, which accelerated the development of ACS in patients with T2DM. The AUC values of the seven ML models were 0.70-0.96, and random forest model had the best performance (accuracy, 0.89; AUC, 0.96; recall, 0.83; precision, 0.91; F1 score, 0.87). Conclusion: ML algorithms, especially random forest model (AUC, 0.961), had higher performance than conventional logistic regression (AUC, 0.801) for assessing new-onset ACS probability in T2DM patients with excellent clinical and diagnostic value.

Repair effect of the poly (D,L-lactic acid) nanoparticle containing tauroursodeoxycholic acid-eluting stents on endothelial injury after stent implantation.

Background: Chronic endoplasmic reticulum stress (ERS) plays a crucial role in cardiovascular diseases. Thus, it can be considered a therapeutic target for these diseases. In this study, poly (D,L-lactic acid) (PDLLA) nanoparticle-eluting stents loaded with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, was fabricated to assess their ability to reduce endothelial cell apoptosis and promote re-endothelialization after stent implantation. Materials and methods: PDLLA nanoparticles loaded with TUDCA were prepared via the emulsification-solvent evaporation method. The cumulative release rates of TUDCA were measured in vitro via high-performance liquid chromatography. The carotid arteries of rabbits were subsequently implanted with stents in vivo. The rabbits were then sacrificed after 4 weeks for scanning electron microscopy. Meanwhile, TUDCA concentration in the homogenate of the peripheral blood and distal vascular tissue after stent implantation was measured. The effect of TUDCA on ERS, apoptosis, and human umbilical vein endothelial cell (HUVEC) function was investigated in vitro by performing cell migration assay, wound healing assay, cell proliferation assays, endoplasmic reticulum (ER)-specific fluorescence staining, immunofluorescence, and western blotting. Results: TUDCA nanoparticles were released slowly over 28 days. In addition, TUDCA-eluting stents enhanced re-endothelialization and accelerated the recovery of endotheliocytes in vivo. ERS and apoptosis significantly increased in H2O2-treated HUVECs in vitro. Meanwhile, TUDCA reduced apoptosis and improved function by inhibiting ERS in H2O2-treated HUVECs. Decreased rates of apoptosis and ERS were observed after silencing XBP-1s in H2O2-treated HUVECs. Conclusion: TUDCA can inhibit apoptosis and promote re-endothelialization after stent implantation by inhibiting IRE/XBP1s-related ERS. These results indicate the potential therapeutic application of TUDCA as a drug-coated stent.

Fucoidan from Fucus vesiculosus attenuates doxorubicin-induced acute cardiotoxicity by regulating JAK2/STAT3-mediated apoptosis and autophagy.

Doxorubicin (DOX) is well-known for its potent antitumor activity but limited by its multiple and serious adverse effects. A major adverse effect is acute cardiotoxicity; yet, its mechanism has not been elucidated. Fucoidan is a multifunctional and nontoxic polysaccharide that is widely studied because of its favorable biological activities and safety. Hence, we proposed that fucoidan may play a protective role in DOX-induced acute cardiotoxicity without causing additional side effects. Sprague-Dawley rats were injected intraperitoneally with a single high dose of DOX to induce acute cardiac injury. Fucoidan was administered orally before DOX injection and AG490, a JAK2 inhibitor, was applied to verify the participation of the JAK2/STAT3 pathway. In vitro, H9C2 cells were treated with the same drugs at different concentrations and intervention times. in vivo and in vitro results demonstrated that DOX administration induced myocardial damage accompanied by acceleratory apoptosis and deficient autophagy in heart tissues or cells, which could be significantly improved by fucoidan supplement. AG490 partly abolished the cardioprotective effects of fucoidan, suggesting the involvement of JAK2 signaling. Additionally, western blotting revealed DOX-induced JAK2/STAT3 pathway activation, which was enhanced by fucoidan and weaken by AG490. Hence, fucoidan exerted a favorable effect on DOX-induced cardiotoxicity by enhancing autophagy and suppressing apoptosis in a JAK2/STAT3-dependent manner, which may provide a promising and novel therapeutic strategy against negative chemotherapy-induced effects.