Metformin promotes the survival of transplanted cardiosphere-derived cells thereby enhancing their therapeutic effect against myocardial infarction

The CDC differentiation at 4 weeks after transplantation analyzed by immunostaining. A–C: Sections of hearts were immunostained with antibodies to (A) the cardiomyocyte marker tropomyosin, (B) the endothelial cell marker von-Willebrand Factor (vWF), and (C) the smooth muscle cell marker α-smooth muscle actin (α-SMA). Antibody to GFP was used for identifying surviving CDC-derived cells and DAPI was used for identifying nuclei. Scale bars = 20 μm. DAPI 4′,6-diamidino-2-phenylindole. (PDF 178 kb

Ginsenoside Rg1 Alleviates Podocyte Injury Induced by Hyperlipidemia via Targeting the mTOR/NF-κB/NLRP3 Axis

Background. Podocyte injury plays an important role in diabetic nephropathy (DN). The aim of this study was to determine the potential therapeutic effects of the ginsenoside Rg1 on hyperlipidemia-stressed podocytes and elucidate the underlying mechanisms. Methods. In vitro and in vivo models of DN were established as previously described, and the expression levels of relevant markers were analyzed by Western blotting, real-time Polymerase Chain Reaction (PCR), immunofluorescence, and immunohistochemistry. Results. Ginsenoside Rg1 alleviated pyroptosis in podocytes cultured under hyperlipidemic conditions, as well as in the renal tissues of diabetic rats, and downregulated the mammalian target of rapamycin (mTOR)/NF-κB pathway. In addition, Rg1 also inhibited hyperlipidemia-induced NLRP3 inflammasome in the podocytes, which was abrogated by the mTOR activator L-leucine (LEU). The antipyroptotic effects of Rg1 manifested as improved renal function in the DN rats. Conclusion. Ginsenoside Rg1 protects podocytes from hyperlipidemia-induced damage by inhibiting pyroptosis through the mTOR/NF-κB/NLRP3 axis, indicating a potential therapeutic function in DN

Lycopene Protects against Hypoxia/Reoxygenation Injury by Alleviating ER Stress Induced Apoptosis in Neonatal Mouse Cardiomyocytes.

Endoplasmic reticulum (ER) stress induced apoptosis plays a pivotal role in myocardial ischemia/reperfusion (I/R)-injury. Inhibiting ER stress is a major therapeutic target/strategy in treating cardiovascular diseases. Our previous studies revealed that lycopene exhibits great pharmacological potential in protecting against the I/R-injury in vitro and vivo, but whether attenuation of ER stress (and) or ER stress-induced apoptosis contributes to the effects remains unclear. In the present study, using neonatal mouse cardiomyocytes to establish an in vitro model of hypoxia/reoxygenation (H/R) to mimic myocardium I/R in vivo, we aimed to explore the hypothesis that lycopene could alleviate the ER stress and ER stress-induced apoptosis in H/R-injury. We observed that lycopene alleviated the H/R injury as revealed by improving cell viability and reducing apoptosis, suppressed reactive oxygen species (ROS) generation and improved the phosphorylated AMPK expression, attenuated ER stress as evidenced by decreasing the expression of GRP78, ATF6 mRNA, sXbp-1 mRNA, eIF2α mRNA and eIF2α phosphorylation, alleviated ER stress-induced apoptosis as manifested by reducing CHOP/GADD153 expression, the ratio of Bax/Bcl-2, caspase-12 and caspase-3 activity in H/R-treated cardiomyocytes. Thapsigargin (TG) is a potent ER stress inducer and used to elicit ER stress of cardiomyocytes. Our results showed that lycopene was able to prevent TG-induced ER stress as reflected by attenuating the protein expression of GRP78 and CHOP/GADD153 compared to TG group, significantly improve TG-caused a loss of cell viability and decrease apoptosis in TG-treated cardiomyocytes. These results suggest that the protective effects of lycopene on H/R-injury are, at least in part, through alleviating ER stress and ER stress-induced apoptosis in neonatal mouse cardiomyocytes

8-Formylophiopogonanone B antagonizes doxorubicin-induced cardiotoxicity by suppressing heme oxygenase-1-dependent myocardial inflammation and fibrosis

Doxorubicin (DOX) is a widely used antitumor drug that causes severe cardiotoxicity in patients; no effective strategy yet exists to address this problem. We previously reported that 8-formylophiopogonanone B (8-FOB), a natural isoflavone in Ophiopogon japonicas, antagonizes paraquat-induced hepatotoxicity. Here, we explored the mechanisms underlying DOX-induced cardiotoxicity as well as whether 8-FOB can alleviate DOX-induced cardiotoxicity. Acute cardiotoxicity was established by injecting C57BL/6J mice with a single dose of DOX (20 mg/kg, intraperitoneal). To elucidate the mechanisms underlying DOX-induced cardiotoxicity, differentially expressed genes between hearts from DOX-treated and control mice were identified from the Gene Expression Omnibus (GEO) database via GEO2R. Using the Cytoscape software plugin cytoHubba, five hub genes associated with DOX-induced cardiotoxicity were identified: CD68, PTEN, SERPINE1, AIF1, and HMOX1. However, of these, only HMOX1 protein expression levels were significantly increased after DOX treatment. We also confirmed that HMOX1-dependent myocardial inflammation and fibrosis were closely associated with DOX-induced cardiotoxicity. More importantly, 8-FOB protected against DOX-cardiotoxicity by ameliorating cardiac injury and dysfunction, reducing cardiac fibrosis and inflammatory cytokine release, and inhibiting HMOX1 expression. In conclusion, our results suggest that inhibition of HMOX1-dependent myocardial inflammatory insults and fibrosis is essential for 8-FOB to ameliorate DOX-caused cardiotoxicity

Integration of transcriptomics, metabolomics, and lipidomics reveals the mechanisms of doxorubicin-induced inflammatory responses and myocardial dysfunction in mice

Doxorubicin (DOX) is an anthracycline antineoplastic agent that has limited clinical utility due to its dose-dependent cardiotoxicity. Although the exact mechanism remains unknown, inflammatory responses have been implicated in DOX-induced cardiotoxicity (DIC). In this study, we analyzed the transcriptomic, metabolomic as well as lipidomic changes in the DOX-treated mice to explore the underlying mechanisms of DIC. We found that continuous intraperitoneal DOX injections (3 mg/kg/d) for a period of five days significantly induced cardiac dysfunction and cardiac injury in male C57BL/6 J mice (8 weeks old). This corresponded to a significant increase in the myocardial levels of IL-4, IL-6, IL-10, IL-17 and IL-12p70. Furthermore, inflammation-related genes such as Ptgs2, Il1b, Cxcl5, Cxcl1, Cxcl2, Mmp3, Ccl2, Ccl12, Nfkbia, Fos, Mapk11 and Tnf were differentially expressed in the DOX-treated group, and enriched in the IL-17 and TNF signaling pathways. Besides, amino acids, peptides, imidazoles, toluenes, hybrid peptides, fatty acids and lipids such as Hex1Cer, Cer, SM, PG and ACCa were significantly associated with the expression pattern of inflammation-related genes. In conclusion, the integration of transcriptomic, metabolomic and lipidomic data identified potential new targets and biomarkers of DIC