Cancer is a destructive disease that causes high levels of morbidity and mortality. Doxorubicin (DOX) is a highly efficient antineoplastic chemotherapeutic drug, but its use places survivors at risk for cardiotoxicity. Many studies have demonstrated that multiple factors are involved in DOX-induced acute cardiotoxicity. Among them, oxidative stress and cell death predominate. In this review, we provide a comprehensive overview of the mechanisms underlying the source and effect of free radicals and dependent cell death pathways induced by DOX. Hence, we attempt to explain the cellular mechanisms of oxidative stress and cell death that elicit acute cardiotoxicity and provide new insights for researchers to discover potential therapeutic strategies to prevent or reverse doxorubicin-induced cardiotoxicity.

Background Circular RNAs (circRNAs) play important roles in cancer development and progression. The purpose of this study is to identify aberrantly expressed circRNAs in gastric cancer (GC), unravel their roles in GC progression, and provide new targets for GC diagnosis and therapy. Methods Bioinformatic analyses were performed to identify the aberrantly expression of hsa_circ_0061137 (termed as circDIDO1) in GC. Gain- and loss-of-function studies were performed to examine the biological roles of circDIDO1 in GC progression. Tagged RNA affinity purification, mass spectrometry, immunofluorescence, co-immunoprecipitation, and Western blot were used to identify circRNA-interacting and circRNA-encoded proteins. RNA sequencing, qRT-PCR, and Western blot were performed to analyze circRNA-regulated downstream target genes and signaling pathways. Mouse tumor models were used to analyze the effects of circDIDO1 on GC growth and metastasis. Results CircDIDO1 was transcribed from human DIDO1 (death-inducer obliterator 1) gene and formed by back-splicing of exons 2–6 of the linear transcript. circDIDO1 was down-regulated in GC tissues and its low levels were associated with larger tumor size, distal metastasis, and poor prognosis. CircDIDO1 overexpression inhibited while knockdown promoted GC cell proliferation, migration and invasion. CircDIDO1 overexpression suppressed GC growth and metastasis in mouse tumor models. Mechanistically, circDIDO1 encoded a novel 529aa protein that directly interacted with poly ADP-ribose polymerase 1 (PARP1) and inhibited its activity. CircDIDO1 also specifically bound to peroxiredoxin 2 (PRDX2) and promoted RBX1-mediated ubiquitination and degradation of PRDX2, which led to the inactivation of its downstream signaling pathways. Conclusions CircDIDO1 is a new circRNA that has tumor suppressor function in GC and it may serve as a potential prognostic biomarker and therapeutic target for GC.

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The poor prognosis of patients with acute myocardial infarction is partially attributed to a large number of cardiomyocyte apoptosis, necrosis, limited cardiac healing and angiogenesis, and cardiac dysfunction. Immune cells dysfunction leads to nonhealing or poor healing of wounds after acute myocardial infarction. Toll-like receptor 9 (TLR9) as an essential part of the innate immune system plays a vital role in regulating cardiomyocyte survival and wound healing. During hypoxia, High Mobility Group Box 1 (HMGB1), as the typical damage-associated molecular patterns (DAMPs) or alarmin, is rapidly released extracellularly and translocates from the nucleus to bind with cytoplasmic TLR9. However, the mechanism by which TLR9 interacts with HMGB1 and regulates myocardial damage remains unclear. Our current study found that the survival rate of TLR9KO mice with a higher rate of cardiac rupture was significantly lower than that in WT mice after 28 days post-operation. The effect of TLR9 knockout on insufficient wound healing in experimental MI was caused by a diminished number of myofibroblast and defective matrix synthetic capability. Moreover, the increased myocardial apoptotic cells and decreased angiogenic capacity were found in TLR9 knockout mice after MI. The results showed contrary in Recombinant Human High Mobility Group Box 1 (rhHMGB1) treated WT mice and similarity after applying rhHMGB1 in TLR9KO mice. This study demonstrates that TLR9 is essential for the repair of infarcted myocardium and interaction of HMGB1 and TLR9 is involved in the survival of myocardial cells, wound healing, and angiogenesis after myocardial infarction.

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The Qinghai–Tibetan Plateau is a very large land unit and an important terrestrial ecosystem within the Eurasian continent. Because of the harsh climate associated with the high altitude, alpine meadows on the plateau are susceptible to degradation from overgrazing. For this region, and for other alpine meadow pastures internationally, there is a need to define the sustainable stocking rate, to develop sound policy pertaining to future land use. Here we report biomass and liveweight gain per animal and per ha for pastures grazed by yaks at high, medium, or low stocking rates over 4 growing seasons from 2010 to 2013. Measures of herbage nutritive value are reported. The influence of inter-year variation in precipitation on standing herbage biomass was also evaluated. Higher precipitation increased standing herbage biomass and herbage nutritive value, indicating that vegetation suffered summer water deficit even in this environment. The sustainable stocking rate in this environment was determined to be approximately 1 yak ha-1 (grown from 80 kg to 120 kg liveweight in 90 d). At this stocking rate, yak weight gain per ha was 88% of that achieved at higher stocking rates typically used by farmers, but with little or no evidence of land degradation.

OX40, which belongs to the tumour necrosis factor (TNF)-receptor family, is a costimulatory receptor that can potentiate T-cell receptor signalling on the surface of T-lymphocytes. The role of OX40 in non-immune systems, particularly the cardiovascular system, has not been defined. In the present study, we observed a noticeable increase in OX40 expression during cardiac remodelling in rodent heart. In the present study, cardiac hypertrophy was induced by aortic banding (AB) in OX40 knockout (KO) mice and wild-type (WT) mice. After 8 weeks, the OX40 KO mice showed significantly attenuated cardiac hypertrophy, fibrosis and inflammation as well as preserved cardiac function compared with the WT mice. Follow-up in vitro studies suggested that CD4 T-lymphocyte proliferation and pro-inflammatory cytokine release were significantly decreased, whereas anti-inflammatory cytokine release was considerably increased in OX40 KO mice compared with WT mice as assessed by Cell Counting Kit-8 (CCK-8) assay and ELISA. Co-culturing neonatal rat cardiomyocytes with the activated supernatant of CD4 T-lymphocytes from OX40 KO mice reduced the hypertrophy response. Interestingly, OX40 KO mice with reconstituted CD4 T-lymphocytes presented deteriorated cardiac remodelling. Collectively, our data indicate that OX40 regulates cardiac remodelling via the modulation of CD4 T-lymphocytes.

The clinical application of doxorubicin (DOX) in cancer chemotherapy is limited by its life-threatening cardiotoxic effects. Chrysophanol (CHR), an anthraquinone compound isolated from the rhizome of Rheum palmatum L., is considered to play a broad role in a variety of biological processes. However, the effects of CHR׳s cardioprotection in DOX-induced cardiomyopathy is poorly understood. In this study, we found that the cardiac apoptosis, mitochondrial injury and cellular PARylation levels were significantly increased in H9C2 cells treated by Dox, while these effects were suppressed by CHR. Similar results were observed when PARP1 activity was suppressed by its inhibitors 3-aminobenzamide (3AB) and ABT888. Ectopic expression of PARP1 effectively blocked this CHR׳s cardioprotection against DOX-induced cardiomyocyte injury in H9C2 cells. Furthermore, pre-administration with both CHR and 3AB relieved DOX-induced cardiac apoptosis, mitochondrial impairment and heart dysfunction in Sprague–Dawley rat model. These results revealed that CHR protects against DOX-induced cardiotoxicity by suppressing cellular PARylation and provided critical evidence that PARylation may be a novel target for DOX-induced cardiomyopathy.