Age-specific cardiovascular disease-related mortality among patients with major gastrointestinal cancers: A SEER population-based study.

BACKGROUND: Studies have reported age as a risk factor for cardiovascular disease (CVD)-related mortality; however, only a few studies have focused on the relationship between age and CVD-related mortality, especially among major gastrointestinal cancers. METHOD: The present retrospective cohort enrolled patients with colorectal, pancreatic, hepatocellular, gastric, and esophageal cancer between 2000 to 2015 from the Surveillance, Epidemiology and End Results Registry (SEER). Standardized mortality ratio (SMR), competing risk regression, and restricted cubic spline (RCS) analyses were used in our study. RESULTS: We analyzed 576,713 patients with major gastrointestinal cancers (327,800 patients with colorectal cancer, 93,310 with pancreatic cancer, 69,757 with hepatocellular cancer, 52,024 with gastric cancer, and 33,822 with esophageal cancer). Overall, CVD-related mortality gradually decreased every year, and the majority were older patients. All cancer patients had a higher CVD-related mortality rate than the general U.S. POPULATION: The adjusted sub-hazard ratios for middle-aged with colorectal cancer, pancreatic cancer, hepatocellular cancer, gastric cancer, and esophageal cancer were 2.55 (95% CI: 2.15-3.03), 1.77 (95% CI: 1.06-2.97), 2.64 (95% CI: 1.60-4.36), 2.15 (95% CI: 1.32-3.51), and 2.28 (95% CI: 1.17-4.44), respectively. The adjusted sub-hazard ratios for older patients with colorectal cancer, pancreatic cancer, hepatocellular cancer, gastric cancer, and esophageal cancer were 11.23 (95% CI: 9.50-13.27), 4.05 (95% CI: 2.46-6.66), 4.47 (95% CI: 2.72-7.35), 7.16 (95% CI: 4.49-11.41), and 4.40 (95% CI: 2.28-8.48), respectively. A non-linear relationship between age at diagnosis and CVD-related mortality was found in colorectal cancer, pancreatic cancer, and esophageal cancer; their reference ages were 67, 69, and 66 years old, respectively. CONCLUSION: This study demonstrated that age was a risk factor for CVD-related mortality among major gastrointestinal cancers.

The histone demthylase KDM3A protects the myocardium from ischemia/reperfusion injury via promotion of ETS1 expression.

Our prior studies have characterized the participation of histone demethylase KDM3A in diabetic vascular remodeling, while its roles in myocardial ischemia/reperfusion (I/R) injury (MIRI) remain to be illustrated. Here we show that KDM3A was significantly downregulated in rat I/R and cellular hypoxia/reoxygenation (H/R) models. Subsequently, gain- and loss-of-function experiments were performed to investigate the effects of KDM3A in the settings of MIRI. KDM3A knockout exacerbated cardiac dysfunction and cardiomyocytes injury both in vivo and in vitro. The deteriorated mitochondrial apoptosis, reactive oxygen species, and inflammation were simultaneously observed. Conversely, KDM3A overexpression developed the ameliorated alternations in MIRI. Mechanistically, the MIRI-alleviating effects of KDM3A were associated with the enhancement of ETS1 expression. ChIP-PCR affirmed that KDM3A bound to the ETS1 promoter and removed dimethylation of histone H3 lysine 9 (H3K9me2), thus promoting ETS1 transcription. Our findings suggest that KDM3A is available for alleviating multi-etiologies of MIRI through the regulation of ETS1.

Syringic acid mitigates myocardial ischemia reperfusion injury by activating the PI3K/Akt/GSK-3ß signaling pathway.

Syringic acid is an abundant phenolic acid compound that possesses anti-oxidant, anti-microbial, anti-inflammatory, and anti-endotoxic properties. However, the research of pretreatment with syringic acid against myocardial ischemia reperfusion is still limited. Thus, our research revealed the protective effect of syringic acid in the rat model with myocardial ischemia reperfusion injury. Histological analysis was performed by hematoxylin and eosin (H&E). The myocardial systolic function was detected by echocardiographic. Myocardial infarct size was measured by Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) double staining. The apoptosis index was recorded by Terminal deoxynucleotidyl transferase dUTP nick end labeling staining (TUNEL). The contents of creatine kinase MB (CK-MB) and lactate dehydrogenase (LDH) in the serum were determined by a commercial kit. The expression of the PI3K/Akt/GSK-3ß signaling pathway-related molecules and apoptosis-associated indicators was detected by western blotting or real-time PCR. We found that pretreatment with syringic acid obviously increased the myocardial systolic function (LVEF and LVFS) and decreased the infarct size, the apoptosis index as well as the serum level of CK-MB and LDH. Meanwhile, syringic acid also remarkably augmented the contents of p-PI3K, p-Akt, p-GSK-3ß, Bcl-2 and mitochondria cytochrome c. However, the expression of caspase-3, -9 and Bax significantly reduced. Interestingly, co-treatment with PI3K inhibitor of LY294002 counteracted those effects induced by syringic acid. In conclusion, pretreatment with syringic acid can mitigate myocardial ischemia reperfusion injury by inhibiting mitochondria-induced apoptosis which is regulated by the PI3K/Akt/GSK-3ß signaling pathway.

LncRNA H19 ameliorates myocardial infarction-induced myocardial injury and maladaptive cardiac remodelling by regulating KDM3A.

Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide, and novel therapeutic targets still need to be investigated to alleviate myocardial injury and the ensuing maladaptive cardiac remodelling. Accumulating studies have indicated that lncRNA H19 might exert a crucial regulatory effect on cardiovascular disease. In this study, we aimed to explore the biological function and molecular mechanism of H19 in MI. To investigate the biological functions of H19, miRNA-22-3p and KDM3A, gain- and loss-of-function experiments were performed. In addition, bioinformatics analysis, dual-luciferase reporter assays, RNA immunoprecipitation (RIP) assays, RNA pull-down assays, quantitative RT-PCR and Western blot analyses as well as rescue experiments were conducted to reveal an underlying competitive endogenous RNA (ceRNA) mechanism. We found that H19 was significantly down-regulated after MI. Functionally, enforced H19 expression dramatically reduced infarct size, improved cardiac performance and alleviated cardiac fibrosis by mitigating myocardial apoptosis and decreasing inflammation. However, H19 knockdown resulted in the opposite effects. Bioinformatics analysis and dual-luciferase assays revealed that, mechanistically, miR-22-3p was a direct target of H19, which was also confirmed by RIP and RNA pull-down assays in primary cardiomyocytes. In addition, bioinformatics analysis and dual-luciferase reporter assays also demonstrated that miRNA-22-3p directly targeted the KDM3A gene. Moreover, subsequent rescue experiments further verified that H19 regulated the expression of KDM3A to ameliorate MI-induced myocardial injury in a miR-22-3p-dependent manner. The present study revealed the critical role of the lncRNAH19/miR-22-3p/KDM3A pathway in MI. These findings suggest that H19 may act as a potential biomarker and therapeutic target for MI.

Nobiletin ameliorates myocardial ischemia and reperfusion injury by attenuating endoplasmic reticulum stress-associated apoptosis through regulation of the PI3K/AKT signal pathway.

BACKGROUND: Nobiletin is a natural polymethoxylated flavone that confers antioxidative, anti-inflammatory and anti-apoptotic efficacies. However, the potential benefits of nobiletin preconditioning on myocardial ischemia and reperfusion injury (MIRI) remains largely unknown. METHODS: MIRI was induced by ligation of the left anterior descending coronary artery and reperfusion. Pre-treatment with nobiletin, with or without PI3K/AKT inhibitor LY294002, was performed at the onset of reperfusion. Histological analyses, apoptotic evaluation, plasma biomarkers of myocardial injury, echocardiographic evaluation of cardiac function and myocardial levels of endoplasmic reticulum stress (ERS)-related molecules were observed. RESULTS: Nobiletin pre-treatment significantly deceased the infract size and number of apoptotic cells in the myocardium of MIRI rats, as determined by Terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Moreover, the plasma levels of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) also markedly decreased. In addition, pre-treatment with nobiletin restored the impaired cardiac systolic function, as evidenced by echocardiographic evaluation results. Importantly, pre-treatment with nobiletin significantly downregulated the myocardial mRNA and protein levels of ERS-related signal molecules, including GRP78, CHOP and caspase-12, but upregulated the levels of p-PI3K and p-AKT. Interestingly, co-treatment with LY294002 significantly abolished the benefits of nobiletin pre-treatment on cardiac function, myocardial apoptosis, cardiomyocyte injuries, and changes in myocardial levels of ERS-related signaling molecules. CONCLUSION: Nobiletin pre-treatment may alleviate MIRI probably via the attenuation of PI3K/AKT-mediated ERS-related myocardial apoptosis.

Silica-coated magnetic nanoparticles labeled endothelial progenitor cells alleviate ischemic myocardial injury and improve long-term cardiac function with magnetic field guidance in rats with myocardial infarction.

Low retention of endothelial progenitor cells (EPCs) in the infarct area has been suggested to be responsible for the poor clinical efficacy of EPC therapy for myocardial infarction (MI). This study aimed to evaluate whether magnetized EPCs guided through an external magnetic field could augment the aggregation of EPCs in an ischemia area, thereby enhancing therapeutic efficacy. EPCs from male rats were isolated and labeled with silica-coated magnetic iron oxide nanoparticles to form magnetized EPCs. Then, the proliferation, migration, vascularization, and cytophenotypic markers of magnetized EPCs were analyzed. Afterward, the magnetized EPCs (1 × 106 ) were transplanted into a female rat model of MI via the tail vein at 7 days after MI with or without the guidance of an external magnet above the infarct area. Cardiac function, myocardial fibrosis, and the apoptosis of cardiomyocytes were observed at 4 weeks after treatment. In addition, EPC retention and the angiogenesis of ischemic myocardium were evaluated. Labeling with magnetic nanoparticles exhibited minimal influence to the biological functions of EPCs. The transplantation of magnetized EPCs guided by an external magnet significantly improved the cardiac function, decreased infarction size, and reduced myocardial apoptosis in MI rats. Moreover, enhanced aggregations of magnetized EPCs in the infarcted border zone were observed in rats with external magnet-guided transplantation, accompanied by the significantly increased density of microvessels and upregulated the expression of proangiogenic factors, when compared with non-external-magnet-guided rats. The magnetic field-guided transplantation of magnetized EPCs was associated with the enhanced aggregation of EPCs in the infarcted border zone, thereby improving the therapeutic efficacy of MI.

Long noncoding RNA UCA1 inhibits ischaemia/reperfusion injury induced cardiomyocytes apoptosis via suppression of endoplasmic reticulum stress.

BACKGROUND: Ischemia heart disease is one of the major causes of death worldwide which often associated with tissue infarction and limit the recovery of function. Multiple factors involved in the I/R-induced cardiomyocyte dysfunction which were consistent with a role of oxidative stress and altered endothelium-dependent responses. However, the pathogenic mechanisms in I/R injury remain unclear. MATERIALS AND METHODS: The H9C2 cells were in the ischaemia/reperfusion (I/R) condition. After I/R, the cells were transfected with or without adenovirus-urothelial carcinoma associated 1(Ad-UCA1). Then qRT-PCR analysis was performed to quantify mRNA expression of different treatment groups. Cell apoptosis rate was assessed using flow cytometry and ER stress biomarker expression were measured by immunoblotting. Intracellular and mitochondrial ROS generation were assayed by fluorescence microscope after staining with the DCFDA or MitoSOX. RESULTS: I/R conditions trigger lncRNAs UCA1 expression, cellular and mitochondria ROS production, resulting in cell apoptosis through the induction of oxidative and ER stress. Overexpression of UCA1 protects H9C2 cells from I/R-induced ER stress and cell apoptosis. Moreover, UCA1 might be a potential regulator in the protective effect of I/R­induced oxidative stress and mitochondria dysfunction. Subsequently, ER stress inhibitor attenuated the effect of siUCA1 induced injury in H9C2 cells. CONCLUSION: The expression of UCA1 against I/R induced oxidative stress and mitochondria dysfunction via suppression of endoplasmic reticulum stress. UCA1 might be a biomarker to improved diagnosis of I/R injury.

RP105 ameliorates hypoxia̸reoxygenation injury in cardiac microvascular endothelial cells by suppressing TLR4̸MAPKs̸NF-κB signaling.

The radioprotective 105 kDa protein (RP105) has been implicated in the pathological process of multiple cardiovascular diseases through its functional and physical interactions with Toll­like receptor 4 (TLR4). However, the effects of RP105 on cardiac microvascular endothelial cells (CMECs) in response to hypoxia̸reoxygenation (H̸R) injury have not been extensively investigated. The aim of the present study was to elucidate the potential roles of RP105 in the protection of CMECs against H̸R injury, and investigate the underlying mechanisms. CMECs isolated from Sprague­Dawley rats were transduced with adenoviral vectors encoding RP105 or green fluorescent protein (GFP). At 48 h post­transfection, CMECs were subjected to hypoxia for 4 h and reoxygenation for 2 h (H̸R) to simulate the in vivo ischemia̸reperfusion model. The mRNA and protein levels of RP105 were detected by reverse transcription­quantitative polymerase chain reaction and western blot analysis, respectively. The effects of RP105 on CMEC proliferation, migration and apoptosis were measured by GFP­8, Transwell chamber and flow cytometry assays, respectively. The secretion of interleukin (IL)­6 and tumor necrosis factor (TNF)­α in the culture medium was measured by ELISA. Moreover, the expression level of TLR4, p38 mitogen­activated protein kinase (MAPK), extracellular-signal-regulated kinase 1̸2, c-Jun N-terminal kinase, nuclear factor (NF)­κB̸p65, IL­6, TNF­α and intercellular adhesion melecule­1 was evaluated by western blot analysis. The results demonstrated that RP105 was minimally expressed in CMECs subjected to H̸R injury. Overexpression of RP105 via adenoviral vectors was able to significantly protect CMECs against H̸R injury, as evidenced by the promotion of cell proliferation and migration, as well as the amelioration of inflammation and apoptosis. These beneficial effects were at least partly mediated through inhibition of TLR4̸MAPKs̸NF­κB signaling. Therefore, RP105 may be a promising candidate for prevention against CMECs­associated H̸R injury.

KDM3A inhibition attenuates high concentration insulin­induced vascular smooth muscle cell injury by suppressing MAPK/NF­κB pathways.

Previous studies have indicated that lysine (K)­specific demethylase 3A (KDM3A) is associated with diverse diabetes­associated cardiovascular complications in response to high glucose levels. However, the effects of KDM3A on the pathological progression of cardiovascular injuries in response to high insulin levels remain unknown. The present study aimed to explore whether KDM3A knockdown may attenuate high insulin­induced vascular smooth muscle cell (VSMC) dysfunction, and to further investigate the underlying mechanisms. Primary VSMCs were isolated from the thoracic aorta of Sprague­Dawley rats. Lentiviral vectors encoding control­small interfering (si)RNA or KDM3A­siRNA were transduced into VSMCs for 72 h, and cells were subsequently incubated in medium containing 100 nM insulin for a further 5 days. Cellular proli-feration, migration and apoptosis were measured by Cell Counting kit­8, Transwell chamber assay and flow cytometry, respectively. Reactive oxygen species (ROS) were detected using the dihydroethidium fluorescent probe. The mRNA expression levels of interleukin­6 and monocyte chemotactic protein­1 were measured by reverse transcription­quantitative polymerase chain reaction. Furthermore, the protein expression levels of KDM3A, mitogen­activated protein kinases (MAPKs), nuclear factor (NF)­κB/p65, B­cell lymphoma 2 (Bcl­2)­associated X protein and Bcl­2 were evaluated by west-ern blotting. Lentivirus transduction with KDM3A­siRNA markedly reduced the elevated expression of KDM3A induced by high insulin stimulation in VSMCs. In addition, inhibition of KDM3A significantly ameliorated insulin­induced VSMC proliferation and migration, which was accompanied by decreased ROS levels, cell apoptosis and inflammatory cytokine levels. Furthermore, KDM3A gene silencing mitigated phosphorylation of MAPKs and NF­κB/p65 activation. In conclusion, KDM3A inhibition may exert numerous protective effects on high insulin­stimulated VSMCs, and the underlying mechanisms may be partly associated with inactivation of MAPK/NF­κB signaling pathways.