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Aims Improvements in cancer treatment have significantly extended the lifespan of patients. However, due to the adverse effects of cancer treatment, cancer survivors are at increased risk of cardiovascular complications. Doxorubicin is a widely used spectrum antitumor drug, but the life-threatening side-effect of cardiotoxicity limits its clinical application. Ammonium chloride (NH4Cl), as a heteropolar compound with pH value regulation, can cause intracellular alkalization and metabolic acidosis thus effecting enzymatic activity and influencing the process of biological system. The underlying effect of NH4CL in DOX-induced cardiomyocyte apoptosis and hypertrophy in mice has never been reported before. Main methods This study we used DOX to induce cardiac remodeling and dysfunction in mice. Myocardial histology was performed using HE staining. Myocardial cell size was measured by wheat germ agglutinin (WGA) staining. Echocardiographic evaluation of cardiac function, qPCR detection of the mRNA expression of cardiac hypertrophy and inflammation markers. Apoptosis was detected by TUNEL method. Transmission electron microscopy (TEM) was used to detect autophagy. Key findings We found that NH4CL effectively improved DOX-induced cardiomyocyte apoptosis and cardiac dysfunction in mice. Our results showed that NH4CL significantly improved DOX-induced contractile dysfunction, inflammation, apoptosis and autophagy in mice. Significance Our results indicate that NH4CL is effective in improving DOX-induced cardiac dysfunction and remodeling. It may therefore be a therapeutic entry point to limit doxorubicin-mediated adverse cardiac reactions.

Aims Progressive cardiac conduction disease (PCCD) is a rare heart disease that usually shows familial inheritance. Potential genetic risk factors for PCCD have been mostly limited to genes that encode ion channels, cardiac transcription factors, T-box transcription factors, gap junction proteins, energy metabolism regulators and structural proteins. Main methods Subjects in the present study came from a family who exhibited the autosomal dominant inheritance of PCCD. The primary proband had syncope and an electrocardiogram typical for PCCD, which started in the left bundle branch block, and passed to the atrioventricular block. The patient received a permanent pacemaker in 2013. Pathogenic mutations in the proband's family were identified using whole-exome sequencing and Sanger sequencing. Key findings The results for the family members were verified using Sanger sequencing, while the results for healthy unrelated individuals were verified using SNaPShot. All patients in the family shared two adjacent missense mutations in the preprodynorphin (PDYN) gene (c.581A > T, c.580G > C; p.D194L). Significance The PDYN double mutation c.581A > T and c.580G > C (p.D194L) may be linked to the onset of familial PCCD. The effects of these mutations on electrophysiology require further investigation.

Atherosclerosis (AS), a chronic arterial disease, is one of the major causes of morbidity and mortality worldwide. Several treatment modalities have been demonstrated to be effective in treating AS; however, the mortality rate due to AS remains high. Sonodynamic therapy (SDT) is a promising new treatment using low-intensity ultrasound in combination with sonosensitizers. Although SDT was developed from photodynamic therapy (PDT), it has a stronger tissue-penetrating capability and exhibits a more focused effect on the target lesional site requiring treatment. Furthermore, SDT has been demonstrated to suppress the formation of atheromatous plaques, and it can increase plaque stability both in vitro and in vivo. In this article, we critically summarize the recent literature on SDT, focusing on its possible mechanism of action as well as the existing and newly discovered sonosensitizers and chemotherapeutic agents for the treatment of AS.

Aims Activation of the rennin-angiotensin system plays a critical role in the development of hypertension and its complication. Our previous study has demonstrated that a cellular “memory” is involved in angiotensin II (Ang II)-induced cardiac hypertrophy. The aim of this study is to investigate the effect of reversal of high Ang II to normal condition on hypertension and vascular damage. Main methods Wild-type male mice were randomly divided into five groups. The vascular function, inflammation, oxidative stress and angiogenesis were examined by aortic ring relaxation studies, histological analysis, real-time PCR and Western blot analysis. Key findings We found that continuous high Ang II infusion for 3 weeks (Ang II 3w) significantly elevated blood pressure, increased aortic wall thickness, collagen deposition, inflammation, oxidative stress, vascular function and activation of p38 MAPK, JNK1/2, STAT3 and NF-κB pathways in mouse aorta compared with saline group. High Ang II exposure for 2 weeks followed by saline for 1 week (Ang II 2 + 1w) failed to reverse these alterations. This phenomenon was named “metabolic memory” (or persistent effect). However, addition of NADPH oxidase inhibitor apocynin during saline infusion (Ang II 2 + 1w + Apo) markedly ameliorated such deleterious effects. Significance These results showed that we report the first that persistent effect or “metabolic memory” of angiotensin II through NADPH oxidase-mediated oxidative stress plays important roles in hypertension and vascular injury.

Aims Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular pattern recognition receptor, which plays an important role in the innate immunity and inflammation. However, its role in myocardial ischemia/reperfusion (I/R) injury remains unknown. In this study, we sought to determine the role of NOD2 on cardiac I/R injury. Main methods Mice were induced 30 min ischemia followed by 24 h of reperfusion. Histological examinations were performed on heart sections with Evans blue and triphenyltetrazolium chloride (TTC) staining, hematoxylin and eosin (H&E) staining, immunohistochemistry and immunofluorescence staining. The messenger RNA (mRNA) expression and protein levels were detected by real-time polymerase chain reaction (RT-PCR) and western blot analysis respectively. Key findings I/R injury markedly upregulated NOD2 expression in heart tissue. Treatment of WT mice with NOD2 ligand (MDP) significantly increased infarct size, the number of apoptotic cells and inflammatory cells, as compared with wild-type mice after I/R injury. Furthermore, MDP enhanced I/R-induced cardiomyocyte apoptosis and inflammation in vitro, and these effects were attenuated by NOD2-siRNA. The mechanism of NOD2 on cardiac I/R injury is partly associated with JNK, p38MAPK and NF-κB signaling pathways. Significance NOD2 aggravates myocardial I/R injury by inducing cardiomyocyte apoptosis and inflammation through JNK, p38MAPK and NF-κB signaling pathways. This study provides insight into better understanding the molecular mechanism of NOD2, which may be served as a potential target for the treatment of myocardial I/R injury.

Although many markers were associated with abdominal aortic aneurysm (AAA), there is no clear consensus on which marker is of the most value. Studies have implicated the role of Notch signaling in the pathogenesis of AAA. We investigate the value of plasma Jagged1, Notch receptors and tumor necrosis factor-α converting enzyme (TACE) in identifying AAA.42 patients with AAA and 36 controls were enrolled in our study. The concentrations of plasma Jagged1, Notch receptors and TACE were measured by enzyme-linked immunosorbent assay (ELISA). The diagnostic value of plasma Notch1 and TACE was assessed by logistic regression and receiver operator characteristic (ROC) curve. Double immunofluorescence staining was used to investigate the distribution of Notch1 and TACE in AAA tissue specimens.The concentrations of plasma Notch1 and TACE were significantly higher in AAA than in the controls, respectively (Notch1: P0.001; TACE: P = 0.0001). The area under the curve (AUC) from ROC curve of plasma Notch1 and TACE in determining the presence of AAA was 0.878 and 0.804, respectively. Combining detection of plasma Notch1 and TACE could improve the accuracy in detecting AAA (AUC 0.984, P0.0001). The predicted probability cutoff of 0.70 gave a sensitivity of 90.5% and a specificity of 100% for combining detection of plasma Notch1 and TACE in predicting AAA.This is the first report revealing that plasma Notch1 and TACE are highly expressed in AAA. Combining detection of plasma Notch1 and TACE may be reliable for identifying the presence of AAA.