A newly synthesized flavone avoids COMT-catalyzed methylation and mitigates myocardial ischemia/reperfusion injury in H9C2 cells via JNK and P38 pathways.

Objectives: Luteolin is a flavone that provides defense against myocardial ischemia/reperfusion (I/R) injury. However, this compound is subjected to methylation mediated by catechol-O-methyltransferase (COMT), thus influencing its pharmacological effect. To synthesize a new flavone from luteolin that avoids COMT-catalyzed methylation and find out the protective mechanism of LUA in myocardial I/R injury. Materials and Methods: Luteolin and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) were used to synthesize the new flavone known as LUAAPH-1 (LUA). Then, the myocardial ischemia/reperfusion injury cell model was established using H9c2 cells to detect the effect in myocardial ischemia/reperfusion regulation and to identify the underlying mechanism. Results: Pretreatment with LUA (20 µmol/l) substantially increased cell viability while reducing cell apoptosis rate and caspase-3 expression induced by I/R, and the protective effect of LUA on cell viability was stronger than diosmetin, which is the major methylated metabolite of luteolin. In addition, intracellular reactive oxygen species (ROS) production and calcium accumulation were both inhibited by LUA. Furthermore, we identified that LUA markedly relieved the promotive effects of I/R stimulation upon JNK and p38 phosphorylation. Conclusion: LUT pretreatment conveys significant cardioprotective effects after myocardial I/R injury, and JNK and p38 MAPK signaling pathway may be involved.

Targeting the Na+/K+ ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a potent chemotherapeutic drug for various cancers. Yet, the cardiotoxic side effects limit its application in clinical uses, in which ferroptosis serves as a crucial pathological mechanism in DOX-induced cardiotoxicity (DIC). A reduction of Na+/K + ATPase (NKA) activity is closely associated with DIC progression. However, whether abnormal NKA function was involved in DOX-induced cardiotoxicity and ferroptosis remains unknown. Here, we aim to decipher the cellular and molecular mechanisms of dysfunctional NKA in DOX-induced ferroptosis and investigate NKA as a potential therapeutic target for DIC. A decrease activity of NKA further aggravated DOX-triggered cardiac dysfunction and ferroptosis in NKAα1 haploinsufficiency mice. In contrast, antibodies against the DR-region of NKAα-subunit (DR-Ab) attenuated the cardiac dysfunction and ferroptosis induced by DOX. Mechanistically, NKAα1 interacted with SLC7A11 to form a novel protein complex, which was directly implicated in the disease progression of DIC. Furthermore, the therapeutic effect of DR-Ab on DIC was mediated by reducing ferroptosis by promoting the association of NKAα1/SLC7A11 complex and maintaining the stability of SLC7A11 on the cell surface. These results indicate that antibodies targeting the DR-region of NKA may serve as a novel therapeutic strategy to alleviate DOX-induced cardiotoxicity.

A Newly Synthesized Flavone from Luteolin Escapes from COMT-Catalyzed Methylation and Inhibits Lipopolysaccharide-Induced Inflammation in RAW264.7 Macrophages via JNK, p38 and NF-κB Signaling Pathways.

Luteolin is a common dietary flavone possessing potent anti-inflammatory activities. However, when administrated in vivo, luteolin becomes methylated by catechol-O-methyltransferases (COMT) owing to the catechol ring in the chemical structure, which largely diminishes its anti-inflammatory effect. In this study, we made a modification on luteolin, named LUA, which was generated by the chemical reaction between luteolin and 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH). Without a catechol ring in the chemical structure, this new flavone could escape from the COMT-catalyzed methylation, thus affording the potential to exert its functions in the original form when administrated in the organism. Moreover, an LPS-stimulated RAW cell model was applied to detect the anti-inflammatory properties. LUA showed much more superior inhibitory effect on LPS-induced production of NO than diosmetin (a major methylated form of luteolin) and significantly suppressed upregulation of iNOS and COX-2 in macrophages. LUA treatment dramatically reduced LPS-stimulated reactive oxygen species (ROS) and mRNA levels of pro-inflammatory mediators such as IL-1ß, IL-6, IL-8 and IFN-ß. Furthermore, LUA significantly reduced the phosphorylation of JNK and p38 without affecting that of ERK. LUA also inhibited the activation of NF-κB through suppression of p65 phosphorylation and nuclear translocation.

Role of nitroxyl (HNO) in cardiovascular system: From biochemistry to pharmacology.

Cardiovascular diseases are recognized to be a major cause of people morbidity and mortality. A host of stress signals contribute to the pathogenesis of cardiovascular disorders. Deficiency of hydrogen sulfide (H2S) or nitric oxide (NO) coordinately plays essential roles in the development of cardiovascular diseases. Recent studies have shown that interaction between the two gaseostransmitters, H2S and NO, may give rise to nitroxyl (HNO), one-electron-reduced product of NO. HNO is found to exhibit a variety of biological and pharmacological properties including positive inotropy and cardiovascular protective effects, etc. In this review, recent progresses regarding HNO generation, detection, biochemical and pharmacological functions are discussed.

Correlates of pericardial adipose tissue volume using multidetector CT scanning in cardiac patients in China.

BACKGROUND: Pericardial adipose tissue (PAT) is an emerging cardiovascular risk factor, yet much less is understood about PAT volume in Chinese adults, especially in relation to physical activity. The study explores associations between demographic and clinical variables and PAT volume, using multidetector computed tomography (MDCT) scanning in China. We also examined the relationship between PAT volume and coronary artery disease (CAD). METHODS: An observational, correlational study design was used. Chinese (n=163) attended a study visit and underwent MDCT scanning between September 2014 and December 2015. RESULTS: Participants were 48.5% male and had a mean age of 60.6 (SD 9.4) years. PAT volume was higher (p=0.001) in males than in females. PAT volume was correlated with age (r=0.388, p=0.001), systolic blood pressure (r=0.205, p=0.009), body mass index (r=0.466, p=0.001), high-density cholesterol (r=-0.282, p=0.001), low-density cholesterol (r=0.177, p=0.024), and triglycerides (r=0.248, p=0.001). Both moderate intensity physical activity energy consumption (r=-0.363, p=0.001) and total physical activity (r=-0.290, p=0.001) had inverse relationships with PAT volume. Total sedentary energy consumption was positively related to PAT volume (r=0.266, p=0.001). Multiple regression revealed that age, male gender, BMI, LDL-C and total physical activity energy consumption were significant predictors of PAT volume (R2=0.465). The relationship between PAT volume and CAD was found to be significant in the adjusted models. CONCLUSIONS: Age, male gender, BMI, LDL-C and total physical activity energy consumption were significant predictors of PAT volume, and PAT volume itself is a predictor of CAD.

[Magnetic resonance characteristics of endometriosis rat model].

OBJECTIVE: To establish a non-invasive, repeatable and dynamic study method in endometriosis rat model using magnetic resonance imaging (MRI), in order to explore the magnetic resonance characteristics of the model. METHOD: Endometrium tissues were transplanted into left abdominal walls of unmated adult female SD rats. After surgery, pathological changes were observed and MRI scanning was made for the ectopic lesions. RESULT: The endometriosis rat model was successfully established and the ectopic lesions imaged strong hyperintense on DWI, hypointense on T1WI, hyperintense on T2WI with a clear border, without enhancement on CE-T1 WI. CONCLUSION: The lesions can be clearly observed in the MRI images on the endometriosis rat model established by this method, which facilitates repeat experiments and continuous observation studies.

[Radiographic and computed tomographic manifestations of chest in patients with acute chlorine gas poisoning].

OBJECTIVE: To investigate the radiographic and computerized tomographic features of chest in patients with acute chlorine poisoning and its diagnostic value. METHODS: Twenty-eight cases of chlorine poisoning were reviewed. And their radiographic and computerized tomographic features were compared and analyzed. RESULTS: Radiographic findings: among 28 patients, 9 cases were normal and 2 cases had no abnormalities on the first chest X-ray and became abnormal one or two days later. And there were abnormal findings in first chest X-ray in 17 patients:acute tracheal inflammation of peribronchitis (n = 3), acute chemical bronchopneumonia (n = 6) and diffuse interstitial and central pulmonary edema (n = 8). CT manifestations: At Days 1-3, the patients of mild poisoning had scattered patchy dense shadow; those of moderate to severe poisoning showed multiple patchy or diffuse infiltration (ground-glass opacity). And partial consolidation, air bronchogram and pleural effusion could be observed. At Days 4-10, the manifestations of mild poisoning were largely absorbed; those of moderate to severe poisoning manifested the absorption of diffuse or multiple patchy effusion and a fading of shadow. And the size of lung consolidation became smaller than before. At Day 10 after onset, 4 patients completely recovered. At Days 30-40, 6 cases showed traces of fibrous shadow and one case showed small punctiform opacities in both lungs. And at Day 42, there was slight ground-glass change. CONCLUSION: Acute chlorine gas poisoning in varying degrees may manifest acute bronchial pneumonia and acute pulmonary edema. During treatment, a series of chest X-ray examinations will help to follow the changes of disease. And CT examination can offer a more accurate evaluation of lung lesions.