Cardiomyocyte hypertrophy is an adaptive response of heart to various stress conditions. During the period of stress accumulation, transition from physiological hypertrophy to pathological hypertrophy results in the promotion of heart failure. Our previous studies found that ZAK, a sterile alpha motif and leucine zipper containing kinase, was highly expressed in infarcted human hearts and demonstrated that overexpression of ZAK induced cardiac hypertrophy. This study evaluates, cellular events associated with the expression of two doxycycline (Dox) inducible Tet-on ZAK expression systems, a Tet-on ZAK WT (wild-type), and a Tet-on ZAK DN (mutant, Dominant-negative form) in H9c2 myoblast cells; Tet-on ZAK WT was found to increase cell size and hypertrophic marker BNP in a dose-dependent manner. To ascertain the mechanism of ZAK-mediated hypertrophy, expression analysis with various inhibitors of the related upstream and downstream proteins was performed. Tet-on ZAK WT expression triggered the p38 and JNK pathway and also activated the expression and nuclear translocation of p-GATA4 and p-c-Jun transcription factors, without the involvement of p-ERK or NFATc3. However, Tet-on ZAK DN showed no effect on the p38 and JNK signaling cascade. The results showed that the inhibitors of JNK1/2 and p38 significantly suppressed ZAK-induced BNP expression. The results show the role of ZAK and/or the ZAK downstream events such as JNK and p38 phosphorylation, c-Jun, and GATA-4 nuclear translocation in cardiac hypertrophy. ZAK and/or the ZAK downstream p38, and JNK pathway could therefore be potential targets to ameliorate cardiac hypertrophy symptoms in ZAK-overexpressed patients.

No abstract

No abstract

Secretion of multifunctional estrogen and its receptor has been widely considered as the reason for markedly higher frequency of heart disease in men than in women. 17β-Estradiol (E2), for instance, has been reported to prevent development of cardiac apoptosis via activation of estrogen receptors (ERs). In addition, protein phosphatase such as protein phosphatase 1 (PP1) and calcineurin (PP2B) are also involved in cardiac hypertrophy and cell apoptosis signaling. However, the mechanism by which E2/ERβ suppresses apoptosis is not fully understood, and the role of protein phosphatase in E2/ERβ action also needs further investigation. In this study, we observed that E2/ERβ inhibited isoproterenol (ISO)-induced myocardial cell apoptosis, cytochrome c release and downstream apoptotic markers. Moreover, we found that E2/ERβ blocks ISO-induced apoptosis in H9c2 cells through the enhancement of calcineurin protein degradation through PI3K/Akt/MDM2 signaling pathway. Our results suggest that supplementation with estrogen and/or overexpression of estrogen receptor β gene may prove to be effective means to treat stress-induced myocardial damage.

15 phenolic amides (PAs) have been synthesized and examinedin vitrousing four tests: (1) prevention of Cu2+-induced human low-density lipoprotein oxidation, (2) scavenging of stable radicals, (3) anti-inflammatory activity, and (4) scavenging of superoxide radicals.

Magnesium sulfate (MgSO₄) ameliorates hypoxia/ischemia-induced neuronal apoptosis in a rat model. This study aimed to investigate the mechanisms governing the anti-apoptotic effect of MgSO₄ on cobalt chloride (CoCl₂)-exposed NB41A3 mouse neuroblastoma cells. MgSO₄ increased the viability of NB41A3 cells treated with CoCl₂ in a dose-dependent manner. MgSO₄ treatment was shown to lead to an increase in the anti-apoptotic Bcl-2 family proteins, with a concomitant decrease in the pro-apoptotic proteins. MgSO₄ also attenuated the CoCl₂-induced disruption of mitochondrial membrane potential (ΔΨ(m)) and reduced the release of cytochrome c form the mitochondria to the cytosol. Furthermore, exposure to CoCl₂ caused activation of the hypoxia-inducible factor 1α (HIF-1α). On the other hand, MgSO₄ markedly reduced CoCl₂-induced HIF-1α activation and suppressed HIF-1α downstream protein BNIP3. MgSO₄ treatment induced ERK1/2 activation and attenuated CoCl₂-induced activation of p38 and JNK. Addition of the ERK1/2 inhibitor U0126 significantly reduced the ability of MgSO₄ to protect neurons from CoCl₂-induced mitochondrial apoptotic events. However, incubation of cultures with the p38 and JNK inhibitors did not significantly affect MgSO₄-mediated neuroprotection. MgSO₄ appears to suppress CoCl₂-induced NB41A3 cell death by activating ERK1/2/ MAPK pathways, which further modulates the role of Bcl-2 family proteins and mitochondria in NB41A3 cells. Our data suggest that MgSO₄ may act as a survival factor that preserves mitochondrial integrity and inhibits apoptotic pathways.

Helioxanthin, an active compound from Taiwania cryptomerioides Hayata, has been shown to have various biological activities. However, their anticancer effect in oral squamous cell carcinoma has not been well established yet. Helioxanthin inhibited the proliferation of oral squamous cell carcinoma cells in a dose-dependent manner by inducing G2/M phase arrest. Similarly, helioxanthin inhibited cyclooxygenase-2, (COX-2), phosphorylated EGFR, and extracellular-signal-regulated kinases (ERK) protein level and further reduced the nuclear accumulation of phosphorylated epidermal growth factor receptor (pEGFR) and activator protein-1(AP-1) family protein, c-fos. Moreover, helioxanthin at the dose of 20 and 30 mg kg for 15 days reduced the tumor growth in animal model. This study demonstrated that Helioxanthin exerts its anticancer activity against oral cancer cells by downregulating EGFR/ERK/c-fos signaling pathway to inhibit COX-2 level and by activating cyclin-dependent kinase inhibitor (p27) to further induce G2/M cell cycle arrest. This helioxanthin may serve as a novel candidate for oral cancer prevention. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 2045-2056, 2016.

Excessive intake of high fat diet (HFD) and associated obese conditions are critical contributors of cardiac diseases. In this study, an active metabolite andrographolide from Andrographis paniculata was found to ameliorate HFD-induced cardiac apoptosis. C57/BL6 mouse were grouped as control (n = 9), obese (n = 8), low dose (25 mg/kg/d) andrographolide treatment (n = 9), and high dose (50 mg/kg/d) andrographolide treatment (n = 9). The control group was provided with standard laboratory chow and the other groups were fed with HFD. Andrographolide was administered through oral gavage for 1 week. Histopathological analysis showed increase in apoptotic nuclei and considerable cardiac-damages in the obese group signifying cardiac remodeling effects. Further, Western blot results showed increase in pro-apoptotic proteins and decrease in the proteins of IGF-1R-survival signaling. However, feeding of andrographolide significantly reduced the cardiac effects of HFD. The results strongly suggest that andrographolide supplementation can be used for prevention and treatment of cardiovascular disease in obese patients.