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Objectives: To assess the effect of sildenafil on monocrotaline-induced right ventricular (RV) remodeling and investigate the possible mechanism., Methods: Rats were subcutaneously injected with monocrotaline to establish an RV remodeling model and then administered sildenafil (25 mg/kg) from days 1 to 28. After 28 days of administration, the RV systolic pressure and the RV hypertrophy index (RVHI) were measured. The morphology of the right ventricle was observed by H&E staining. The ultrastructure of the right ventricle was observed using a transmission electron microscope. The myocardial apoptosis of the right ventricle was evaluated by TUNEL staining. The protein expression of apoptosis-related proteins and PPARs were examined by western blotting., Key Findings: The results indicated that sildenafil decreased the RV systolic pressure and RVHI, and improved the microstructure and ultrastructure of the right ventricle in monocrotaline-induced rats. In addition, sildenafil suppressed myocardial apoptosis and promoted the protein expression of PPARs of the right ventricle in monocrotaline-induced rats., Conclusion: Sildenafil inhibits RV remodeling in monocrotaline-induced rats, which might be partially mediated by reducing myocardial apoptosis and activating PPARs., (© The Author(s) 2021. Published by Oxford University Press on behalf of Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Interleukin (IL)-17A is pro-inflammatory cytokine which has been identified as a noninvasive marker of the pathogenesis of non-alcoholic steatohepatitis (NASH). However, the underlying role of IL-17A in NASH progression remains unclear. This study was designed to investigate the biological function and molecular mechanism of IL-17A in the induction of NASH. The results showed that IL-17A was highly expressed in high-fat diet (HFD)-induced NASH mouse model. Intravenous injection of IL-17A exacerbated steatohepatitis process via promoting hepatocyte apoptosis. Furthermore, IL-17A-induced apoptosis was mediated by ERK1/2/p65 signaling pathway. In conclusion, we demonstrated that IL-17A-mediated ERK1/2/p65 signaling pathway was a promising target for the treatment of NASH. © 2018 IUBMB Life, 71(3):302-309, 2019., (© 2018 International Union of Biochemistry and Molecular Biology.)

In this study we demonstrated that Triticuside A, one of the flavonoid compounds isolated from wheat bran, induced apoptosis and inhibited proliferation of human breast cancer cells. Triticuside A inhibited the proliferation of human breast cancer cells (MCF-7 and MDA-MB-231) in a dose-dependent manner but barely showed cytotoxicity to the normal human fibroblasts. Triticuside A-induced apoptosis was accompanied by a significant decrease of Mcl-1 and Bcl-2 proteins and by an increase of cleavage of caspases-3, -7, -9, and PARP. Triticuside A also suppressed the level of phospho-Akt and its downstream targets, mTOR and P70 S6 kinase. LY294002, a specific inhibitor of PI3K, significantly enhanced the Triticuside A-induced apoptosis. Moreover LY294002 not only downregulated the level of phospho-Akt but also enhanced the inhibition of Mcl-1 expression when combined with Triticuside A. Our results demonstrate for the first time the specific apoptogenic activity of Triticuside A in tumor cells and involvement of the mitochondrial apoptosis pathway and Akt/mTOR signaling pathway. Thus, Triticuside A may be a potentially useful wheat bran component that can be used for prevention or treatment of breast cancer.

Ectopic epigenetic mechanisms play important roles in facilitating tumorigenesis. Here, we first demonstrated that ANKDD1A is a functional tumor suppressor gene, especially in the hypoxia microenvironment. ANKDD1A directly interacts with FIH1 and inhibits the transcriptional activity of HIF1α by upregulating FIH1. In addition, ANKDD1A decreases the half-life of HIF1α by upregulating FIH1, decreases glucose uptake and lactate production, inhibits glioblastoma multiforme (GBM) autophagy, and induces apoptosis in GBM cells under hypoxia. Moreover, ANKDD1A is highly frequently methylated in GBM. The tumor-specific methylation of ANKDD1A indicates that it could be used as a potential epigenetic biomarker as well as a possible therapeutic target.

Background/Aim: Apoptosis and oxidative stress have been considered as key events in the pathogenesis of Alzheimer's disease (AD). Senegenin (Sen), the major and most effective ingredient of Radix Polygalae, which has anti-apoptotic and anti-oxidative effects. The aim of this study was to investigate the anti-apoptotic and anti-oxidant effects of Sen on Aβ1-42-induced PC12 cells apoptosis and oxidative stress as well as its possible signaling pathway. Methods: Rat pheochromocytoma (PC12) cells were treated by 20 μM Aβ1-42 and then divided into 5 different treatment groups (Control; Aβ1-42 20 μM; Aβ1-42 20 μM + Sen 10 μM; Aβ1-42 20 μM + Sen 30 μM; Aβ1-42 20μM + Sen 60 μM). PC12 cells activity was detected by MTT assay. Colony formation assay was performed to assess the clonogenic ability of cells. The cell apoptosis was detected by Annexin-V/PI staining. The pro-apoptotic protein (Bax), anti-apoptotic protein (Bcl-2), anti-oxidative stress factor (HO-1, Nuclear Nrf2, Total Nrf2) and pathway-related protein (Akt, P-Akt, PI3K, P-PI3K) were tested by Western blot. The reactive oxygen species (ROS) level was assessed with a DCFH-DA probe. Results: The results indicated that Sen dose-dependently increased cell viability and reduced the number of apoptotic cells. The ratio of P-PI3K/PI3K and P-Akt/Akt increased in a dose-dependent manner under the treatment of Sen, suggesting that Sen might activate the PI3K/Akt signaling pathway. Moreover, Sen upregulates the ratio of Bcl-2/Bax. Further study revealed that Sen can play an antioxidant role in enhancing HO-1, promoting Nrf2 nuclear translocation and reducing ROS accumulation to reduce oxidative stress. Conclusion: Sen is effective in inhibiting apoptosis and oxidative stress in Aβ1-42-induced PC12 cells, which likely contribute to the development of novel therapies for AD. [ABSTRACT FROM AUTHOR]

[Display omitted] • LvSPARC-L contained an open reading frame of 1002 bp, encoding 333 amino acids. • LvSPARC-L was mainly expressed in hemocyte, stomach and pleoplod. • LvSPARC-L was significantly up-regulated by WSSV challenge. • IE1 - VP28 were significantly increased in LvSPARC-L -silenced shrimp. • LvP53 and LvCaspase3 was extremely decreased in LvSPARC-L -silenced shrimp. Secreted protein acidic and rich in cysteine (SPARC) is an extracellular and non-structural glycoprotein. In shrimp, a significant function of SPARC in WSSV infection remains unclear. In this study, the full-length cDNA sequence of a secreted protein acidic and rich in cysteine -like was cloned from shrimp Litopenaeus vannamei (named as LvSPARC-L). LvSPARC-L contained an open reading frame of 1002 bp, encoding 333 amino acids. Bioinformatics analysis showed that LvSPARC-L contained a SPARC Ca2+-binding region in the C-terminus, a Kazal-type serine protease inhibitor domain and a BUD22 domain. Tissue distribution assay indicated that LvSPARC-L generally expressed in all tissues selected with a higher expression in hemocyte, stomach and pleoplod. In hepatopancreas and intestine, the relative expression of LvSPARC-L was significantly up-regulated following the WSSV challenge. Besides, the relative expression of viral immediately early gene IE1 and a late gene VP28 was significantly increased in the LvSPARCL -silenced shrimp. Furthermore, the relative expression of LvP53 and LvCaspase3 was extremely decreased in the stomach of ds LvSPARC-L treated shrimp, while that of LvP38 was not affected significantly. All data together suggest that LvSPARC-L might play an antiviral role by regulating apoptosis. [ABSTRACT FROM AUTHOR]