Evodiamine, a Novel NOTCH3 Methylation Stimulator, Significantly Suppresses Lung Carcinogenesis in Vitro and in Vivo.

Lung cancer is a leading cause of cancer-related deaths worldwide. NOTCH3 signaling is mainly expressed in non-small cell lung carcinoma (NSCLC), and has been proposed as a therapeutic target of NSCLC. While, few agents for preventing or treating NSCLC via targeting NOTCH3 signaling are used in modern clinical practice. Evodiamine (EVO), an alkaloid derived from Euodiae Fructus, possesses low toxicity and has long been shown to exert anti-lung cancer activity. However, the underlying anti-lung cancer mechanisms of EVO are not yet fully understood. In this study, we explored the involvement of NOTCH3 signaling in the anti-lung cancer effects of EVO. Urethane-induced lung cancer mouse model and two NSCLC cell models, A549 and H1299, were used to evaluate the in vivo and in vitro anti-lung cancer action of EVO. A DNA methyltransferase inhibitor was employed to investigate the role of NOTCH3 signaling in the anti-lung cancer effects of EVO. Results showed that EVO potently reduced tumor size and tumor numbers in mice, and inhibited NOTCH3 in the tumors. EVO also dramatically reduced cell viability, induced G2/M cell cycle arrest, inhibited cell migration and reduced stemness in cultured NSCLC cells. Mechanistic studies showed that EVO potently inhibited NOTCH3 signaling by activation of DNMTs-induced NOTCH3 methylation. Importantly, inhibition of NOTCH3 methylation in NSCLC cells diminished EVO's anti-NSCLC effects. Collectively, EVO, a novel NOTCH3 methylation stimulator, exerted potent anti-lung cancer effects partially by inhibiting NOTCH3 signaling. These findings provide new insight into the EVO's anti-NSCLC action, and suggest a potential role of EVO in lung cancer prevention and treatment.

Asymmetric synthesis and evaluation of danshensu-cysteine conjugates as novel potential anti-apoptotic drug candidates.

We have previously reported that the danshensu-cysteine conjugate N-((R)-3-benzylthio-1-methoxy-1-oxo-2-propanyl)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanamide (DSC) is a potent anti-oxidative and anti-apoptotic agent. Herein, we further design and asymmetrically synthesize two diastereoisomers of DSC and explore their potential bioactivities. Our results show that DSC and its two diastereoisomers exert similar protective effects in hydrogen peroxide (H2O2)-induced cellular injury in SH-SY5Y cells, as evidenced by the increase of cell viability, superoxide dismutase (SOD), and reduced glutathione (GSH) activity, and glutathione peroxidase (GPx) expression, and the decrease of cellular morphological changes and nuclear condensation, lactate dehydrogenase (LDH) release, and malondialdehyde (MDA) production. In H2O2-stimulated human umbilical vein endothelial cells (HUVEC), DSC concentration-dependently attenuates H2O2-induced cell death, LDH release, mitochondrial membrane potential collapse, and modulates the expression of apoptosis-related proteins (Bcl-2, Bax, caspase-3, and caspase-9). Our results provide strong evidence that DSC and its two diastereoisomers have similar anti-oxidative activity and that DSC exerts significant vascular-protective effects, at least in part, through inhibition of apoptosis and modulation of endogenous antioxidant enzymes.

Late reconstruction of posterior acetabular wall fractures using iliac crest.

BACKGROUND: Reconstructing late posterior acetabular wall fractures is challenging. This study evaluates the use of the iliac crest strut graft for posterior acetabular wall reconstruction. METHODS: From 1990 to 2004, seven patients (five males and two females) with traumatic posterior acetabular wall defects were reconstructed using autogenous iliac crest strut grafts. The mean age of the patients was 31 years. The mean time from injury to reconstruction was 6.4 months. The clinical (modified Merle d'Aubigné-Postel score) and radiologic evaluation (Matta score) were recorded at the final follow-up. RESULTS: The mean duration of follow-up was 76 months. On the basis of the modified Merle d'Aubigné-Postel scoring system, the clinical outcomes at final follow-up were as follows: excellent for a pediatric patient; good for three adult patients without posttraumatic osteoarthritis of the hip at the time of reconstruction; and poor for three other adult patients with posttraumatic osteoarthritis of the hip at the time of reconstruction. Radiologic grading at the final follow-up was good in the pediatric patient; fair in three adult patients without posttraumatic osteoarthritis of the hip; and poor in three other patients with posttraumatic osteoarthritis of the hip. CONCLUSIONS: The reconstruction of the posterior acetabular wall defects using an iliac crest strut graft is a noteworthy technique for late posterior acetabular wall fracture. The technique may be an option for pediatric patients or adults without posttraumatic osteoarthritis of the hip at the time of reconstruction. However, it is not recommended for adult patients with posttraumatic osteoarthritis of the hip. In this case, total hip arthroplasty is a better choice. LEVEL OF EVIDENCE: IV, therapeutic study.