Melatonin sensitises shikonin-induced cancer cell death mediated by oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway.

Recent research suggests that melatonin (Mel), an endogenous hormone and natural supplement, possesses anti-proliferative effects and can sensitise cells to anti-cancer therapies. Although shikonin (SHK) also possesses potential anti-cancer properties, the poor solubility and severe systemic toxicity of this compound hinders its clinical usage. In this study, we combined Mel and SHK, a potentially promising chemotherapeutic drug combination, with the aim of reducing the toxicity of SHK and enhancing the overall anti-cancer effects. We demonstrate for the first time that Mel potentiates the cytotoxic effects of SHK on cancer cells by inducing oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway. Particularly, Mel-SHK treatment induced oxidative stress, increased mitochondrial calcium accumulation and reduced the mitochondrial membrane potential in various cancer cells, leading to apoptosis. This drug combination also promoted endoplasmic reticulum (ER) stress, leading to AKT dephosphorylation. In HeLa cells, Mel-SHK treatment reduced SIRT3/SOD2 expression and SOD2 activity, while SIRT3 overexpression dramatically reduced Mel-SHK-induced oxidative stress, ER stress, mitochondrial dysfunction and apoptosis. Hence, we propose the combination of Mel and SHK as a novel candidate chemotherapeutic regimen that targets the SIRT3/SOD2-AKT pathway in cancer.

Icariin-loaded electrospun PCL/gelatin nanofiber membrane as potential artificial periosteum.

Due to the significant role of the periosteum in bone regeneration, we hypothesised that using a specially engineered artificial periosteum could lead to an enhancement in osteogenesis in bone grafts. Herein, we describe our work aimed at fabricating an electrospun fibrous membrane as an artificial periosteum that exhibits flexibility, permeability and osteoinduction. This membrane was designed to cover the complex surface of bone grafts to facilitate and accelerate bone regeneration. The traditional Chinese medicine icariin (ICA) was subsequently introduced into poly (ε-caprolactone) (PCL) /gelatin nanofibers to fabricate an artificial periosteum for the first time. The effects of ICA content on morphology, physical properties, drug release profile, in vitro degradability, biocompatibility and osteogenic differentiation properties were investigated. The ICA-loaded electrospun membranes showed significant improvement in hydrophilicity, high mechanical strength, appropriate degradation rates and excellent biocompatibility. Furthermore, clear enhancement in alkaline phosphatase (ALP) activity, as well as an increase in osteocalcin (OCN) and type collagen I (COL I) expression in MC3T3-E1 cells were detected. Furthermore, we observed clear calcium deposition content in MC3T3-E1 cells cultured on ICA-loaded fibrous matrix. The membrane loaded with 0.05 wt.% ICA displayed properties contributing to cell attachment, proliferation and differentiation. These results indicate the huge potential of this ICA-loaded PCL/gelatin electrospun membrane as a biomimetic artificial periosteum to accelerate bone regeneration.