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To investigate the effects and mechanism of diosmetin on acute hepatic failure (AHF), an AHF murine model was established through administration of lipopolysaccharides/D-galactosamine (LPS/D-GalN). In vitro, diosmetin scavenged free radicals. In vivo, diosmetin decreased mortality among mice, blocked the development of histopathological changes and hepatic damage, and suppressed levels of inflammatory mediators and cytokines. In addition, diosmetin prevented the expression of phosphorylated IKK, IκBα, and NF-κB p65 in the NF-κB signaling pathway, and JNK and p38 in the MAPK signaling pathway. Diosmetin also inhibited hepatocyte apoptosis. Thus, diosmetin exerts protective effects against endotoxin-induced acute hepatic failure in mice. The underlying mechanisms are antioxidation, NF-κB signaling inhibition, inflammatory mediator/cytokine attenuation, and hepatocyte apoptosis suppression. Diosmetin is thus a potential drug candidate for use in the treatment of acute hepatic failure.

Dense extracellular matrix (ECM) severely impedes the spread of drugs in solid tumors and induces hypoxia, reducing chemotherapy efficiency. Different proteolytic enzymes, such as collagenase (Col) or bromelain, can directly attach to the surface of nanoparticles and improve their diffusion, but the method of ligation may also impair the enzymatic activity due to conformational changes or blockage of the active site. Herein, a “nanoenzyme capsule” was constructed by combining collagenase nanocapsules (Col-nc) with heavy-chain ferritin (HFn) nanocages encapsulating the chemotherapy drug doxorubicin (DOX) to enhance tumor penetration of the nanoparticles by hydrolyzing collagen from the ECM. Col-nc could protect the activity of the enzyme before reaching the site of action while being degraded under mildly acidic conditions in tumors, and the released proteolytic enzyme could digest collagen. In addition, HFn as a carrier could effectively load DOX and had a self-targeting ability, enabling the nanoparticles to internalize into cancer cells more effectively. From in vivo and in vitro studies, we found that collagen was effectively degraded by Col-nc/HFn­(DOX) to increase the accumulation and penetration of nanoparticles in the solid tumor site and could alleviate hypoxia inside the tumor to enhance the antitumor effects of DOX. Therefore, the strategy of increasing nanoparticle penetration in this system is expected to provide a potential approach for the clinical treatment of solid tumors.

The current studies reveal that the clock gene Per2 is expressed at lower levels in a variety of tumors and plays a significant tumor suppressor role. However, the biological functions and mechanism of Per2 in OSCC (OSCC: oral squamous cell carcinoma) remain unclear. In this study, OSCC cells with stable overexpression or silencing of Per2 were established to explore their biological functions and mechanism in vivo and in vitro. We discovered that the expression of Per2 decreases in OSCC cells. Overexpression of Per2 promoted autophagy and apoptosis in OSCC cells and inhibited proliferation. The opposite results were obtained in Per2-silenced OSCC cells. In Per2-overexpressing OSCC cells, the expression levels of PIK3CA, p-AKT, p-mTOR, p62 and Beclin1 were significantly reduced and the LC3B II/I ratio was significantly increased. In contrast, in Per2-silenced OSCC cells, the expression levels of PIK3CA, p-AKT, p-mTOR, p62 and Beclin1 were significantly enhanced and the LC3B II/I ratio was significantly reduced. When the AKT activator SC79 was added to Per2-overexpressing OSCC cells, the increased autophagy, apoptosis and decreased proliferation were significantly rescued. Furthermore, when autophinib, an autophagy inhibitor, was added to Per2-overexpressing OSCC cells, the decreased proliferation and increased apoptosis were significantly restored. An in vivo tumorigenesis assay also confirmed that overexpression of Per2 suppresses the growth of OSCC. In conclusion, our research results demonstrate that Per2 suppresses OSCC progression by motivating autophagy, as well as inhibiting cell proliferation and promoting apoptosis, which were mediated by autophagy, in a PI3K/AKT/mTOR pathway-dependent manner. Per2 could potentially be used as a valuable therapeutic marker for OSCC.