BackgroundTraumatic brain injury (TBI) induces a complex sequence of apopototic cascades that contribute to secondary tissue damage. The aim of this study was to investigate the effects of salidroside, a phenolic glycoside with potent anti-apoptotic properties, on behavioral and histological outcomes, brain edema, and apoptosis following experimental TBI and the possible involvement of the phosphoinositide 3-kinase/protein kinase B (PI3K)/Akt signaling pathway.Methodology/Principal FindingsMice subjected to controlled cortical impact injury received intraperitoneal salidroside (20, or 50 mg/kg) or vehicle injection 10 min after injury. Behavioral studies, histology analysis and brain water content assessment were performed. Levels of PI3K/Akt signaling-related molecules, apoptosis-related proteins, cytochrome C (CytoC), and Smac/DIABLO were also analyzed. LY294002, a PI3K inhibitor, was administered to examine the mechanism of protection. The protective effect of salidroside was also investigated in primary cultured neurons subjected to stretch injury. Treatment with 20 mg/kg salidroside_significantly improved functional recovery and reduced brain tissue damage up to post-injury day 28. Salidroside_also significantly reduced neuronal death, apoptosis, and brain edema at day 1. These changes were associated with significant decreases in cleaved caspase-3, CytoC, and Smac/DIABLO at days 1 and 3. Salidroside increased phosphorylation of Akt on Ser473 and the mitochondrial Bcl-2/Bax ratio at day 1, and enhanced phosphorylation of Akt on Thr308 at day 3. This beneficial effect was abolished by pre-injection of LY294002. Moreover, delayed administration of salidroside at 3 or 6 h post-injury reduced neuronal damage at day 1. Salidroside treatment also decreased neuronal vulnerability to stretch-induced injury in vitro.Conclusions/SignificancePost-injury salidroside improved long-term behavioral and histological outcomes and reduced brain edema and apoptosis following TBI, at least partially via the PI3K/Akt signaling pathway.

Background/Aim: Ursolic acid (UA), a triterpene compound present in natural plants, has been shown to induce cytotoxic effects on many human cancer cells through induction of cell-cycle arrest and apoptosis. This study investigated the effects of UA on human lung cancer NCI-H292 cells in vitro. Materials and Methods: Flow cytometric assay was used to measure the percentage of cell viability, apoptotic cell death by double staining of annexin V and propidium iodide (PI), production of reactive oxygen species (ROS) and Ca 2+ , and mitochondriaI membrane potential (Ψ m). UA-induced chromatin condensation and DNA fragmentation were examined by 4',6-diamidino-2-phenylindole staining and DNA gel electrophoresis, respectively. Western blotting was used to examine the changes of apoptosis-associated protein expression in NCI-H292 cells. Results: UA reduced cell viability and induced apoptotic cell death. UA increased Ca 2+ production, reduced Ψ m , but did not affect ROS production in NCI-H292 cells. UA increased apoptosis-inducing factor (AIF) and endonuclease G in NCI-H292 cells. Conclusion: Based on these observations, we suggest UA induces apoptotic cell death via AIF and Endo G release through a mitochondria-dependent pathway in NCI-H292 cells. Lung cancer is the leading cause of cancer-associated death worldwide (1) and divided into non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). The most common type is NSCLC accounting for about 80-85% (2, 3), with poor prognosis and a high incidence of recurrence (4). NSCLC includes adenocarcinoma, squamous cell carcinoma, and large-cell carcinomas (5). Although advanced diagnostics and therapeutics have been developed, the treatment and outcome of lung cancer is still unsatisfactory (4, 6-8). Characteristics of cancer include uncontrolled cell-cycle progression and deregulation of apoptosis. One of the therapeutic strategies for chemotherapy is to induce cancer cell apoptosis. Apoptosis plays a critical role in the balance between cellular replication and death, in particular for elimination of unwanted, damaged or infected cells (9, 10). Much evidence has shown that chemotherapy drugs in clinical used for patients with cancer via the activation of apoptotic pathways in cancer cells (11-13). When the mitochondria membrane potential (Ψ m) decreases, cytochrome c binds to 383 This article is freely accessible online.

Sulforaphane (SFN) is an isothiocyanate, inducing cytotoxic effects in various human cancer cells, including leukemia cells through cell cycle arrest and apoptosis. However, the effect of SFN on the immune responses in a leukemia mouse model remains to be investigated. The present study investigated whether SFN has an effect on the immune responses in a WEHI‑3‑induced leukemia mouse model in vivo. Normal BALB/c mice were injected with WEHI‑3 cells to generate the leukemia mouse model, and were subsequently treated with placebo or SFN (0, 285, 570 and 1,140 mg/kg) for 3 weeks. Following treatment, all mice were weighted and blood samples were collected. In addition, liver and spleen samples were isolated to determine cell markers, phagocytosis and natural killer (NK) cell activities, and cell proliferation was examined using flow cytometry. The results indicated that SFN treatment had no significant effect on the spleen weight, however it decreased liver and body weight. Furthermore, SFN treatment increased the percentage levels of CD3 (T cells) and CD19 (B cell maker), however had no effect on the levels of CD11b (monocytes) or Mac‑3 (macrophages), compared with the WEHI‑3 control groups. The administration of SFN increased the phagocytosis of macrophages from peripheral blood mononuclear cells and peritoneal cavity, and increased the activity of NK cells from splenocytes. Administration of SFN promoted T and B cell proliferation following stimulation with concanavalin A and lipopolysaccharide, respectively.

The cover image is based on the Research Article Cardamonin induces immune responses and enhances survival rate in WEHI‐3 cell‐generated mouse leukemia in vivo by Nien‐Chieh Liao et al., https://doi.org/10.1002/tox.22881.