Ferroptosis is a form of regulated cell death triggered by lipid peroxidation after inhibition of the cystine/glutamate antiporter system X. However, key regulators of system X activity in ferroptosis remain undefined. Here, we show that BECN1 plays a hitherto unsuspected role in promoting ferroptosis through directly blocking system Xc activity via binding to its core component, SLC7A11 (solute carrier family 7 member 11). Knockdown of BECN1 by shRNA inhibits ferroptosis induced by system X inhibitors (e.g., erastin, sulfasalazine, and sorafenib), but not other ferroptosis inducers including RSL3, FIN56, and buthionine sulfoximine. Mechanistically, AMP-activated protein kinase (AMPK)-mediated phosphorylation of BECN1 at Ser90/93/96 is required for BECN1-SLC7A11 complex formation and lipid peroxidation. Inhibition of PRKAA/AMPKα by siRNA or compound C diminishes erastin-induced BECN1 phosphorylation at S93/96, BECN1-SLC7A11 complex formation, and subsequent ferroptosis. Accordingly, a BECN1 phosphorylation-defective mutant (S90,93,96A) reverses BECN1-induced lipid peroxidation and ferroptosis. Importantly, genetic and pharmacological activation of the BECN1 pathway by overexpression of the protein in tumor cells or by administration of the BECN1 activator peptide Tat-beclin 1, respectively, increases ferroptotic cancer cell death (but not apoptosis and necroptosis) in vitro and in vivo in subcutaneous and orthotopic tumor mouse models. Collectively, our work reveals that BECN1 plays a novel role in lipid peroxidation that could be exploited to improve anticancer therapy by the induction of ferroptosis.

This paper explores whether dog behavioral characteristics predict the quality of the relationship between dogs and their owners (i.e., owner attachment to dog), and whether relations between dog behavior and owner attachment are moderated by demographic characteristics. In this study, N = 92 children and N = 60 adults from 60 dog-owning families completed questionnaires about their attachment to their pet dog, their level of responsibility for that dog, and their general attitudes toward pets. They also rated their dogs on observable behavioral characteristics. Individuals who held positive attitudes about pets and who provided much of their dog's care reported stronger attachments to their dogs. The strength of owners' attachments to their dogs was associated with dog trainability and separation problems. Relationships between owner attachment and both dog excitability and attention-seeking behavior were further moderated by demographic characteristics: for Caucasians but not for non-Caucasians, dog excitability was negatively associated with owner attachment to dog; and for adults, dog attention-seeking behavior was positively associated with owner attachment, but children tended to be highly attached to their dogs, regardless of their dogs' attention-seeking behaviors. This study demonstrates that certain dog behavioral traits are indeed associated with the strength of owners' attachments to their dogs. NIH-PA Author ManuscriptContributing to the literature on for whom and under what conditions dog ownership is beneficial to humans, this paper explores whether dog behavioral characteristics are predictive of the quality of the relationship between dogs and their owners (i.e., owner attachment to dog), and whether relations between dog behavior and owner attachment are the same across genders, ages, and races/ethnicities. The effects of dog behavior and owner demographics on owner attachment to dog might elucidate why some studies suggest that pet ownership can be beneficial to human health (Barker & Wolen, 2008;Cutt, Giles-Corti, Knuiman, & Burke, 2007;El-Alayli, Lystad, Webb, Hollingsowrth, & Ciolli, 2006;Friedmann & Son, 2009;Headey & Grabka, 2011;O'Haire, 2010;Wells, 2009), while others have failed to detect such positive findings (for a review, see Herzog, 2011). An important distinction between studies that have reported beneficial health effects of humananimal interactions (HAI) and those that have not is that the latter have all focused specifically on pet ownership as the primary predictor and not on attachment to or attitudes toward pets. Evidence indicates that the stress-reducing benefits of HAI are moderated by attachments to companion animals (Garrity, Stallones, Marx, & Johnson, 1989;Sable, 1995), and interaction with a dog lowers cardiovascular stress reactivity for individuals with positive attitudes toward dogs but increases stress reactivity for individuals with negative attitudes toward dogs (Friedmann, Zuck Locker, & Lockwood, 1990). Such findings indicate that the benefits of HA...

It is well known that the lipotoxic mechanism of palmitic acid (PA), a main constituent of triglyceride, is dependent on reactive oxygen species (ROS). Recently, it has also been reported that PA is an autophagy inducer. However, the causal association and underlying mechanism of induced autophagy and ROS in PA toxicity remain unclear. The present study demonstrates for the first time that PA-induced autophagy enhances ROS generation via activating the calcium ion/protein kinase Cα/nicotinamide adenine dinucleotide phosphate oxidase 4 (Ca2+/PKCα/NOX4) pathway in human umbilical vein endothelial cells (HUVECs). It was revealed that PA treatment resulted in a significant increase in ROS generation and autophagic activity, leading to endothelial dysfunction as indicated by downregulated nitric oxide synthesis, decreased capillary-like structure formation and damaged cell repair capability. Furthermore, PA effectively activated the Ca2+/PKCα/NOX4 pathway, which is indicative of upregulated cytosolic Ca2+ levels, activated PKCα and increased NOX4 protein expression. 3-Methyladenine was then used to inhibit autophagy, which significantly reduced PA-induced ROS generation and blocked the Ca2+/PKCα/NOX4 pathway. The endothelial dysfunction caused by PA was ameliorated by downregulating ROS generation using a NOX4 inhibitor. In conclusion, PA-induced autophagy contributes to endothelial dysfunction by increasing oxidative stress via the Ca2+/PKCα/NOX4 pathway in HUVECs.

Background/Purpose Nurses engaged in the care of people living with HIV (PLWH) are commonly exposed to workplace stress. This study aimed to explore the stress experiences and coping strategies among nurses taking care of PLWH in China. Methods Nurses were recruited from the AIDS department of a public, general, third-grade class-A hospital, which has the largest HIV care department in the Hunan Province of China. Thirty-three nurses working in the AIDS Department were recruited in this qualitative study. Eight nurses participated in a focus group and 25 nurses underwent in-depth individual interviews aimed at characterizing the nurse’s feelings and struggles with stress during caregiving for PLWH. The interviews were audio-recorded, transcribed verbatim, anonymized, and imported into NVivo 8.0 software. The data were coded and subjected to thematic analysis. Results Concerns about occupational exposure, heavy workload, mental health problems and risk behaviors of patients, and discrimination towards nurses caring for PLWH were the four main sources of stress. The negative impact of stress included problems with emotion regulation, somatic health and sleep, and work performance. Some participants also reported a positive impact of work stress on their mental health. Using personality strengths, problem-solving, help-seeking, concealing and avoiding/suppression were common coping strategies employed by nurses caring for PLWH. Conclusion Our findings help characterize the stress experienced by nurses caring for PLWH in the Chinese cultural context, and may inform specific interventions to help manage stress and promote mental health of nurses.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) contributes to dysfunction of endothelial cells via its receptor, Fn14. However, its role in the production of reactive oxygen species (ROS), particularly mitochondrial ROS (mtROS) and the subsequent decrease in nitric oxide (NO) in endothelial cells remains unclear. In this study, the effect of TWEAK/Fn14 on generation of ROS, mtROS and NO in endothelial cells and its potential mechanism was investigated. Human umbilical vein endothelial cells (HUVECs) were treated with TWEAK with Fn14 small interfering (si)RNA or negative control RNA. It was demonstrated that TWEAK induced the production of ROS and mtROS in HUVECs, which were detected by fluorescent microscope, and flow cytometry. In addition, TWEAK decreased the generation of NO as indicated using the Nitric Oxide Assay kit. Furthermore, TWEAK aggravated mtDNA damage as measured by quantitative polymerase chain reaction analysis. Inhibition of Fn14 by Fn14 siRNA decreased TWEAK‑induced ROS and mtROS production, as well as mtDNA damage, while it increased the production of NO in endothelial cells. In addition, TWEAK inhibited the expression of active AMP‑activated protein kinase (AMPK) and its downstream protein peroxisome proliferator‑activated receptor‑γ coactivator-1α (PGC‑1α) and manganese superoxide dismutase (MnSOD). Notably, Fn14 siRNA enhanced the expression of the aforementioned proteins. Taken together, TWEAK/Fn14 contributes to endothelial dysfunction through modulation of ROS and mtROS. In addition, the underlying mechanism is implicated in the AMPK/PGC‑1α/MnSOD signaling pathway.