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The oxytosis/ferroptosis regulated cell death pathway recapitulates many features of mitochondrial dysfunction associated with the aging brain and has emerged as a potential key mediator of neurodegeneration. It has thus been proposed that the oxytosis/ferroptosis pathway can be used to identify novel drug candidates for the treatment of age-associated neurodegenerative diseases that act by preserving mitochondrial function. Previously, we identified cannabinol (CBN) as a potent neuroprotector. Here, we demonstrate that not only does CBN protect nerve cells from oxytosis/ferroptosis in a manner that is dependent on mitochondria and it does so independently of cannabinoid receptors. Specifically, CBN directly targets mitochondria and preserves key mitochondrial functions including redox regulation, calcium uptake, membrane potential, bioenergetics, biogenesis, and modulation of fusion/fission dynamics that are disrupted following induction of oxytosis/ferroptosis. These protective effects of CBN are at least partly mediated by the promotion of endogenous antioxidant defenses and the activation of AMP-activated protein kinase (AMPK) signaling. Together, our data highlight the potential of mitochondrially-targeted compounds such as CBN as novel oxytotic/ferroptotic inhibitors to rescue mitochondrial dysfunction as well as opportunities for the discovery and development of future neurotherapeutics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Because old age is the greatest risk factor for Alzheimer's disease (AD), it is critical to target the pathological events that link aging to AD in order to develop an efficient treatment that acts upon the primary causes of the disease. One such event might be the activation of oxytosis/ferroptosis, a unique cell death mechanism characterized by mitochondrial dysfunction and lethal lipid peroxidation. Here, a comprehensive library of >900 natural compounds was screened for protection against oxytosis/ferroptosis in nerve cells with the goal of better understanding the chemical nature of inhibitors of oxytosis/ferroptosis. Although the compounds tested spanned structurally diverse chemical classes from animal, microbial, plant and synthetic origins, a small set of very potent anti-oxytotic/ferroptotic compounds was identified that was highly enriched in plant quinones. The ability of these compounds to protect against oxytosis/ferroptosis strongly correlated with their ability to protect against in vitro ischemia and intracellular amyloid-beta toxicity in nerve cells, indicating that aspects of oxytosis/ferroptosis also underly other toxicities that are relevant to AD. Importantly, the anti-oxytotic/ferroptotic character of the quinone compounds relied on their capacity to target and directly prevent lipid peroxidation in a manner that required the reducing activity of cellular redox enzymes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1) and ferroptosis suppressor protein 1 (FSP1). Because some of the compounds increased the production of total reactive oxygen species while decreasing lipid peroxidation, it appears that the pro-oxidant character of a compound can coexist with an inhibitory effect on lipid peroxidation and, consequently, still prevent oxytosis/ferroptosis. These findings have significant implications for the understanding of oxytosis/ferroptosis and open new approaches to the development of future neurotherapies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ferroptosis was first described in 2012 as an iron- and lipid peroxidation-dependent form of regulated cell death. Since its initial description, these two characteristics have informed numerous cell culture studies where inhibitors of lipid peroxidation and/or iron chelators have been shown to prevent cell death induced by a wide range of insults. However, it is not clear whether these two characteristics are sufficient to distinguish ferroptosis from other forms of regulated cell death. Thus, the primary goal of this study was to determine whether a unique combination of features could be identified that would provide an approach to more clearly separate ferroptosis from other forms of regulated cell death. To this end, multiple pharmacological inhibitors based on a variety of studies were tested. Many of these inhibitors were previously shown to protect cells from oxytosis, a regulated cell death pathway that mechanistically overlaps with ferroptosis and is induced by some of the same chemicals as ferroptosis. These inhibitors were not only tested against both known ferroptosis and oxytosis inducers but also a number of other insults that have been suggested to induce ferroptosis. The results show that a pharmacological fingerprint for ferroptosis can be established and used to categorize toxic insults into those that overlap with oxytosis/ferroptosis and those that do not., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To assess the objective and subjective cure rates after the tension-free vaginal tape (TVT) procedure in women with urinary incontinence., Methods: We performed a retrospective analysis of 112 consecutive women with genuine stress (n = 88) and mixed (n = 24) incontinence. The objective cure rate was evaluated by clinical and urodynamic examinations and the subjective cure rate using the Contilife questionnaire. The mean follow-up time was 25 months (range 18 to 34)., Results: The mean operative time was 30 minutes (range 25 to 50). Most patients (58%) underwent surgery with locoregional anesthesia. The overall complication rate was 37.5% (42 of 112). The perioperative complication rate was 14.3%, including 13 bladder injuries (11.6%). Five (38.5%) of the latter occurred in 7 patients with a previous history of incontinence surgery (P <0.001). The early postoperative complication rate was 32.1%. The main complication was voiding difficulties, diagnosed in 14 patients. Ten (71.4%) required intermittent self-catheterization for less than 15 days and four for a mean duration of 28 days (range 15 to 90). The late postoperative complication rate was 29.4%, including 29 cases of de novo urge symptoms (25.9%). Anticholinergic drugs were effective in only 15 (51.7%) of the 29. The objective cure rate was 89.3%. No difference was found between patients with genuine stress incontinence and those with mixed incontinence. The subjective cure rate was 66%. The difference in cure rates between the objective and subjective evaluations was significant (P <0.05). The subjective cure rate in patients with de novo urge symptoms was 37.9%., Conclusions: Our results demonstrate that the TVT procedure is a safe and effective surgical method. The lower subjective cure rate was related to the high incidence of de novo urge symptoms.