Cathepsin B is an executioner of ferroptosis.

Ferroptosis is a necrotic form of cell death caused by inactivation of the glutathione system and uncontrolled iron-mediated lipid peroxidation. Increasing evidence implicates ferroptosis in a wide range of diseases from neurotrauma to cancer, highlighting the importance of identifying an executioner system that can be exploited for clinical applications. In this study, using pharmacological and genetic models of ferroptosis, we observed that lysosomal membrane permeabilization and cytoplasmic leakage of cathepsin B unleashes structural and functional changes in mitochondria and promotes a not previously reported cleavage of histone H3. Inhibition of cathepsin-B robustly rescued cellular membrane integrity and chromatin degradation. We show that these protective effects are independent of glutathione peroxidase-4 and are mediated by preventing lysosomal membrane damage. This was further confirmed when cathepsin B knockout primary fibroblasts remained unaffected in response to various ferroptosis inducers. Our work identifies new and yet-unrecognized aspects of ferroptosis and identifies cathepsin B as a mediator of ferroptotic cell death

The Effects of Monosodium Glutamate and Tannic Acid on Adult Rats

BACKGROUND: Monosodium glutamate (MSG) is a widely-used flavor enhancer and stabilizer in ready-made or packaged foods. The excessive use of MSG has been shown to increase oxidative stress in different organ systems and causes glucose metabolism disorders, obesity, and coronary diseases. OBJECTIVES: In this study, the antioxidant activity of tannic acid was investigated experimentally with respect to its protective effects against overdosed MSG-induced oxidative stress in rats. The study took place in Turkey in August 2013. METHODS: Four groups (n = 7) of three- to four-month-old Sprague-Dawley female rats were used in this study. The first group was the control, who were administered saline. The second group received tannic acid (50 mg/kg, 3 days) intraperitoneally (i.p.). The third group received MSG (2 g/kg, 7 days) i.p., and the fourth group received both tannic acid (50 mg/kg, 3 days, pretreatment) and MSG (2 g/kg, 7 days) i.p. The animals were euthanized ten days later. Blood was collected for determining the hematological values and blood glucose levels. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were determined in the brain, liver, and kidney homogenates, and in the erythrocyte hemolysate. Histopathological examination of the brain, liver, and kidneys was conducted through hematoxylin-eosin staining. RESULTS: The data showed that the tannic acid treatment statistically decreased the MDA levels in the brain tissues of the group administered MSG and tannic acid (P < 0.001) when compared to the corresponding values of the control group. The SOD activities in the blood hemolysates of the MSG and tannic acid group increased when compared to the corresponding values for the MSG group (P < 0.01). Additionally, we found that pretreatment with tannic acid reduced blood glucose levels in comparison to the levels of the MSG group (P = 0.029). The results of our study show that tannic acid pretreatment in adult rats decreased blood glucose levels and oxidative stress. CONCLUSIONS: In the literature, it was observed that short-term MSG exposure does not cause significant histological changes in the kidneys, liver, or brain cortex. These findings should be re-evaluated in additional long-term studies

ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), continues to cause significant morbidity and mortality in the ongoing global pandemic. Understanding the fundamental mechanisms that govern innate immune and inflammatory responses during SARS-CoV-2 infection is critical for developing effective therapeutic strategies. While IFN-based therapies are generally expected to be beneficial during viral infection, clinical trials in COVID-19 have shown limited efficacy and potential detrimental effects of IFN treatment during SARS-CoV-2 infection. However, the underlying mechanisms responsible for this failure remain unknown. In this study, we found that IFN induced ZBP1-mediated inflammatory cell death, PANoptosis, in human and murine macrophages and in the lungs of mice infected with ??-coronaviruses, including SARS-CoV-2 and mouse hepatitis virus (MHV). In patients with COVID-19, expression of the innate immune sensor ZBP1 was increased in immune cells from those who succumbed to the disease compared with those who recovered, further suggesting a link between ZBP1 and pathology. In mice, IFN-?? treatment following ??-coronavirus infection increased lethality, and genetic deletion of Zbp1 or its Z?? domain suppressed cell death and protected the mice from IFN-mediated lethality during ??-coronavirus infection. Overall, our results identify that ZBP1 induced during coronavirus infection limits the efficacy of IFN therapy by driving inflammatory cell death and lethality. Therefore, inhibiting ZBP1 activity may improve the efficacy of IFN therapy, paving the way for the development of new and critically needed therapeutics for COVID-19 as well as other infections and inflammatory conditions where IFN-mediated cell death and pathology occur