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Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation. It plays a crucial role in various pathological conditions, including neurodegenerative diseases, cancer, ischemia–reperfusion injury, and organ failure. This review systematically explores the key mechanisms underlying ferroptosis, including polyunsaturated fatty acidcontaining phospholipid (PUFA-PL) peroxidation, iron metabolism, and mitochondrial dysfunction. Additionally, we summarize major endogenous ferroptosis defense systems, including the SLC7A11-glutathione (GSH)-glutathione peroxidase Show less

Reactive molecules, including oxygen and nitrogen species, serve dual roles in human physiology. While they function as essential signaling molecules under normal physiological conditions, they contribute to cellular dysfunction and damage when produced in excess by normal metabolism or in response to stressors. Oxidative/nitrosative stress is a pathological state, resulting from the overproduction of reactive species exceeding the antioxidant capacity of the body, which is implicated in several chronic human diseases. Antioxidant Show less

Researchers are using new molecules, engineered immune cells and gene therapy to kill senescent cells and treat age-related diseases. Researchers are using new molecules, engineered immune cells and gene therapy to kill senescent cells and treat age-related diseases. Show less

Brain cancer is regarded as one of the most life-threatening forms of cancer worldwide. Oxidative stress acts to derange normal brain homeostasis, thus is involved in carcinogenesis in brain. The Nrf2/Keap1/ARE pathway is an important signaling cascade responsible for the maintenance of redox homeostasis, and regulation of antiinflammatory and anticancer activities by multiple downstream pathways. Interestingly, Nrf2 plays a somewhat, contradictory role in cancers, including brain cancer. Nrf2 has traditionally been regarded as a tumor suppressor Show less

Brain cancer is regarded as one of the most life-threatening forms of cancer worldwide. Oxidative stress acts to derange normal brain homeostasis, thus is involved in carcinogenesis in brain. The Nrf2/Keap1/ARE pathway is an important signaling cascade responsible for the maintenance of redox homeostasis, and regulation of antiinflammatory and anticancer activities by multiple downstream pathways. Interestingly, Nrf2 plays a somewhat, contradictory role in cancers, including brain cancer. Nrf2 has traditionally been regarded as a tumor suppressor Show less

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease. Show less

AbstractProfiling approaches have been increasingly employed for the characterization of disease‐relevant phenotypes or compound perturbation as they provide a broad, unbiased view on impaired cellular states. We report that morphological profiling using the cell painting assay (CPA) can detect modulators of de novo pyrimidine biosynthesis and of dihydroorotate dehydrogenase (DHODH) in particular. The CPA can differentiate between impairment of pyrimidine and folate metabolism, which both affect cellular nucleotide pools. The identified morphological signature is shared by inhibitors of DHODH and the functionally tightly coupled complex III of the mitochondrial respiratory chain as well as by UMP synthase, which is downstream of DHODH. The CPA appears to be particularly suited for the detection of DHODH inhibitors at the site of their action in cells. As DHODH is a validated therapeutic target, the CPA will enable unbiased identification of DHODH inhibitors and inhibitors of de novo pyrimidine biosynthesis for biological research and drug discovery. Show less

Few data are available on the clinical impact of drug-drug interactions (DDIs). Most of the studies are limited to the analysis of exposure to potential DDI or the targeted impact of the combination of a few drugs or therapeutic classes. The analysis of adverse drug reaction (ADR) reports could be a mean to study generally the adverse effects identified due to a DDI. Our objective was to describe the characteristics of ADRs resulting from DDIs reported to the French Pharmacovigilance system and to identify the drugs most often implicated in these ADRs. Considering all ADR reports from January 01, 2012, to December 31, 2016, we identified all cases of ADR resulting from a DDI (DDI-ADRs). We then described these in terms of patients' characteristics, ADR seriousness, drugs involved (two or more per case), and ADR type. Of the 4,027 reports relating to DDI-ADRs, 3,303 were related to serious ADRs. Patients with serious DDI-ADRs had a median age of 76 years (interquartile range: 63-84); 53% were male. Of all serious DDI-ADRs, 11% were life-threatening and 8% fatal. In 36% of cases, the DDI causing the ADR involved at least three drugs. Overall, 8,424 different drugs were mentioned in the 3,303 serious DDI-ADRs considered. Altogether, drugs from the "antithrombotic agents" subgroup were incriminated in 34% of serious DDI-ADRs. Antidepressants were the second most represented therapeutic/pharmacological subgroup (5% of serious DDI-ADRs). Among the 3,843 ADR types reported in the 3,303 serious DDI-ADRs considered, the most frequently represented were hemorrhage (40% clinical hemorrhage; 6% biological hemorrhage), renal failure (8%), pharmacokinetic alteration (5%), and cardiac arrhythmias (4%). Hemorrhagic accidents are still an important part of serious ADRs resulting from DDIs reported in France. The other clinical consequences of DDIs seem less well identified by pharmacovigilance. Moreover, more than one-third of serious DDI-ADRs involved at least three drugs. Show less

The transcription factor Nrf2 is a critical regulator of inflammatory responses. If and how Nrf2 also affects cytosolic nucleic acid sensing is currently unknown. Here we identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells. Here, Nrf2 activation decreases STING expression and responsiveness to STING agonists while increasing susceptibility to infection with DNA viruses. Mechanistically, Nrf2 regulates STING expression by decreasing STING mRNA stability. Repression of STING by Nrf2 occurs in metabolically reprogrammed cells following TLR4/7 engagement, and is inducible by a cell-permeable derivative of the TCA-cycle-derived metabolite itaconate (4-octyl-itaconate, 4-OI). Additionally, engagement of this pathway by 4-OI or the Nrf2 inducer sulforaphane is sufficient to repress STING expression and type I IFN production in cells from patients with STING-dependent interferonopathies. We propose Nrf2 inducers as a future treatment option in STING-dependent inflammatory diseases. Show less

Aminotriazole (ATZ) is commonly used as a catalase (CAT) inhibitor. We previously found ATZ attenuated oxidative liver injury, but the underlying mechanisms remain unknown. Acetaminophen (APAP) overdose frequently induces life-threatening oxidative hepatitis. In the present study, the potential hepatoprotective effects of ATZ on oxidative liver injury and the underlying mechanisms were further investigated in a mouse model with APAP poisoning. The experimental data indicated that pretreatment with ATZ dose- and time-dependently suppressed the elevation of plasma aminotransferases in APAP exposed mice, these effects were accompanied with alleviated histological abnormality and improved survival rate of APAP-challenged mice. In mice exposed to APAP, ATZ pretreatment decreased the CAT activities, hydrogen peroxide (H2O2) levels, malondialdehyde (MDA) contents, myeloperoxidase (MPO) levels in liver and reduced TNF-α levels in plasma. Pretreatment with ATZ also downregulated APAP-induced cytochrome P450 2E1 (CYP2E1) expression and JNK phosphorylation. In addition, posttreatment with ATZ after APAP challenge decreased the levels of plasma aminotransferases and increased the survival rate of experimental animals. Posttreatment with ATZ had no effects on CYP2E1 expression or JNK phosphorylation, but it significantly decreased the levels of plasma TNF-α. Our data indicated that the LD50 of ATZ in mice was 5367.4 mg/kg body weight, which is much higher than the therapeutic dose of ATZ in the present study. These data suggested that ATZ might be effective and safe in protect mice against APAP-induced hepatotoxicity, the beneficial effects might resulted from downregulation of CYP2E1 and inhibiton of inflammation. Show less