The phenol red compound: A potential artifact in pharmacological induction of ferroptosis.

Phenol red (PR) is a commonly used compound in culture media as a pH indicator. However, it is unknown whether this compound can interfere with the pharmacological induction of ferroptosis. Here, using high-content live-cell imaging death analysis, we determined that the presence of PR in the culture medium preconditioned normal and tumor cells to ferroptosis induced by system xc- inhibition mediated by imidazole ketone erastin (IKE) or GPX4 blockade in response to RSL-3, but had no significant effects against treatment with the endoperoxide FINO2. Mechanistically, we revealed that PR decreases the levels of the antiferroptotic genes Slc7a11, Slc3a2, and Gpx4, while promoting the overexpression de Acls4, a key inducer of ferroptosis. Additionally, through superresolution analysis, we determined that the presence of PR mislocalizes the system xc- from the plasma membrane. Thus, our results show that the presence of PR in the culture medium can be a problematic artifact for the accurate interpretation of cell sensitivity to IKE or RSL-3-mediated ferroptosis induction.

Pharmacological targets for the induction of ferroptosis: Focus on Neuroblastoma and Glioblastoma.

Neuroblastomas are the main extracranial tumors that affect children, while glioblastomas are the most lethal brain tumors, with a median survival time of less than 12 months, and the prognosis of these tumors is poor due to multidrug resistance. Thus, the development of new therapies for the treatment of these types of tumors is urgently needed. In this context, a new type of cell death with strong antitumor potential, called ferroptosis, has recently been described. Ferroptosis is molecularly, morphologically and biochemically different from the other types of cell death described to date because it continues in the absence of classical effectors of apoptosis and does not require the necroptotic machinery. In contrast, ferroptosis has been defined as an iron-dependent form of cell death that is inhibited by glutathione peroxidase 4 (GPX4) activity. Interestingly, ferroptosis can be induced pharmacologically, with potential antitumor activity in vivo and eventual application prospects in translational medicine. Here, we summarize the main pathways of pharmacological ferroptosis induction in tumor cells known to date, along with the limitations of, perspectives on and possible applications of this in the treatment of these tumors.

Sulfasalazine exposure during pregnancy and lactation induces alterations in reproductive behavior in adult female rat offspring.

AIMS: Sulfasalazine (SAS) is the first line drug in the treatment of chronic inflammatory bowel diseases in pregnant women. SAS and its metabolites cross the placenta and can be transferred through the milk. However, the long-term consequences to the reproductive system of offspring from dams exposed to SAS have not yet been studied. Thus, our study investigated the effects of SAS treatment during gestational and lactational periods on maternal care in F0 and reproductive outcomes in F1 females. MAIN METHODS: Wistar female rats (n = 10/group) received 300 mg/kg/day of SAS dissolved in carboxymethyl cellulose (CMC), by gavage, from gestational day 0 to lactation day 21 and 3 mg/kg/day of folic acid during gestation. The control group received CMC only. On PND 21, the female pups were selected for reproductive evaluation at different time points: infancy and adulthood. The reproductive parameters evaluated were installation of puberty (vaginal opening and first estrus), estrous cyclicity, reproductive organs weight, histological analysis of the ovary follicles and uterus, analysis of oxidative stress in ovarian tissue, reproductive behavior (sexual and maternal), and fertility. KEY FINDINGS: SAS treatment decreased the retrieving behavior in F0 females. The F1 females presented an increase in the lordosis score, frequency of lordosis of magnitude 3, and lipid peroxidation of ovarian tissues in both infancy and adult life. SIGNIFICANCE: The SAS effects observed in the current study represent a relevant concern for public health, as they demonstrated that treatment with SAS compromised the maternal motivation of dams and induced reproductive alterations in F1 females.

Ferroptosis Mechanisms Involved in Neurodegenerative Diseases.

Ferroptosis is a type of cell death that was described less than a decade ago. It is caused by the excess of free intracellular iron that leads to lipid (hydro) peroxidation. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. Since the 1960s, increased concentration of iron in the central nervous system has been associated with oxidative stress, oxidation of proteins and lipids, and cell death. Here, we review the main mechanisms involved in the process of ferroptosis such as lipid peroxidation, glutathione peroxidase 4 enzyme activity, and iron metabolism. Moreover, the association of ferroptosis with the pathophysiology of some neurodegenerative diseases, namely Alzheimer's, Parkinson's, and Huntington's diseases, has also been addressed.