The cystine/glutamate antiporter, also known as system Xc−, has two roles: (1) imports cystine used to form glutathione (GSH), (2) regulates the extracellular concentration of glutamate. These roles are essential for brain function, as GSH is the most important antioxidant in the brain, and glutamate is the main excitatory neurotransmitter. This antiporter is composed of two subunits: xCT (encoded by the gene Slc7a11) and a heavy chain, CD98 (encoded by the gene Slc3a2). xCT is the subunit responsible for cystine/glutamate transport, while CD98 is responsible for the translocation of system Xc− to the membrane. The antioxidant function of xCT has been highlighted by the discovery of ferroptosis, a distinctive form of programmed cell death triggered by lipid peroxidation and the accumulation of reactive oxygen species. In addition, numerous types of cancers have been shown to overexpress xCT to evade ferroptosis. The mechanisms by which healthy cells regulate xCT expression, the mechanisms responsible for xCT overexpression in cancer cells, and whether different types of cancers employ identical mechanisms to upregulate xCT have not been systematically studied. To answer these questions, we conducted a systematic review to consolidate the regulatory mechanisms governing xCT expression. We found that xCT expression is regulated at nearly all known levels, including epigenetic, transcriptional, post-transcriptional, translational, post-translational, and by protein-protein interactions, with some cell-type- and context-specific mechanisms. Overall, our work highlights the role of xCT and the breadth of axes through which its expression can be modulated.
Multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein-associated disease (MOGAD) are the major types of demyelinating disorders of the central nervous system (CNS). Demyelinating disorders impact women disproportionately and frequently present during reproductive years. These conditions can cause significant neurological disability and psychosocial challenges, especially for women. Because they often present during reproductive years, clinicians frequently manage contraception, pregnancy, and the postpartum period alongside disease control. Sex-specific evidence, therefore, becomes especially important for treatment decisions. Despite this, sex-specific differences in epidemiology, immunopathology, clinical features, and therapeutic response remain inconsistently addressed in both clinical practice and research. In this review, we synthesize current evidence on the factors underlying the female predominance observed in MS, NMOSD, and MOGAD, and discuss the clinical consequences of these findings. We investigate the influence of sex hormones, X-chromosome–mediated immune regulation, and immunological changes associated with pregnancy and the postpartum period, as well as disease-specific mechanisms. We also examine how these factors affect diagnosis, prognosis, therapeutic decision-making, pregnancy management, and quality of life. Finally, we highlight important gaps in knowledge and underscore the necessity for a sex-informed approach to the diagnosis, management, and research of autoimmune demyelinating diseases.
Characterizing the genetic structure and connectivity between populations of endangered species can be used to inform management actions. In vagile species with high gene flow or recently established populations, such characterizations can be difficult to undertake using traditional genetic markers, and genetic stock identification (GSI) may be confounded by allele-sharing between populations. Loggerhead sea turtles (Caretta caretta) in the southeastern United States comprise seven management units (MUs) based on female philopatry inferred via mitochondrial DNA sequences, yet nuclear microsatellite data do not reflect divergence. Further, loci for accurate GSI are not currently known. To address this, we generated genome-wide single nucleotide polymorphism (SNP) data from 146 females nesting at individual sites representative of each southeastern United States MU. We found weak (FST=0.001–0.003) but significant divergence among all MUs, with more notable divergence between the Gulf Coast and Atlantic Ocean MUs, and amongst the Atlantic Ocean MUs. We then used an iterative leave-one-out approach to identify candidate loci for GSI. This approach identified loci that could assign individuals to natal ocean basins (i.e., to the Gulf Coast or to the Atlantic Ocean), and to individual MUs within the Atlantic Ocean, with high (≥90
Objective: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of chemotherapeutic agents used in the treatment of cancer patients. Peripheral Neuropathy (PN) may arise due to the disease itself or as a consequence of treatment with chemotherapeutic agents, such as proteasome inhibitors, platinum-based compounds, and vinca alkaloids, which are widely known as CIPN. However, the underlying mechanisms of CIPN remain poorly understood. The objective of this study was to investigate the presence of CIPN in a rat model and identify potential biomarkers associated with the induction of neuronal damage and consequent neuropathy. Materials and Methods: CIPN was induced in experimental rats by administering Bortezomib (BTZ), Cisplatin (CIS), and Vincristine (VIN). The onset and progression of CIPN in these rats were assessed by the Hot and Cold plate experiments. The ELISA method was used to measure the levels of neuronal damage-related biomarkers NSE, S100B, and inflammatory biomarkers IL-6, TNF alpha, and IL-10 using plasma and sciatic nerve, collected from the experimental rats. Results: Our findings revealed significant alterations in body weight, as well as abnormal responses in the hot plate and cold plate tests, which are indicative of CIPN. Our results showed a significant increase in NSE, S100B, IL-6, and TNF alpha levels in the plasma of rats that showed symptoms of CIPN. However, the IL-10 levels were elevated in the sciatic nerve and plasma of the CIPN rats. Conclusion: These findings suggest that NSE, S100B, IL-6, TNF alpha, and IL-10 could serve as biomarkers for detecting CIPN induced by chemotherapeutic agents. Further research is necessary to fully understand the roles of these biomarkers in the development and progression of CIPN.
Sexual abuse and assault are a major public health problem with high prevalence rates and potentially negative mental health consequences. Men and masculine-identifying individuals who are members of the sexual and gender minority (SGM) community are at high risk of being sexually assaulted and face with unique barriers to seeking and engaging in mental health treatment such as structural stigma, minority stress, and mistrust of services. At the conclusion of a randomized trial of a peer-led online mental health treatment, qualitative interviews were conducted with 101 SGM male survivors about their past mental health treatment experiences and preferences for psychotherapy and pharmacotherapy. The vast majority reported that they had previously engaged briefly in formal mental health treatment, though most explained that they had never discussed trauma or related issues. Concerns regarding side effects of medication were prevalent. Barriers to psychotherapy engagement included perceived experiences of discrimination, difficulty accessing care (i.e., unsure how to find an SGM-affirmative provider, insurance, and financial cost), or perceived poor fit with the therapy or therapist. Most expressed willingness to seek treatment in the future, particularly individual psychotherapy with a licensed mental health professional. Understanding past mental health treatment experiences and preferences of this marginalized population can inform outreach as well as clinical services.
