Aggregation of misfolded protein and resultant intracellular inclusion body formation are common hallmarks of mutant superoxide dismutase (mSOD1)-linked familial amyotrophic lateral sclerosis (FALS) and have been associated with the selective neuronal death. Protein disulfide isomerase (PDI) represents a family of enzymatic chaperones that can fold nascent and aberrant proteins in the endoplasmic reticulum (ER) lumen. Recently, our group found that S-nitrosylated PDI could contribute to protein misfolding and subsequent neuronal cell death. However, the exact role of PDI in the pathogenesis of ALS remains unclear. In this study, we propose that PDI attenuates aggregation of mutant/misfolded SOD1 and resultant neurotoxicity associated with ER stress. ER stress resulting in PDI dysfunction therefore provides a mechanistic link between deficits in molecular chaperones, accumulation of misfolded proteins, and neuronal death in neurodegenerative diseases. In contrast, S-nitrosylation of PDI inhibits its activity, increases mSOD1 aggregation, and increases neuronal cell death. Specifically, our data show that S-nitrosylation abrogates PDI-mediated attenuation of neuronal cell death triggered by thapsigargin. Biotin switch assays demonstrate S-nitrosylated PDI both in the spinal cords of SOD1 (G93A) mice and human patients with sporadic ALS. Therefore, denitrosylation of PDI may have therapeutic implications. Taken together, our results suggest a novel strategy involving PDI as a therapy to prevent mSOD1 aggregation and neuronal degeneration. Moreover, the data demonstrate that inactivation of PDI by S-nitrosylation occurs in both mSOD1-linked and sporadic forms of ALS in humans as well as mice.
A Li6.75La3Zr2Al0.25O12 (LLZAO)-coated LiNi0.7Co0.15Mn0.15O2 (LNCM) cathode is synthesized using a simple one-step calcination process. LLZAO is a fast ionic conductor that could effectively enhance the lithium-ion diffusion at the electrode/electrolyte interface. The LLZAO-coated LNCM exhibits relatively better electrochemical performance than pristine LNCM, with a superior initial discharge capacity of 191 mAh g−1 and good rate capability at a high rate of 5C. Furthermore, electrochemical impedance spectroscopy measurement indicates that the interfacial resistance of the LLZAO-coated sample is lower than that of pristine LNCM, which strongly indicates that coating LNCM in LLZAO improves the lithium-ion transport at the electrode/electrolyte interface.
Background There is limited comprehensive evidence on the potential association between early menarche and subsequent health outcomes. Aim To evaluate the existing evidence for the association of early menarche with later health outcomes and assess the strength and validity of the evidence for these associations. Design Umbrella review Methods We searched PubMed, Web of Science, Embase, CINAHL, Cochrane Database of Systematic Reviews, and Google Scholar, and manually screened retrieved references to find systematic reviews and meta-analyses from inception to July 2021. Early menarche was defined taking into account the ethnicity and birth year, and the outcomes were long-term consequences in adulthood. Results Thirteen reviews encompassing 283 original articles and over 6.8 million participants from 39 countries across five continents were included. In categorical outcomes, early menarche was associated with metabolic syndrome (n = 37,543, pooled adjusted relative risk [aRR] 1.56, 95% CI 1.33-1.83; high certainty [Hi]), endometrial cancer (n = 874,188, aRR 1.40, 95% CI 1.17-1.68; Hi), type 2 diabetes mellitus/impaired glucose tolerance (n = 1,185,444, aRR 1.30, 95% CI 1.19-1.42; Hi), breast cancer (n = 103,574, aRR 1.19, 95% CI 1.06-1.33; Hi), death from all causes (n = 152,747, aRR 1.11, 95% CI 1.03-1.19; Hi), obesity (n = 54,006, aRR 1.68, 95% CI 1.53-1.84; moderate certainty [Mod]), gestational diabetes mellitus (n = 48,535, aRR 1.32, 95% CI 1.09-1.58; Mod), hypertension (n = 1,682,689, aRR 1.24, 95% CI 1.20-1.29; Mod), endometriosis (n = 885,390, aRR 1.22, 95% CI 1.09-1.37; Mod), ovarian cancer (n = 1,022,451, aRR 1.17, 95% CI 1.04-1.31; Mod), and asthma (n = 22,859, aRR 1.31, 95% CI 1.09-1.57; low certainty [Lo]). For continuous outcomes, early menarche was associated with increased BMI in adults ≥40 years of age (n = 121,943, adjusted pooled standardized mean difference [aSMD] 0.30, 95% CI 0.28-0.32; Mod), BMI in adults <40 years of age (n = 124,728, aSMD 0.39, 95% CI 0.36-0.43; Mod), serum fasting insulin level (n = 17,020, aSMD 0.52, 95% CI 0.48-0.57; Mod), and homeostatic model assessment of insulin resistance (n = 7,925, aSMD 0.27, 95% CI 0.19-0.35; Mod). Conclusion We found varied levels of evidence for the association between early menarche and the development of subsequent health problems. Our results recommend that physicians should pay attention to these associations, as early menarche can be a potential indicator of metabolic disorders and female-specific cancer and cause death in women.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2025 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.