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The endoplasmic reticulum (ER) is the main cellular Ca2+ storage unit. Among other signalling outputs, the ER can release Ca2+ ions, which can, for instance, communicate the status of ER protein folding to the cytosol and to other organelles, in particular the mitochondria. As a consequence, ER Ca2+ flux can alter the apposition of the ER with mitochondria, influence mitochondrial ATP production or trigger apoptosis. All aspects of ER Ca2+ flux have emerged as processes that are intimately controlled by intracellular redox conditions. In this review, we focus on ER-luminal redox-driven regulation of Ca2+ flux. This involves the direct reduction of disulfides within ER Ca2+ handling proteins themselves, but also the regulated interaction of ER chaperones and oxidoreductases such as calnexin or ERp57 with them. Well-characterized examples are the activating interactions of Ero1a with inositol 1,4,5-trisphosphate receptors (IP3Rs) or of selenoprotein N (SEPN1) with sarco/endoplasmic reticulum Ca2+ transport ATPase 2 (SERCA2). The future discovery of novel ER-luminal modulators of Ca2+ handling proteins is likely. Based on the currently available information, we describe how the variable ER redox conditions govern Ca2+ flux from the ER. [ABSTRACT FROM AUTHOR]

Background and Aims: Opioid agonist treatment (OAT) is established for opioid use disorder, but limited data on adverse effects exist. We aimed to review relative risks of adverse effects across opioid agonists., Methods: Systematic review with pair-wise meta-analysis of randomized clinical trials. A search in Embase, Medline, PsycInfo, CENTRAL and the Web of Science Core Collection was performed from inception to 11 April 2024 (PROSPERO: CRD42022322722). Two reviewers independently extracted data and used the Cochrane Risk of Bias Assessment Tool. Certainty of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). Primary outcomes were constipation, sedation, pruritus, sweating, nausea and vomiting, headache and any non-headache pain., Results: We identified 25 eligible trials, including 4892 participants. Reported agonists were methadone, levomethadone, methadyl acetate, buprenorphine, buprenorphine/naloxone, slow-release oral morphine (SROM), diacetylmorphine, hydromorphone and opium tincture. Buprenorphine (all formulations combined) was associated with a lower risk of sedation than methadone [risk ratio (RR) = 0.68 (95% confidence interval = 0.56-0.82)]; 1558 participants, 9 studies]. Methadone had a lower risk of sedation compared with SROM [RR = 0.63 (0.58-0.69); 356 participants, 2 studies] and a lower risk of nausea than methadyl acetate [RR = 0.56 (0.37-0.85); 913 participants, 3 studies]. There was high overall risk of bias in 92% of included trials due to limited and non-systematic outcome assessment. Certainty of evidence was low or very low for all but one comparison with moderate certainty., Conclusions: There is currently insufficient data to determine whether the rates of adverse effects differ across opioid agonist treatments for most outcomes, with several exceptions. Moreover, the certainty of evidence is currently low or very low due to a lack of rigorous outcome assessment., (© 2025 Society for the Study of Addiction.)

Objectives: This is a protocol for a Cochrane Review (prognosis). The objectives are as follows: To evaluate the predictive value of the prognostic factor HRD status, as determined by various clinically validated HRD assays at the time of staging laparotomy, compared to BRCA1/2 mutation status for progression-free survival and overall survival in patients with tubo-ovarian high-grade serous carcinoma treated in the first-line setting with a combination of surgery and platinum-based chemotherapy and/or maintenance with PARP inhibitors., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Up-to-date guidance on comprehensive study identification for systematic reviews is crucial. According to current recommendations, systematic searching should combine electronic database searching with supplementary search methods. One such supplementary search method is citation tracking. It aims at collecting directly and/or indirectly cited and citing references from "seed references". Tailored and evidence-guided recommendations concerning the use of citation tracking are strongly needed. Objective: We intend to develop recommendations for the use of citation tracking in systematic literature searching for health-related topics. Our study will be guided by the following research questions: What is the benefit of citation tracking for systematic literature searching for health-related topics? Which methods, citation indexes, and other tools are used for citation tracking? What terminology is used for citation tracking methods? Methods: Our study will have two parts: a scoping review and a Delphi study. The scoping review aims at identifying methodological studies on the benefit and use of citation tracking in systematic literature searching for health-related topics with no restrictions on study design, language, and publication date. We will perform database searching in MEDLINE (Ovid), CINAHL (EBSCOhost), Web of Science Core Collection, two information science databases, web searching, and contact experts in the field. Two reviewers will independently perform study selection. We will conduct direct backward and forward citation tracking on included articles. Data from included studies will be extracted using a prespecified extraction sheet and presented in both tabular and narrative form. The results of the scoping review will inform the subsequent Delphi study through which we aim to derive consensus recommendations for the future practice and research of citation tracking., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Hirt J et al.)

Oxidative folding in the endoplasmic reticulum (ER) involves ER oxidoreductin 1 (Ero1)-mediated disulfide formation in protein disulfide isomerase (PDI). In this process, Ero1 consumes oxygen (O2) and releases hydrogen peroxide (H2O2), but none of the published Ero1 crystal structures reveal any potential pathway for entry and exit of these reactants. We report that additional mutation of the Cys(208)-Cys(241) disulfide in hyperactive Ero1α (Ero1α-C104A/C131A) potentiates H2O2 production, ER oxidation, and cell toxicity. This disulfide clamps two helices that seal the flavin cofactor where O2 is reduced to H2O2. Through its carboxyterminal active site, PDI unlocks this seal by forming a Cys(208)/Cys(241)-dependent mixed-disulfide complex with Ero1α. The H2O2-detoxifying glutathione peroxidase 8 also binds to the Cys(208)/Cys(241) loop region. Supported by O2 diffusion simulations, these data describe the first enzymatically controlled O2 access into a flavoprotein active site, provide molecular-level understanding of Ero1α regulation and H2O2 production/detoxification, and establish the deleterious consequences of constitutive Ero1 activity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cellular metabolism is inherently linked to the production of oxidizing by-products, including reactive oxygen species (ROS) hydrogen peroxide (H2O2). When present in excess, H2O2 can damage cellular biomolecules, but when produced in coordinated fashion, it typically serves as a mobile signaling messenger. It is therefore not surprising that cell health critically relies on both low-molecular-weight and enzymatic antioxidant components, which protect from ROS-mediated damage and shape the propagation and duration of ROS signals. This review focuses on H2O2-antioxidant cross talk in the endoplasmic reticulum (ER), which is intimately linked to the process of oxidative protein folding. ER-resident or ER-regulated sources of H2O2 and other ROS, which are subgrouped into constitutive and stimulated sources, are discussed and set into context with the diverse antioxidant mechanisms in the organelle. These include two types of peroxide-reducing enzymes, a high concentration of glutathione derived from the cytosol, and feedback-regulated thiol-disulfide switches, which negatively control the major ER oxidase ER oxidoreductin-1. Finally, new evidence highlighting emerging principles of H2O2-based cues at the ER will likely set a basis for establishing ER redox processes as a major line of future signaling research. A fundamental problem that remains to be solved is the specific, quantitative, time resolved, and targeted detection of H2O2 in the ER and in specialized ER subdomains., (Copyright © 2015 Elsevier Inc. All rights reserved.)