cells Editorial Special Issue: “Inflammation, Oxidative Stress and Protein Aggregation; Any Links?” Eva Žerovnik 1, * , Salvador Ventura 2 and Nataša Kopitar Jerala 1 1 Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, 1000 Ljubljana, Slovenia; natasa.kopitar@ijs.si 2 Institute of Biotechnology and Biomedicine & Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, 08193 Bellaterra, Spain; salvador.ventura@uab.es * Correspondence: eva.zerovnik@ijs.si  Received: 30 October 2020; Accepted: 10 November 2020; Published: 11 November 2020  Inflammation is a complex immune response that enables survival during infection and maintains tissue homeostasis. In response to pathogens, damaged cells, or irritants a cascade of signals leads to the recruitment of immune cells. Sustained robust inflammation may lead to serious disorders due to the overproduction of pro-inflammatory cytokines and tissue damage. Proteostasis (proportion between the synthesis, translation, folding, and degradation of proteins) should be in balance in a healthy cell, including neurons. However, due to different stressors among them, such as heat (fever, infection), acidification (lack or excess of nutrients), and oxidative stress, the mis-folding and aggregation of otherwise normal sequences of proteins occurs. Oxidative stress increases upon protein aggregation, due to metals binding to the aggregates, membrane perturbation, or permeabilization by soluble aggregates. In this Special Issue, papers have been collected in which authors discuss how oxidative stress influences the inflammatory immune response: which external factors influence protein aggregation, and how neuro-regeneration can be restored by dietary means. In the first paper by Santos et al., Ventura, the authors describe an empirical equation to model the pH-dependent aggregation of intrinsically disordered proteins (IDPs) [1]. Their assumption is that both the global protein charge and lipophilicity depend on the solution pH. This simple phenomenological approach showed unprecedented accuracy in predicting pH dependence of the aggregation of both pathogenic and functional amyloidogenic IDPs. In the second paper by Trstenjak-Prebanda et al., the authors examined the role of cysteine proteinase inhibitor—stefin B (cystatin B) in oxidative stress [2]. Specifically, the authors investigated how does Lipopolysaccharide (LPS)-induced oxidative stress affected the protein levels and redox status of redox sensitive proteins—thioredoxin, peroxiredoxins, and superoxide dismutases in macrophages and spleens of LPS-injected mice. LPS challenge was found to result in a marked elevation in mitochondrial peroxiredoxin 3, sulfiredoxin, and superoxide dismutase 2 in stefin B-deficient macrophages and spleens. In addition, they determined that sulfiredoxin was targeted to mitochondria after LPS challenge. They concluded that the upregulation of mitochondrial redox-sensitive proteins, peroxiredoxin 3 and mitochondrial superoxide dismutase 2 in stefin B-deficient cells, implies a protective role of stefin B in mitochondrial function. In the third paper by Carija et al., Ventura, the authors explore how proteins’ 3D structures evolved to minimize the risk of aggregation in natural environments [3]. By exploiting the AGGRESCAN3D structure-based approach to predict the aggregation propensity of >600 Escherichia coli proteins, they show that the structural aggregation propensity of globular proteins is connected with their abundance, length, essentiality, subcellular location, and quaternary structure. The proteome-wide analysis thus suggests that prevention of aggregation upon misfolding plays a key role in sequence Cells 2020, 9, 2461; doi:10.3390/cells9112461 www.mdpi.com/journal/cells Cells 2020, 9, 2461 2 of 3 evolution and that the avoidance of protein aggregation has contributed to shape the structural properties of proteins. Figure 1 shows different scenarios of Gibbs free energy towards energy of Cells 2020, 9, xwhose activation, FOR PEER REVIEW ratio determines the relative propensity to aggregation. 2 of 3 Figure1.1. Schematic Figure Schematicrepresentation representationofofthetheenergy energydiagrams diagramsforfor aggregation aggregation processes. TheThe processes. ensemble of ensemble folded proteins in solution is considered as one thermodynamic system. The aggregated of folded proteins in solution is considered as one thermodynamic system. The aggregated state state represents in all cases the represents global in all casesminimum the globalof Gibbs minimumenergy. Activation of Gibbs energies energy. (Eact ) are Activation a barrier energies (Eactthat ) aredetermine a barrier the rate of transition. (A) Proteins with low STAP, such as highly abundant, short, and that determine the rate of transition. (A) Proteins with low STAP, such as highly abundant, short, essential ones and proteins active as monomers, are protected from aggregation by a high energy barrier. and essential ones and proteins active as monomers, are protected from aggregation by a high energy (B) Proteins with higher barrier. (B)STAP, suchwith Proteins as low abundant, higher STAP,long and such asnon-essential low abundant, oneslong and and proteins active in oligomeric non-essential ones and forms, have to cross a lower energy barrier. (C) Mutations that increase the STAP without conferring proteins active in oligomeric forms, have to cross a lower energy barrier. (C) Mutations that increase additional functional advantages would be purged out by natural selection, since they decrease the the STAP without conferring additional functional advantages would be purged out by natural energy barrier for aggregation from the initially folded state. STAP = structural aggregation propensity. selection, since they decrease the energy barrier for aggregation from the initially folded state. STAP Figure is taken from the third paper [3]. = structural aggregation propensity. Copyright to Cells, the same as Figure 13, taken from [3]. In the fourth review paper, by Pogačnik, Ota and Poklar-Ulrih, the authors explore what clinical In the fourth review paper, by Pogačnik, Ota and Poklar-Ulrih, the authors explore what clinical studies tell about the possible positive effect of lifelong consumption of dietary anti-oxidant substances, studies tell about the possible positive effect of lifelong consumption of dietary anti-oxidant such as phytochemicals (e.g., polyphenols) and endogenous substances (e.g., acetyl-l-carnitine, substances, such as phytochemicals (e.g., polyphenols) and endogenous substances (e.g., coenzyme Q10, n-3 polysaturated fatty acids) [4]. Can such a regime postpone protein aggregation acetyl-L-carnitine, coenzyme Q10, n-3 polysaturated fatty acids) [4]. Can such a regime postpone in neurodegenerative diseases? They stress the importance of availability of these substances to the protein aggregation in neurodegenerative diseases? They stress the importance of availability of central nervous system, where they have to be present in high enough concentrations in order to these substances to the central nervous system, where they have to be present in high enough exhibit their neuroprotective properties. Their aim was to summarize their mechanisms of action and concentrations in order to exhibit their neuroprotective properties. Their aim was to summarize their therapeutic considerations, including bioavailability and safety data. mechanisms of action and therapeutic considerations, including bioavailability and safety data. Funding: This research received no external funding. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest. References 1. Santos, J.; Iglesias, V.; Santos-Suárez, J.; Mangiagalli, M.; Brocca, S.; Pallarès, I.; Ventura, S. pH-Dependent Aggregation in Intrinsically Disordered Proteins Is Determined by Charge and Lipophilicity. Cells 2020, 9, 145. 2. Trstenjak Prebanda, M.; Završnik, J.; Turk, B.; Kopitar Jerala, N. Upregulation of Mitochondrial Redox Sensitive Proteins in LPS-Treated Stefin B-Deficient Macrophages. Cells 2019, 8, 1476. Cells 2020, 9, 2461 3 of 3 References 1. Santos, J.; Iglesias, V.; Santos-Suárez, J.; Mangiagalli, M.; Brocca, S.; Pallarès, I.; Ventura, S. pH-Dependent Aggregation in Intrinsically Disordered Proteins Is Determined by Charge and Lipophilicity. Cells 2020, 9, 145. [CrossRef] 2. Trstenjak Prebanda, M.; Završnik, J.; Turk, B.; Kopitar Jerala, N. Upregulation of Mitochondrial Redox Sensitive Proteins in LPS-Treated Stefin B-Deficient Macrophages. Cells 2019, 8, 1476. [CrossRef] [PubMed] 3. Carija, A.; Pinheiro, F.; Iglesias, V.; Ventura, S. Computational Assessment of Bacterial Protein Structures Indicates a Selection Against Aggregation. Cells 2019, 8, 856. [CrossRef] [PubMed] 4. Pogačnik, L.; Ota, A.; Ulrih, N.P. An Overview of Crucial Dietary Substances and Their Modes of Action for Prevention of Neurodegenerative Diseases. Cells 2020, 9, 579. [CrossRef] [PubMed] Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).