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Oxidative stress (OS) develops in critically ill patients as a metabolic consequence of the immunoinflammatory and degenerative processes of the tissues. These induce increased and/or dysregulated fluxes of reactive species enhancing their pro‐oxidant activity and toxicity. At the same time, OS sustains its own inflammatory and immunometabolic pathogenesis, leading to a pervasive and vitious cycle of events that contribute to defective immunity, organ dysfunction and poor prognosis. Protein damage is a key player of these OS effects; it generates increased levels of protein oxidation products and misfolded proteins in both the cellular and extracellular environment, and contributes to forms DAMPs and other proteinaceous material to be removed by endocytosis and proteostasis processes of different cell types, as endothelial cells, tissue resident monocytes‐macrophages and peripheral immune cells. An excess of OS and protein damage in critical illness can overwhelm such cellular processes ultimately interfering with systemic proteostasis, and consequently with innate immunity and cell death pathways of the tissues thus sustaining organ dysfunction mechanisms. Extracorporeal therapies based on biocompatible/bioactive membranes and new adsorption techniques may hold some potential in reducing the impact of OS on the defective proteostasis of patients with critical illness. These can help neutralizing reactive and toxic species, also removing solutes in a wide spectrum of molecular weights thus improving proteostasis and its immunometabolic corelates. Pharmacological therapy is also moving steps forward which could help to enhance the efficacy of extracorporeal treatments. This narrative review article explores the aspects behind the origin and pathogenic role of OS in intensive care and critically ill patients, with a focus on protein damage as a cause of impaired systemic proteostasis and immune dysfunction in critical illness. [ABSTRACT FROM AUTHOR]

Aim: Force expression is characterized by an interplay of biological and molecular determinants that are expected to differentiate males and females in terms of maximal performance. These include muscle characteristics (muscle size, fiber type, contractility), neuromuscular regulation (central and peripheral factors of force expression), and individual genetic factors (miRNAs and gene/protein expression). This research aims to comprehensively assess these physiological variables and their role as determinants of maximal force difference between sexes. Methods: Experimental evaluations include neuromuscular components of isometric contraction, intrinsic muscle characteristics (proteins and fiber type), and some biomarkers associated with muscle function (circulating miRNAs and gut microbiome) in 12 young and healthy males and 12 females. Results: Male strength superiority appears to stem primarily from muscle size while muscle fiber‐type distribution plays a crucial role in contractile properties. Moderate‐to‐strong pooled correlations between these muscle parameters were established with specific circulating miRNAs, as well as muscle and plasma proteins. Conclusion: Muscle size is crucial in explaining the differences in maximal voluntary isometric force generation between males and females with similar fiber type distribution. Potential physiological mechanisms are seen from associations between maximal force, skeletal muscle contractile properties, and biological markers. [ABSTRACT FROM AUTHOR]

Melatonin (MLT) is a cytoprotective agent holding potential to prevent cadmium (Cd) toxicity and its impact in testicular function and fertility. In this study, we explored such potential in porcine pre‐pubertal Sertoli cells (SCs). Cd toxicity resulted in impaired SC viability and function, abnormal cellular H2O2 generation and efflux, and induction of reductive stress by the upregulation of Nrf2 expression and activity, cystine uptake and glutathione biosynthesis, glutathione‐S‐transferase P (GSTP) expression, and protein glutathionylation inhibition. Cd toxicity also stimulated the activity of cellular kinases (MAPK‐ERK1/2 and Akt) and NFkB transcription factor, and cJun expression was increased. MLT produced a potent cytoprotective effect when co‐administered with Cd to SCs; its efficacy and the molecular mechanism behind its cytoprotective function varied according to Cd concentrations. However, a significant restoration of cell viability and function, and of H2O2 levels, was observed both at 5 and 10 μM Cd. Mechanistically, these effects of MLT were associated with a significant reduction of the Cd‐induced activation of Nrf2 and GSTP expression at all Cd concentrations. CAT and MAPK‐ERK1/2 activity upregulation was associated with these effects at 5 μM Cd, whereas glutathione biosynthesis and efflux were involved at 10 μM Cd together with an increased expression of the cystine transporter xCT, of cJun and Akt and NFkB activity. MLT protects SCs from Cd toxicity reducing its H2O2 generation and reductive stress effects. A reduced activity of Nrf2 and the modulation of other molecular players of MLT signaling, provide a mechanistic rational for the cytoprotective effect of this molecule in SCs. [ABSTRACT FROM AUTHOR]

Unfolded protein response (UPR) and endoplasmic reticulum (ER) stress are aspects of SARS‐CoV‐2‐host cell interaction with proposed role in the cytopathic and inflammatory pathogenesis of this viral infection. The role of the NF‐kB pathway in these cellular processes remains poorly characterized. When investigated in VERO‐E6 cells, SARS‐CoV‐2 infection was found to markedly stimulate NF‐kB protein expression and activity. NF‐kB activation occurs early in the infection process (6 hpi) and it is associated with increased MAPK signaling and expression of the UPR inducer IRE‐1α. These signal transduction processes characterize the cellular stress response to the virus promoting a pro‐inflammatory environment and caspase activation in the host cell. Inhibition of viral replication by the viral protease inhibitor Nelfinavir reverts all these molecular changes also stimulating c‐Jun expression, a key component of the JNK/AP‐1 pathway with important role in the IRE‐1α‐mediated transcriptional regulation of stress response genes with anti‐inflammatory and cytoprotection function. The present study demonstrates that UPR signaling and its interaction with cellular MAPKs and the NF‐kB activity are important aspects of SARS‐CoV‐2‐host cell interaction that deserve further investigation to identify more efficient therapies for this viral infection. [ABSTRACT FROM AUTHOR]

The trace element selenium (Se) is an essential component of selenoproteins and plays a critical role in redox signaling via regulating the activity of selenoenzymes such as thioredoxin reductase‐1 and glutathione peroxidases. Se compounds and its metabolites possess a wide range of biological functions including anticancer and cytoprotection effects, modulation of hormetic genes and antioxidant enzyme activities. Radiation‐induced injury of normal tissues is a significant side effect for cancer patients who receive radiotherapy in the clinic and the development of new and effective radioprotectors is an important goal of research. Others and we have shown that seleno‐compounds have the potential to protect ionizing radiation‐induced toxicities in various tissues and cells both in in vitro and in vivo studies. In this review, we discuss the potential utilization of Se compounds with redox‐dependent hormetic activity as novel radio‐protective agents to alleviate radiation toxicity. The cellular and molecular mechanisms underlying the radioprotection effects of these seleno‐hormetic agents are also discussed. These include Nrf2 transcription factor modulation and the consequent upregulation of the adaptive stress response to IR in bone marrow stem cells and hematopoietic precursors. [ABSTRACT FROM AUTHOR]

Glutathione is considered the major non‐protein low molecular weight modulator of redox processes and the most important thiol reducing agent of the cell. The biosynthesis of glutathione occurs in the cytosol from its constituent amino acids, but this tripeptide is also present in the most important cellular districts, such as mitochondria, nucleus, and endoplasmic reticulum, thus playing a central role in several metabolic pathways and cytoprotection mechanisms. Indeed, glutathione is involved in the modulation of various cellular processes and, not by chance, it is a ubiquitous determinant for redox signaling, xenobiotic detoxification, and regulation of cell cycle and death programs. The balance between its concentration and redox state is due to a complex series of interactions between biosynthesis, utilization, degradation, and transport. All these factors are of great importance to understand the significance of cellular redox balance and its relationship with physiological responses and pathological conditions. The purpose of this review is to give an overview on glutathione cellular compartmentalization. Information on its subcellular distribution provides a deeper understanding of glutathione‐dependent processes and reflects the importance of compartmentalization in the regulation of specific cellular pathways. © 2018 BioFactors, 45(2):152–168, 2019 [ABSTRACT FROM AUTHOR]

Among the numerous functions of melatonin, the control of survival and differentiation of mesenchymal stem cells ( MSCs) has been recently proposed. MSCs are a heterogeneous population of multipotent elements resident in tissues such as bone marrow, muscle, and adipose tissue, which are primarily involved in developmental and regeneration processes, gaining thus increasing interest for tissue repair and restoration therapeutic protocols. Receptor-dependent and receptor-independent responses to melatonin are suggested to occur in these cells. These involve antioxidant or redox-dependent functions of this indolamine as well as secondary effects resulting from autocrine and paracrine responses. Inflammatory cytokines and adipokines, proangiogenic/mitogenic stimuli, and other mediators that influence the differentiation processes may affect the survival and functional integrity of these mesenchymal precursor cells. In this scenario, melatonin seems to regulate signaling pathways that drive commitment and differentiation of MSC into osteogenic, chondrogenic, adipogenic, or myogenic lineages. Common pathways suggested to be involved as master regulators of these processes are the Wnt/ β-catenin pathway, the MAPKs and the, TGF- β signaling. In this respect melatonin emerges a novel and potential modulator of MSC lineage commitment and adipogenic differentiation. These and other aspects of the physiological and pharmacological effects of melatonin as regulator of MSC are discussed in this review. [ABSTRACT FROM AUTHOR]

RATIONALE Thiodiglycolic acid (TDGA) is a urinary metabolite of the oxazaphosphorine class of chemotherapeutics, in particular of ifosfamide. Ifosfamide metabolism generates chloroacetaldehyde (CAA), a toxic compound associated with neurotoxicity, nephrotoxicity, urotoxicity and cardiotoxicity. CAA, in turn, interacts with cellular thiol groups leading to GSH depletion, cell death and generation of thiodiglycolic acid (TDGA), as a final product. TDGA is mainly excreted in the urine. The ability to accurately measure TDGA in urine, therefore, will be a useful way of monitoring exposure to ifosfamide during chemotherapy. METHODS TDGA in urine samples was measured with liquid chromatography coupled to mass spectrometry (LC/MS) by means of a novel Surface-Activated Chemical Ionization-Electrospray (SACI-ESI) or a classical ESI ion source alone. RESULTS The SACI-ESI and ESI alone based methods for analysis of urinary TDGA were optimized and compared. A strong reduction in matrix effect together with enhanced quantification performances was obtained with the SACI-ESI when compared with ESI. In particular, an increase in quantification precision (from 85 to 95%) and accuracy (from 59 to 90%) were observed, which allowed for optimal detection of TDGA. CONCLUSIONS The LC/SACI-ESI-MS approach provides a very sensitive and quantitative method for the analysis of TDGA. Thanks to the enhancement in sensitivity and matrix effect reduction, the SACI-ESI source enables the use of a relatively low-cost ion-trap mass spectrometer in the analysis of this toxicity biomarker in urine. Due to these characteristics, this approach would constitute an invaluable tool in the clinical laboratory, for measuring TDGA and other toxicity related biomarkers of chemotherapy with proper sensitivity and accuracy. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Melatonin (MLT) plays a role in preserving bone health, a function that may depend on homeostatic effects on both mature osteoblasts and mesenchymal stem cells (MSCs) of the bone tissue. In this study, these functions of MLT have been investigated in rat bone (femur) and in human adipose MSC (hMSC) during chronic exposure to low‐grade cadmium (Cd) toxicity, a serious public health concern. The in vivo findings demonstrate that MLT protects against Cd‐induced bone metabolism disruption and accumulation of bone marrow adipocytes, a cue of impaired osteogenic potential of skeletal MSC niches. This latter symptom was recapitulated in hMSCs in which Cd toxicity stimulated adipogenic differentiation. MLT was found to rescue, at least in part, the osteogenic differentiation properties of these cells. This study reports on a new bone cytoprotection function of MLT pertinent to Cd toxicity and its interfering effect on skeletal MSC differentiation properties that is worth investigating for its possible impact on human bone pathophysiology. [ABSTRACT FROM AUTHOR]