Redox Network Research Articles

Peptide-Bound Methionine Sulfoxide (MetO) Levels and MsrB2 Abundance Are Differentially Regulated during the Desiccation Phase in Contrasted Acer Seeds.

Norway maple and sycamore produce desiccation-tolerant (orthodox) and desiccation-sensitive (recalcitrant) seeds, respectively. Drying affects reduction and oxidation (redox) status in seeds. Oxidation of methionine to methionine sulfoxide (MetO) and reduction via methionine sulfoxide reductases (Msrs) have never been investigated in relation to seed desiccation tolerance. MetO levels and the abundance of Msrs were investigated in relation to levels of reactive oxygen species (ROS) such as hydrogen peroxide, superoxide anion radical and hydroxyl radical (•OH), and the levels of ascorbate and glutathione redox couples in gradually dried seeds. Peptide-bound MetO levels were positively correlated with ROS concentrations in the orthodox seeds. In particular, •OH affected MetO levels as well as the abundance of MsrB2 solely in the embryonic axes of Norway maple seeds. In this species, MsrB2 was present in oxidized and reduced forms, and the latter was favored by reduced glutathione and ascorbic acid. In contrast, sycamore seeds accumulated higher ROS levels. Additionally, MsrB2 was oxidized in sycamore throughout dehydration. In this context, the three elements •OH level, MetO content and MsrB2 abundance, linked together uniquely to Norway maple seeds, might be considered important players of the redox network associated with desiccation tolerance.

A Quantitative Tissue-Specific Landscape of Protein Redox Regulation during Aging

Mammalian tissues engage in specialized physiology that is regulated through reversible modification of protein cysteine residues by reactive oxygen species (ROS). ROS regulate a myriad of biological processes, but the protein targets of ROS modification that drive tissue-specific physiology invivo are largely unknown. Here, we develop Oximouse, a comprehensive and quantitative mapping of the mouse cysteine redox proteome invivo. We use Oximouse to establish several paradigms of physiological redox signaling. We define and validate cysteine redox networks within each tissue that are tissue selective and underlie tissue-specific biology. We describe a common mechanism for encoding cysteine redox sensitivity by electrostatic gating. Moreover, we comprehensively identify redox-modified disease networks that remodel in aged mice, establishing a systemic molecular basis for the long-standing proposed links between redox dysregulation and tissue aging. We provide the Oximouse compendium as a framework for understanding mechanisms of redox regulation in physiology and aging.

100th Anniversary of Macromolecular Science Viewpoint: Fundamentals for the Future of Macromolecular Nitroxide Radicals.

Macromolecular radicals, radical polymers, and polyradicals bear unique functionalities derived from their pendant radical groups. The increasing need for organic functional materials is driving the growth in research interest in macromolecular radicals for batteries, electronics, memory, and imaging. This Viewpoint summarizes the current state-of-knowledge regarding the macromolecular nitroxide radicals' redox mechanism, conductivity, chain conformation, controlled polymerization, network structure, conjugated forms, and applications. The nitroxide radical group is the focus because it is the most widely studied. Although most literature focuses upon applications, an emerging body of work is highlighting the fundamental physicochemical properties of macromolecular radicals. To this end, this Viewpoint recommends areas of opportunity in fundamental studies and best practices in reporting.

Peri/Epicellular Thiol Oxidoreductases as Mediators of Extracellular Redox Signaling.

Significance: Supracellular redox networks regulating cell-extracellular matrix (ECM) and organ system architecture merge with structural and functional (catalytic or allosteric) properties of disulfide bonds. This review addresses emerging evidence that exported thiol oxidoreductases (TORs), such as thioredoxin, protein disulfide isomerases (PDIs), quiescin sulfhydryl oxidases (QSOX)1, and peroxiredoxins, composing a peri/epicellular (pec)TOR pool, mediate relevant signaling. pecTOR functions depend mainly on kinetic and spatial regulation of thiol-disulfide exchange reactions governed by redox potentials, which are modulated by exported intracellular low-molecular-weight thiols, together conferring signal specificity. Recent Advances: pecTOR redox-modulates several targets including integrins, ECM proteins, surface molecules, and plasma components, although clear-cut documentation of direct effects is lacking in many cases. TOR catalytic pathways, displaying common patterns, culminate in substrate thiol reduction, oxidation, or isomerization. Peroxiredoxins act as redox/peroxide sensors, contrary to PDIs, which are likely substrate-targeted redox modulators. Emerging evidence suggests important pecTOR roles in patho(physio)logical processes, including blood coagulation, vascular remodeling, mechanosensing, endothelial function, immune responses, and inflammation. Critical Issues: Effects of pecPDIs supporting thrombosis/platelet activation have been well documented and reached the clinical arena. Roles of pecPDIA1 in vascular remodeling/mechanosensing are also emerging. Extracellular thioredoxin and pecPDIs redox-regulate immunoinflammation. Routes of TOR externalization remain elusive and appear to involve Golgi-independent routes. pecTORs are particularly accessible drug targets. Future Directions: Further understanding mechanisms of thiol redox reactions and developing assays for assessing pecTOR redox activities remain important research avenues. Also, addressing pecTORs as disease markers and achieving more efficient/specific drugs for pecTOR modulation are major perspectives for diagnostic/therapeutic improvements.

Computational simulation of the reactive oxygen species and redox network in the regulation of chloroplast metabolism

Cells contain a thiol redox regulatory network to coordinate metabolic and developmental activities with exogenous and endogenous cues. This network controls the redox state and activity of many target proteins. Electrons are fed into the network from metabolism and reach the target proteins via redox transmitters such as thioredoxin (TRX) and NADPH-dependent thioredoxin reductases (NTR). Electrons are drained from the network by reactive oxygen species (ROS) through thiol peroxidases, e.g., peroxiredoxins (PRX). Mathematical modeling promises access to quantitative understanding of the network function and was implemented by using published kinetic parameters combined with fitting to known biochemical data. Two networks were assembled, namely the ferredoxin (FDX), FDX-dependent TRX reductase (FTR), TRX, fructose-1,6-bisphosphatase (FBPase) pathway with 2-cysteine PRX/ROS as oxidant, and separately the FDX, FDX-dependent NADP reductase (FNR), NADPH, NTRC-pathway for 2-CysPRX reduction. Combining both modules allowed drawing several important conclusions of network performance. The resting H2O2 concentration was estimated to be about 30 nM in the chloroplast stroma. The electron flow to metabolism exceeds that into thiol regulation of FBPase more than 7000-fold under physiological conditions. The electron flow from NTRC to 2-CysPRX is about 5.32-times more efficient than that from TRX-f1 to 2-CysPRX. Under severe stress (30 μM H2O2) the ratio of electron flow to the thiol network relative to metabolism sinks to 1:251 whereas the ratio of e- flow from NTRC to 2-CysPRX and TRX-f1 to 2-CysPRX rises up to 1:67. Thus, the simulation provides clues on experimentally inaccessible parameters and describes the functional state of the chloroplast thiol regulatory network.

Developmental programming: intrauterine caloric restriction promotes upregulation of mitochondrial sirtuin with mild effects on oxidative parameters in the ovaries and testes of offspring.

According to the developmental origins of health and disease (DOHaD) hypothesis, changes in the maternal environment are known to reprogram the metabolic response of offspring. Known for its redox modulation, caloric restriction extends the lifespan of some species, which contributes to diminished cellular damage. Little is known about the effects of gestational caloric restriction, in terms of antioxidant parameters and molecular mechanisms of action, on the reproductive organs of offspring. This study assessed the effects of moderate (20%) caloric restriction on redox status parameters, molecular expression of sirtuin (SIRT) 1 and SIRT3 and histopathological markers in the ovaries and testes of adult rats that were subjected to gestational caloric restriction. Although enzyme activity was increased, ovaries from female pups contained high levels of oxidants, whereas testes from male pups had decreased antioxidant enzyme defences, as evidenced by diminished glyoxalase I activity and reduced glutathione content. Expression of SIRT3, a deacetylase enzyme related to cellular bioenergetics, was increased in both ovaries and testes. Previous studies have suggested that, in ovaries, diminished antioxidant metabolism can lead to premature ovarian failure. Unfortunately, there is little information regarding the redox profile in the testis. This study is the first to assess the redox network in both ovaries and testes, suggesting that, although intrauterine caloric restriction improves molecular mechanisms, it has a negative effect on the antioxidant network and redox status of reproductive organs of young adult rats.

Thioredoxin and protein-disulfide isomerase selectivity for redox regulation of proteins in Corynebacterium glutamicum.

Thioredoxins (Trxs) and protein-disulfide isomerases (PDIs) are believed to play a pivotal role in ensuring the proper folding of proteins, facilitating appropriate functioning of proteins, and maintaining intracellular redox homeostasis in bacteria. Two thioredoxins (Trxs) and three thiol-disulfide isomerases (PDIs) have been annotated in Corynebacterium glutamicum. However, nothing is known about their functional diversity in the redox regulation of proteins. Thus, we here analyzed the Trx- and PDI-dependent redox shifts of ribonucleotide reductase (RNR), insulin, 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB), and several thiol-dependent peroxidases by measuring enzyme activity and thiol status in vitro. We found that the two Trxs and the three PDIs had activities in the cleavage of the disulfidebond, whereas the PDIs had a lower efficiency than the two Trxs. Trx2 could activate thiol-dependent peroxidases with an efficiency comparable with that of Trx1, but the PDIs were inefficient. The redox-active Cys-X-X-Cys motif harbored in both Trxs and PDIs was essential to supply efficiently the donor of reducing equivalents for protein disulfides. In addition, stress-responsive extracytoplasmic function (ECF)-sigma factor H (SigH)-dependent Trxs and PDIs expressions were observed. These results contributed importantly to our overall understanding of reducing functionality of the Trx and PDI systems, and also highlighted the complexity and plasticity of the intracellular redox network.

Melatonin-Nitric Oxide Crosstalk and Their Roles in the Redox Network in Plants.

Melatonin, an amine hormone highly conserved during evolution, has a wide range of physiological functions in animals and plants. It is involved in plant growth, development, maturation, and aging, and also helps ameliorate various types of abiotic and biotic stresses, including salt, drought, heavy metals, and pathogens. Melatonin-related growth and defense responses of plants are complex, and involve many signaling molecules. Among these, the most important one is nitric oxide (NO), a freely diffusing amphiphilic biomolecule that can easily cross the cell membrane, produce rapid signal responses, and participate in a wide variety of physiological reactions. NO-induced S-nitrosylation is also involved in plant defense responses. NO interacts with melatonin as a long-range signaling molecule, and helps regulate plant growth and maintain oxidative homeostasis. Exposure of plants to abiotic stresses causes the increase of endogenous melatonin levels, with the consequent up-regulation of melatonin synthesis genes, and further increase of melatonin content. The application of exogenous melatonin causes an increase in endogenous NO and up-regulation of defense-related transcription factors, resulting in enhanced stress resistance. When plants are infected by pathogenic bacteria, NO acts as a downstream signal to lead to increased melatonin levels, which in turn induces the mitogen-activated protein kinase (MAPK) cascade and associated defense responses. The application of exogenous melatonin can also promote sugar and glycerol production, leading to increased levels of salicylic acid and NO. Melatonin and NO in plants can function cooperatively to promote lateral root growth, delay aging, and ameliorate iron deficiency. Further studies are needed to clarify certain aspects of the melatonin/NO relationship in plant physiology.

Response of Solanum lycopersicum L. to diclofenac – Impacts on the plant’s antioxidant mechanisms

One emerging problem that recently has become a vastly acknowledged topic of concern is the environmental contamination by pharmaceuticals. Diclofenac (DCF) is one of the most common pharmaceuticals found, due to its high utilization and low removal rate in wastewater treatment processes. In this work, Solanum lycopersicum L. was used as a model to unravel how DCF contamination can affect crops, focusing on the internal mechanisms triggered by this exposure. For this purpose, plants were exposed to two different DCF concentrations (0.5 mg L−1 and 5 mg L−1). Results obtained here point towards a loss of shoot performance when plants were exposed to very high concentrations of DCF, but no delay or loss of yield in the flowering and fruit stages were ascribed to DCF contamination. Our data shows that a state of oxidative stress due to high reactive oxygen species accumulation was associated with this contamination, with very high DCF levels leading to a rise of lipid peroxidation, possibly accentuated by the inhibition of ROS-scavenging enzymes and unable to be counteracted by the visible upregulation of proline and the thiol-based redox network. Overall, these results allow to infer that in the current environmental context, no noticeable negative effects should be associated with the presence of DCF in soils where this crop is cultivated. However, the oxidative stress and lower biomass associated with the highest concentration are alarming, since DCF levels in the environment are continuously increasing and further measures are necessary to assess this problematic.

Role of Melatonin to Enhance Phytoremediation Capacity

Phytoremediation is a green technology that aims to take up pollutants from soil or water. Metals are one of the targets of these techniques due to their high toxicity in biological systems, including plants and animals. Their elimination or, at least, decrease will help keep them from being incorporated in the trophic chain and thus reaching animal and human food. The metal removal efficiency of plants is closely related to their growth rate, tolerance, and their adaptability to different environments. Melatonin (N-acetyl-5-methoxytryptamine) is a ubiquitous molecule present in animals, plants, fungi, and bacteria. In plants, it plays an important role related to antioxidant activity, but also as an important redox network regulator. Thus, melatonin has been defined as a biostimulator of plant growth, especially under environmental stress conditions, whether abiotic (water deficit and waterlogging, extreme temperature, UV radiation, salinity, alkalinity, specific mineral deficit/excess, metals and other toxic compounds, etc.) or biotic (bacteria, fungi, and viruses). Exogenous melatonin treated plants have been seen to have a high tolerance to stressors, minimizing possible harmful effects through the control of reactive oxygen species (ROS) levels and activating antioxidative responses. Furthermore, important gene expression changes in stress specific transcription factors have been demonstrated. Melatonin is capable of mobilizing toxic metals, through phytochelatins, transporting this, while sequestration adds to the biostimulator effect of melatonin on plants, improving plant tolerance against toxic pollutants. Furthermore, melatonin improves the uptake of nitrogen (N), phosphorus (P), and sulfur (S) in stress situations, enhancing cell metabolism. In light of the above, the application of melatonin seems to be a useful option for clearing toxic pollutants from the environment by improving phytoremediation. Interestingly, a variety of stressors induce melatonin biosynthesis in plants, and the study of this endogenous response in hyperaccumulator plants may be even more interesting as a natural response of the phytoremediation of diverse plants.

MpTCP1 controls cell proliferation and redox processes in Marchantia polymorpha.

TCP transcription factors are key regulators of angiosperm cell proliferation processes. It is unknown whether their regulatory growth capacities are conserved across land plants, which we examined in liverworts, one of the earliest diverging land plant lineages. We generated knockout mutants for MpTCP1, the single TCP-P clade gene in Marchantia polymorpha, and characterized its function by conducting cell proliferation and morphological analyses as well as messenger RNA expression, transcriptome, chemical, and DNA binding studies. Mptcp1ge lines show a reduced vegetative thallus growth and extra tissue formation in female reproductive structures. Additionally, mutant plants reveal increased hydrogen peroxide (H2 O2 ) levels and an enhanced pigmentation in the thallus caused by formation of secondary metabolites, such as aminochromes. MpTCP1 proteins interact redox dependently with DNA and regulate the expression of a comprehensive redox network, comprising enzymes involved in H2 O2 metabolism. MpTCP1 regulates Marchantia growth in a context-dependent manner. Redox sensitivity of the DNA binding capacity of MpTCP1 proteins provides a mechanism to respond to altered redox conditions. Our data suggest that MpTCP1 activity could thereby have contributed to diversification of land plant morphologies and to adaptations to abiotic and biotic challenges, as experienced by liverworts during early land plant colonization.

Redox Systems Biology: Harnessing the Sentinels of the Cysteine Redoxome.

Significance: Cellular redox processes are highly interconnected, yet not in equilibrium, and governed by a wide range of biochemical parameters. Technological advances continue refining how specific redox processes are regulated, but broad understanding of the dynamic interconnectivity between cellular redox modules remains limited. Systems biology investigates multiple components in complex environments and can provide integrative insights into the multifaceted cellular redox state. This review describes the state of the art in redox systems biology as well as provides an updated perspective and practical guide for harnessing thousands of cysteine sensors in the redoxome for multiparameter characterization of cellular redox networks. Recent Advances: Redox systems biology has been applied to genome-scale models and large public datasets, challenged common conceptions, and provided new insights that complement reductionist approaches. Advances in public knowledge and user-friendly tools for proteome-wide annotation of cysteine sentinels can now leverage cysteine redox proteomics datasets to provide spatial, functional, and protein structural information. Critical Issues: Careful consideration of available analytical approaches is needed to broadly characterize the systems-level properties of redox signaling networks and be experimentally feasible. The cysteine redoxome is an informative focal point since it integrates many aspects of redox biology. The mechanisms and redox modules governing cysteine redox regulation, cysteine oxidation assays, proteome-wide annotation of the biophysical and biochemical properties of individual cysteines, and their clinical application are discussed. Future Directions: Investigating the cysteine redoxome at a systems level will uncover new insights into the mechanisms of selectivity and context dependence of redox signaling networks.

Melatonin and reactive oxygen and nitrogen species: a model for the plant redox network

Melatonin (N-acetyl-5-methoxytryptamine) was discovered in plants in 1995; since then numerous functions have been attributed to this molecule in vascular plants. In addition to its recognized role as a universal antioxidant, other relevant functions have been studied in plants such as its rhizogenic- and vegetative-growth effects, protection against leaf senescence and influences on photosynthesis and on the stomatal apparatus. Also, melatonin has a protective role in stress situations (biotic and abiotic), acting as an osmoregulation and a metabolic corrector when confronted with different stresses. One of the most outstanding aspects is the involvement of melatonin as a multi-signaling molecule in plants. The dual roles of melatonin in physiological stress situations involve both its direct action (free of receptor action) as an antioxidant and its role as a regulator of gene expression. Its relationship with central elements of the plant redox network such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) and the regulation of relevant elements is discussed. All recent data on melatonin are incorporated to present an updated model, where the balance between ROS and RNS, and between these and melatonin is a regulatory key center in the responses.

Enzyme activation by a flavoprotein redox network

Enzyme activation by a flavoprotein redox network

Redox Balance-DDR-miRNA Triangle: Relevance in Genome Stability and Stress Responses in Plants.

Plants are continuously faced with complex environmental conditions which can affect the oxidative metabolism and photosynthetic efficiency, thus leading to the over-production of reactive oxygen species (ROS). Over a certain threshold, ROS can damage DNA. DNA damage, unless repaired, can affect genome stability, thus interfering with cell survival and severely reducing crop productivity. A complex network of pathways involved in DNA damage response (DDR) needs to be activated in order to maintain genome integrity. The expression of specific genes belonging to these pathways can be used as indicators of oxidative DNA damage and effective DNA repair in plants subjected to stress conditions. Managing ROS levels by modulating their production and scavenging systems shifts the role of these compounds from toxic molecules to key messengers involved in plant tolerance acquisition. Oxidative and anti-oxidative signals normally move among the different cell compartments, including the nucleus, cytosol, and organelles. Nuclei are dynamically equipped with different redox systems, such as glutathione (GSH), thiol reductases, and redox regulated transcription factors (TFs). The nuclear redox network participates in the regulation of the DNA metabolism, in terms of transcriptional events, replication, and repair mechanisms. This mainly occurs through redox-dependent regulatory mechanisms comprising redox buffering and post-translational modifications, such as the thiol-disulphide switch, glutathionylation, and S-nitrosylation. The regulatory role of microRNAs (miRNAs) is also emerging for the maintenance of genome stability and the modulation of antioxidative machinery under adverse environmental conditions. In fact, redox systems and DDR pathways can be controlled at a post-transcriptional level by miRNAs. This review reports on the interconnections between the DDR pathways and redox balancing systems. It presents a new dynamic picture by taking into account the shared regulatory mechanism mediated by miRNAs in plant defense responses to stress.

Development of coupled redox active network in Ca-alginate polymer for immobilization of Pseudomonas putida 1046 on electrode surface

Redox activated polymeric gels on the anode surface present an approach for creating artificial biofilms thus ensuring highly effective extracellular electron transfer (EET) of electrogens in microbial fuel cells (MFCs). A new coupled redox reaction network was developed for functionalization of alginate polymerized on carbon felt and fast immobilization of bacteria. For this purpose, four different fabricated polymer-modified materials, consisting of single or mixed redox active dyes have been examined toward electrochemical activity and stability at abiotic as well as biotic conditions. The designed electrodes consisting of thiazolyl blue formazan/phenazine methosulfate (PMS) showed well-defined reduction and oxidation peaks with a formal potential of +91 mV (vs. SHE). The peaks' current exceeded two times those of PMS-alginate and over ten times those of thiazolyl blue formazan-alginate electrodes, while the alginate control did not express any activity. Selected redox polymer matrices on carbon felt supports were used for immobilization of bacteria Pseudomonas putida 1046. The modified bioanodes have been poised continuously at positive potentials +0.605 V and +0.705 V (vs. SHE) and current density of 35 ± 2 mA/m2 has been achieved. The redox activity and charge transfer properties of the modified bioanodes were investigated by means of cyclic voltammetry and electrochemical impedance spectroscopy. The results in this study show that the non-conductivity of the alginate polymer can be overcome by the addition of artificial redox dyes thiazolyl blue formazan and PMS, creating a coupled redox network or by expression of cellular produced redox compound mediating the electron transfer though the polymer, so that the fabricated bioelectrodes can be applied as bioanodes in MFC.

The Role of the Plant Antioxidant System in Drought Tolerance.

Water deficiency compromises plant performance and yield in many habitats and in agriculture. In addition to survival of the acute drought stress period which depends on plant-genotype-specific characteristics, stress intensity and duration, also the speed and efficiency of recovery determine plant performance. Drought-induced deregulation of metabolism enhances generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) which in turn affect the redox regulatory state of the cell. Strong correlative and analytical evidence assigns a major role in drought tolerance to the redox regulatory and antioxidant system. This review compiles current knowledge on the response and function of superoxide, hydrogen peroxide and nitric oxide under drought stress in various species and drought stress regimes. The meta-analysis of reported changes in transcript and protein amounts, and activities of components of the antioxidant and redox network support the tentative conclusion that drought tolerance is more tightly linked to up-regulated ascorbate-dependent antioxidant activity than to the response of the thiol-redox regulatory network. The significance of the antioxidant system in surviving severe phases of dehydration is further supported by the strong antioxidant system usually encountered in resurrection plants.

Redox Systems Biology of Nutrition and Oxidative Stress

Diet and nutrition contribute to both beneficial and harmful aspects of oxidative processes. The harmful processes, termed oxidative stress, occur with many human diseases. Major advances in understanding oxidative stress and nutrition have occurred with broad characterization of dietary oxidants and antioxidants, and with mechanistic studies showing antioxidant efficacy. However, randomized controlled trials in humans with free-radical-scavenging antioxidants and the glutathione precursor N-acetylcysteine have provided limited or inconsistent evidence for health benefits. This, combined with emerging redox theory, indicates that holistic models are needed to understand the interplay of nutrition and oxidative stress. The purpose of this article is to highlight how recent advances in redox theory and the development of new omics tools and data-driven approaches provide a framework for future nutrition and oxidative stress research. Here we describe why a holistic approach is needed to understand the impact of nutrition on oxidative stress and how recent advances in omics and data analysis methods are viable tools for systems nutrition approaches. Based on the extensive research on glutathione and related thiol antioxidant systems, we summarize the advancing framework for diet and oxidative stress in which antioxidant systems are a component of a larger redox network that serves as a responsive interface between the environment and an individual. The feasibility for redox network analysis has been established by experimental models in which dietary factors are systematically varied and oxidative stress markers are linked through integrated omics (metabolome, transcriptome, proteome). With this framework, integrated redox network models will support optimization of diet to protect against oxidative stress and disease.

Emerging Therapeutic Targets in Oncologic Photodynamic Therapy.

Reactive oxygen species sustain tumorigenesis and cancer progression through deregulated redox signalling which also sensitizes cancer cells to therapy. Photodynamic therapy (PDT) is a promising anti-cancer therapy based on a provoked singlet oxygen burst, exhibiting a better toxicological profile than chemo- and radiotherapy. Important gaps in the knowledge on underlining molecular mechanisms impede on its translation towards clinical applications. The main objective of this review is to critically analyse the knowledge lately gained on therapeutic targets related to redox and inflammatory networks underlining PDT and its outcome in terms of cell death and resistance to therapy. Emerging therapeutic targets and pharmaceutical tools will be documented based on the identified molecular background of PDT. Cellular responses and molecular networks in cancer cells exposed to the PDT-triggered singlet oxygen burst and the associated stresses are analysed using a systems medicine approach, addressing both cell death and repair mechanisms. In the context of immunogenic cell death, therapeutic tools for boosting anti-tumor immunity will be outlined. Finally, the transcription factor NRF2, which is a major coordinator of cytoprotective responses, is presented as a promising pharmacologic target for developing co-therapies designed to increase PDT efficacy. There is an urgent need to perform in-depth molecular investigations in the field of PDT and to correlate them with clinical data through a systems medicine approach for highlighting the complex biological signature of PDT. This will definitely guide translation of PDT to clinic and the development of new therapeutic strategies aimed at improving PDT.

Thiol redox-regulation for efficient adjustment of sulfur metabolism in acclimation to abiotic stress.

Sulfur assimilation and sulfur metabolism are tightly controlled at the transcriptional, post-transcriptional, and post-translational levels in order to meet the demand for reduced sulfur in growth and metabolism. These regulatory mechanisms coordinate the cellular sulfhydryl supply with carbon and nitrogen assimilation in particular. Redox homeostasis is an important cellular parameter intimately connected to sulfur by means of multiple thiol modifications. Post-translational thiol modifications such as disulfide formation, sulfenylation, S-nitrosylation, persulfidation, and S-glutathionylation allow for versatile switching and adjustment of protein functions. This review focuses on redox-regulation of enzymes involved in the sulfur assimilation pathway, namely adenosine 5´-phosphosulfate reductase (APR), adenosine 5´-phosphosulfate kinase (APSK), and γ-glutamylcysteine ligase (GCL). The activity of these enzymes is adjusted at the transcriptional and post-translational level depending on physiological requirements and the state of the redox and reactive oxygen species network, which are tightly linked to abiotic stress conditions. Hormone-dependent fine-tuning contributes to regulation of sulfur assimilation. Thus, the link between oxylipin signalling and sulfur assimilation has been substantiated by identification of the so-called COPS module in the chloroplast with its components cyclophilin 20-3, O-acetylserine thiol lyase, 2-cysteine peroxiredoxin, and serine acetyl transferase. We now have a detailed understanding of how regulation enables the fine-tuning of sulfur assimilation under both normal and abiotic stress conditions.