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Advances in melanoma research have unveiled critical insights into its genetic and molecular landscape, leading to significant therapeutic innovations. This review explores the intricate interplay between genetic alterations, such as mutations in BRAF, NRAS, and KIT, and melanoma pathogenesis. The MAPK and PI3K/Akt/mTOR signaling pathways are highlighted for their roles in tumor growth and resistance mechanisms. Additionally, this review delves into the impact of epigenetic modifications, including DNA methylation and histone changes, on melanoma progression. The tumor microenvironment, characterized by immune cells, stromal cells, and soluble factors, plays a pivotal role in modulating tumor behavior and treatment responses. Emerging technologies like single-cell sequencing, CRISPR-Cas9, and AI-driven diagnostics are transforming melanoma research, offering precise and personalized approaches to treatment. Immunotherapy, particularly immune checkpoint inhibitors and personalized mRNA vaccines, has revolutionized melanoma therapy by enhancing the body's immune response. Despite these advances, resistance mechanisms remain a challenge, underscoring the need for combined therapies and ongoing research to achieve durable therapeutic responses. This comprehensive overview aims to highlight the current state of melanoma research and the transformative impacts of these advancements on clinical practice.

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Plant peroxisomes are subcellular compartments involved in many biochemical pathways during the life cycle of a plant but also in the mechanism of response against adverse environmental conditions. These organelles have an active nitro-oxidative metabolism under physiological conditions but this could be exacerbated under stress situations. Furthermore, peroxisomes have the capacity to proliferate and also undergo biochemical adaptations depending on the surrounding cellular status. An important characteristic of peroxisomes is that they have a dynamic metabolism of reactive nitrogen and oxygen species (RNS and ROS) which generates two key molecules, nitric oxide (NO) and hydrogen peroxide (H2 O2 ). These molecules can exert signaling functions by means of post-translational modifications that affect the functionality of target molecules like proteins, peptides or fatty acids. This review provides an overview of the endogenous metabolism of ROS and RNS in peroxisomes with special emphasis on polyamine and uric acid metabolism as well as the possibility that these organelles could be a source of signal molecules involved in the functional interconnection with other subcellular compartments.

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Despite of their economical and nutritional interest, the biology of fruits is still little studied in comparison with reports of other plant organs such as leaves and roots. Accordingly, research at subcellular and molecular levels is necessary not only to understand the physiology of fruits, but also to improve crop qualities. Efforts addressed to gain knowledge of the peroxisome proteome and how it interacts with the overall metabolism of fruits will provide tools to be used in breeding strategies of agricultural species with added value. In this work, special attention will be paid to peroxisomal proteins involved in the metabolism of reactive oxygen species (ROS) due to the relevant role of these compounds at fruit ripening. The proteome of peroxisomes purified from sweet pepper (Capsicum annuum L.) fruit is reported, where an iron-superoxide dismutase (Fe-SOD) was localized in these organelles, besides other antioxidant enzymes such as catalase and a Mn-SOD, as well as enzymes involved in the metabolism of carbohydrates, malate, lipids and fatty acids, amino acids, the glyoxylate cycle and in the potential organelles' movements.

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Plant peroxisomes are organelles with a very active participation in the cellular regulation of the metabolism of reactive oxygen species (ROS). However, during the last two decades peroxisomes have been shown to be also a relevant source of nitric oxide (NO) and other related molecules designated as reactive nitrogen species (RNS). ROS and RNS have been mainly associated to nitro-oxidative processes; however, some members of these two families of molecules such as H2O2, NO or S-nitrosoglutathione (GSNO) are also involved in the mechanism of signaling processes mainly through post-translational modifications. Peroxisomes interact metabolically with other cell compartments such as chloroplasts, mitochondria or oil bodies in different pathways including photorespiration, glyoxylate cycle or ß-oxidation, but peroxisomes are also involved in the biosynthesis of phytohormones including auxins and jasmonic acid (JA). This review will provide a comprehensive overview of peroxisomal RNS metabolism with special emphasis in the identified protein targets of RNS inside and outside these organelles. Moreover, the potential interconnectivity between peroxisomes and other plant organelles, such as mitochondria or chloroplasts, which could have a regulatory function will be explored, with special emphasis on photorespiration.

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In plant cells, as in most eukaryotic organisms, peroxisomes are probably the major sites of intracellular H2O2 production, as a result of their essentially oxidative type of metabolism. In recent years, it has become increasingly clear that peroxisomes carry out essential functions in eukaryotic cells. The generation of the important messenger molecule hydrogen peroxide (H2O2) by animal and plant peroxisomes and the presence of catalase in these organelles has been known for many years, but the generation of superoxide radicals (O2·- ) and the occurrence of the metalloenzyme superoxide dismutase was reported for the first time in peroxisomes from plant origin. Further research showed the presence in plant peroxisomes of a complex battery of antioxidant systems apart from catalase. The evidence available of reactive oxygen species (ROS) production in peroxisomes is presented, and the different antioxidant systems characterized in these organelles and their possible functions are described. Peroxisomes appear to have a ROS-mediated role in abiotic stress situations induced by the heavy metal cadmium (Cd) and the xenobiotic 2,4-D, and also in the oxidative reactions of leaf senescence. The toxicity of Cd and 2,4-D has an effect on the ROS metabolism and speed of movement (dynamics) of peroxisomes. The regulation of ROS production in peroxisomes can take place by post-translational modifications of those proteins involved in their production and/or scavenging. In recent years, different studies have been carried out on the proteome of ROS metabolism in peroxisomes. Diverse evidence obtained indicates that peroxisomes are an important cellular source of different signaling molecules, including ROS, involved in distinct processes of high physiological importance, and might play an important role in the maintenance of cellular redox homeostasis.

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BACKGROUND AND AIMS: Pepper (Capsicum annuum) contains high levels of antioxidants, such as vitamins A and C and flavonoids. However, information on the role of these beneficial compounds in the physiology of pepper fruit remains scarce. Recent studies have shown that antioxidants in ripe pepper fruit play a key role in responses to temperature changes, and the redox state at the time of harvest affects the nutritional value for human consumption. In this paper, the role of antioxidant metabolism of pepper fruit during ripening and in the response to low temperature is addressed, paying particular attention to ascorbate, NADPH and the superoxide dismutase enzymatic system. The participation of chloroplasts, mitochondria and peroxisomes in the ripening process is also investigated. SCOPE AND RESULTS: Important changes occur at a subcellular level during ripening of pepper fruit. Chloroplasts turn into chromoplasts, with drastic conversion of their metabolism, and the role of the ascorbate-glutathione cycle is essential. In mitochondria from red fruits, higher ascorbate peroxidase (APX) and Mn-SOD activities are involved in avoiding the accumulation of reactive oxygen species in these organelles during ripening. Peroxisomes, whose antioxidant capacity at fruit ripening is substantially affected, display an atypical metabolic pattern during this physiological stage. In spite of these differences observed in the antioxidative metabolism of mitochondria and peroxisomes, proteomic analysis of these organelles, carried out by 2-D electrophoresis and MALDI-TOF/TOF and provided here for the first time, reveals no changes between the antioxidant metabolism from immature (green) and ripe (red) fruits. CONCLUSIONS: Taken together, the results show that investigation of molecular and enzymatic antioxidants from cell compartments, especially chloroplasts, mitochondria and peroxisomes, is a useful tool to study the physiology of pepper fruit, particularly in the context of expanding their shelf-life after harvest and in maintaining their nutritional value.

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The production of reactive oxygen species (ROS) is the unavoidable consequence of aerobic life. ROS is a collective term that includes both oxygen radicals, like superoxide (O 2. -) and hydroxyl (·OH) radicals, and other non-radicals such as hydrogen peroxide (H2O2), singlet oxygen ((1)O2 or (1)Δg), etc. In plants, ROS are produced in different cell compartments and are oxidizing species, particularly hydroxyl radicals and singlet oxygen, that can produce serious damage in biological systems (oxidative stress). However, plant cells also have an array of antioxidants which, normally, can scavenge the excess oxidants produced and so avoid deleterious effects on the plant cell bio-molecules. The concept of 'oxidative stress' was re-evaluated in recent years and the term 'oxidative signalling' was created. This means that ROS production, apart from being a potentially harmful process, is also an important component of the signalling network that plants use for their development and for responding to environmental challenges. It is known that ROS play an important role regulating numerous biological processes such as growth, development, response to biotic and environmental stresses, and programmed cell death. The term reactive nitrogen species (RNS) includes radicals like nitric oxide (NO· ) and nitric dioxide (NO2.), as well as non-radicals such as nitrous acid (HNO2) and dinitrogen tetroxide (N2O4), among others. RNS are also produced in plants although the generating systems have still not been fully characterized. Nitric oxide (NO·) has an important function as a key signalling molecule in plant growth, development, and senescence, and RNS, like ROS, also play an important role as signalling molecules in the response to environmental (abiotic) stress. Similarly, NO· is a key mediator, in co-operation with ROS, in the defence response to pathogen attacks in plants. ROS and RNS have been demonstrated to have an increasingly important role in biology and medicine.

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BACKGROUND AND AIMS: The development of seedlings involves many morphological, physiological and biochemical processes, which are controlled by many factors. Some reactive oxygen and nitrogen species (ROS and RNS, respectively) are implicated as signal molecules in physiological and phytopathological processes. Pepper (Capsicum annuum) is a very important crop and the goal of this work was to provide a framework of the behaviour of the key elements in the metabolism of ROS and RNS in the main organs of pepper during its development. METHODS: The main seedling organs (roots, hypocotyls and green cotyledons) of pepper seedlings were analysed 7, 10 and 14 d after germination. Activity and gene expression of the main enzymatic antioxidants (catalase, ascorbate-glutathione cycle enzymes), NADP-generating dehydrogenases and S-nitrosoglutathione reductase were determined. Cellular distribution of nitric oxide ((·)NO), superoxide radical (O2 (·-)) and peroxynitrite (ONOO(-)) was investigated using confocal laser scanning microscopy. KEY RESULTS: The metabolism of ROS and RNS during pepper seedling development was highly regulated and showed significant plasticity, which was co-ordinated among the main seedling organs, resulting in correct development. Catalase showed higher activity in the aerial parts of the seedling (hypocotyls and green cotyledons) whereas roots of 7-d-old seedlings contained higher activity of the enzymatic components of the ascorbate glutathione cycle, NADP-isocitrate dehydrogenase and NADP-malic enzyme. CONCLUSIONS: There is differential regulation of the metabolism of ROS, nitric oxide and NADP dehydrogenases in the different plant organs during seedling development in pepper in the absence of stress. The metabolism of ROS and RNS seems to contribute significantly to plant development since their components are involved directly or indirectly in many metabolic pathways. Thus, specific molecules such as H2O2 and NO have implications for signalling, and their temporal and spatial regulation contributes to the success of seedling establishment.

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The presence of peroxisomes in olive (Olea europaea L.) fruits and different antioxidant enzymes occurring in this plant tissue is reported for the first time. Ultrastructural analysis showed that olive cells were characterized by the presence of large vacuoles and lipid drops. Plastids, mitochondria and peroxisomes were placed near the cell wall, showing some type of association with it. Olive fruit peroxisomes were purified by sucrose density-gradient centrifugation, and catalase, glutathione reductase and ascorbate peroxidase were found in peroxisomes. In olive fruit tissue the presence of a battery of antioxidant enzymes was demonstrated, including catalase, four superoxide dismutase isozymes (mainly an Fe-SOD plus 2 Cu,Zn-SOD and a Mn-SOD), all the enzymes of the ascorbate-glutathione cycle, reduced and oxidized glutathione, ascorbate, and four NADPH-recycling dehydrogenases. The knowledge of the full composition of antioxidants (enzymatic and non-enzymatic) in olive fruits is crucial to be able to understand the processes regulating the antioxidant composition of olive oil.

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Pepper (Capsicum annuum L.) is the second worldwide most consumed vegetable nowadays, with southern European countries being among the major producer areas. Pepper fruits contain high levels of vitamins A and C (ascorbate) and low calories what makes this produce greatly appropriate for human diet. In fact, fruits have enormous interest from the culinary and gastronomic points of view and can be used as raw, canned, condiment and food colorant, among others. Ripening of pepper fruits, an ethylene-independent process in this plant species, is somehow modulated by nitric oxide (NO), and the profile of several reactive nitrogen species (RNS) could be used as an index of this physiological stage. Regarding to the antioxidants' metabolism in fruits [1,2], it has been hypothesized that ascorbate plays an important role as a redox buffer during the ripening process. Furthermore, the interplay among enzymatic antioxidants protects pepper fruits against damage promoted by chilling conditions. The oxidative metabolism of peroxisomes seems to also participate in the regulation of the ripening process of fruits.

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Peroxisomes are very dynamic and metabolically active organelles and are a very important source of reactive oxygen species (ROS), H2O2, O2 (.-) and · OH, which are mainly produced in different metabolic pathways, including fatty acid ß-oxidation, photorespiration, nucleic acid and polyamine catabolism, ureide metabolism, etc. ROS were originally associated to oxygen toxicity; however, these reactive species also play a central role in the signaling network regulating essential processes in the cell. Peroxisomes have the capacity to rapidly produce and scavenge H2O2 and O2 (.-) which allows to regulate dynamic changes in ROS levels. This fact and the plasticity of these organelles, which allows adjusting their metabolism depending on different developmental and environmental cues, makes these organelles play a central role in cellular signal transduction. The use of catalase and glycolate oxidase loss-of-function mutants has allowed to study the consequences of changes in the levels of endogenous H2O2 in peroxisomes and has improved our knowledge of the transcriptomic profile of genes regulated by peroxisomal ROS. It is now known that peroxisomal ROS participate in more complex signaling networks involving calcium, hormones, and redox homeostasis which finally determine the response of plants to their environment.

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Nitric oxide is a gaseous free radical with a wide range of direct and indirect actions in plant cells. However, the enzymatic sources of NO and its subcellular localization in plants are still under debate. Among the different subcellular compartments where NO has been found to be produced, peroxisomes are the best characterized since in these organelles it has been demonstrated the presence of NO and it has been biochemically characterized a L-arginine-dependent nitric oxide synthase activity. This chapter summarizes the present knowledge of the NO metabolism and its derived reactive nitrogen species (RNS) in plant peroxisomes and how this gaseous free radical is involved in natural senescence, and is released to the cytosol under salinity stress conditions acting as a signal molecule.

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Sweet pepper is susceptible to changes in the environmental conditions, especially temperatures below 15 °C. In this work, two sets of pepper fruits (Capsicum annuum L.) which underwent distinct temperature profiles in planta were investigated. Accordingly, two harvesting times corresponding to each set were established: Harvest 1, whose fruits developed and ripened at 14.9 °C as average temperature; and Harvest 2, with average temperature of 12.4 °C. The oxidative metabolism was analyzed in all fruits. Although total ascorbate content did not vary between Harvests, a shift from the reduced to the oxidized form (dehydroascorbate), accompanied by a higher ascorbate peroxidase activity, was observed in Harvest 2 with respect to Harvest 1. Moreover, a decrease of the ascorbate-generating enzymatic system, the γ-galactono-lactone dehydrogenase, was found at Harvest 2. The activity values of the NADP-dependent dehydrogenases analyzed seem to indicate that a lower NADPH synthesis may occur in fruits which underwent lower temperature conditions. In spite of the important changes observed in the oxidative metabolism in fruits subjected to lower temperature, no oxidative stress appears to occur, as indicated by the lipid peroxidation and protein oxidation profiles. Thus, the antioxidative systems of pepper fruits seem to be involved in the response against temperature changes.

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Protein tyrosine nitration is a post-translational modification (PTM) mediated by reactive nitrogen species (RNS) that is linked to nitro-oxidative damages in plant cells. During the last decade, the identification of proteins undergoing this PTM under adverse environmental conditions has increased. However, there is also a basal endogenous nitration which seems to have a regulatory function. The technological advances in proteome analysis have allowed identifying these modified proteins and have shown that the number and identity of the nitrated proteins change among plant species, analysed organs and growing/culture conditions. In this work, the current knowledge of protein tyrosine nitration in higher plants under different situations is reviewed.

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Low temperature is an environmental stress that affects crop production and quality and regulates the expression of many genes, and the level of a number of proteins and metabolites. Using leaves from pepper (Capsicum annum L.) plants exposed to low temperature (8 °C) for different time periods (1 to 3 d), several key components of the metabolism of reactive nitrogen and oxygen species (RNS and ROS, respectively) were analysed. After 24 h of exposure at 8 °C, pepper plants exhibited visible symptoms characterized by flaccidity of stems and leaves. This was accompanied by significant changes in the metabolism of RNS and ROS with an increase of both protein tyrosine nitration (NO(2) -Tyr) and lipid peroxidation, indicating that low temperature induces nitrosative and oxidative stress. During the second and third days at low temperature, pepper plants underwent cold acclimation by adjusting their antioxidant metabolism and reverting the observed nitrosative and oxidative stress. In this process, the levels of the soluble non-enzymatic antioxidants ascorbate and glutathione, and the activity of the main NADPH-generating dehydrogenases were significantly induced. This suggests that ascorbate, glutathione and the NADPH-generating dehydrogenases have a role in the process of cold acclimation through their effect on the redox state of the cell.

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In this work the differential response of adult and young leaves from pea (Pisum sativum L.) plants to the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) (23 mm) applied by foliar spraying was investigated. The concentration of 2,4-D (23 mm) and the time of treatment (72 h) were previously optimized in order to visualize its toxic effects on pea plants. Under these conditions, the herbicide induced severe disturbances in mesophyll cells structure and proliferation of vascular tissue in young leaves and increased acyl-CoA oxidase (ACX), xanthine oxidase (XOD) and lipoxygenase (LOX) activities in young leaves, and only ACX and LOX in adult leaves. This situation produced reactive oxygen species (ROS) over-accumulation favoured by the absence of significant changes in the enzymatic antioxidants, giving rise to oxidative damages to proteins and membrane lipids. An increase of ethylene took place in both young and adult leaves and the induction of genes encoding the stress proteins, PRP4A and HSP 71,2, was observed mainly in young leaves. These results suggest that ROS overproduction is a key factor in the effect of high concentrations of 2,4-D, and ROS can trigger a differential response in young and adult leaves, either epinasty development in young leaves or senescence processes in adult tissues.

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Dr. Christine Foyer (B.Sc. 1974; Ph.D. 1977) is recognized here as a Redox Pioneer because she has published an article on redox biology that has been cited more than 1000 times, 4 other articles that have been cited more than 500 times, and a further 32 articles that have been each cited more than 100 times. During her Ph.D. at the Kings College, University of London, United Kingdom, Dr. Foyer discovered that ascorbate and glutathione and enzymes linking NADPH, glutathione, and ascorbate are localized in isolated chloroplast preparations. These observations pioneered the discovery of the ascorbate-glutathione cycle, now known as Foyer-Halliwell-Asada pathway after the names of the three major contributors, a crucial mechanism for H(2)O(2) metabolism in both animals and plants. Dr. Foyer has made a very significant contribution to our current understanding of the crucial roles of ascorbate and glutathione in redox biology, particularly in relation to photosynthesis, respiration, and chloroplast and mitochondrial redox signaling networks. "My view is that science…is compulsive and you have to keep with it all the time and not get despondent when things do not work well. Being passionate about science is what carries you through the hard times so that it isn't so much work, as a hobby that you do for a living. It is the thrill of achieving a better understanding and finding real pleasure in putting new ideas together, explaining data and passing on knowledge that keeps you going no matter what!" --Prof. Christine Helen Foyer.

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Fruit ripening is a developmental complex process which occurs in higher plants and involves a number of stages displayed from immature to mature fruits that depend on the plant species and the environmental conditions. Nowadays, the importance of fruit ripening comes mainly from the link between this physiological process in plants and the economic repercussions as a result of one of the human activities, the agricultural industry. In most cases, fruit ripening is accompanied by colour changes due to different pigment content and increases in sugar levels, among others. Major physiological modifications that affect colour, texture, flavour, and aroma are under the control of both external (light and temperature) and internal (developmental gene regulation and hormonal control) factors. Due to the huge amount of metabolic changes that take place during ripening in fruits from higher plants, the accomplishment of new throughput methods which can provide a global evaluation of this process would be desirable. Differential proteomics of immature and mature fruits would be a useful tool to gain information on the molecular changes which occur during ripening, but also the investigation of fruits at different ripening stages will provide a dynamic picture of the whole transformation of fruits. This subject is furthermore of great interest as many fruits are essential for human nutrition. Thus far different maturation profiles have been reported specific for each crop species. In this work, a thorough review of the proteomic database from fruit development and maturation of important crop species will be updated to understand the molecular physiology of fruits at ripening stages.

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Peroxisomes are single membrane-bounded subcellular organelles with an essentially oxidative type of metabolism and are probably the major sites of intracellular H(2)O(2) production. These organelles also generate superoxide radicals (O(2)(-)) and besides catalase they have a complex battery of antioxidative enzymes. In recent years the existence of l-arginine-dependent nitric oxide synthase (NOS) activity and the generation of the reactive nitrogen species (RNS) nitric oxide (NO) have been demonstrated in plant peroxisomes. The inter-cellular and intracellular NO carrier S-nitrosoglutathione (GSNO) can be generated inside peroxisomes and the presence of this RNS has been demonstrated in peroxisomes from several plant species. This review analyzes the available evidence concerning the properties of the NOS activity and the generation of the RNS messengers NO and GSNO in peroxisomes in the context of the cellular function of these organelles as a source of RNS signaling molecules. The important physiological functions displayed by NO and other RNS in intra- and inter-cellular communication in different organisms indicate that more attention should be payed to the RNS signaling function of peroxisomes in human, animal and fungal cells, where it is very likely that similar mechanisms to those found in plant peroxisomes are also operative.

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