Fibrosis is a pathological feature of a variety of chronic inflammatory diseases that can affect almost all organs, which can cause severe consequences and even lead to death. Fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) due to disruption of the balance between ECM production and degradation. Although overabundance of ECM proteins has long been the focus of studies on fibrosis, another facet of the problem—impaired degradation of the ECM—is gaining increasing attention. Matrix metalloproteinase (MMP) and the tissue inhibitor of metalloproteinase (TIMP) system is the main molecular system contributing to ECM degradation, and macrophages are the major regulators of ECM. However, the relationship among macrophages, the MMP/TIMP system and the ECM is not fully understood in the context of fibrosis. Here, we discuss in detail the role played by the ECM in the development of fibrosis and highlight the macrophage-MMP-ECM interaction that is involved in fibrogenesis and may be a potential therapeutic target for fibrosis. Fibrosis results from abnormal wound healing under chronic inflammation or during ongoing injury and is characterized by the excessive accumulation of extracellular matrix (ECM) in and around inflamed or damaged tissue, which may impair the physiological function of the affected tissue and eventually lead to organ failure. , 2 FibroThe ECM plays an important role in the pathogenesis of fibrosis. The dynamic equilibrium between ECM production and degradation plays an important role in the maintenance of tissue homeostasis . HoweverMacrophages, the main producers of proteases in tissues, can regulate both the progression and regression of fibrosis. Macrophages release cytokines to regulate the immune response; phagocytize pathogens, apoptotic cells and ECM; and secrete proteases and their inhibitors to mediate tissue remodeling . MoreoveAs noted above, the interaction of ECM, proteases and macrophages plays a core role in the pathogenesis of fibrosis. However, the interaction pathway and regulatory mechanism of the macrophage-MMP-ECM interaction are unclear. Therefore, we first summarize the mechanism of multiple ECM components in fibrogenesis. Then, we describe a certain kind of macrophage that is critical for ECM degradation in fibrosis. Finally, we elucidated the interactions among macrophages, MMPs and the ECM, which may provide clues for the treatment of fibrosis.The ECM is a three-dimensional, noncellular structure composed of approximately 300 proteins, including 43 collagen subunits, 36 proteoglycans and nearly 200 complicated glycoproteins . DependiECM  and its dynamic changes in composition and structure are important to the pathogenesis and development of fibrosis. Excessive deposition of ECM at a fibrotic site is a common pathological feature, and the identification of this deposition is the gold standard for the diagnosis of fibrosis. Generally, in solid organs (liver and kidney fibrosis), elastin deposition in vessel walls leads to local blood supply disorders and damage to parenchymal cells , which eventually result in organ dysfunction , 16. In ECM is not only a pathological feature of fibrosis but is also an exacerbating factor of fibrosis by either affecting the course of primary disease or by facilitating ECM accumulation. First, when accumulated, multiple components of the ECM may worsen primary fibrotic disease. Reese-Petersen AL’s team found that type I and type III collagen expression was upregulated in the left atrium of patients with atrial fibrillation (AF), and the accumulated collagen affected the electrical conductance of the entire heart by influencing atrial myocyte action potential timing and conductivity, ultimately resulting in more frequent and worsening AF . Second,In chronic inflammation, the production and degradation of ECM deviate from the equilibrium, eventually leading to irreversible excess deposition of ECM in tissues and organs.  AlthoughMacrophages are the drivers of fibrosis in most organs such as liver, lung and skin , but in fact, the function of macrophages in injury repair and fibrosis is plastic and complicated . They caHowever, M1/M2 status is, in fact, an oversimplified classification that does not adequately describe the complex role played by macrophages in the fibrosis of different organs and at different stages. Therefore, an increasing number of studies have classified macrophages according to their specific functions in tissue injury and fibrosis. In the early stage of tissue injury, a subset of macrophages can promote fibrosis by releasing proinflammatory cytokines, inducing the activation and proliferation of ECM-producing cells and recruiting more macrophages to an injury site; hence, these cells are called profibrotic macrophages . In addiIn this article, we describe macrophages from distinct organs that serve similar functions to express ECM degradation-related genes to promote the resolution of fibrosis as fibrolytic macrophages, and their characteristics are described in Table hi (Gr1hi) monocytes in peripheral blood were recruited to sites of injury or inflammation [hi monocytes transformed into Ly6Clo monocytes, which further differentiated into Ly6Clo fibrolytic macrophages through the regulation of CX3CR1 expression [Fibrolytic macrophages consist of macrophage subsets from multiple sources, of which two main sources are the phenotypically changed tissue-resident macrophages and monocytes recruited from peripheral blood. Stimulation of upstream signaling by the tissue microenvironment can trigger the functional regulation and phenotypic change of tissue-resident macrophages, resulting in their acquisition of the anti-fibrotic phenotype. For instance, IL-4-activated macrophages displayed increased expression of cathepsin S and L and reduced activity of phagosomal NADPH oxidase 2 (NOX2), which greatly enhanced the proteolytic capacity of their phagosomes . Moreoveammation , 54. Aftpression . In addipression .The secretion of MMP and the ingestion of ECM components by macrophages are two main ECM degradation pathways in fibrosis. Therefore, we aimed to elucidate the common mechanisms and regulation of fibrolytic macrophages in fibrosis from the perspective of the interaction of macrophages, MMPs and the ECM. We also discuss how relevant mechanisms can be transformed into potential targets for anti-fibrosis therapy.MMPs are the main proteases involved in ECM degradation. Their activity is low under normal conditions but increases during repair or inflammation . MMPs clNumerous studies have demonstrated significant changes in the levels of MMP/TIMP in patients with fibrotic diseases as well as in experimental models of fibrosis. For example, patients with cardiac fibrosis exhibited significantly higher levels of free MMPs  in peripheral blood and lesions compared with healthy controls, 65. In Macrophages can regulate the production and activity of MMPs. The regulation of MMP production by fibrolytic macrophages is categorized into transcriptional regulation and secretory regulation. A variety of transcription factors, such as EGR1, GATA1, and NF-κB, the AP-1 family and STAT3C are involved in the transcriptional regulation of MMPs. The iniThe process of MMP secretion is essential to regulate MMP activity. Initially, secreted pro-MMPs are non-functional due to the interaction of the unpaired cysteine sulfhydryl group in the propeptide domain with the zinc ion-containing active site. Disruption of the bond between the sulfhydryl group of the conserved cysteine in the propeptide domain and the active site zinc ion causes activation of the latent enzyme, a mechanism called the cysteine switch of pro–MMP activation . FibrolyOn the other hand, MMPs can regulate the function of fibrolytic macrophages. MMPs  are endogenous inhibitors of macrophage recruitment in inflammation.  For examIn addition to secreting MMPs to degrade ECM, macrophages ingest ECM components and digest them through the lysosomal pathway. Integrin-mediated phagocytosis is the classical pathway involved in macrophage ECM ingestion. Furthermore, proved in renal and pulmonary fibrosis, receptor-mediated endocytosis plays an important role in ECM ingestion, and this pathway includes the urokinase plasminogen activator receptor-associated protein (uPARAP/Endo180) and CD206 pathways . A recenConversely, ECM components in the fibrotic microenvironment can regulate the function of macrophages. In fibrosis, with increases in the amount of ECM, the properties of the ECM change markedly. The accumulation of specific ECM components during fibrosis and the products of ECM degradation all make fibrotic ECM different from the ECM in normal tissue . The uniMacrophages are the main cells that secrete MMPs, and MMPs are important proteases in ECM degradation. Based on the relationships between fibrolytic macrophages, MMPs and ECM, macrophage-MMP-ECM interaction is established in fibrotic sites Figure .Fig. 1MaAlthough the macrophage-MMP-ECM interaction can promote ECM degradation and fibrosis regression, the ECM continues to deposit with the progression of fibrosis, making the situation worse and possibly irreversible. This outcome suggests that many factors in the fibrotic microenvironment hinder the occurrence and advancement of ECM degradation.Macrophages can be anti-fibrotic, but the phenotype and function of macrophages vary markedly, and therefore, macrophages may become promoters of fibrosis. In the early stage of injury in organs such as lung, skin and liver, M1 macrophages promote ECM deposition and fibrosis by producing proinflammatory cytokines  and activating fibroblasts and pericytes . The pheMMPs not only can degrade excessive ECM in fibrosis but can also disrupt the normal structure of the ECM, resulting in tissue damage and aggravated fibrosis. In renal fibrosis, TGF-β-activated macrophages release MMP-9, which specifically degrades the tubular basement membrane, leading to tubular cell EMT and ultimately kidney fibrosis. Inhibition of MMP-9 activity can reduce macrophage recruitment and infiltration, prevent the EMT and reduce the degree of fibrosis, making MMP-9 a potential therapeutic target in renal fibrosis. MatricrBecause of these profibrotic factors, macrophage-MMP-ECM interaction may promote ECM deposition rather than degradation in fibrotic sites. In this regard, eliminating profibrotic factors or enhancing anti-fibrotic factors may be a therapeutic strategy for fibrosis because they can induce macrophage switching into a fibrolytic phenotype by altering upstream signals or inhibiting the profibrotic functions of certain MMPs.ECM deposition is not only a feature of fibrotic diseases but is also the core pathological process in fibrosis. Research on ECM degradation in fibrosis is increasing, and targeting ECM degradation to treat fibrosis shows great potential. On the one hand, this approach can significantly alleviate established fibrosis through symptomatic treatment. More importantly, the restoration of ECM homeostasis can improve the tissue microenvironment and potentially inhibit overactivation of fibroblasts. The macrophage-MMP-ECM interaction is a major pathway in ECM degradation during fibrosis, and macrophages are the main producers and regulators of MMPs. Hence, we suggest that precisely regulating the function of fibrolytic macrophages may better contribute to the degradation of ECM and the alleviation of fibrosis. Further investigations are needed to identify the role played by fibrolytic macrophages in fibrosis, including 1) the origin and transformation of fibrolytic macrophages in different stages of fibrotic disease and 2) the mechanism of interaction between fibrolytic macrophages and fibroblasts. Nonetheless, the macrophage-MMP-ECM interaction can lead to better understanding of the pathogenesis and progression of fibrosis from a different angle, and targeting this interaction may be a promising therapeutic strategy for fibrosis.


Our physiology is modified by the environment during critical periods of development from gestational to infancy, even in some cases during adolescence. Stressful experiences are often a challenge to physiological homeostasis. Thus, when exposure to stressful experiences occurs during critical periods such as embryonic development or early life, these experiences have a “programming” effect on the health, changing the developmental trajectory and generating long-lasting changes in the structure and/or function of different organs and systems . Early lEpidemiological, experimental and literature review studies as those included in this collection are essential to understand the impact of the early environment on the wide spectrum of systems that end up ruling physiological fitness.Maternal care is clearly one relevant stress factor. In this Research Topic, Dumas reviews the history of maternal care research, highlighting the importance of this key social interaction shaping adult mental and physical health.Ding et al. conducted a brain imaging study on left-behind children in China. They demonstrated that left-behind children, in addition to deficits in their social-emotional skills, show a decrease in synchronization strength and asymmetry in the right middle frontal gyrus during joint attention. The authors suggested that those might be vulnerability factors in the development of left-behind children. In line with this, Leon el al. provides the first evidence of mother-child epigenetic mark of neglectful caregiving. Nine differentially methylated regions (DMR) were found in common among mothers with neglectful and neglected children, some DMRs contained genes related to childhood adversity, neonatal and infant diabetes, obesity, hypertension, posttraumatic stress, and cancer.Han et al. studied the effect of pregestational exposure to serotonin, and found evidence suggesting that maternal pre-pregnancy serotonin exposure could affect the development of the offspring, partially through reduction in hormone secretion and placental inflammation.Stress disrupts aspects of serotonergic signaling in the brain and, conversely, serotonergic drugs can modulate the effects of stress. In addition, serotonin plays an important role in the female reproductive system, especially in the development of follicles and embryos. In this Research Topic, Corredor et al., report that enriched environment has beneficial effects on anxiety-like behaviors in a sex-dependent manner, suggesting that this system is highly plastic during development and have a time window for potential interventions.As more is known about the health consequences of early-life stress exposure, interest in finding interventions to prevent or reverse these effects is growing. The use of enriched environments is one of the most studied methods for this purpose. Avalos et al. assessed neurobiological mechanisms underlying the influence of chronic restraint stress on the sensitized response to the psychomotor-stimulating effects of cocaine. The authors shed light on the impairment of glutamate signaling on this phenomenon that would be potentially relevant also in the context of development. Henríquez Martínez et al. evaluated the impact of stress exposure on behavior and regeneration ability using zebrafish. Their findings suggest that there is a relationship between chronic stress, regeneration, and behavior in zebrafish. The authors found that the impact of stress was age-dependent. Interestingly, this study suggests that at least some of the mechanisms underlying the effects of the early environment on physiological fitness could be conserved.Besides the critical developmental windows, chronic stress is able to trigger or impair some psychological conditions, including anxiety disorders and major depression . In thisThis Research Topic introduces papers that, using different animal models and also human studies, help to clarify some of the mechanisms associated to early-life stress exposure. These findings will be important in order to develop effective treatments for stress-related disorders.


Organizational democracy (OD) refers to broad-based, and institutionalized employee participation that is not occasional in nature. Written rules, regulations and boards enable employees to exert influence on tactical and strategic decisions. This is realized through direct or representative co-determination or collective self-determination of the employees . Additionally, employees often hold a share of their organization's equity capital (employee ownership)  at two measurement points from different nations and industries. The results of the SEM analyses confirmed that CSR perceptions partially mediated the relationship between OD and meaningful work. Hence, OD can play a direct role in increasing the experience of meaningful work, but also an indirect role trough employees' experience of CSR.The relationship between OD and meaningful work considering corporate social responsibility (CSR) as a potential mediator was investigated by Pap et al. deals with the protective function of a participative climate and supervisor support on service employees of a large clothing shop chain in Belgium. The authors applied a multi-level analysis and showed that participative climate (at the work-unit level) and supervisor support (at the employee level) significantly moderated the negative relationship between perceived customer incivility and job satisfaction.The final article of this Research Topic by Unterrainer et al.), at least the following research gaps and desiderata appear in addition to the new findings already mentioned:Considering the articles gathered in this Research Topic together with existing research reviews from recent years  and methodological problems have been clearly identified  ied Kim, . Neverthied Kim, ). Such lcontrast to economistically reduced motivation theories  is noticeable in their majority. Authors of the present Research Topic refer in this respect to humanistically oriented theories like Deci and Ryan's self-determination theory, Pierce et al.'s psychological ownership theory, Bandura's social-cognitive theory, Kohlberg's approach of moral education, Grant's relational job design framework, Freeman's participation theory, and various offshoots of Pateman's spillover hypothesis. It seems to us an important task of future theoretical contributions in the field of organizational democracy research to investigate to what extent the included components of these theories are compatible with each other. To the extent that they are, appropriate theoretical elements could be integrated into a more complex theoretical framework. This could help to explore the interplay of societal and organizational conditions of democracy in the enterprise, participatory practices , collective and individual basic needs, values, motives, attitudes, experiences, and competencies, and resulting personal, organizational, and societal outcomes.(2) Even if the following tendency is not in the foreground of the contributions to this Research Topic, a ofGeçkil, Svendsen and Jønsson, and Pap et al. suggest that the extent of organizational democracy experienced by employees correlates positively with indicators of wellbeing and negatively with health-related indicators. Both a meta-analysis  provided evidence that the impact potential of substantive organizational democracy (as opposed to non-binding workplace participation and voice) in terms of self-actualization, wellbeing (with the exception of job satisfaction), and psycho-physical health of workers has hardly been explored so far. Looking at recent research reviews from the field of Positive Psychology  Finally, the contributions Salanova ), it is Salanova  have staSalanova . TherefoWW and CU wrote the original draft of this editorial jointly. TJ reviewed and revised it. All authors contributed to the article and approved the submitted version.


Keloids are fibroproliferative skin disorder caused by abnormal healing of injured or irritated skin and are characterized by excessive extracellular matrix (ECM) synthesis and deposition, which results in excessive collagen disorders and calcinosis, increasing the remodeling and stiffness of keloid matrix. The pathogenesis of keloid is very complex, and may include changes in cell function, genetics, inflammation, and other factors. In this review, we aim to discuss the role of biomechanical factors in keloid formation. Mechanical stimulation can lead to excessive proliferation of wound fibroblasts, deposition of ECM, secretion of more pro-fibrosis factors, and continuous increase of keloid matrix stiffness. Matrix mechanics resulting from increased matrix stiffness further activates the fibrotic phenotype of keloid fibroblasts, thus forming a loop that continuously invades the surrounding normal tissue. In this process, mechanical force is one of the initial factors of keloid formation, and matrix mechanics leads to further keloid development. Next, we summarized the mechanotransduction pathways involved in the formation of keloids, such as TGF-β/Smad signaling pathway, integrin signaling pathway, YAP/TAZ signaling pathway, and calcium ion pathway. Finally, some potential biomechanics-based therapeutic concepts and strategies are described in detail. Taken together, these findings underscore the importance of biomechanical factors in the formation and progression of keloids and highlight their regulatory value. These findings may help facilitate the development of pharmacological interventions that can ultimately prevent and reduce keloid formation and progression. Skin is the largest organ of the human body, covering the entire surface of the human body, with the functions of protection, excretion, body temperature regulation, and others . As the Pathological scar, mainly including hypertrophic scar and keloid, are skin fibroproliferative disease characterized by an abnormal wound healing process, massive production of ECM mainly composed of collagen disorders and calcinosis, and hyperplasia of dermal tissue . A hyperKeloid formation and progression is a complex process, which is believed to be independently or jointly driven by changes in cellular function, genetics, inflammation, and other factors. Of particular interest is the recent evidence that biomechanical factors play a key role in the formation and progression of keloids. Here we begin with an introduction to the various factors involved in the progression of keloid pathology and then describe the recent advances in biomechanical regulation of keloids as accumulated evidence suggests that several mechanotransduction signaling pathways, such as TGF-β/Smad signaling pathway, Integrin signaling pathway, YAP/TAZ signaling pathway, and calcium ion pathway, are involved in the process of keloid fibrosis, and have been proved to play an important role in keloid development. Finally, some potential therapeutic concepts and strategies based on biomechanical factors are described.A keloid is a skin disorder caused by excessive proliferation of skin fibers. The exact mechanism underlying keloid formation is still not fully understood. Current studies suggest that changes in cell function, genetics, inflammation, and biomechanical factors all play an important role in keloid formation.During the process of keloid formation, the function of many types of cell populations abnormally changes. Fibroblasts are the most abundant cell type in all connective tissues of the body. As far as skin is concerned, fibroblasts mainly form the ECM by constructing different proportions of collagen and elastin to maintain the structural integrity and normal physiological functions of the skin . FibroblSome studies have suggested that keloid formation is associated with metabolic reprogramming of keloid fibroblasts, including the transition from oxidative phosphorylation to aerobic glycolysis. Compared with normal skin, the keloid tissue showed upregulated GLUT-1 expression and enhanced expressions of several glycolytic enzymes, such as HK1, HK2, PFK1, PFK2, PDK1, and PKM2, . Keloid Although keloid fibroblasts are still believed to be responsible for keloid formation, recent studies have shifted focus to recognizing the potential role of abnormal epidermal cell populations in scar formation. Basic abnormalities found in keloid keratinocytes with regard to the secretion of wound healing mediators, differentially expressed genes, paracrine action of co-cultured cells, and epithelial-mesenchymal transition (EMT) all support a more active role of keratinocytes in keloid formation . In addiRecent studies have shown that race, genetic susceptibility, age, and gender are patient characteristics that may influence susceptibility to keloids. There are significant differences in scarring among different ethnicities, with worldwide keloid prevalence ranging from 0.09% in the United Kingdom to 16% in Congo, suggesting that individuals with darker skin are more likely to develop it . In addivia Smad5 signal transduction mediated by sponging miR-124-3p to promote keloid formation.There is increasing evidence indicating that various different and reversible epigenetic modifications, represented by DNA methylated histone modifications and non-coding RNAs, play key roles in the gene regulation of keloid and downstream fibroblast functions . HistoneStudies have shown that inflammatory mediators and inflammatory cells are involved in the entire process of wound healing . It is bThe abovementioned studies mainly focus on the role of biological factors in keloid formation and have made great progress. They initially revealed the mechanism of occurrence and development of keloids, but the clinical efficacy was not significant after intervention with different targets, indicating that previous studies were incomplete. Recent studies have focused on the role of the external environment, particularly the local mechanical wound environment. Current scientific basis and clinical evidence clearly indicate that biomechanical factors play an important role in keloid formation, contracture, and abnormal keloid development and treatment. Next, we will summarize the research in this area and explore the role of biomechanical factors in keloid formation.Skin injury is a common phenomenon in the human body, and the recovery of anatomical continuity and functional reconstruction of tissue after injury is a complex and dynamic process. Early observations in anatomy and surgery suggest the importance of mechanical tension in wound healing outcomes. For example, Langer lines in the human skin correspond to tension bands that occur naturally in the skin because of the interaction of collagen fibrils and fibroblasts. Conventional assumptions point to the alignment of the underlying ECM, cell orientation and contraction, and muscle involvement in the formation of these invisible lines. Surgical incisions made parallel to these lines reduce tension and heal more easily, with less scarring than incisions made perpendicular to them . The mecResearch has shown that keloids clearly tend to occur in areas of high stress. Rei Ogawa’s map of 1,500 keloid lesions in 483 Japanese patients showed 733 (48.9%) in the anterior thoracic region and 403 (26.9%) in the scapular region, which are the regions usually exposed to continuous or intermittent tension stimulation during daily life activities. Keloid incidence was lower in areas where the skin stretched and contracted less , even in patients with multiple or large keloids . Dohi etin vitro technology to simulate the tension experience of normal skin and keloid tissue in vivo. The results showed that three tension-related genes  were up-regulated in keloid fibroblasts under stress, which promoted ECM synthesis and cell proliferation , the higher the expression of the pro-fibrotic gene α-SMA in keloid fibroblasts . Kenny eBased on the importance of matrix mechanics in the current process of keloid fibrosis, studies have been conducted to investigate whether targeting keloid matrix mechanics has the potential to treat or even reverse fibrosis. Obviously, the most direct approach toward altering keloid matrix mechanics is to inhibit and slow the increase in keloid stiffness during fibrosis. From this viewpoint, it is possible to reduce the stiffness of keloid matrix by influencing or reducing the factors that promote the stiffening of keloid matrix. As one of the main components of fiber matrix, collagen plays a key role in regulating the mechanical properties of ECM. Therefore, it is possible to reduce the stiffness of ECM and slow down the process of keloid fibrosis by reducing collagen synthesis in ECM or excessive deposition of collagen degraded by collagenase. Transmembrane protein 88 (TMEM88) belongs to the TMEM family and is involved in the regulation of tumorigenesis and fibrogenesis. In conclusion, current studies suggest that mechanical stimulation can lead to excessive proliferation of fibroblasts at the wound site, ECM deposition, and secretion of more pro-fibrotic factors, thus promoting the continuous increase of ECM stiffness in keloids. At the same time, the matrix mechanics of ECM further promotes the fibrotic phenotype of keloid fibroblasts, thus forming a loop and resulting in continuous invasion of the surrounding normal tissues by keloids. During this process, the mechanical force is one of the initiating factors of keloid formation, and matrix mechanics leads to further keloid development .In the pathological process of gradual stiffening of keloid matrix, the cells in keloid sense changes in mechanical properties of the microenvironment and activate mechanical transduction pathways, thus transforming external mechanical stimuli into biochemical signals and ultimately guiding cellular behavior . How matAs a classical signaling pathway, the TGF-β signaling pathway has been proved to be an important signaling pathway involved in fibrosis progression during mechanical regulation . The traIntegrin family is a kind of cell adhesion, signal pathway hub and the function of mechanical force signal sensing dimers proteins across the membrane. They are the link of ECM to the actin cytoskeleton in the cell and regulate specific signal transduction cascade reactions. Therefore, the protein is mediated the effect of matrix–cell and the cell–cell interaction, so as to promote the reshaping of the ECM . Wound tYes-associated protein (YAP) and transcriptional coactivator with a PDZ-binding domain (TAZ) are among the activated mechanosensory pathways. YAP/TAZ can read a wide range of mechanical cues, such as ECM stiffness and topology, shear stress, and cell shape, and translate these into cell-specific biological effects . This ab2+ influx, which is associated with a response to mechanical forces. The Gq-coupled receptor activated by stretch stimulation can activate PLCβ and produce DAG and IP3  have been designed to target TGF-β/Smad signaling to interfere with fibroblast-mediated keloid progression . GinsenoSurgeons have long known that optimizing incision design is an effective means to reduce wound mechanical tension and prevent postoperative scar hyperplasia. Surgical incisions are usually designed to be parallel to skin Langer’s lines, and vertical incision should not be made as far as possible to reduce skin tension. During plastic surgery, Z-plasty, W-plasty, and V-Y plasty are often used to repair scars, so as to disperse the mechanical tension of the incision and reduce the possibility of postoperative scar widening and recurrence . After kKeloids are a fibroproliferative disease caused by excessive growth of fibroblasts and excessive secretion of collagen. Many factors, including changes in cell function, genetic factors, and inflammation factors, play an important role in the occurrence and development of keloids. Biomechanical factors are a basic but relatively unexplored area for understanding keloids. Both macroscopic physical mechanical factors and microscopic matrix mechanical factors at a cellular or molecular level have been proved to have an important impact on the progression of keloid fibrosis and treatment research. Further study on the role of biomechanical factors in the keloid development and modification of mechanical forces or mechanical transduction signals will provide a direction for the development of new therapeutic strategies.


Chronic exposure to toxic levels of trace elements might lead to gene expression dysfunction and abnormal metabolic pathways such as those linked to trace element detoxification and the reproductive performances of animals. It has been a subject consisting of a series of studies testing the physiological outputs when exposed to these trace elements and the underlying epigenetic modulation mechanisms such as DNA/RNA methylation, histone modifications, and microRNA dysregulation. Epigenetics plays a pivotal role in gene expression and is vulnerable to environmental challenges, including the supply of nutritional factors, such as vitamins and minerals. Minerals usually function as cofactors in the activation of epigenetically activating enzymes. As it is true for most epigenetically active factors, the mineral balance mostly determines the epigenome generation during embryonic development, but changes can be triggered throughout life as part of life-term epigenome editing. It has also been proved that alterations induced by minerals accumulation during aging could be passed on to the next generation. Together, mineral supplementation is suggested to prevent dysplasia originating from errors in establishing the epigenome or correct epigenetic disturbances to benefit animal health.The actions of trace element metabolism and epigenetics on animal health and disease” in Frontiers in Veterinary Science is to highlight and stimulate discussion regarding trace element accumulation-induced epigenetic modulation and toxicity/diseases  and the possible detoxication strategies. This topic has collected 4 scientific contributions from highly qualified research groups focusing on trace element metabolism in 4 different animal models including rabbit, pig, goat, and hen.The aim of this Research Topic “Li et al. performed a series of examinations to access the consequences of dietary administration of diverting concentrations of Zn and Cu on anti-oxidant, mineral contamination and excretion, digestion ability, metal transport, and meat quality in finishing pigs. They demonstrated that Zn and Cu supplementation have no side effects on pigs growth performance or meat quality. Nevertheless, mineral contamination and excretion, the enzymes involved in digestion and anti-oxidation, as well as metal transporters were sensitized to these treatments at the finishing stage. These data would better reflect practical concerns on the safe utilization of mineral supplies.Trace elements also known as coenzyme elements of several metal enzymes, exert pivotal actions in human and animal growth, metabolism, digestion, and absorption. Especially, zinc (Zn) and copper (Cu) are critical mineral elements for maintaining health, preventing diseases, and stimulating the growth and the immune system of livestock and poultry. Chen et al. was that organic trace elements  did not affect the growth performance but increased metal and zinc transporter similar to that of the aforementioned study. Moreover, the haugh unit, egg yolk weight, eggshell weight, and eggshell thickness were not changed. However, eggshell strength, illus height, and villus concealment ratio were remarkably improved together with the elevated serum Cu, Fe, Zn levels. It concluded that low levels of organic trace elements benefit late-laying hens' production performance .Another interesting finding in hens from Kucková et al. evaluated the effects of Zn and thyme extract administration on the antioxidant capacities and mineral status in the blood and tissues of growing rabbits. In this model, the authors predicted that Zn and/or aromatic herb T. vulgaris supplementation would perform positive anti-oxidation actions in rabbits. The results exhibited that Zn administration significantly increased the glutathione peroxidase, total antioxidant, and thiol group levels in the kidney. Intriguingly, T. vulgaris and Zn supplementation significantly reduced the Zn concentration in the kidney and Cu content in the muscle, respectively. These suggested that the simultaneous supplementation of organic Zn and T. vulgaris improved the antioxidant response in rabbit kidneys to facilitate protection against oxidative stress.Given that Zn is one of the crucial redox inactive trace elements to perform the antioxidant roles by activating antioxidant enzymes and the stabilization of sulfhydryl groups, via diminishing reactive oxygen species and lipid peroxidation. In this regard, Tian et al. tested the selenium-yeast (SY) on goats growth performance, meat quality, fatty acids, and amino acids profiles, along with the antioxidant activities in muscle at the growing stage. The data reflected that goats supplemented with SY did not impair growth performance, muscle chemical composition, pH values, and the loss of water, drip, and cooking. High-dose SY at 4.8 mg/kg supply improves the meat quality by enhancing dressing percentage, eye muscle area, and meat color associated with muscle total antioxidant enzyme activities. Furthermore, owing to the critical benefits of polyunsaturated fatty acids (PUFAs) for livestock health, the authors also provide the evidences that SY treatment markedly remodeled the fatty acid and amino acid profiles to strengthen the anti-oxidation protection accordingly.Besides the organic mineral elements including Zn, Cu, Fe, and Mn, selenium (Se) also plays potential anti-oxidative roles in livestock Exogenous trace element supplies are vital components of metalloproteins and cofactors of enzymic activities for many cellular processes. However, chronic exposure to high doses of trace elements may lead to epigenetic dysregulation and various kinds of diseases. Therefore, the development of new models and methods to monitor trace element absorption and disposition is highly needed. In addition, as an accumulation of trace elements is inevitable, investigation of the subsequent epigenetic modulation such as DNA and histone modification and microRNA regulation may help us reveal the mechanism of the toxicity and predict and prevent the toxicity effectively. Although the epigenetic regulations were not mentioned in these documents, these studies provided a better understanding of trace element metabolism and relative anti-oxidation functions in animals.DC wrote the introduction, conclusion, and the central part with comments on the cited papers and references. DC, DW, and MT contributed to the review and editing. All authors contributed to the article and approved the submitted version.This work was supported by the Natural Science Foundation of Jiangsu Province (BK20200932), Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (20KJB230001), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Plant stress is one of the most significant factors affecting plant fitness and, consequently, food production. However, plant stress may also be profitable since it behaves hormetically; at low doses, it stimulates positive traits in crops, such as the synthesis of specialized metabolites and additional stress tolerance. The controlled exposure of crops to low doses of stressors is therefore called hormesis management, and it is a promising method to increase crop productivity and quality. Nevertheless, hormesis management has severe limitations derived from the complexity of plant physiological responses to stress. Many technological advances assist plant stress science in overcoming such limitations, which results in extensive datasets originating from the multiple layers of the plant defensive response. For that reason, artificial intelligence tools, particularly Machine Learning (ML) and Deep Learning (DL), have become crucial for processing and interpreting data to accurately model plant stress responses such as genomic variation, gene and protein expression, and metabolite biosynthesis. In this review, we discuss the most recent ML and DL applications in plant stress science, focusing on their potential for improving the development of hormesis management protocols. Environ or well .Whether a stressor will harm or benefit an organism depends entirely on the intensity of its incidence . This obThe acquaintance of hormetic responses of plants to stressors is the basis for implementing hormesis management, which refers to the deliberate exposure of crops to eustress for eliciting desirable attributes . This prSeveral factors shape the defensive responses of plants, including the type of stressor, the genetic identity of the individual, its developmental stage, its nutritional stage, and the responding tissue or cell . ConsequArtificial intelligence (AI) is an evolving branch of computer science with great potential to solve a variety of complex problems of the modern world. From using advanced fuzzy logic models for wastewater treatment , estimatLiterature reviews assessing the use of machine learning for plant stress research focus mainly on analyzing the numerous findings on the identification, classification, quantification, and early prediction of deleterious plant stress responses ,21,22,23The hormesis model is rapidly gaining recognition and acceptance within academia for depicting the responses to external stimuli of any given biological system . NeverthAt present, low-dose stimulation has multiple applications in clinical medicine, environmental risk assessment, ecology, crop management, and sustainable agriculture ,28. SevePlants possess complex defensive mechanisms to deal with the many biotic and abiotic challenges they may encounter in the wild. Protected agriculture diminishes these challenges causing plants to underdevelop defensive mechanisms and making them more susceptible to environmental stress and pests or decreasing their production of desirable specialized metabolites . In thisThe specificity of defensive responses depends directly on the plant species, the type of stressor, and the responding tissue. As a result, plant stress responses are diverse, and so are the methods for their analysis . Each stThe analysis of a substantial number of pathosystems has permitted the description of many receptor-to-response routes . HoweverThe convenience of choosing one variable or another as the output of hormesis management depends on the target crop, the cultivation conditions, and the productivity objective. For example, increasing the drought tolerance of a food crop cultivated in a controlled environment would be irrelevant, whereas augmenting its yield would be paramount. Therefore, the description of plant defensive responses must consider several endpoints (response variables) to possess technological significance. Fortunately, collecting a considerable amount of data from biological systems is becoming more frequent, thanks to the latest advances in analytical instrumentation and techniques .High-throughput analyses increase the chances to elucidate physiological processes and ecological interactions of plants from the broadened perspective of systems biology . The genIn the following subsections, we will briefly describe the main types of data each omics approach can deliver when applied to plant hormesis research.Genomics refers to the sequencing, assembly, and functional analysis of the genome of a plant, and it has advanced more rapidly than any other omics in plant science . Only inGenome sequencing has several applications in plant stress science. The structural analysis of DNA is not only fundamental for classifying organisms but also for identifying stress-driven mutations, which occur in plants under heat , droughtSNPs genotyping in combination with other data sets from high-throughput analyses such as phenomics or enviromics has also led to the development of genomic selection for optimizing crop breeding . With thThe rapid advances in sequencing technologies and bioinformatics have also substantially impelled RNA analyses . The synThe computational analysis of transcriptomic datasets precedes the reconstruction of gene regulatory networks and the crosstalk by which they interconnect during specific physiological processes . In partProteins are the main regulatory molecules in every cell process. Therefore, the ensemble of differentially translated proteins in response to a given stimulus is an additional dataset that contains essential information for ascertaining hormetic cellular mechanisms . MoreoveDetecting differential changes in plant proteome is especially useful for studying plant stress responses since relatively small variations in the dose of a stressor result in a significant difference in the proteome at both mild and severe stressor incidence . FurtherProteome analyses make it possible to identify and characterize novel proteins, and along with bioinformatics, proteomics enables tracking variations in protein abundance, form, cellular location, and activity following a stressors incidence . AdditioA number of the differentially expressed proteins resulting from stress incidence are regulators that activate and shape specialized metabolic pathways inside the cell . MetabolMany plant specialized metabolites are an active part of plant internal signaling pathways or exert bioactivity on other organisms . FurtherBeing an adaptive response, the activation of plant metabolism also exhibits a hormetic behavior ,88,89, aGiven the structural diversity of plant metabolites, the main limitation of metabolomics resides in developing comprehensive extraction techniques and analytical methods to detect a big heterogeneous ensemble of chemical compounds simultaneously. Nevertheless, thanks to the recent advances in coupled analytical technologies and bioinformatics, particularly Mass Spectrometry (MS), Nuclear Magnetic Resonance (NMR), and hybrid MS/NMR methods , it is nPlant phenotyping is the measurement of phenotypic traits either at the cell, organ, or whole plant level for understanding the underlying mechanisms of the interactions of plants with their environment . MoleculImage-based phenotyping is useful to detect leaf morphological variations in plants . Red-greYellowing is the most notable symptom of leaf senescence, and it appears due to seasonal developmental processes, pathogen attack, and abiotic stressors incidence, indicating a decrease in the photosynthetic rate . ChloropImaging techniques can also be used to analyze plant physiological processes and identify stress even in the absence of symptoms unobservable for the unaided eye. Magnetic resonance imaging can be applied to plant systems to elucidate plant-water relationships and as a post-harvest control to determine maturity and mechanical damage of agricultural products . ThermogGiven the intricacy of physiological responses, the elucidation of the adaptive mechanisms of plants to low-dose stress must be carried out from a multidimensional approach, utilizing comprehensive analyses for detecting the differential changes stimulated in different layers of the stress response. Understanding such mechanisms and, in particular, characterizing the hormetic dose-response curve allows eustress treatments to be implemented to enhance stress tolerance and increase food production and quality . NeverthHigh-throughput analyses of functional molecules such as genes, transcripts, proteins, and metabolites, produce a tremendous amount of data from biological systems. However, without proper processing, such data lack biological significance. Therefore, the advances in analytical methods and instrumentation have also generated the need for processing tools capable of describing mechanistic associations and interactions. The persisting escalation of computing power has triggered a diversification of artificial intelligence (AI) tools to address various problems in plant science. AI algorithms are remarkably advantageous to identify and classify individual characteristics within an extensive set of experimental data, and thus they are a promising means for analyzing plant stress mechanisms . FurtherA considerable number of AI applications on plant stress research implement Machine Learning (ML) and its subtype Deep Learning (DL). Such techniques have been applied in the paradigm of the four categories for analyzing the process of plant stress: identification, classification, quantification, and prediction (ICQP) . Most ofML and DL techniques have extended the reach of traditional statistics for modeling non-linear systems such as biological processes . Hence, The majority of the studies listed in this literature revision are based on supervised algorithms whose quality depends on the data sources, the feature extraction from the available data, and the selection of the output variables and the learning algorithms . The mosGiven that data available for understanding biological systems continues growing, the complexity of AI systems keeps increasing, and thus new high-performance artificial neural networks (ANN) were needed for the cases in which conventional ML techniques have fallen short. Such networks are currently known as deep learning, a technology that consists of the assembly of machine learning algorithms, increasing the number of levels and non-linear transformations in the neural networks and the efficiency of the training process .Before the current heyday of DL, a disinterest towards it existed for several years, mainly due to hardware limitations and lack of funding. However, these techniques were reassessed as soon as more powerful hardware became available, especially Graphics Processing Units (GPUs) . These dThe use of high-performance software allows DL to be used to evaluate many problems in systems biology. Computational models have been applied to simulate protein interactions, a universal process in biological systems, and a key process for understanding the mechanism of physiological responses . Using iWhen it comes to DL, there is an impression that an expensive computational infrastructure is necessary, which is not entirely false considering the cost of high-performance GPUs. However, there are many platforms for training DL models through cloud computing. For example, platforms such as Amazon Web Service (AWS), Google Colab, Microsoft Azure provide CPUs, Hard Disks, GPUs, or TPUs through the command terminal, which allows one to utilize high-performance hardware from an average computer with internet access and sufficient bandwidth. Additionally, some of these platforms offer a free version, meaning that cloud computing can be performed for a few hours without cost. This approach avoids the cost of a local computing cluster, the specialized space to house them, and the required electricity, all considerable limitations to perform this kind of computing due to the long time needed to train a DL model at a high performance. In addition to exploiting hardware features, it is also essential to take account of the existing software to ensure an adequate running performance when training ML networks. Several platforms enable the implementation of ML and DL algorithms, and many of the available frameworks are open-source software, which has led to the rapid adoption of computer modeling for many agricultural technology . Among tHormesis management increases crop yield and quality, stimulates specialized metabolism, and enhances stress tolerance . NeverthDL would be an efficient tool to address hormesis management limitations because it can expose complex non-linear relations between environmental conditions and gene expression to decipher gene networks and signaling pathways . ConvoluIn this review, we have discussed the advantages of ML for assessing research problems in plant-stressor systems from a subcellular to an ecosystem scale. Nevertheless, there are also relevant limitations to consider for proposing the implementation of ML tools, particularly for hormesis modeling.Firstly, given the vast diversity of ML and DL platforms, selecting an appropriate architecture to carry out the proposed strategy constitutes a significant challenge. Furthermore, every architecture performs differently depending on the number and type of deep networks and the running hardware, complicating, even more, the tool selection. In response to this challenge, the number of scientific publications discussing ML tool-pairs, their performance, and new models designed specifically to perform a given task constantly increases .The second challenge to assess refers to AI’s fundamental limitations. The power of ML methods offers advantages over conventional statistics, but they do not explicitly infer or provide confidence boundaries such as p values. This is a problem since scientists commonly rely on confidence intervals and model interpretation to support decision-making. Moreover, increasing the complexity of the network architecture turns ML systems into “black-boxes.” Consequently, most ML and DL methods do not allow a straightforward interpretation or the basis for the resulting predictions . TherefoThe third challenge arises from the input data. The success of ML depends on the availability of appropriate databases, that is, extensive collections of data sharing specific features . NonetheThe aim of elucidating plant stress responses is to develop cost-effective methods for producers to manipulate plant systems and obtain desirable phenotypes. Nevertheless, given the diversity of the technologies and methods currently available to measure variables associated with plant stress responses, the standardization of the experimental conditions and the integration of different dataset collections is a significant challenge. Moreover, most of the research around stress focuses on the adverse effects it causes on the plant system and completely ignores eustress and the hormetic behavior of plant defense.Interestingly, it could be possible to develop robust models of plant responses if we consider that the behavior of stress responses is generalizable and varies within the limits of biological plasticity rather than depending only on the genetic identity or the developmental stage of individual systems . However


Usual extraction processes for analyzing foods, supplements, and nutraceutical products involve massive amounts of organic solvents contributing to a negative impact on the environment and human health. In recent years, a new class of green solvents called natural deep eutectic solvents (NADES) have been considered a valid alternative to conventional solvents. Compared with conventional organic solvents, NADES have attracted considerable attention since they are sustainable, biodegradable, and non-toxic but also are easy to prepare, and have low production costs. Here we summarize the major aspects of NADEs such as the classification, preparation method physicochemical properties, and toxicity. Moreover, we provide an overview of novel extraction techniques using NADES as potential extractants of bioactive compounds from foods and food by-products, and application of NADEs in food analysis. This review aims to be useful for the further development of NAES and for broadening the knowledge of these new green solvents in order to increase their use for the extraction of bioactive compounds and in food analysis. The analysis of foods is a comprehensive process of extraction, identification, and quantification of several classes of compounds from natural matrices. The detection and quantification of primary metabolites , contaminants , and secondary metabolites  is a crucial practice for ensuring the safety and quality of foods and related functional products. Due to the variable structure of food analytes, a gap in a universal method suitable for the extraction and analysis of all compounds is lacking. Moreover, conventional extractants are usually made of organic solvents and common extraction techniques usually require a long extraction time to exhaust the matrix . The actThe development of ionic liquid (ILs) solvents started in the 90s. Despite their nontoxic behavior as pure solvents, several steps of purification should be used to produce ILs that negatively affect economic and environmental sustainability . Thus, dSince 2014, natural deep eutectic solvents (NADES) have been developing as a special group of DES. These emerging systems are made by the combination of natural molecules, allowing further improvement in the impact on the environmental and toxicity risk compared with other deep eutectic solvents. NADES have been studied since 2011 and a rising number of papers highlighted their applications in several fields of chemistry. Among the reported studies, since 2014, the focus on NADES’ applications, physiochemical properties, and combination with innovative extraction techniques was particularly detailed for their applications in foods analysis .Generally, the subgroup of NADESs uses HBD and HBA made by sugars, alcohols, organic acids, amino acids, or amines naturally occurring in plant metabolism or eucaryotic cellular systems . NADESs The advantage of these solvents is related to chemical properties, such as low melting points, low volatility, nonflammability, low vapor pressure, polarity, chemical and thermal stability, and miscibility solubility ,7,14,15.The intermolecular interactions, mainly hydrogen bond interactions, between the HBA and the HBD are responsible for the physicochemical properties of the DES ,18. By cGenerally, the high viscosity of HDA and HDB mixtures cause a low mass transfer phenomenon affecting the extraction efficiency. Temperature can drastically reduce the viscosity but a mediation with the thermolability of natural compounds must be considered. Added water, reported in a range of 10% to 80% , disruptPolarity is the key property to solubilizing metabolites in a solid-liquid extraction. Fixing the choline chloride (ChCl) as HBA, the use of different HBD can affect the polarity of the system. Craveiro et al., 2016 reported the use of sugars  and organic acids  generating different polarity systems. In particular, NADES composed of ChCl and organic acids resulted more polar than those combined with sugars . The watComplete profiling of complex food matrices by using organic solvents allows the extraction of hydrophilic components or lipophilic components separately while the ignored components that remain in the extraction residues are discarded from the analysis. The advantage to use hydrophilic or hydrophobic NADES is the efficient enhancement of bioactive components with various polarities. The density of hydrophilic or hydrophobic solvents can change allowing a double-phase separation. The two-phase system formed with hydrophilic NADES and hydrophobic NADES can resolve the problem of extraction selectivity and could simultaneously extract the bioactive compounds with various polarities from plant materials. In 2015, Van Osch et al. developed a NADES two-phase system and evaluated the recovery of volatile fatty acids from dilute aqueous solutions . A two-pThe NADESs can be produced from different natural compounds such as ChCl, sugars, amino acids, and polyols. These compounds are in solid form and only after mixing, in a specific combination and molar rates, do they turn into a liquid state . Five meThermal mixing is a simpler and faster approach that involves mixing and stirring at a temperature of 50–80 °C of two components with water until a colorless liquid is formed ,33,34.Vacuum evaporation is also similar; the components are dissolved in water and evaporated at about 50 °C in rotary evaporation, and finally, the resulting liquid is placed in a desiccator to reach a constant weight ,34.Freeze-drying involves dissolving the components in water, then freezing and drying them, resulting in a viscous, transparent solution ,35.Microwave-assisted synthesis exploits the production of microwaves that upon interaction with precursors generate collisions between molecules and between the hydrogen bond donor and hydrogen bond acceptor components due to dipole rotation resulting in dielectric heating that speeds up the synthesis time ,37. AccoUltrasound-assisted is a little-explored but effective way of preparing NADESs. The cavitation process promotes, through the release of heat and pressure exerted because of bubbles implosion, the interaction between the hydrogen bond acceptor (HBA) and the hydrogen bond donor (HBD) . AccordiThe preparation of NADES through the different methods  generateA. sinensis. The combination of NADES with microwaves that promote plant cell rupture compared to conventional methods allows implementation of the recovery of molecules by reducing while maintaining the process with low environmental impact and high efficiency .,39.33,39ficiency .The green chemistry approach requires minimizing the risks and hazards associated with the process and its impact on the environment and human health. It is precisely for this motive that numerous scholars have begun to move toward the use of safer and more environmentally friendly solvents. At this juncture are NADES, which are considered nontoxic, environmentally sustainable, and biodegradable, thanks mainly to the fact that they are made up of compounds of natural origin. Choline chloride (ChCl), for example, one of the main HBAs, is widely used for the preparation of NADES and used commercially on a large scale as an additive for chicken feed, in addition, NADES are also used for the solubilization of drugs for oral dosing in rats, and the synthesis of biodegradable polyesters with antibacterial properties . The emeBacillus subtilis and Streptococcus aureus and two Gram- strains Escherichia coli and Pseudomonas aeruginosa, while cytotoxicity was considered on Artemia salina. The results show that phosphonium-based deep eutectic solvents have higher toxicity on all bacterial strains, highlighting a possible antibacterial effect, unlike choline chloride-based NADES. However, for both types of HBAs, the mixture of NADES was more toxic than the individual components, even for cytotoxicity, the ammonium-based deep eutectic solvents showed a greater effect on Artemia salina than the individual components. Justifications for this behavior may be due to several factors such as hydrogen bonding between HBD and the salt anion. It is known that the delocalization of charge that occurs during hydrogen bonding makes the mixture more toxic; in fact, substances with delocalized charges are more toxic than chemicals with localized charges. The lack of oxygen and high viscosity that impairs the movement of A. salina may also influence by modifying the toxicity of the mixture. Further experiments conducted by Hayyan et al., 2013 also hypothesize that NADES can interact with cell surfaces and that their accumulation and aggregation may cause increased cytotoxicity [The toxicity of NADES has long been evaluated by considering only the single toxicity data of all the components used in the preparation, which are reported to be safe . Howevertoxicity . Still, toxicity . The restoxicity .Green chemistry plays an important role in the development of a sustainable process for food manipulation. The optimization of food analysis is a compromise between the reduction of solvents, toxic for human health and environmental pollution, reagents, and energy along with the necessity for high sensitivity, precision, and accuracy for validated analytical methods. NADES have been currently used in green chemistry procedures for sample preparation and analytical workflow focusing on achieving accurate results and prioritizing the sustainability of the processes . In the The extraction is the core procedure for the recovery of phytochemicals, bioactive compounds from natural sources. The aim to optimize the extraction procedure by choosing solvents, experimental conditions, and extraction techniques is to provide the highest amount of target compounds with minimal contamination of other undesired compounds . Solid–lv/v. The improved resolution of the chromatography is explained by the mechanism of binding of both hydrogen-bond donors and hydrogen acceptors combined with the C-18 adsorption of the analytes [Chromatography is a crucial tool for the analysis of complex food matrices assisting the pre-concentration, separation, and isolation steps in the usual workflows. NADESs are used as stationary phases or eluent in several chromatographic procedures assisting the separation of target compounds from natural products. Tang et al., 2015 used NADES-based stationary phase sorbents. Functionalized spheres were packed in a 250 × 4.6 mm column creating a high-performance size-exclusion chromatography (HP-SEC) system for the separation of metabolites with different shapes and sizes by using water as a mobile phase to separate three polysaccharides alginic acid, fucoidan, and laminarin . A refraanalytes .v/v), quercetin and daidzein by hexane/ethyl acetate/MeOH/H2O , and kaempferol was isolated by hexane/ethyl acetate/MeOH/H2O . They obtained a recovery of 95.7, 94.6, 97.0, and 96.7% for rutin, quercetin, kaempferol, and daidzein respectively [v/v) of water ruptures the NADES structure, a simple dilution allowed an anthocyanin recovery of 99.46%, and a highly efficient solvent recycling (yield 96.8%) when authors diluted the grape-pomace extract in 80% of water. The cleanness of the NADES after recycling was proved using NMR spectrometry and no significant differences between freshly synthesized and recycled NADES in 1H NMR spectra were observed. These results implicate that NADES structures should be disturbed prior to recycling via dilution with >50% amount of water (v/v) to release anthocyanins and make them available for better adsorption on macroporous resins [Despite the interesting approaches of NADES in analytics, the interference of extractants constituents in testing samples causes a complex pattern of signals reducing the performances of the characterization and deconvolution of the data files. A treatment of the extract by NADES removal, aimed to improve the quality of signals and analysis, could be necessary. In view of green methodology for the extraction of target compounds, NADES can be recycled. Normally, distillation is the current method used for the recycling of organic solvents for the easy recovery of target compounds. The evaporation of NADES extractants is a difficult task because of low vapor pressure and peculiar physiochemical properties causing a problem for industrial applications ,55. The ectively . Anotherectively . Instancectively . On the ectively . Similarectively . Panìc es resins .Momordica charantia) monitored by TPC, TFC, DPPH, and FRAP assays. The tests showed a higher amount of phenolics in agreement with the optimal antioxidant activity for the extracts obtained in the conditions reported in Cytinus hypocistis extracted by three different choline chloride, proline, and xylitol-based NADES systems compared with conventional solvents, as detailed in Annona muricata L.) was investigated by Castro Leal et al., 2022. HPLC-DAD monitoring of the main antioxidants rutin and catechin showed the extraction capacity of all the selected NADES systems revealing those composed of glycerol and xylitol as hydrogen bond donors presented the higher extraction indexes [Sustainable and highly efficient extraction of bioactive natural compounds from natural sources is considered an important task for the development of nutraceuticals and food supplements. The biodegradability, low toxicity, and adjustable solvent properties of NADES along with their extraordinary solubilizing power for natural products of diverse polarity, accent the interest in their use for the extraction of bioactive compounds from natural sources. Coumaric acid derivatives, flavonoids, anthocyanins, and resveratrol are only a few metabolites ranked in the several classes of phenolics contained in functional foods exerting antioxidant properties. Several studies reported a higher efficiency for the extraction of phenolics from different matrices as reported in  indexes . Chen et indexes . Bajkacz indexes .w:w) [Angelica sinensis radix. It was found that choline chloride and citric acid were the optimized combination for the extraction of essential oil. The higher composition of the essential oils extracted by the ChCl/citric acid system was analyzed by gas chromatography-mass spectrometry (GC-MS), highlighting the occurrence of ligustilide as the main component of Angelica sinensis essential oil [The versatile polarity modulation of NADES systems allows the recovery of a bioactive molecule with non-polar behavior from natural matrices. Several lipid-soluble compounds such as curcumin and lycopene are considered for industrial importance for both their coloring attributes but also for their bioactive properties such as antioxidant, anticancer, and immunomodulatory . Alioui w:w) . Essentiw:w) . Fun andtial oil .foods-1The awareness for the optimization of natural resources and the environmentally sound management of chemicals and all wastes throughout their life cycle is growing . A big aThe olive oil industry produces large biomass of not-edible products, olive pomace is at least 60–65% of the total weight of olives. As well as the whole olive, pomace is considered a source of phenolic bioactive compounds. The NADES selective extraction of phenolics from this complex matrix was performed by Chanioti et Tzia 2018 . The NADThe recovery of anthocyanins by using NADES from grape pomace was studied by Panić et al., 2019. A comparative study of several NADES for the optimization of composition, physiochemical characteristics, anthocyanins extraction power, and solvent price was investigated and performed on a larger scale-up extraction process with NADES recycling. The highest content of all the anthocyanins, evaluated by the sum of all HPLC signals, was attributed to the ChCl/citric acid and ChCl/proline/malic acid systems by using an ultrasound microwave-assisted extraction technique . In the 3O4) was functionalized with a choline chloride/urea NADES system used as a new sorbent in the in-syringe dispersive μSPE method. A comparative GC-MS study between 3DGA-Fe3O4 and the modified 3DGA-Fe3O4/NADES obtained samples showed that functionalization with natural NADES resulted in higher extraction efficiencies (1.4–1.7 fold) [While natural phenolic compounds are involved in plant biological processes such as growth, reproduction, and defense mechanisms, synthetic phenolic compounds  are precursors of nylon, and detergents used to produce polyphenoxy polymers, fertilizers, paints, or explosives. The World Health Organization, WHO, lists some of these phenolic compounds as priority pollutants due to their toxicity, so it is necessary to remove them, to a concentration below the legal limit before wastewater discharge . G. Sas .7 fold) . As disc.7 fold) . Seresht.7 fold) .In addition to organic pollutants, the presence of metals in foods is currently an environmental and health problem. Cadmium (Cd) is a common and toxic ecological pollutant, which originates from swift industrial operations, the overuse of fertilizers, composts and sewage sediments, and municipal activities ,100. In The determination of mycotoxins also interferes with the food safety guarantee. Zearalenone is one of the most common mycotoxins produced by Fusarium fungi . PochivaThe selective extraction of allergens from food is required to ensure the health care of consumers with alimentary allergies and intolerances. Gluten is the main allergen commonly diffused in everyday products based on flavors of cereals such as grains such as wheat, rye, barley, and oats. In food processing, the removal of the protein occurring in the endosperm of cereals is obtained by extraction with an ethanol–water solution. The current approach could produce oxidated forms and structure degradation of the protein causing the incomplete extraction of modified peptides from the food. Lores et al. 2017 performed an ultrasound-assisted extraction in combination with the use of fructose/citric acid NADES . After tThe selection of the optimum extraction solvent is a crucial step to achieving a good extraction efficiency of target analytes, and at the same time minimizing the interfering compounds, reducing the environmental impact. The growing awareness to decrease pollution and energy dispersion suggests the replacement of organic solvents with alternative systems characterized by lower environmental impact and human toxicity. In this view, the green solvents NADES has been increasingly used as sustainable solvents in several applications of food analysis in both the research community and the food industry. The current review collects several studies about the physicochemical properties of NADES, their preparation methods, evaluation of toxicity, and their use in combination with green extraction techniques for providing a green chemistry approach to several aspects of food analysis. In addition, this review also provides an update on a series of new applications of NADES in the extraction of bioactive compounds from foods and their by-products and in the determination of contaminants in foods. However, a deeper understanding about the safety of NADES systems on human health and their chemical stability is also another aspect that deserves to be further researched.


In the context of all-digital radar systems, phase-modulated continuous wave (PMCW) based on pseudorandom binary sequences (PRBSs) appears to be a prominent candidate modulation scheme for applications such as autonomous driving. Among the reasons for its candidacy are its simplified transmitter architecture and lower linearity requirements , as well as its high velocity unambiguity and multiple-input multiple-output operation capability, all of which are characteristic of digital radars. For appropriate operation of a PMCW radar, choosing a PRBS whose periodic autocorrelation function (PACF) has low sidelobes and high robustness to Doppler shifts is paramount. In this sense, this article performs an analysis of Doppler shift tolerance of the PACFs of typically adopted PRBSs in PMCW radar systems supported by simulation and measurement results. To accurately measure the Doppler-shift-induced degradation of PACFs, peak power loss ratio (PPLR), peak sidelobe level ratio (PSLR), and integrated-sidelobe level ratio (ISLR) were used as metrics. Furthermore, to account for effects on targets whose ranges are not multiples of the range resolution, oversampled PACFs are analyzed. Also known as code-modulated, spread spectrum or pseudonoise (PN) radars, phase-modulated continuous-wave (PMCW) radars ,2,3 are Although inherently high data rates to digital radar systems based on modulation schemes such as orthogonal frequency-division multiplexing (OFDM) ,10 and oRegardless of whether single-input single-output (SISO) or MIMO operation is aimed, the adopted PRBS by a PMCW radar system should ideally yield an autocorrelation function with low sidelobes and negligible main lobe power degradation under influence of Doppler shifts, so that both erroneous interpretation of sidelobes as targets and signal-to-noise ratio (SNR) loss are avoided. Recent studies in the literature include, e.g., investigation of the sidelobe degradation of the autocorrelation functions of some of the typically used PRBSs in PMCW radars  as well An overview of typically adopted PRBSs in PMCW radar systems, namely m-sequences, Gold sequences, Kasami sequences, almost perfect autocorrelation sequences (APASs), zero correlation zone (ZCZ) sequences, and Golay sequences, and their implications on range and velocity ambiguities for different PRBS lengths. For the aforementioned analyses, an automotive  device, which is capable of transmitting PMCW signals and receiving echoes off targets. The aforementioned signals consist of a carrier signal modulated by a stream of identical PRBSs, having therefore a so-called constant envelope. In this SISO-PMCW radar system, a carrier frequency The processing chain of the considered SISO-PMCW radar system in this study is represented in H targets toward the SISO-PMCW radar system. Next, the receiver antenna with gain The transmit signal After amplification by a low-noise amplifier, n corresponds to the convolution of n in Rss,nB, the maximum range is jointly limited by the usable length In order for targets ’reflections to be appropriately distinguished from one another and from noise in the range profile  ones in ,24. ThosFurther constraints on the quality of the range profile h of the radar targets has been omitted for the sake of simplicity. Based on previous studies in the literature, it is expected that the effectively compressed PRBS The pulse compression in this equation can be interpreted as resulting from the periodic cross-correlation function (PCCF) of the pseudorandom sequence essed as (7)RsDs,shift fD . In thisBased on the carried-out discussion in the previous section, it can be concluded that the quality of the range profile equences , it doesin ι∈N≥0 . In thisParameters that can be used to compare the oversampled PACFs of different sequences under Doppler shifts are the PSLR and ISLR , which a PPLR as (10)PPLRThe mainlobe power reduction measured by the PPLR can be interpreted as an SNR loss or a reduction of the processing gain of ussed in .Based on the aforementioned parameters, an analysis of the degradation of main lobe and sidelobe levels of the PACF of typical PRBSs for PMCW radar caused by Doppler shifts can be performed to facilitate the choice of an appropriate PRBS that yields in tolerable distortion of obtained range profile. In this article, such an analysis is presented in In this section, a comparative analysis of the PACFs of typically used PRBSs in PMCW radar systems is performed based on the introduced performance metrics in The investigated PRBSs in this article are m-sequences, Gold sequences, Kasami sequences, binary APASs, binary ZCZ sequences, and binary Golay sequences. Those are the most typically used PRBSs in PMCW radar systems, and their most relevant characteristics for the analysis in this article are discussed as follows.Also known as maximum-length sequence (MLSs), PN sequences, or pseudorandom sequences, m-sequences  are a tyGold sequences ,28 and K systems . This, hBinary APASs are PRBSs whose non-oversmapled PACFs are nearly ideal in the absence of Doppler shifts. In this article, APASs based on p-ary m-sequences  are consme power ,32.Similarly to APASs, binary ZCZ sequences are PRBSs whose non-oversampled PACFs are only ideal within a limited interval of samples in the absence of Doppler shifts, which defines its usable length thm from , which pe length , the latBinary Golay sequences are defined in complementary pairs , whose sGiven the investigated PRBSs, Defining a frequency resolution as fD/Δf . Besides systems ,35, and To illustrate the effect of Doppler shifts on the PACFs of the considered PRBSs, To accurately quantify the Doppler shift-induced degradation of the oversampled PACFs for different The attained PPLR results are shown in The achieved results show a negligible PPLR of only As for the sum of the PACFs of the complementary sequences Golay A and B, much more relevant PPLR degradation is observed, with worse values than us study .Next, the simulated PSLR results for all PRBSs from Overall, very similar PSLR performance is achieved by most of the considered PRBSs, which also present relatively stable PSLR values over the considered Focusing on Unlike in the PPLR and PSLR results, where nearly all PRBSs perform equally and only small differences are observed, more relevant changes in the ISLR are observed due to the fact that it considers the whole range of sidelobes associated with The simulated and mean measured ISLR results are shown in Finally, it is worth highlighting that, although the PSLR and ISLR enable an objective comparison among the considered PRBSs, which is the aim of this article, they must be analyzed with care when assessing the overall quality of obtained range profiles. Among the reasons for this are (i) the fact that the nearest sidelobe to the mainlobe dominates the PSLR performance for most considered PRBSs and sequence lengths This article presented an analysis of Doppler shift tolerance of the oversampled PACFs of typically adoped PRBSs in PMCW radars, namely m-sequences, Gold sequences, Kasami sequences, APASs, ZCZ sequences, and Golay sequences. After a mathematical formulation of the problem of range estimation via correlation in PMCW radar systems under Doppler shifts, the need for evaluating oversampled PACFs to capture effects on targets that are not at distances that are exact multiples of the range resolution was discussed. Next, PSLR, ISLR, and PPLR parameters were adopted for measuring the Doppler shift-induced degradation of oversampled PACFs of the aforementioned PRBSs and consequently ultimately generated range profiles. Finally, a numerical analysis supported by simulation and measurement results was carried out.The achieved results showed that, to avoid unwanted high sidelobes, only a short section of the output range profiles from the correlation operation is used in PMCW radar systems based on ZCZ sequences, Golay A and B sequences  without sum of their oversampled PACFs, and APASs. Consequently, these PRBSs yield the lowest maximum unambiguous range values compared with the remaining PRBSs of same length. Furthermore, if the oversampled PACFs of complementary Golay sequences are to be summed, then a multiplexing strategy has to be adopted. In this article, TDM was the chosen approach to keep the baseband PMCW signal binary, which leads to a higher transmission time for the samples associated with a single range profile and consequently lower tolerable relative radial velocities.As for the Doppler shift-induced degradation of oversampled PACFs, it was shown that all sequences yield the same PPLR results. The only exception is the sum of the oversampled PACFs of the complementary sequences Golay A and B, which is severely degraded for certain Doppler shift values due to non-coherent sum or accumulation of the complementary sequences. In terms of PSLR, most sequences present negligible degradation. An exception is the combination of the complementary sequences Golay A and B due to the main lobe degradation observed in the PPLR analysis. Furthermore, ZCZ sequences, Golay A and B sequences used as individual sequences, and Kasami sequences of low PRBS length also present PSLR degradation, which was of less than