Physical activity interventions could potentially increase mental and physical self-perception of quality of life during pregnancy.Self-perception of health status  is considered one of the best indicators of health and well-being. However, during pregnancy, it could be impacted not only by physiological and anatomical changes, but by poor lifestyle habits like high sedentary behaviour or bad nutrition. This study assesses the effects of physical activity RCT interventions during pregnancy on both mental and physical components of quality of life. A systematic review and two meta-analyses were performed (PROSPERO registration number: CRD42022370467). Of the 207 articles captured both in English and Spanish, seven articles were deemed eligible for inclusion. The two analyses performed found that physically active pregnant women had better scores of mental self-perception of quality of life (z = 2.08,  Pregnancy, arguably one of the most important periods in human life, could be associated with a plethora of physiological and anatomical changes that also could severely alter one’s self-perception and, subsequently, mental health. Reports indicate an upward trajectory in emotional pathologies, with a prevalence of prenatal depression, anxiety, or stress ,2 being QoL not only depends on the time course of pregnancy but can be detrimentally affected by factors such as nausea, sleep difficulties, environment factors  , financiGiven the relationship between mental health status and QoL, strategies to effectively attenuate these pathologies during pregnancy should beneficially impact QoL. In this context, as physical activity continues to be integrated into the daily routines of diverse populations, including pregnant individuals, acquiring substantiated evidence regarding the ramifications of prenatal physical activity on women’s quality of life stands as a matter of significant scientific intrigue. However, exploration into this realm remains limited in the current literature. A comprehensive examination of the impact of physical activity during pregnancy reveals consistently favorable outcomes, a notion corroborated by recent investigations . It has This systematic review was performed under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) and registered in the International Prospective Register of Systematic reviews (PROSPERO) with the following registration number: CRD42022370467.Pregnant women without obstetrical contraindication to exercise  participating in a physical activity intervention during pregnancy were the target population ,20.Any type of measurable physical activity intervention during pregnancy  which included more than one study group to compare intervention results was eligible. Where applicable/available, studies with co-intervention  were retrieved for descriptive purposes, but not analyzed. Pregnant women who were not engaged in a physical activity intervention  were compared with intervention group women.Eligible study outcomes were physical and mental self-perception of health status. Although there is no scientific consensus on the use of a specific questionnaire to assess the quality of life of pregnant women, we decided to analyze the most commonly used validated tools, which are: Short Form 8 (SF-8), Short Form 12 (SF-12), and Short Form 36 (SF-36) Health Surveys and the World Health Organization Quality of Life questionnaire in its brief version (WHOQOL-BREF), each with 0–100 as a minimum and maximum score. To perform this systematic review, only studies with a randomized control trial design, involving a quantifiable physical activity intervention and with previously described outcomes of interest included, were eligible. English: Health status perception or quality of life or health status AND pregnancy or pregnant or prenatal or antenatal or perinatal or maternal AND exercise or physical activity or fitness or sport aerobic training or strength training or cardiovascular training AND randomized controlled trials or rct or randomised control trials or randomized AND intervention.Spanish: Percepción del estado de salud o calidad de vida o estado de salud Y embarazo o embarazada o prenatal o antenatal o perinatal o materno Y ejercicio o actividad física o fitness o deporte o entrenamiento aeróbico o entrenamiento de fuerza o entrenamiento cardiovascular Y ensayo clínico aleatorizado o eca o ensayo controlado aleatorizado o aleatorizado Y intervención.A comprehensive literature search was performed using the following databases: EBSCO , ClinicalTrials.gov, Web of Science, Scopus, the Cochrane Database of Systematic Reviews, and the Physiotherapy Evidence Database (PEDro). Articles published between 2010 and 2022 written in English and Spanish were retrieved. The search began in October 2022 and ended in November 2022. Search terms were: Initially, titles and abstracts were screened by two reviewers and full articles were retrieved if they were deemed to meet the criteria. Full-text articles were reviewed, and if the article did not meet the inclusion criteria, it was reviewed by others to ensure exclusion was warranted. Data were independently extracted from articles meeting our inclusion criteria by one researcher and later reviewed by two different researchers. In cases where the mean or standard deviation of the target outcomes was not reported or data were not available for extraction, the authors were contacted; if no answer was received, the articles were discarded. Cochrane Handbook [The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework using its GRADEpro Guideline Development Tool was used to assess the quality of evidence ,22. RiskHandbook . SelecteReview Manager (RevMan version 5.4) software was used to perform two different meta-analyses related to self-perception of health status (i) focusing on the physical component or dimension and (ii) examining the mental or psychological dimension. As we included different QoL questionnaires, the overall confidence intervals (CIs) and standardized mean differences (SMDs) were calculated for these analyses using a random effects model. Effect sizes were calculated taking into account Hedges’ G, which was small (0.2), moderate (0.4), or large (0.8). Alpha error was set as 95%. 2 statistic was used to determine the presence of heterogeneity in each analysis, assessing the percentage of total variability attributable to study heterogeneity. Heterogeneity was considered low when I2 = 25%; moderate when I2 = 50%; and high when I2 = 75%. Since high heterogeneity was perceived in one meta-analysis, due to the limited number of eligible articles, subgroup analyses were not performed. For the meta-analyses, a relative weight, depending on the study group sample size, was assigned to each eligible article. IThe PRISMA diagram below  illustraThe included articles had physical activity intervention programs that lasted between 6 and 20 weeks, with weekly frequencies between one and five sessions comprising exercises of light and moderate intensity of 15 to 60 min of duration per session, including aerobic, strengthening, pelvic floor, stretching, and relaxation exercises. Six of seven interventions were supervised. The analyzed studies are described in p = 0.03) in the physical component scores of the QoL questionnaires was shown for participants randomized to a physical activity intervention during pregnancy compared with the control , as described in Seven articles included compatible questionnaire scores assessing the physical component/dimension of quality of life ,28,29,30p = 0.04) in women who performed a physical activity intervention during pregnancy compared with the control group, as represented in 2 = 76%, Pheterogeneity = 0.000).Overall, seven articles examined the mental component of QoL scores ,28,29,30All the articles selected were randomized clinical trials. Due to the importance of the outcomes retrieved, the quality-of-evidence assessment resulted in high certainty and critical importance. The risk of bias varied between low, uncertain, and high in five different sources of bias , with more than 50%  having a low risk of bias among the sources, as is shown in The aim of this systematic review and meta-analysis was to assess the effects of physical activity interventions during pregnancy on both the mental and physical components of self-perceived QoL; finally, seven articles (with four different questionnaires) were analyzed.Our findings from the seven eligible RCTs suggest that there is “high”-quality evidence from physical activity interventions, indicating that prenatal PA could help pregnant women to improve their quality of life during their pregnancies with significantly better results in intervention group women than in control group participants. Specifically, our data showed improvements in both the physical and mental components of QoL. Although not assessing QoL per se, our results are consistent with previously published articles showing the mental health benefits of PA programs during pregnancy ,18. ThesPrenatal PA is known to benefit health by reducing the odds of having macrosomia without increasing the odds of having a small newborn , while aInterestingly, only one article  in the mHeterogeneity was high in the physical component of QoL when high levels in the mental component meta-analysis were not reported. Although the mean age of the participants across the studies was nearly 30 years, there was one article  that hadOur findings are aligned with other published systematic reviews, specifically a paper published by Lagadec et al. , whose aConsidering the significance of maternal quality of life during pregnancy in enhancing the health of both the expectant mother and her future offspring, the outcomes of the current investigation substantiate the guidelines set forth by international bodies, advocating for a minimum of 150 min of moderate physical activity per week throughout pregnancy for women devoid of obstetric contraindications . From anFurthermore, the absence of moderate physical activity during pregnancy warrants recognition as a notable risk factor for significant complications and pathologies, resulting in a notable decline in the woman’s quality of life. This assertion finds validation in an extensive corpus of contemporary scientific literature and should be embraced by healthcare practitioners entrusted with the holistic care of pregnant women, as well as the pregnant population.2 of 76%. If we had been able to perform various subgroup analyses, then heterogeneity might have been attenuated, but the shortage of articles and the difficulty to assess a common factor included in all the articles to split them into subgroups made this option impossible. Additionally, QoL was assessed using various tools, necessitating the inclusion of all types in one analysis, thereby limiting our ability to perform subgroup analyses by tool. The risk of bias was generally low, except in some sources of bias that were had an unclear or high risk of bias. However, the quality of evidence and certainty of outcomes were categorized as high. Positively, seven articles were assessed representing six different countries and also five publications reported compliance to intervention above 62.5%. More physical activity intervention trials during pregnancy involving different self-perception of health status tools and retrieving other previous medical problems that could influence QoL are needed for a more comprehensive overview that could address the impact of exercise type, intensity, frequency, and duration.One limitation in this study was the scarcity of articles published using PA as an intervention to improve quality of life during pregnancy. Also, the mental/psychological component of self-perception of health status analysis showed high heterogeneity, with an IPhysical activity interventions supervised by a professional could have an important effect on improving both mental and physical self-perceived health status of pregnant women without contraindications.


Multiple lines of evidence showed the complex regulation of PEPCKs, including PTMs. Herein, we present PEPCKs as an example of the integration of combined mechanisms modulating enzyme activity and metabolic pathways. PEPCK studies strongly advanced after the production of the recombinant enzyme and the establishment of standardized biochemical assays. Finally, we discuss emerging open questions for future research and the challenges in integrating all available data into functional biochemical models.Abstract. Data on protein post-translational modifications (PTMs) increased exponentially in the last years due to the refinement of mass spectrometry techniques and the development of databases to store and share datasets. Nevertheless, these data per se do not create comprehensive biochemical knowledge. Complementary studies on protein biochemistry are necessary to fully understand the function of these PTMs at the molecular level and beyond, for example, designing rational metabolic engineering strategies to improve crops. Phospho enol pyruvate carboxykinases (PEPCKs) have diverse roles in plant physiology, including C4 and crassulacean acid metabolism (CAM) photosynthesis, carbon fixation in algae, gluconeogenesis during seed germination and fruit maturation, stress response, and amino and organic acids metabolisms. PEPCKs exemplify the complex regulation of metabolic enzymes, encompassing allosteric effectors (metabolites and dipeptides), proteolysis, and phosphorylation, which are explained in detail in this review. Further research is needed to deepen our understanding of this intricate regulation and advance metabolic engineering and synthetic biology in plants.Plant biochemistry studies enzymes and metabolic pathways regulation in plants, crucial for devising effective crop improvement strategies. The advent of advanced mass spectrometry techniques, protocols, and specialized databases has facilitated access to valuable post-translational modification data on plant proteins. Phospho This reaction is the initial step of the Calvin–Benson–Bassham cycle (CBBc), a chloroplast carbon cycle that sustains all life on earth  photosynthesis evolved from C3 ancestors to mitigate the detrimental effects of photorespiration and water loss by transpiration, respectively  and bundle sheath cells (BSC), as well as CO2-concentrating mechanisms. The latter include the initial fixation of CO2 by phosphoenolpyruvate carboxylase (PEPC) in mesophyll cells, transport of C4 acids to BSC and decarboxylation near RuBisCO, enabling efficient carbon fixation via the CBBc. Based on the primary decarboxylase employed in the process, plant lineages were classified as NAD-dependent malic enzyme , NADP-dependent malic enzyme  and PEPCK subtypes , PEPC and Mal dehydrogenase, and the product Mal is then stored in the vacuole. During the day, the hydroxy acid undergoes decarboxylation by NAD(P)-ME or PEPCK, releasing CO2 near RuBisCO to feed the CBBc (4 plants) present in CAM plants, at similar levels  and PEPCK2 (At5g65690). The PEPCK1 gene is predominantly expressed during seed germination, while PEPCK2 expression is less abundant and restricted to specific plant tissues  or fruit-specific promoters  cycle is crucial to prevent their accumulation in specific metabolic situations. These enzymatic steps, known as cataplerotic reactions, are critical to cellular homeostasis  Fig. 2DFig. 2D.  sativum  or the u4+ and Gln), suggesting a potential role in their metabolism and the regulation of cytosolic pH through Mal formation and dissimilation  were reduced, while Asp (produced from OAA) increased compared to WT plants , those derived from PEP , and Ala derived from Pyr . In grapin vitro. The enzymes from Urochloa panicoides, Chloris gayana and Panicum maximum (C4 plants) are inhibited by the glycolytic intermediates 3PGA, Fru6P, Fru1,6bisP and DHAP under certain conditions (4 photosynthesis) PEPCK, sensitivity to 3PGA inhibition is only evident in the enzyme’s N-terminal proteolyzed form (Ananas comosus (a CAM species) revealed differential regulation between its carboxylase and decarboxylase activities , which allow for maximal activity. However, the concentration of this metal in plant cells remains within the micromolar range , there are differences in the regulation of AthPEPCK1 and AthPEPCK2  proved to be a valuable tool for mining novel small molecule regulators  simple mutants as well as [atg4(4a/4b) and nbr1-2/atg5] double mutants exhibited reduced dipeptides levels upon heat stress when compared to the WT , cannot be avoided by protease inhibitors and does not alter the quaternary structure of the enzyme (AthPEPCK1 is a target of the cysteine-protease METACASPASE9 (AthMC9)  generated protein forms with similar kinetic parameters and quaternary structure compared to the WT enzyme. However, the activation by Mal and inhibition by Glc6P were abolished in the Δ101 mutant  Does PEPCK have an important role in non-PEPCK C4 and CAM plants, in particular, under stress situations? More research is needed to answer these questions but results will likely come from a combination of in vitro and in vivo biochemical approaches. The pioneer studies of Richard Leegood and Robert P. Walker with the enzyme purified from plant sources were key to studying the biochemical properties of plant PEPCKs  How do different PTMs regulate enzyme activity, and how do they integrate with allosteric regulation? (ii) What are the biological outcomes of the different PTMs?; (iii) What are the modifying enzymes and signalling cascades acting on PEPCKs? (iv) Are dipeptides physiologically important modulators of PEPCK t PEPCKs , 2002. Nin vivo, followed by the analysis of the resulting plants’ phenotypic and metabolic effects. The PEPCK example is similar to what happens with other highly regulated enzymes . The current challenge is integrating data from multiple regulations on enzyme activity, generated in vitro and in vivo, to develop general models and reduce the existing gap between both approaches (for some good examples, we suggest reading the work of In the era of Big Data in biology, vast amounts of transcriptomic, metabolomics and proteomic data are added each day to public databases. Some examples of useful tools are BRENDA (


Traumatic brain injury (TBI) is a leading cause of mortality, sensorimotor morbidity, and neurocognitive disability. Neuroinflammation is one of the key drivers causing secondary brain injury after TBI. Therefore, attenuation of the inflammatory response is a potential therapeutic goal. This review summarizes the most important neuroinflammatory pathophysiology resulting from TBI and the clinical trials performed to attenuate neuroinflammation. Studies show that non-selective attenuation of the inflammatory response, in the early phase after TBI, might be detrimental and that there is a gap in the literature regarding pharmacological trials targeting specific pathways. The complement system and its crosstalk with the coagulation system play an important role in the pathophysiology of secondary brain injury after TBI. Therefore, regaining control over the complement cascades by inhibiting overshooting activation might constitute useful therapy. Activation of the complement cascade is an early component of neuroinflammation, making it a potential target to mitigate neuroinflammation in TBI. Therefore, we have described pathophysiological aspects of complement inhibition and summarized animal studies targeting the complement system in TBI. We also present the first clinical trial aimed at inhibition of complement activation in the early days after brain injury to reduce the risk of morbidity and mortality following severe TBI.The online version contains supplementary material available at 10.1007/s13311-022-01306-8. Traumatic brain injury (TBI) presents a great challenge to public health worldwide. TBI is responsible for over a third of all traumatic deaths, and each year, 80–90.000 new cases of long-term disability due to TBI occur in the USA . The dynTBI-induced neuroinflammation has been hypothesized to contribute very substantially to the pathological progression of brain injury, in addition to the primary injury itself , 6. It iAfter the (sub)acute phase of injury, a prolonged state of chronic inflammation may linger for years after TBI and predispose patients to develop other neurodegenerative disorders, such as dementia , 9. ProbEarly attenuation of neuroinflammation is therefore considered an important target for TBI treatment, especially in the early in-hospital phase. Despite the vast amount of research performed to improve our understanding of the pathophysiology in TBI, the field has repeatedly experienced collective failures to translate research from animals to successful therapeutic application in humans , 12. ThiThe primary effects of moderate and severe TBI include diffuse injuries such as diffuse axonal injury (DAI) and focal brain damage, such as epidural and subdural hematomas (ASDH) and intracerebral hematomas/contusions (tICH). In the first hours after head trauma, expansion of hematomas is the main threat, whereas during the following days, the pathophysiological consequences of neuroinflammation may subsequently increase ICP . Interna2+ levels lead to mitochondrial damage, lipid peroxidation, production of free radicals, and activation of caspases and other proteases involved in membrane and nucleosomal DNA changes. This results in synapse elimination and neuronal apoptosis [Cerebral ischemia and direct traumatic apoptosis after TBI lead to disruption of cerebral energy metabolism due to depletion of cellular adenosine triphosphate (ATP) stores. In this state, cells produce energy via the less efficient pathway of anaerobic glycolysis. Cell metabolic impairment is followed by membrane depolarization and release of excitatory glutamate . Excess poptosis , 18.Cell injury in the brain results in the release of intracellular components such as ATP, other damage-associated molecular patterns (DAMPs), and complement components which activate pattern recognition receptors (PRRs) on glial cells. As such, injury of brain cells initiates and perpetuates a post-traumatic neuroinflammatory response , 20.Microglia are brain cells acting as support cells for neurons and other metabolic and immunological processes and play a critical role in neuroinflammation as the first line of defense. Microglial cell activation is prominent at the perilesional area and in ipsilateral and contralateral regions of the contusion area . In the Important factors in the promotion of neuroinflammation are proinflammatory cytokines. Well known is IL-1β, involved in oligodendrocyte damage and early microglia activation. Levels of IL-1β correlate with Glasgow Coma Scale (GCS) scores, ICP, and outcome , 28. ProBesides their role in neuroinflammation, proinflammatory cytokines may also challenge the integrity of the BBB vasculature. This could lead to vasogenic brain edema and penetration of serum proteins into brain interstitium, such as complement components and fibrin which can further activate glial cells . The BBBLeukocyte recruitment into the CNS is mediated by upregulation of endothelial and leukocyte adhesion molecules and activated complement fragments, as discussed later on . NeutropThe complement system functions to eliminate foreign pathogens and substances and remove debris and apoptotic cells . ComplemComplement has a key contribution to pathophysiological events that sequester the initial impact of injury and may radiate damage from the contusion core to the penumbra after TBI. For instance, glial synthesis of complement C3 and clusterin, a regulator of complement, was found in the vicinity of experimental brain contusion . FurtherHigh-quality preclinical evidence suggests that inhibition of various complement factors can improve neurological performance and reduce inflammation Table . For exaFacilitation of phagocytosis is another important contribution of complement activation to secondary damage in TBI. Cerebral biosynthesis of most complement proteins is induced in response to trauma and adds to the pool of complement proteins which penetrate the compromised BBB . IntraceActivated microglial cells induce a proinflammatory phenotype to astrocytes via secretion of C1q, IL-1α, and TNFα, contributing to the rapid death or functional disability of neurons and oligodendrocytes . ProinflIn addition to the complement components which are synthesized by neurons and glial cells within the CNS , 53, theIn TBI, hemostasis is often derailed, either leading to a hypo-coagulopathic state on one end of the spectrum, causing cerebral bleeding disorders leading to progression of contusions into growing t-ICHs and ASDHs, and to a hyper-coagulopathic state that contributes to ischemic lesions due to (micro)vascular thrombosis in lesioned areas . The intIn TBI patients, high levels of C4, C3, and MAC have been found in serum , 71–76, The complement system is further triggered by secondary insults . ExpressStudies on the dysregulated inflammatory response are important to serve as a roadmap for future clinical trials aiming at “targeted” pharmacological neuroprotection and improved neurological recovery after TBI. Although all of the described interventions within trials up to now Table  have shoLast and most importantly, most trials did not focus on a targeted dysregulated part of neuroinflammation after the first TBI impact. The steroid trials, as described in Table Currently, no clinical trials are present in literature aiming to inhibition complement activation in brain injury. Only a few drugs, C1-esterase inhibitors (C1-INH), Cinryze, Berinert and Ruconest, and C5-inhibitors, eculizumab and ravulizumab, are approved complement inhibitory drugs, but many others are in clinical development. The indications for the current approved drugs are hereditary angioedema (C1-INH) and paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and neuromyelitis optica (C5). A trial with C5-antibodies in patients with aneurysmal subarachnoid hemorrhage (SAH) is now recruiting participants . As it hNeuroinflammation is one of the “nonsurgical” key drivers causing secondary brain injury after TBI. Attenuation of the inflammatory response is a potential therapeutic target. This review covers the most important neuroinflammatory drivers resulting from TBI and summarizes the clinical work performed to date directed to attenuate neuroinflammation. The complement system play an important role in the pathophysiology of TBI, and therefore therapies targeting this pathway might contribute to future targeted therapy, currently evaluated in a clinical trial.Supplementary file1 (PDF 114 kb)Supplementary file2 (PDF 508 kb)Supplementary file3 (PDF 119 kb)Supplementary file4 (PDF 123 kb)Supplementary file5 (PDF 3188 kb)Supplementary file6 (PDF 2260 kb)Supplementary file7 (PDF 119 kb)Supplementary file8 (PDF 435 kb)Below is the link to the electronic supplementary material.


Diabetic kidney disease (DKD) is one of the most common and severe microvascular complications of diabetes mellitus (DM), and has become the leading cause of end-stage renal disease (ESRD) worldwide. Although the exact pathogenic mechanism of DKD is still unclear, programmed cell death has been demonstrated to participate in the occurrence and development of diabetic kidney injury, including ferroptosis. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has been identified to play a vital role in the development and therapeutic responses of a variety of kidney diseases, such as acute kidney injury (AKI), renal cell carcinoma and DKD. In the past two years, ferroptosis has been well investigated in DKD patients and animal models, but the specific mechanisms and therapeutic effects have not been fully revealed. Herein, we reviewed the regulatory mechanisms of ferroptosis, summarized the recent findings associated with the involvement of ferroptosis in DKD, and discussed the potential of ferroptosis as a promising target for DKD treatment, thereby providing a valuable reference for basic study and clinical therapy of DKD. In recent years, the number of individuals with diabetes kidney disease (DKD) is growing as the prevalence of diabetes mellitus (DM) has increasedThe concept of ferroptosis was firstly proposed by Dixon et al., who verified its existence in cancer cells induced by erastinFigure 1).Over the past decade, the understanding of ferroptotic mechanisms has made rapid progress. Beginning with the discovery of the part of cysteine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) signaling in inhibition of ferroptosis, the executioner position of lipid peroxidation in ferroptosis is now convinced. Moreover, GPX4-independent ferroptosis surveillance mechanisms have been disclosed. Herein, we will briefly illustrate the major mechanisms in the occurrence of ferroptosis (3+) binds to transferrin (TF) and is transported into cells intermediated by the membrane protein transferrin receptor 1 (TFR1). Subsequently, Fe3+ is reduced into ferrous iron (Fe2+) by six-transmembrane epithelial antigen of prostate 3 (STEAP3). Divalent metal transporter 1 (DMT1) regulates the release of Fe2+ into the labile iron pool (LIP) for further utilization, and extra Fe2+ is retained in ferritin. Ferritin is composed of ferritin light chain (FTL) and ferritin heavy chain 1 (FTH1), and it can catalyze Fe2+ conversion to Fe3+ to maintain iron homeostasis in the cytoplasm 2O2). Oxidative stress is caused by an imbalance in the rate of free radical formation and detoxification, which ultimately triggers ferroptosis via lipid peroxidation2+ induces the activation of ferric enzymes such as lipoxygenases (LOXs) and further promotes lipid peroxidation in cytomembrane, which eventually results in cell death2+. Nuclear receptor coactivator 4 (NCOA4) is the crucial regulator of ferritinophagyUnder general physiological conditions, circulating ferric iron  was also implicated in driving lipid peroxidation2) at a ratio of 1:1 through the cystine/glutamate anti transporter (system Xc-). System Xc-, a disulfide heterodimer consisting of light chain subunits (SLC7A11) and heavy chain subunits (SLC3A2), is extensively distributed in cellular membranes2 can be reduced to cysteine (Cys) for the following synthesis of GSH, which is catalyzed by glutamate cysteine ligase (GCL) and glutathione synthetase (GSS)-, thereby promoting ferroptosis progressionUnder normal conditions, cells exchange intracellular glutamate (Glu) and extracellular cystine (Cysits SLC7A and heav2) utilizing NADPH. CoQ10 eventually removes lipid peroxides through an oxidation reaction2 and deplete PUFAsUndoubtedly, GPX4 is the core regulator of ferroptosis. However, three pathways independent of GPX4 have been identified in the past few years, including ferroptosis suppressor protein 1 (FSP1)/coenzyme Q10 (CoQ10), GTP cyclohydrolase 1 (GCH1) and dihydroorotate dehydrogenase (DHODH). FSP1 can regenerate the reduced form of CoQ10  and AMP-activated protein kinase (AMPK)The effect of p53 on ferroptosis is double-sidedTable 1.Given the multiple regulators in the occurrence of ferroptosis, targeting certain pathways can induce or inhibit this process. Ferroptosis induction can be applied to eliminate cancer cells, and suppression of ferroptosis can be a potent therapy in other diseases, such as cardiovascular disease, neurodegenerative diseases and DKDPrevious studies have found that iron overload was directly associated with proteinuria and tubular damage in DKD patients and streptozotocin (STZ)-induced rat models of type 1 diabetes db/db miceNowadays, numerous studies have proven that ferroptosis occurs in RTECs in diabetic animal models and prompts kidney function deterioration. Wang et al. confirmed that ferroptosis was involved in kidney injury in STZ-induced type 1 diabetic mice and Figure 2).With deepening research on ferroptosis in various diseases, increasingly regulatory mechanisms of ferroptosis have been discoveredIn DKD, almost all pathogenesis is inseparable from the overactivation of ROS, which is the connection point between metabolism abnormalities and hemodynamic changesAlong with the decline in cellular antioxidant capacity, there are many ways to produce ROS in DKD. In consideration of the surplus iron in DKD, the Fenton reaction is an essential part of ROS generationTo sum up, ROS act as a junction in the action of DKD-induced ferroptosis. As a result, using antioxidants  was considered as a clinical therapy for DKD patients, but the trials are still at the stage of animal studiesAbundant evidence indicates that inflammation is important in the progression of DKDInflammation can be inhibited by negative regulators of ferroptosis. AA is a precursor of bioactive proinflammatory mediators. During the catalytic process, the level of cellular lipid peroxides directly affects the activity of enzymes, including cyclooxygenases (COXs) and LOXs. LOXs activation can also be blocked when the cell is in a redox state, such as the activation of GPX4Conversely, several inflammatory cytokines, such as prostaglandin E2 (PGE2), IL-1β and IL-6, have been confirmed to directly affect the onset of ferroptosisAccording to mounting evidence, the onset of ferroptosis is always accompanied by the presence of inflammation. More intriguingly, the cross-link between ferroptosis and inflammation is mutually induced and drives a local autoamplification loopMitochondria are the core organelles of cellular energy metabolism2+ overload, which ultimately induces mitochondrial dysfunction and the loss of mitochondrial membrane integrityMitochondrial homeostasis is pivotal in maintaining normal kidney functions, and the typical morphological feature of ferroptosis is mitochondrial damage. However, what causes irreversible mitochondrial damage during ferroptosis? Studies suggest that erastin and its analogs antagonize the functions of free tubulin on voltage-dependent anion channel 2/3 (VDACs) and induce the opening of VDACs. VDACs contribute to regulating the passive diffusion of anionic hydrophilic mitochondrial metabolitesA reduction in glycolytic progress was detected in erastin-induced ferroptosis, which might be caused by increased synthesis of ATP and oxidative phosphorylation (OXPHOS)-/-GPX4 kidneys+ T cell ferroptosis in a CD36-dependent mannerMoreover, fatty acid (FA) metabolism in mitochondria has a close relationship with lipid oxidation in ferroptosis. Citrate synthase (CS) and acyl-CoA synthetase family member 2 (ACSF2), which regulate FA activation and synthesis respectively, were identified to be highly correlated with erastin-induced ferroptosisIn DKD, the key regulators of ferroptosis involved in typical metabolic pathways illustrated above have been broadly explored. Therefore, in this section, we will introduce the emerging molecular mechanisms of ferroptosis regulation in DKD.Nrf2 is a transcription factor of the basic region leucine zipper familyNowadays, researchers have paid more attention to the connection between Nrf2 and ferroptosis. Activated Nrf2 was firstly found to inhibit ferroptosis by regulating the expression of NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1) and FTH1 in hepatocellular carcinomadb/db mice were associated with elevated levels of HIF-1α and HO-1, which led to iron accumulation in renal tubules by downregulation of ferritin. Inhibition of HO-1 mitigated iron accumulation, thereby preventing lipid peroxidation by reducing ROS productionHO-1 catalyzes the rate-limiting step in the catabolism of heme into biliverdin, carbon monoxide (CO) and iron. Numerous studies have demonstrated that HO-1/biliverdin/CO is involved in the progression of anti-inflammatory and antioxidant stressHMGB1 is a ubiquitously expressed nuclear protein engaged in the progression of nucleosome stabilization and DNA binding. It has been found to act as a proinflammatory cytokine in many pathologies, such as sepsis, IRI and cancerZIP14 is a divalent iron import protein that is distributed in both the proximal and distal tubules, and mainly takes up nontransferrin-bound iron from the lumenN-acetylcysteine (NAC) is a sulfhydryl compound that is an acetylated form of L-cysteine. NAC is a precursor of reduced glutathione, which exhibits direct or indirect antioxidant propertiesdb/db mice, previous studies found that AMPK activation could reduce ROS production and increase mitochondrial biogenesis and ETC activity to alleviate kidney damage in diabetic modelsAMPK, as a central regulator of energy homeostasis, has been widely investigated in diverse human diseases and is considered a promising interference target in DKD. It was observed that the expression of AMPK is downregulated in the renal tissue of high-fat diet (HFD)-induced obese ratsVezf1 gene, mmu_ circRNA_ 0000309, could upregulate GPX4 expression by competitively binding miR-188-3p, which further alleviated mitochondrial and podocyte damage by inhibiting ferroptosis. However, hsa_circ_0000309 is totally different from mmu_circ_0000309. For application to human DKD, the candidate gene needs to be discoveredFPR3, C3AR1, CD14, ITGB2, RAC2 and ITGAM are hub genes related to ferroptosis at the onset of DKDIn addition to the regulatory mechanisms described above, several new mechanisms have been revealed recently. For example, Jin et al. found that a murine Table 2).Given its contribution to the pathologic process of DKD, ferroptosis is an emerging target in treating and preventing the progression of kidney damage. In this section, we aim to describe the recent progress of experimental drugs targeting ferroptosis in diabetic animal or cell models. It can be concluded that suppressing ferroptosis has great potential for the remedy of DKD  can reduce blood glucose levels and are mainly associated with enhanced insulin sensitivityIn conclusion, it is not difficult to find that the effect of hypoglycemic drugs on hypoglycemic or renal protection is closely connected with iron metabolism, Nrf2 and lipid metabolism in addition to the classical mechanisms. Therefore, in some ways, it reflects that ferroptosis plays an important role in the progression of DKD.As a result of a decreased glomerular filtration rate, metabolic disorders and renin-angiotensin system activation, hypertension is often accompanied by DKD. Many hypotensive drugs can reduce the urinary albumin excretion rate and slow the progression of kidney diseasesEntresto, also known as LCZ696, is composed of sacubitril and valsartan and has been approved for treating heart failure in clinicIn addition to the new discoveries of clinical pills, the designation of new therapeutic strategies is indispensable. Traditional Chinese medicines have shown protective effects, whether in antioxidation or anti-inflammation, so they possess huge potential for slowing the development of DKD. Recent studies have found many traditional Chinese herb components have a beneficial effect in suppressing ferroptotic cell death in DKD.Rhizoma Curcuma, was found to improve ferroptosis-induced kidney injury in db/db mice via the ROS-GSH-GPX4 axis. In MPC5 cells cultured with high glucose, inhibition of ferroptosis alleviated high glucose-induced podocyte mitochondrial damage, and mmu_circRNA_0000309 played an important role in this processRhodiola, was proven to reshape the gut microbiotadb/db mice, it was found that salidroside could reduce blood glucose levels, which could be regulated by changing gut microbiota and regulating iron metabolism16H12O5), an isoflavone extracted from the root stem of Astragali Radix, has anti-inflammatory, immunoregulatory, antiviral and antioxidant propertiesdb/db mice and HK-2 cells cultured with high glucose, calycosin inhibited high glucose-induced ferroptosis by affecting GPX4 and NCOA4 levelslicorice. It has been shown to exert hypoglycemic and protective effects on DM and its complicationsPlatycodon grandiflorum, is a triterpenoid saponin with multiple pharmacological properties, including antitumor, antiviral, anti-inflammatory, antiaging and neuroprotective effects. It was reported that platycodin D could inhibit high glucose-induced ferroptosis in HK-2 cells by upregulating GPX4Schisandra chinensis, is used as a tonic agent in traditional Chinese medicine. It could inhibit ferroptosis and protect against kidney injury by reducing ROS production, mitigating the inflammatory response and alleviating mitochondrial damage through the adiponectin receptor 1 (AdipoR1)/AMPK/Nrf2/HO-1/GPX4 pathway in HFD/STZ-induced diabetic micedb/db mice and HK-2 cells induced by high glucose, thereby retarding the progression of DKDGermacrone, the main bioactive component of In this review, we introduced the major mechanisms of the development and progression of ferroptosis, including iron overload, decreased antioxidant capacity and lipid peroxides accumulation. Then, we discussed the advances in research on the connection between ferroptosis and DKD and emphasized the role of ferroptotic mediators in DKD. Moreover, we summarized the pharmacological progress of targeting ferroptosis in DKD in the hope of providing new therapeutic strategies for patients with DKD.To date, accumulating evidence supports the crucial role of ferroptosis in the onset and progression of DKD, and ferroptosis inhibition exerts a protective effect in DKD modelsOverall, concerning the positive impact of ferroptosis inhibition on the progression of DKD, developing new therapeutic targets is quite valuable. Meanwhile, continuing comprehensive studies on ferroptosis and DKD are indispensable to better understand the key regulatory signaling pathways and underlying potential pathogenesis. Therefore, more in-depth research is required to focus on the role of ferroptosis in the development of DKD, which is of great significance for the clinical diagnosis and treatment of DKD in the future.


Redox imbalance plays essential role in the pathogenesis of cardiovascular diseases. Chronic heart failure (CHF) and hypertension are associated with central oxidative stress, which is partly mediated by the downregulation of antioxidant enzymes in the central autonomic neurons that regulate sympathetic outflow, resulting in sympathoexcitation. Antioxidant proteins are partially regulated by the transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2). Downregulation of Nrf2 is key to disrupting central redox homeostasis and mediating sympathetic nerve activity in the setting of Chronic heart failure and hypertension. Nrf2, in turn, is regulated by various mechanisms, such as extracellular vesicle-enriched microRNAs derived from several cell types, including heart and skeletal muscle. In this review, we discuss the role of Nrf2 in regulating oxidative stress in the brain and its impact on sympathoexcitation in Chronic heart failure and hypertension. Importantly, we also discuss interorgan communication via extracellular vesicle pathways that mediate central redox imbalance through Nrf2 signaling. Cardiovascular diseases are the leading cause of morbidity and mortality worldwide, posing a huge health and economic burden . While dAlthough the entire class of cardiovascular diseases comprises different pathologies, including cardiomyopathies, vascular dysfunction, stroke, and arrhythmias, to name only a few, heart failure and hypertension are the two most common forms of cardiovascular diseases . Heart fHeart failure can be divided into heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). In HFrEF, the ejection fraction (the proportion of blood pumped from the vernicles) is usually ≤40% due to weakened or impaired contractility of the myocardium . ConversThe pathophysiology of CHF is complex and usually begins with a precipitating event such as coronary artery disease, myocardial infarction, and dilated cardiomyopathy, resulting in reduced contraction of the ventricles . ConsequHypertension is one of the most significant risk factors for CHF and other causes of death . One in Before we discuss the role of the Nrf2 in the modulation of central sympathetic nerve activity, it is also necessary to discuss the role of the renin-angiotensin system and reactive oxygen species in central sympathoexcitation in CHF and hypertension. We will therefore provide an overview of these mechanisms before discussing the role of Nrf2 in regulating central sympathoexcitation, including inter-organs communication pathway between the heart and sympathoregulatory areas in the central nervous system via cargos enriched extracellular vesicles (EVs) that modulate Nrf2 activity in the brain.The renin-angiotensin system (RAS) plays a critical role in cardiovascular homeostasis, body fluid regulation, and electrolyte balance . In CHF Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE that converts Ang II to Ang one to seven, which subsequently acts upon Mas receptors whose actions counterbalance several deleterious effects of Ang II. As such, ACE2 and Ang one to seven have been thought to be protective to the cardiovascular system .In addition to circulating Ang II, all RAS components have now been identified in the brain . The RASReactive oxygen species (ROS) are highly reactive oxygen-containing compounds produced by all aerobic cells . NormallIn mammalian cells, ROS are mainly generated from the incomplete reduction of molecular oxygen via enzymatic reactions that involve nicotine adenine dinucleotide phosphate NAD(P)H, xanthine oxidase, mitochondrial electron transport chain, uncoupling of nitric oxide synthase, and through the action of cyclooxygenases, and cytochrome P450 reductases .Reactive oxygen species in the central nervous system are best known for their association with neurodegenerative diseases and ischemic conditions, such as stroke . HoweverThe elevation of central oxidative stress along with a reduction in antioxidant proteins contribute to either sensitization or activation of certain populations of neurons via alterations in potassium and calcium channels activity . In addiUnder normal conditions, the sympathetic tone is necessary to maintain peripheral vascular resistance and arterial pressure for adequate tissue perfusion. The receptors that adjust this sympathetic tone are primarily located in the great vessels (baroreceptors), the heart, and the aortic and carotid bodies (chemoreceptors). Basic and clinical studies have demonstrated that the ability of these receptors to transmit arterial pressure, blood volume, and oxygen tension information is markedly impaired in the setting of CHF and many forms of hypertension . Early w+2 signaling, thus increasing contractility and myocardial oxygen demand. β1 adrenergic receptor inhibitors, such as propranolol, are often used clinically to reduce sympathetic heart tone in order to decrease cardiac metabolic demand. Renal sympathetic nerve activity causes afferent arteriolar constriction, resulting in decreased glomerular filtration rate, high sodium and water retention, and renin release, thus stimulating the RAS activity  play important roles in maintaining redox homeostasis in various types of cells, including neurons . Figure The transcription factor Nrf2 is a master regulator of several antioxidant enzymes in many cell types, including neurons. Current evidence suggests that oxidative stress is a potent mediator of enhanced sympathetic outflow in CHF and hypertension settings . While aIndeed, in the RVLM of animals with CHF, high norepinephrine levels are associated with reduced Nrf2 mRNA and protein expression. Interestingly, normalized Nrf2 expression in whole cell lysates of the RVLM showed a correlation with ejection fraction or cardiac function for both protein and mRNA . While tA variety of mechanisms contribute to the reduced Nrf2 levels in the RVLM in CHF and hypertension. The studies mentioned above clearly demonstrated a reduction in Nrf2 transcription. In addition, enhanced Nrf2 ubiquitination and nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB) signaling may also contribute to the reduced Nrf2 levels. Nrf2 binds to the nuclear protein CREB Binding Protein (CBP) in a similar fashion to NFKB. Because NFKB and Nrf2 are redox-sensitive transcription factors, the competition for binding to CBP may be a key regulator of oxidative stress in the central neurons involved in the regulation of sympathetic outflow. Liu et al. have shown that Nrf2 displaces NFKB from CBP through competitive interaction with a specific Creb Binding Protein (CBP) domain . ImportaThe role of Nrf2 as a mediator of sympathoexcitation in CHF and in response to ANG II has recently been demonstrated in animal models . DownregThe other side of the coin is what happens if Nrf2 is selectively overexpressed in the RVLM in a disease setting. This question has recently been addressed using two mouse models, as shown in Substantial evidence now indicates that ExT can normalize the autonomic imbalance, especially in the setting of CHF. Clinical trials have shown that ExT increases survival and reduces cardiovascular events and hospitalization in patients with CHF . VarietiInterestingly, in the RVLM, Nrf2 expression varies as a function of cardiac function, independent of the sedentary and exercise status of animals . This maAlthough it is generally accepted that the benefits of ExT in CHF rely, in part, on the upregulation of central antioxidant enzymes, it is not completely clear how the act of ExT is transduced into a change in antioxidant enzymes expression in the brain. In this regard, three possibilities have been proposed. First, the increased metabolic activity of the pre-sympathetic neurons during exercise allows these neurons to cope with oxidative stress. For instance, ROS generated during skeletal muscle contraction provides a circulating stimulus to remote tissues, including the brain stem, triggering an adaptive response to upregulate antioxidant enzymes, potentially via Nrf2. A second intriguing pathway that may be important in the setting of CHF, hypertension, and other sympathoexcitatory disorders is the modulation of the balance between the redox-sensitive transcription factors Nrf2 and NFKB. Although the interaction between these transcription factors in sympathoregulatory areas of the brain has never been explored, we speculate that in CHF and hypertension, Nrf2 and NFKB CBP-binding competition may be an important pathway. A third possibility is the notion that extracellular vesicles (EVs) shed from exercising muscles can influence remote tissues such as the brain stem, where EVs and their enzymatic and non-enzymatic cargo can regulate antioxidant pathways, potentially via the Nrf2 signaling pathway.Angiotensin-converting enzyme 2 is a carboxypeptidase expressed in the brain stem and hypothalamic brain areas and contributes to regulating blood pressure and peripheral resistance by modulating the sympathetic outflow . Because+/+) mice model. In this model, the human ACE2 gene (hACE2) is controlled by the synapsin promoter to induce human ACE2 expression in the brain  imaging after administration of isolated and labeled EVs into normal mice via intraperitoneal injection revealed their uptake by some organs. However, the brain appeared to concentrate these exosomes after 24 h. Histological examination of RVLM revealed that RVLM neurons take up these EVs, and the distribution of these EVs seemed to be concentrated in the perinuclear region within the neuronal cells. Furthermore, EVs isolated from the brain stem of CHF rats contain not only Nrf2 targeting miRNA but also other miRNAs that are thought to be cardiac specific, including miRNA-1, miRNA 208a, and miRNA-499 (Circulating EVs seem to pass through the blood-brain barrier and are taken up by RVLM neurons . In VivoiRNA-499 , suggestiRNA-499 , suggestThe role of cardiac-derived EVs in sympathoexcitation has been demonstrated via the transference of pathological phenotypes of CHF rats into normal rats. Microinjections of labeled EVs harvested from CHF rats into the RVLM of normal rats resulted in increased plasma norepinephrine, increased RSNA, and baroreflex impairment . InteresSeveral animal studies have demonstrated that Nrf2 activation is beneficial in the setting of CHF and Hypertension. Nrf2 activation in the skeletal muscle of coronary artery ligation-induced CHF mice improves exercise capacity . In addiAlthough antioxidant-based therapies seem to mitigate sympathetic overdrive in animal models of cardiovascular disease, most clinical trials that have attempted to examine the therapeutic effect of antioxidant vitamin therapy in cardiovascular disease have failed. The reason for these failed trials is not completely clear. However, it may relate to facts that these trials targeted only one oxidant species using one antioxidant, or the antioxidant vitamins may not have scavenged the specific ROS driving the pathological conditions. Because Nrf2 is an upstream transcription factor for a variety of antioxidant enzymes and given the detoxification and anti-inflammatory effects of proteins encoded by Nr2 target genes, Nrf2 activator trials in cardiovascular disease may provide promising redox-based therapy. For instance, in patients with mitochondrial myopathy, the Nrf2 activator, omaveloxolone, improved mitochondrial function and submaximal exercise tolerance , which cWhile Nrf2 activation protects against various cardiac insults, growing evidence has shown a detrimental role of Nrf2 in pathological cardiac remodeling and dysfunction. In pressure overload-induced cardiac injury, cardiac autophagy is impaired, which activates Nrf2-driven angiotensinogen expression, contributing to cardiac pathological remodeling and dysfunction . FurtherIn summary, there is robust evidence that Nrf2 contributes to the regulation of oxidative stress in the RVLM and impacts sympathoexcitation in CHF and hypertension. Studies using genetic models clearly demonstrated that the RVLM knockdown of Nrf2 exacerbates sympathetic nerve activity and oxidative stress in CHF and in response to central Ang II administration, while the RVLM overexpression of Nrf2 ameliorates sympathetic nerve activity in CHF. In addition, EV-mediated heart-brain communication evokes sympathoexcitation in the RVLM through miRNAs targeting Nrf2 signaling in CHF.+/+ supports the notion that Nrf2 may at least partially mediates ACE2-induced reduction of blood pressure in response to central Ang II administration.The role of Nrf2 as a mediator of ExT-induced reduction of sympathetic nerve activity in CHF is speculative and necessitates further mechanistic investigations. However, given the high Nrf2 expression in the RVLM of CHF mice following ExT, Nrf2 could potentially mediates the upregulation of antioxidant enzymes, thereby reducing oxidative stress and attenuating sympatho-excitation in the setting of CHF. Similarly, higher Nrf2 expression in the RVLM of syn-hACEA previous study has demonstrated that the cardioprotective effect of ExT following ischemic-reperfusion injury in mice was abrogated when Nrf2 gene was selectively removed from their skeletal muscle . Given t


The study of chromatin modifications and the use of newly developed tools to manipulate different chromatin marks and the epigenome has permeated to all areas of research: from diabetes to neurodegenerative disorders, growth and development, plant-pathogen interactions, and crop biotechnology, to mention but a few.In some 20 years, scientific publications on epigenetics have increased exponentially, with more than hundred thousand articles published so far on this topic. In the light of this considerable amount of data, we must tackle step by step the intricacies of each epigenetic mechanisms to effectively benefit from their analyses.Crop performance is one of the long-term threats facing humanity, and an important area of research. One of the key challenges is to unravel epigenetic mechanisms that plants have evolved to cope with biotic and abiotic stresses and develop a stress memory which help them to enhance intra-, inter- and trans-generationally responses against recurring stresses. In the near future, we must be able to edit and manipulate the epigenome as novel directions to drive plant breeding and improve crops. As examples, the generation of new beneficial traits through the creation of novel epialleles or the selection of advantageous epigenetic states seem to be particularly promising.The goal of this Research Topic was to amalgamate some of the recent advances concerning the role of epigenetics in crop biotechnology, as well as to enhance and promote interactions among high quality researchers from different disciplines. Here we present four research articles, one review and a method that will certainly have an impact on crop epigenetics.Bvindi et al. demonstrate that two histone lysine methyltransferases, SET Domain Group 33 (SDG33) and SDG34  mediate nitrogen (N) responses of shoots and roots in tomato (Solanum lycopersicum L.) in a partially overlapping manner. Interestingly, using transcriptomic profiling of CRISPR edited mutants, authors found that SDG33 and SDG34 control N-responsive gene regulatory networks in an organ-specific manner, suggesting that histone methylation is an epigenetic mechanism involved in N-mediated root plasticity. In addition, SDG33 and SDG34 are involved in maintaining the chlorophyll a/b ratio in leaves when the N level changes. Finally, because SDG8 in Arabidopsis functions as a regulatory hub between N and pathogen responses, authors speculated whether it is the same for SDG33 and SDG34 in tomato.In a first research article, Han et al. deliver very intriguing results as to the impact of the linker histone H1 on DNA methylation and gene regulation at imprinted loci. As a first step, authors shown, in Arabidopsis, that loss of linker histone H1 affects the expression of known imprinted genes MEA and FIS2, encoding two essential components of the PRC2 complex, as well as FWA, encoding a transcription factor that controls flowering. Then, they observed that a loss of maternal H1 indirectly influences DEMETER-mediated DNA demethylation and chromatin architecture in the central cell and endosperm and suggested that H1-bound heterochromatin may act as a barrier to limit DEMETER DNA demethylation. Nevertheless, the loss of maternal H1 does not dramatically alter overall gene transcription and/or imprinting in the endosperm, and other selected imprinted genes presented variable dysregulation and methylation changes. Together, these results underline the extreme complexity of crosstalk between different epigenetic mechanisms, such as DNA methylation and chromatin accessibility to regulate gene expression.In a second research article, Guo et al. describe the identification and characterization of linker histones in castor bean (Ricinus communis) in comparison to other economically important Euphorbiaceae species  and also the model plant Arabidopsis thaliana. Authors demonstrate how linker histones vary within and between populations and species and reveal their putative functions in castor bean and possibly more broadly, as many lines of possible future research projects.Related to this work, Xiao et al., describe how they identified and cloned TaDREB2B from a wild species of sugarcane (Tripidium arundinaceum), a member of the DREB (Dehydration Responsive Element-Binding) subfamily transcription factor known to play a crucial role in plant drought response. Then, under the control of a drought-inducible promoter previously identified, authors expressed TaDREB2B in a commercial sugarcane cultivar and managed to improve its drought tolerance in the field by enhancing water retention capacity and reducing membrane damage, without affecting yield. Considering the ongoing climate change, drought-resistance is undoubtedly a key trait in crop breeding and studying epigenetic mechanisms involved in its regulation appears now essential for future crop improvements.In a last research article, Huang et al. focuses on how the transcriptionally corepressor HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE 15 (HOS15) epigenetically regulates flowering. In addition, authors highlight how HOS15 may contribute to integrate both endogenous and exogenous cues to establish an optimal trade-off between development and environmental adaptations.Besides these two research articles, the mini-review by Moebes et al. present a method enabling optimal RT-qPCR analyses of low-expression epigenetic genes in rapeseed with applications in stress response and crop improvement.Finally, In conclusion, this Research Topic issue highlights the importance of diversify our models and our approaches in order to better understand how epigenetic changes contribute to modulate plant responses and adaptation in a changing environment.RA-V wrote the first draft of the article. AB made a substantial intellectual contribution to the work and approved it for publication.


Ferroptosis is an iron-dependent programmed cell death pattern that is characterized by iron overload, reactive oxygen species (ROS) accumulation and lipid peroxidation. Growing viewpoints support that the imbalance of iron homeostasis and the disturbance of lipid metabolism contribute to tissue or organ injury in various kidney diseases by triggering ferroptosis. At present, the key regulators and complicated network mechanisms associated with ferroptosis have been deeply studied; however, its role in the initiation and progression of kidney diseases has not been fully revealed. Herein, we aim to discuss the features, key regulators and complicated network mechanisms associated with ferroptosis, explore the emerging roles of organelles in ferroptosis, gather its pharmacological progress, and systematically summarize the most recent discoveries about the crosstalk between ferroptosis and kidney diseases, including renal cell carcinoma (RCC), acute kidney injury (AKI), diabetic kidney disease (DKD), autosomal dominant polycystic kidney disease (ADPKD), renal fibrosis, lupus nephritis (LN) and IgA nephropathy. We further conclude the potential therapeutic strategies by targeting ferroptosis for the prevention and treatment of kidney diseases and hope that this work will provide insight for the further study of ferroptosis in the pathogenesis of kidney-related diseases. Kidney diseases have become a prominent threat of human death. At present, there are approximately 850 million patients with kidney diseases worldwide, and the number of people suffering from kidney disease in China has exceeded 100 millionRegulated cell death is indispensable for maintaining normal physiological homeostasis, and either excessive or insufficient cell death can lead to the initiation of diseasesThe pathophysiological relevance of ferroptosis was first found in acute kidney injury (AKI) and renal cell carcinoma (RCC). Since then, a growing body of evidence has reported that ferroptosis plays a core role in multiple kidney diseases, such as CKD and lupus nephritis (LN)In this review, we browse and summarize the current research progress considering the role of ferroptosis in different types of kidney diseases. We discuss the characteristics, potential mechanisms and pharmacological progress of ferroptosis, further elucidate the disorders of iron and lipid metabolism encountered in kidney diseases and describe their potential connection with ferroptosis. We hope this review will provide new perspectives regarding the pathological role of ferroptosis in kidney diseases.Table 1). Morphologically, it is mainly characterized by mitochondrial atrophy, increased membrane density and decreased or absent mitochondrial cristae. Biochemically, it is mainly glutathione depletion and GPX4 activity decline. Genetically, ferroptosis-related mechanisms are complex and mediated by multiple genes, mainly involving gene changes in iron homeostasis, lipid peroxidation and amino acid metabolism. Although the dysregulation of iron metabolism and lipid metabolism is closely related to ferroptosis, it still has no specific molecular indicators at present, except for detecting the levels of intracellular lipid peroxides and the occurrence of cell death inhibited by ferroptosis inhibitors or iron chelatorsEarly classifications of cell death mainly refer to apoptosis, autophagy, necrosis, and pyroptosis. However, over time, a variety of new cell death models have been proposed, such as ferroptosis-/glutathione peroxidase 4 (GPX4) system, ferroptosis suppressor protein 1 (FSP1)/ubiquinol (CoQ10) system, dihydroorotate dehydrogenase (DHODH)/dihydroubiquione (CoQH2) system, and GTP cyclohydrolase 1 (GCH1)/tetrahydrobiopterin (BH4)/dihydrofolate reductase (DHFR) system .In contrast to other types of cell death, the characteristics of ferroptosis mainly manifest as iron overload and lipid peroxide accumulation. During the process of renal injury, in addition to the classical abnormal regulation of iron metabolism and lipid peroxidation, a growing number of novel metabolic pathways have also been uncovered in ferroptosis, such as the system XcIron is an important mediator in many physiological activities in mammals. Iron deficiency leads to iron deficiency anemia, whereas its overload can produce abundant ROS and further cause oxidative damage in tissues or organs, such as kidney injury3+ can be transformed into Fe2+ through transferrin (TF) and transferrin receptor 1 (TFR1) and then released into the labile iron pool (LIP) of the cytoplasm, while excessive iron is stored in ferritin (FT). As the key component of FT, ferritin heavy chain 1 (FTH1) has ferroxidase activity and can catalyze the conversion of Fe2+ to Fe3+17. In the case of abnormal iron transport, the upregulation of TFR1 and downregulation of FTH1 lead to the overload of Fe2+. Subsequently, excessive Fe2+ reacts with hydrogen peroxide to produce hydroxyl radicals, which can directly catalyze the formation of lipid peroxides through the Fenton reaction and eventually promote cell ferroptosisUnder common conditions, systemic FeLipid peroxidation refers to the process by which PUFAs are oxidized by ROS via enzymatic or nonenzymatic reactions to form lipid peroxides, which is closely related to ferroptosis-.Glutathione (GSH) is the main intracellular antioxidant in mammals and is synthesized by glutamate, cysteine and glycine under the catalysis of glutamine cysteine ligase (GCL) and glutathione synthesis (GSS)- is composed of transporter protein solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (SLC3A2), which can transport intracellular glutamate to the outside and uptake extracellular cystine into cells to reduce it to cysteineSystem XcGpx4 knockout in mice causes embryonic lethality, whereas conditional knockout of Gpx4 leads to dysfunctions of the immune system, liver, kidney, brain and other tissues and organs in mice- will reduce GPX4 activity and limit cell antioxidant capacity, ultimately resulting in ferroptosis. Therefore, maintaining metabolic homeostasis of the system Xc-/GPX4 axis might be a core factor in counteracting ferroptosis.GPX4 is a GSH-dependent enzyme that can convert reduced glutathione to oxidized glutathione (GSSG) and reduce lipid hydroperoxide (L-OOH) to lipid alcohol (L-OH) to protect against lipid peroxidation. As a well-characterized ferroptosis suppressor, GPX4 can inhibit the accumulation of iron-dependent lipid peroxides and participates in modulating a variety of physiological functions-/GPX4 axis, genome-wide screening has recently identified FSP1 as another ferroptosis suppressor10/NADPH system is independent of the intracellular expression levels of GSH, GPX4 and ACSL4 and can protect cells from GPX4 inhibition-induced ferroptosis10/NADPH system inhibits lipid peroxidation and ferroptosis by blocking the formation of the MDM2-MDMX complex. Overexpressing FSP1 in cells lacking GPX4 expression significantly reduced specific phospholipid peroxidation products compared to control cells. Moreover, cells lacking FSP1 expression have increased sensitivity to ferroptosis inducers, including the GPX4 inhibitor ML162 and the system Xc- inhibitor erastin.In addition to the system Xc is needed.FSP1 overexpression can also induce cell death and reduce the sensitivity of cells to ferroptosis. Clinical studies found that the FSP1 level was significantly related to the lower overall survival rate of many cancer patients; thus, it can be used as a prognostic marker. Additionally, in clinical treatment, GPX4 upregulation promotes ferroptosis of tumor cells and may fail to achieve the desired effect because of the activation of the compensatory mechanism of the FSP1 system. Therefore, increasing the expression of GPX4 and FSP1 can synergistically promote the ferroptosis of tumor cells. In short, subcellular localization and expression levels and the activity of NADPH oxidoreductase are the key factors by which FSP1 inhibits cell ferroptosis; however, the underlying molecular mechanism has not yet reached a consensus. At present, studies on the mechanism by which FSP1 regulates ferroptosis are still in the initial stage, so comprehensive and in-depth explorationRecently, genome-wide CRISPR/cas9 screening technology identified a GPX4-independent novel ferroptosis inhibitory mechanism called the GCH1/BH4/DHFR system2). A recent study reported that DHODH plays a key role in preventing the occurrence and development of ferroptosis2. Notably, mitochondrial GPX4 and DHODH can jointly inhibit lipid peroxidation through mutual compensationMitochondria are the major site of aerobic respiration and the main source of ROS in cells, and mitochondrial ROS are crucial in initiating lipid peroxidation and ferroptosis2 and mitochondrial GPX4 constitute two major ferroptosis defense systems to eliminate cell damage or death caused by the accumulation of mitochondrial lipid peroxides, and preclinical studies have shown that targeting DHODH can promote ferroptosisThe ferroptosis defense system is mainly divided into two parts: the GPX4 system and the CoQH2 system; the former includes cytosolic GPX4 and mitochondrial GPX4, and the latter includes FSP1 and mitochondrial DHODH. This classification of ferroptosis defense may be beneficial to reduce the accumulation of lipid peroxides in mitochondria and cope with the double membrane structure of mitochondriaFerroptosis is a complex regulatory network involving multiple regulatory factors, and various transcription factors can control the expression of downstream genes related to ferroptosis. Many studies have shown that transcription factors such as p53, Nrf2, ATF3, ATF4, YAP1, TAZ, SP1, HIF1A, BACH1, TFEB, JUN and HNF4A play key roles in regulating ferroptosis through transcriptional- or nontranscriptional-dependent mechanisms. Herein, we described the mechanisms of several key transcription factors, such as p53, Nrf2, ATF4, YAP1, and TAZ, in regulating ferroptosis in kidney diseases . Therefore, exploring the relationship between ferroptosis and organelles is conducive to understanding ferroptosis from a new perspective, which will provide new ideas for basic and clinical studies on the prevention and treatment of kidney disease.Organelles play important roles in maintaining cellular homeostasis, and their damage or dysfunction promotes cell death and induces the development of many diseases, including kidney diseases. Ferroptosis is closely related to and regulated by organelle stress. Mitochondria, lysosomes, the endoplasmic reticulum and the Golgi apparatus are involved in regulating ferroptosis, and the relevant regulatory mechanism is due to the lipid bilayer membrane structure of organelles, which is related to lipid metabolism  can alleviate ferroptosis caused by cysteine deprivation. In addition, lipid peroxidation of the mitochondrial membrane is also an important source of lipid peroxides during ferroptosis. Under the condition of cysteine deficiency, mitochondrial TCA is enhanced, and lipid ROS production is increased, which promote the hyperpolarization and final collapse of the mitochondrial membrane, thereby resulting in ferroptosisDuring the process of pathological stimulation, the accumulation of misfolded and unfolded proteins leads to ER dysfunction and triggers ER stress (ERS)In addition, ferroptosis has a common regulatory pathway with other types of cell deathThe Golgi apparatus is the key protein processing factory in eukaryotic cells. As an important membranous organelle, the Golgi apparatus can process, modify, classify and package proteins synthesized by the ER and further transport them to specific parts of cells. Inhibiting Golgi apparatus homeostasis induces autophagy, apoptosis, and ferroptosisLysosomes are organelles rich in multiple acid hydrolases, which are involved in regulating cell metabolism, signal transduction, cell death and other cellular processesTable 2.As the role of ferroptosis in the occurrence and development of various kidney diseases have been gradually recognized, alleviating the progress of diseases via the inhibition or activation of ferroptosis has become a hot research topic. At present, a variety of natural and synthetic drugs associated with ferroptosis have been found, including inducers and inhibitors. For nonneoplastic kidney diseases, renal function can be improved by the application of ferroptosis inhibitors, such as lipid peroxidation pathway inhibitors, iron homeostasis regulators, and ROS generation inhibitors. However, in renal cell carcinoma, ferroptosis inducers can be used to prevent the development of cancer. The inhibitors and inducers that modulate ferroptosis are described in Figure 3).Ferroptosis-induced tissue dysfunction has long been considered a noticeable critical factor in the progression of a variety of kidney diseasesRenal cell carcinoma (RCC) is a frequent human malignancy and accounts for approximately 90% of malignant renal tumors. Epidemiological statistics show that the incidence rate of RCC is significantly increased and ranks second in urogenital system tumors around the worldVHL) is a major tumor suppressor gene, and overexpression of VHL in ccRCC could effectively inhibit ferroptosis by reducing lipid peroxide accumulation, indicating that VHL-induced ferroptosis might be a promising target for ccRCC treatmentThe Hippo pathway plays a key role in cell density and confluency, and high cell density leads to ferroptosis. TAZ, a key transcription regulator in the Hippo pathway, is highly expressed in ccRCC and closely associated with cell density-influenced ferroptosis susceptibilityKLF2metallothionein 1 G (MT1G)KDM5C83 also play positive roles in preventing or delaying ccRCC development by promoting GSH metabolism and inhibiting lipid peroxidation. Ferrinophagy is a type of cell-selective autophagy mediated by NCOA4, which can degrade ferritin autophages, leading to the release of ferritin-bound iron into free ironACSL4 is a ferroptosis indicator that is downregulated in ccRCC and is considered a valuable biomarker for ccRCC treatmentRecently, with the rapid study of traditional Chinese medicine, a variety of Chinese herb components have been found to prevent the progression of ccRCC by inducing ferroptosis in drug-resistant renal carcinoma cells, such as artesunateAKI is characterized by a rapid decline in renal function and is caused by various pathological factors, such as rhabdomyolysis (RM), oxidative stress, inflammation, hypoxia, infection, ischemia‒reperfusion injury (IRI), sepsis, and nephrotoxic drugs2+ released from Mb degradation catalyzes the production of lipid peroxides through the Fenton reaction, which eventually induces ferroptosis and AKI. It was reported that ferroptosis was involved in the development of RM-induced AKI, and desferrilamine or curcumin could effectively alleviate kidney damageRM-induced renal failure accounts for 15% of AKI, and myoglobin (Mb) accumulation in the kidney is the core mechanismSince the kidney is highly sensitive to IRI, IRI is considered one of the major triggers for AKI and leads to renal tubular cell death and progressive kidney tissue damagemiR-124-3p.1 could regulate the LPCAT3-mediated ferroptosis pathway in SA-AKI, thereby indicating the importance of ferroptosis in SA-AKI.Sepsis is another major cause of AKI, and further exploration of its mechanism will provide more possibilities for the prevention and treatment of SA-AKI. A recent study found that renal tubular epithelial cell ferroptosis occurred in SA-AKI mice, and Maresin conjugates in tissue regeneration 1 (MCTR1) suppressed ferroptosis in LPS-induced HK-2 cells and SA-AKI mice by activating Nrf2AKI induced by nephrotoxic drugs, such as cisplatin and folic acid (FA), is also closely related to ferroptosis. Guo et al.Multiple studies have shown that cisplatin can promote renal tubular cell ferroptosis and enhance kidney damage in cisplatin-induced AKI (CI-AKI) mice, and inhibiting ferroptosis significantly reduces the levels of urea nitrogen and blood creatinine and further alleviates oxidative damage and fibrosis in kidney tissuesDBA/2J micedb/db miceDBA/2J miceDKD is a common and frequent microvascular complication of diabetes and has become the predominant cause of end-stage renal disease (ESRD)Interestingly, studies on noncoding RNAs and DKD found that circ ASAP2PKD1 or PKD2, is one of the most common dominant hereditary kidney diseases and is characterized by the progressive development of bilateral renal epithelial cystsADPKD, caused by mutations in PKD1 mutant kidney cells and mice showed that the expression levels of system Xc-, ferroportin and GPX4 were significantly decreased, accompanied by increased levels of TFR1 and DMT1. In addition, both ADPKD cell and mouse models displayed high iron content, low GPX4 activity, increased lipid peroxide accumulation, and a tendency toward ferroptosis; ferroptosis inhibitors effectively suppressed ferroptotic cell death and cyst growth in ADPKD1 mutant miceOxidative stress, inflammation, hypoxia and cell death play key roles in cyst formation and progression in ADPKD. Interestingly, several studies strongly supported that ferroptosis was involved in ADPKD developmentWhen the kidney is stimulated by multiple pathogenic factors and with the inflow of fibrosis factors and cytokines, intrinsic renal cells undergo transdifferentiation, thereby inducing massive proliferation of fibroblasts and myofibroblasts and excessive accumulation of extracellular matrix, which further leads to glomerulosclerosis and tubular fibrosis and ultimately results in the loss of renal functionRecent studies have suggested that ferroptosis plays a key role in the progression of renal tubular injury to renal fibrosisA recent study by Li et al. also reported that roxadustat (FG-4592) pretreatment ameliorated renal injury and renal fibrosis by inhibiting renal tubular epithelial cell ferroptosis via the Akt/GSK3β/Nrf2 signaling pathway in folic acid-induced AKILupus nephritis (LN) is an immune injury caused by systemic lupus erythematosus involving different pathological types of kidneys. The pathogenesis of LN involves multiple factors, including environmental factors, genetic factors, hormone regulation, immune complex clearance, and cell metabolismRecent findings revealed a close linkage between ferroptosis and LNIgA nephropathy is one of the most common primary glomerular diseases. Previous studies suggested that abnormal glycosylation of IgA1 is a key link in the progression of IgA nephropathyFerroptosis is a kind of programmed death that can be regulated by various mechanisms and characterized by iron overload and lipid peroxidation. A growing body of evidence has proven that ferroptosis plays an important role in many chronic diseasesCurrently, the study of ferroptosis in kidney diseases is in the early stages, and no specific biomarkers have been determinedAt present, in view of extensive research on key mechanisms and regulators of ferroptosis, a large number of small molecule drugs have been found to induce or inhibit ferroptosis to alleviate renal tissue injury in various kidney diseases, such as RSL3, erastin, Fer-1, vitamin K and quercetin. However, these drugs have not been transformed into clinical applications to benefit patients with kidney diseasesAlthough many studies have reported the close relationship between ferroptosis and kidney diseases, compared with the extensive evidence on ferroptosis in oncology, studies on ferroptosis in kidney diseases are still scarce, and the regulatory mechanisms, modulators, signaling pathways and drug targets still need to be expanded. Currently, investigations on ferroptosis and kidney diseases are mainly focused on RCC and AKI; however, there are relatively few studies on other types of kidney diseases. Therefore, it is of great significance to conduct a profound study on the mechanism and role of ferroptosis in renal fibrosis, DKD, LN, ADPKD and IgA nephropathy. To date, ferroptosis-related inducers and inhibitors for the treatment of kidney injury have made great progress, but the vast majority of them remain in the animal and preclinical experimental stages. Therefore, it is worth looking forward to the clinical transformation and the development of new precision drugs (such as nano-targeted drugs). In summary, although this study aims to comprehensively review the pathogenesis of ferroptosis in different kidney diseases, we still believe it has some shortcomings, such as the limitations of research perspectives. Notably, with in-depth studies on ferroptosis in renal diseases and the elucidation of its mechanism, we believe it will provide new intervention targets for the prevention and treatment of various kidney diseases in the future, and we are also planning to regularly conduct systemic summaries of this field of research.


Although TiO2 has been categorized as a bioinert material, recent evidence has demonstrated different toxicity profiles of TiO2 nanoparticles (NPs) and a potential health risk to humans. Studies indicated that titanium dioxide enters the systemic circulation and accumulates in the lungs, liver, kidneys, spleen, heart, and central nervous system and may cause oxidative stress and tissue damage in these vital organs. Recently, some studies have raised concerns about the possible detrimental effects of TiO2 NPs on glucose homeostasis. However, the findings should be interpreted with caution due to the methodological issues. This article aims to evaluate current evidence regarding the effects of TiO2 NPs on glucose homeostasis, including possible underlying mechanisms. Furthermore, the limitations of current studies are discussed, which may provide a comprehensive understanding and new perspectives for future studies in this field.Titanium dioxide (TiO 2) is used as a white pigment in a wide array of products and is generally considered to be toxicologically inert. However, once human beings are exposed to TiO2 NPs, they can be absorbed, and accumulated in several vital organs, potentially leading to adverse effects on human health. Recently, the result of some studies showed the possible effect of TiO2 NPs on glucose homeostasis. In this review, we evaluate and discuss current evidence regarding the effects of TiO2 NPs on glucose homeostasis.Titanium dioxide (TiO The chosen articles were limited to articles published in the English language. Moreover, we did not limit the type of studies included, and all sorts of original studies  were considered. Articles were excluded if they were editorials, poster abstracts, or had no full text available.Original studies that examine the effect of TiO2.3Our initial search started with a screening of the 210 papers. After removing duplicates and irrelevant studies according to their titles and abstracts, the eligibility of the remaining 40 papers was reviewed based upon their full text. Ultimately, 13 studies were included in this review by assessing their full texts , and found that TiO2 NPs stimulated insulin resistance, indicated by impaired glycogen synthesis and reduced activation of the insulin signaling pathway. Similarly, in mice, TiO2 NPs disturbed plasma glucose homeostasis, marked by increased plasma glucose levels, and impaired glucose tolerance, with no difference in plasma insulin levels compared with untreated controls , the level of HbA1c, insulin, and an increase in the level of glucagon in female rats compared with controls, but male rats treated with the same regimen displayed elevated plasma glucose at 60 min and increased plasma glucose AUC in the OGTT and decreased in the level of plasma insulin and C‐peptide, and glucagon  kinases p38 (MAPK38) and c‐Jun N‐terminal kinases (JNKs), resulting in the induction of abnormal insulin signaling , TiO2 NPs has been shown to increase ROS production. This was shown by reduced in the liver and serum levels of total superoxide dismutase (T‐SOD) and glutathione synthetase (GSH) and increased methane dicarboxylic aldehyde (MDA) which together indicates increased ROS   and Drosophila melanogaster as an in vivo model. Acute exposure to TiO2 NPs concentrations caused a significant decrease in transport of glucose across the gut epithelium due to transformation in microvilli. These findings were verified by a complementary study in D. melanogaster where TiO2 ingestion caused reduced glucose content. In rats exposed to TiO2 NPs for 30 days, small intestinal structure was altered, with villous atrophy, indicated by reduced length and number of small intestinal villi, reducing the area available for absorption  at varying doses  for 30 consecutive days leads to no obvious differences in the blood glucose level despite TiO2 NP‐induced intestinal epithelium injury.Richter et al.  assessed2 NPs during pregnancy was examined. It was observed that the rats' fasting glucose levels raised significantly at gestation day (GD) 10 and GD17 after exposure to TiO2 NPs, which they hypothesized might be caused by gut microbiota. They identified the flora composition, and the abundance of specific genera, including Ellin6075, Clostridiales, and Dehalobacteriaceae, was altered in the second trimester and late pregnancy stage. The output of phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) has shown the enhancement of the T2DM‐related genes and reduction of taurine and hypotaurine metabolism at the second trimester in TiO2 NP‐treated rats  in liver cells leading to the decline in insulin sensitivity, resulting in insulin resistance  pancreas raises the possibility that T2D could be crystal‐caused inflammatory pancreas disease. However, it is highly possible that the formation of these crystals is a result of inflammation of the pancreas. Previous studies have shown that chronic pancreatitis gave rise to the development of different crystal types, including calcium carbonate crystals in the form of calcite  assess the potentially toxic effects of TiO2 NPs using more realistic low‐dose through various routes of exposure; (2) apply a thorough and homogeneous exposure classification to elucidate the association of chemical and physical properties of TiO2 NPs with their adverse effect on glucose homeostasis; (3) carry out the epidemiological investigations on exposed consumers and workers to identify the possible correlation of human exposure to TiO2 NPs and risk of glucose homeostasis disruption; and (4) clarify the potential molecular mechanisms behind the toxicity of TiO2 NPs as the underlying molecular mechanisms are still mostly unknown.Considering increasing global manufacturing and the potential applications of TiOThe authors have no conflict of interest to report.