Food security in Small Island Developing States (SIDS) is an international policy priority. SIDS have high rates of nutrition-related non-communicable diseases, including obesity and type 2 diabetes, micronutrient deficiencies and, in many, persistent childhood stunting. This is associated with an increasing reliance on imported processed food of poor nutritional quality. Calls have been made for strengthening local food systems, resilient to climate change, to increase the consumption of nutritious locally produced food. We aimed to systematically review interventions intended to improve diet in SIDS, and specifically explore whether these interventions applied a local food approach.The search strategy was applied to 11 databases, including in health, social science and agriculture. Screening of titles, abstracts and data extraction was undertaken in duplicate. Risk of bias was assessed using Cochrane tools. Narrative synthesis of the results was undertaken. The study protocol was registered (PROSPERO registration number: 2020CRD42020201274).From 26 062 records, 154 full texts were reviewed and 24 were eligible. Included studies were from the Caribbean, Pacific, Mauritius and Singapore. Five were a randomised study design, one an interrupted time series analysis, eight controlled and ten uncontrolled pre-test and post-test. Nine studies included some aspect of a local food approach. Most interventions (n=15) included nutrition education, with evidence of effectiveness largely limited to those that also included practical skills training, such as vegetable gardening or food preparation. Three studies were considered low risk of bias, with the majority (n=13) of moderate risk.There is a lack of robust evidence on interventions to improve diet in SIDS. The evidence suggests that multifaceted approaches are likely to be the most effective, and local food approaches may promote effectiveness, through mechanisms of cultural and contextual relevance. Further development and evaluation of interventions is urgently required to increase the comparability of these studies, to help guide policy on improving nutrition in SIDS. Increasing local nutritious food production is suggested for improving local diets and food security in Small Island Developing States (SIDS).Multifaceted interventions show greatest promise.Local food approaches may promote effectiveness through mechanisms of cultural and contextual relevance.We require high-quality, multifaceted SIDS-based dietary interventions, informed by local cultures and contexts.Small Island Developing States (SIDS) are disproportionately impacted by the triple burden of malnutrition.The major determinant of these challenges is attributed to rapid dietary changes in SIDS, associated with the ‘nutrition transition’.An increase in sustainable, local food production, particularly the production of diverse, unprocessed or minimally processed foods, that promotes intra-regional trade and links within local communities, is envisaged by the United Nations (UN), Food and Agricultural Organisation (FAO) and SIDS governments as a major component in addressing the triple malnutrition burden.The protocol for this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO registration number: 2020CRD42020201274) and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidance.Specific objectives of this review were (1) to identify published and grey literature evaluating interventions in SIDS, from any part of the food system, that aim to improve diet or nutrition knowledge; (2) to evaluate the quality of these studies; and (3) to provide narrative and, as appropriate, statistical summaries of the findings, highlighting interventions that aim to improve diet by increased consumption of locally produced foods.Inclusion and exclusion criteria are summarised in Box 1Inclusion criteriaInterventions implemented and evaluated in one or more SIDS.Any experimental, quasi-experimental and natural experimental evaluation design.Quantitative outcomes reported—impact on any aspect of diet .Interventions implemented since January 2000.Publications in any language.Exclusion criteriaMulti-setting interventions that do not disaggregate SIDS data.No intervention implemented .Alcohol consumption as only measure of dietary intake.Breastfeeding interventions (excluded at title and abstract screen).Interventions implemented before January 2000..A comprehensive search strategy, in 11 databases from health, social and agricultural sciences was developed, piloted and then conducted in July 2020 in 11 databases Of the 24 eligible studies, 4 were from separate arms of two multi-country projects.(S5) Guam,(S6) Federated States of Micronesia (FSM),(S14) Samoa,(S23) Solomon Islands(S24) and Tonga, (S20) and two in Fiji. Eight were conducted in the Caribbean; one in Barbados,(S16) one in Dominican Republic(S13), three in Puerto Rico and three in Trinidad and Tobago. Eight were based in the Atlantic, Indian Ocean, Mediterranean and South China Sea (AIMS region); two in Mauritius and six in Singapore.Eight studies were conducted in the Pacific region; one each in American Samoa, 8 controlled pre/post-test  and 1 interrupted time series study.(S16) Five were randomised study designs; three individually randomised parallel group trials, one individually randomised multi-arm parallel group trial(S17) and one cluster-randomised parallel group trial.(S8)Nineteen of the studies employed a non-randomised study design; 10 uncontrolled pre/post-test,  clinic  or workplace setting,(S2) children at school or young adults at university,(S10) and four targeted women only.  Three of the education interventions included a skill acquisition component, such as gardening or cooking workshops, and four provided additional support through individual face-to-face sessions,(S11) mindfulness lessons to promote healthy diets,(S10) food coaching from an app(S9) or counselling from a dietitian.(S12) Two interventions implemented a tax  and one hypothetical tax on high-calorie products via an online choice experiment.(S17) An online, hypothetical choice experiment evaluated different types of front-of-pack nutrition labelling.(S1) Four interventions were multifaceted, including education, social marketing, community gardens and advocacy for change among manufacturers and retailers; two of these were implemented at population level and the other two targeted secondary school children. The final four interventions implemented strategies for building capacity for improved diets in a variety of ways  a portion guidance plate for hospital staff,(S2) targeted advertising and marketing of unhealthy foods to children(S18) and marine protected areas to protect community fish stocks.(S24) Six of the interventions included a physical activity component.A large proportion of interventions focused on nutrition education (n=15) and included education that targeted adults in the community,  of the 24 studies included some form of local approach  Further details on these studies are documented in (S9) Five of these nine interventions included a practical food production component, such as teaching skills for own food production.Nineapproach . Eight o(S24) The intervention that improved nutrition knowledge involved culturally appropriate strategies to educate adults in American Samoa.(S5)Of the eight studies that specifically promoted locally produced food, four showed significant improvements in dietary intake and one study that did not measure dietary intake showed significant improvement in nutrition knowledge. Of those that improved dietary intake, two were garden-based nutrition education interventions, supplemented with practical skills components (one in Dominican Republic and one in FSM), an education-only intervention targeting adults in Mauritius, and a study that implemented marine protected areas in the Solomon Islands to improve food security for local communities.(S6) and two separate arms of the regional Pacific Obesity Prevention in Communities Project in Fiji(S21) and Tonga.(S22)Three studies included a practical local food production component but were not shown to improve diet. These included a summer camp-based intervention in Guam(S9) of the nine studies applied a local approach to process-related components. This included involving local communities,(S24) non-government organisations or national government(S23) in the prioritisation or development phase of the intervention, employing strategies to enhance the cultural appropriateness of the intervention  translating intervention resources or evaluation tools into the most commonly used language) or recruiting local facilitators, such as local non-government organisations to deliver culturally appropriate education or implement the intervention.All but one Four studies demonstrated mixed effectiveness across measures of intake and six were ineffective. The three studies that measured impact of tax or labelling interventions on purchasing or sales of unhealthy products were effective. For details of all study findings, see The findings from the non-local studies showed mixed effectiveness on dietary intake. Only two showed consistent evidence for improving dietary intake, both using lessons and educational materials to teach adults about nutrition. All were non-randomised studies and the main sources of risk were for confounding and missing data in study reports.This systematic review identified 24 studies of interventions in SIDS that aimed to improve diet. Variation in study objectives, measured outcomes and quality makes it difficult to draw generalisable conclusions on the effectiveness of these interventions, or to conclude whether incorporating a local food approach into interventions made them more or less effective than their non-local equivalents. However, as there is a particular interest in SIDS in strengthening local, sustainable food systems to address drivers of malnutrition,In placing the findings of this review in the wider context of what is required for change, it is important to consider how SIDS food systems function and where interventions could promote a shift in how people source their food, the type of food they source and consume, and their diet-related health. One example of research in SIDS that has taken a food systems perspective used group model building methodology with local stakeholders to represent food systems as causal loop diagrams in Jamaica, St Vincent and the Grenadines, and St Kitts and Nevis.(S14) They highlight the perceived desirability of imported alternatives over local food (in the Pacific) and emphasise the importance of challenging these perceptions. This requires understanding of the wider sociocultural context, including the food traditions and values attached to different food sources and food types.This breadth of potential levels of intervention was not reflected in the research identified by this review. The most implemented type of intervention across the included studies was education (63% (n=15)). Although effectiveness of these interventions varied, those that supplemented education with practical skills training (such as vegetable gardening or cooking demonstrations) showed greatest promise with improvement in dietary intake across all three studies, two taking a local food approach. This is consistent with the findings of educational interventions conducted in other settings, whereby those with additional components such as cooking classes or gardening are more likely to be effective. support the notion that cultural relevance, combined with improvements in nutrition knowledge, has the potential to act as a mechanism to dietary change in these settings.The effective and culturally ‘strong’, nutrition education and practical skills interventions in this reviewThe findings from this review suggest that local approaches may add a level of contextual relevance to support local food production and the consumption of that food in SIDS that is missing from non-local interventions. This is particularly evident within education and skills interventions that are relatively low-cost and feasible in these resource-limited settings, and already being implemented by local non-government organisations. Such approaches have the potential to reshape perceptions, at individual level, around food preferences which are largely driven by strong sociocultural factors, and therefore should be encouraged as part of future interventions to increase demand for local, healthy foods. However, higher level government intervention is also required, and research into how local governance structures can be strengthened to prioritise local produce over corporate and import markets has been identified as important in SIDS settings.For SIDS and similar settings, cross-sectional data suggest that the way food is sourced may impact the diversity of diets and/or whether it was locally  grown or produced. However, we acknowledge the multitude of ways that ‘local food’ could be defined, such as the felt ‘sense’ of locality that varies between individuals,Our aim to identify and classify interventions that took a local food approach was challenging to realise, both in terms of clearly defining what we meant by ‘local food’  and inte(S6) but it is important to acknowledge that ‘local’ may not necessarily mean ‘healthy’, and in this context it is important that definitions of local food, explicitly refer to minimally processed, seasonal and nutritious food.Understanding the nutritional implications of consuming local over imported food is important, especially for SIDS that are disproportionately impacted by the globalised food system, its drivers and consequences.We considered whether including local versus non-local stakeholders to intervention components impacted effectiveness. However, while acknowledging potential value engaging local stakeholders, there were too few studies describing intervention development to draw generalisable conclusions. In addition, it is possible that the long-term effectiveness of these programmes is enhanced by such engagement. Thus, the true value of ‘local approach’ interventions may not be fully portrayed by the relatively short follow-up in most of the studies we found.how these interventions are effective, and the inclusion criteria for this review were not designed to find accompanying qualitative studies.Our review is subject to a general limitation of nutrition-related research, that is, by the accuracy and reliability of the dietary assessment methods, particularly issues obtaining valid dietary recall data using subjective, retrospective methods.It is crucial that we understand the effectiveness of interventions that aim to improve diet in SIDS to inform future strategies to reduce the very high burdens of poor nutrition. This review provides a summary of the evidence on the impact of interventions on aspects of diet and indicates that there appears to be potential for promoting effectiveness by applying a local food approach, through mechanisms of cultural and contextual relevance. However, standard tools, indices and definitions, are required to increase the comparability of these studies.Additional references can be found in 10.1136/bmjnph-2021-000410.supp2Supplementary data


Whereas metronidazole-induced hepatotoxicity is quite rare in the general population, in individuals carrying a nucleotide excision repair disorder, namely Cockayne syndrome, there is a high risk of developing this complication.We report the case of a 44-year-old man, affected by xeroderma pigmentosum, who was admitted to the hospital presenting aspiration pneumoniae caused by worsening dysphagia and with severe hepatotoxicity during the hospitalization.Acute hepatitis, which was leading to acute liver failure, occurred during antibiotic treatment with metronidazole and ceftazidime with an elevation of liver enzymes consistent with hepatocellular damage pattern.Hydration with glucose 5% solution, pantoprazole and vitamin K were administered, meanwhile other causes of hepatitis were ruled out and the ongoing antibiotic treatment was stopped suspecting a drug-induced liver injury.Liver function nearly completely recovered 1 month later with a first rapid improvement, within few days, of aminotransferases and coagulation studies, and slower of cholestatic enzymes.We describe the first case available in the literature of hepatotoxicity associated with metronidazole treatment in a xeroderma pigmentosum patient. Clinicians therefore, based on this report and according to the possible underlying mechanism shared by other genetic diseases characterized by alterations in the pathway of DNA-repair, should consider such adverse event also in patients affected by this rare disease. Alteration in this pathway results in several rare diseases characterized by a wide spectrum of clinical features with photosensitivity as a common trait. NER disorders include XP, trichothiodystrophy, Cockayne syndrome (CS), and cerebro-oculo-facio-skeletal-syndrome. Metronidazole (MTZ) is a nitroimidazole antibiotic which is widely used for gastrointestinal infections and dental complications. While MTZ-induced hepatotoxicity is quite rare in the general population, and MTZ is not listed among causes of drug-induced liver injury and acute liver failure, in individuals carrying a NER disorder, namely CS, there is a high risk of developing MTZ hepatotoxicity.–6Xeroderma pigmentosum (XP) is a rare genetic autosomal recessive syndrome, characterized by an enzymatic defect in the DNA-repair pathway known as nucleotide excision repair (NER).Here we report the first case of a XP patient who developed severe hepatoxicity during the treatment with MTZ.22 was 99% in high-dose oxygen from a reservoir mask at 15 L/min. A physical examination revealed bilateral reduced vesicular murmurs and neurological signs compatible with the underlying disease. Coagulation, renal and liver exams were normal. Computed tomography scan showed large pneumoniae involvement in left inferior lobe. Since other episodes of inhalation occurred, antibiotic therapy was potentiated with the introduction of MTZ 500 mg every 8 hours. Three days after the start of MTZ, severe abnormalities in liver function appeared with progressive elevation of liver enzymes and a prothrombin ratio greater than 1.5. As reported in Figure A 44-year-old man, known to have XP with multisystemic involvement  diagnosed since the age of 2 years, was admitted to our medical department because of suspected aspiration pneumonia. The neurological involvement indeed, with a sensory and motor polyneuropathy, mixed cerebellar and sensory ataxia, hypoacusia and trigeminal neuralgia, led progressively to loss of autonomy in daily activities and dysphagia. This symptom worsened in the last few months before the admission, and treatment with escitalopram and alprazolam was started to control anxiety and panic attacks before meals. At the admission in our ward, an empiric antibiotic therapy with ceftazidime (CAZ) 2 grams every 8 hours was ongoing, started since the Emergency Room admission 2 days before because of acute respiratory failure and elevation of inflammation indices after inhalation at home. On presentation, the patient was alert, afebrile (axillary temperature of 37 °C), tachycardic (heart rate of 120 per min) with blood pressure of 160/100 mm Hg, SaO3 the acute liver damage observed in our XP patient may be ascribed to the treatment with MTZ and CAZ. The time to onset reaction and the improvement after cessation of the treatment were highly suspicious of this association, and other causes of acute hepatitis were ruled out. Both MTZ and CAZ can be equally suspected, but data available in the literature suggest the predominant role of MTZ. The cephalosporins, indeed, have been associated with little hepatotoxicity and only rarely DILI due to these agents has been published in general population, mostly confounded by usage of other potential hepatotoxic medications and with no other cases reported selectively in patient affected by NER disorders. A special exception is ceftriaxone which has a unique clinical phenotype of liver injury with biliary sludge and stones due to crystallization of ceftriaxone in the biliary tract that we did not observe in our case. Whereas acute and clinically relevant liver injury from MTZ is also rare and MTZ is not listed among causes of DILI and acute liver failure, this has been reported in case of individuals with CS.–6 CS is a NER disorder characterized by profound postnatal decline of somatic and brain growth, with characteristic facies  and a poor prognosis (patients with CS have a very short life expectancy and rarely survive > 30 years). As previously mentioned, there are clinical reports of MTZ hepatotoxicity in CS. These cases displayed a short latency (1–7 days) to onset of jaundice, a hepatocellular pattern of enzyme elevations and a severe course with a high mortality rate. The mechanisms of MTZ hepatotoxicity are not known. MTZ is a prodrug metabolized in the liver by oxidative processes through the reduction of its nitrogroup and cyto-toxicity may be activated by deleterious interactions with DNA resulting in DNA strand breaks in susceptible microorganisms. The pathogenic mechanism favouring MTZ hepatoxicity in CS patients is undetermined but the constitutional DNA repair disorder affecting these patients may play a role, considering also that an underlying hepatic dysfunction is not unusual in CS patients. The association between CS and MTZ hepatotoxicity is now well-known and reported as an alert in the MTZ datasheet by various drug regulatory agency such as Emergency Medicines Agency and Food and Drug Administration.According to Roussel Uclaf Causality Assessment Method in assessing causality of drug induced liver injury,R value >5) and a severe course (high risk of liver failure). We supposed that the underlying mechanism of injury might be similar and related to the defect in the pathway of DNA-repair since both CS and XP belong to the group of NER disease. In the second phase, the prolonged cholestatic damage pattern that we observed, without dilation of the biliary tract and despite the gradually parallel decrease of aminotransferases, remains unclear. We considered the hypothesis of a vanishing bile duct syndrome secondary to DILI, which self-resolved, but could not be confirmed through a liver biopsy and we acknowledge this is the limit of the present case report.In our case, the first phase of the liver damage presented with a pattern of hepatotoxicity like the one typical of CS: short latency , a hepatocellular pattern (In summary, we presented the first case available in the literature of hepatotoxicity associated with MTZ treatment in a XP patient. Clinicians therefore, based on this report and according to the possible underlying mechanism shared with other genetic diseases characterized by alterations in the pathway of DNA-repair, should consider such adverse event also in patients affected by this rare disease.Conceptualization: Chiara Invernizzi, Jennifer Vanoli, Miriam Nava.Data curation: Chiara Invernizzi, Fabio Panizzuti, Miriam Nava.Supervision: Guido Grassi, Jennifer Vanoli.Validation: Guido Grassi.Writing – original draft: Miriam Nava.Writing – review & editing: Guido Grassi, Jennifer Vanoli.


The human epidermis is one of the first tissues in which the existence of stem cells was recognized and is one of the few in which ex vivo expansion for tissue repair is established clinically. Nevertheless, the nature of stem cells has been elusive. Using clonal growth assays of cultured keratinocytes as a quantitative measure of their abundance, several candidate stem cell markers have been described. Recently, the volume and quality of single-cell RNA-sequencing datasets have increased exponentially, providing new opportunities to explore the nature of epidermal stem cells and test the validity of in vitro experimental models. This Review is part of a series of articles invited from lectures presented at the 2021 Meeting of the European Society for Dermatological Research in celebration of its 50th Anniversary.The human interfollicular epidermis (IFE) is one of the tissues in the human body with a high cell turnover rate. Throughout adulthood, stem cells that are attached to the basal layer self-renew and give rise to the differentiating cells of the suprabasal spinous and granular layers, before losing their nucleus and cytoplasmic organelles and forming cornified cells that are shed from the skin surface . Under sEarly studies in rodents established that the basal cells of the IFE differ from one another. In some regions of mouse IFE, the keratinocytes are arranged in columns underlying a single stack of cornified cells . Basal cTo label slowly cycling stem cells, neonatal mice can be subjected to long-term DNA labeling with tritiated thymidine or BrdU, the rationale being that as the skin is expanding in the first days after birth, both stem and transit-amplifying cells are dividing and will be labeled . In adulAn elegant strategy was subsequently developed that enables fluorescent labeling of slow-cycling cells, thereby facilitating flow sorting of viable cells for further characterization. Transgenic mice expressing histone H2B–GFP through a tetracycline-responsive regulatory element are crossed with mice expressing a tet repressor under the control of a basal epidermal layer‒specific promoter. Adult mice are fed tetracycline for several weeks, corresponding to the chase period in DNA labeling studies, and the cells that retain GFP are slow-cycling cells .Whole-mount epidermal labeling methods have greatly facilitated the detection and quantitation of slow-cycling basal cells and also of basal cells that have initiated terminal differentiation. Intact sheets of human and mouse epidermis are separated from the underlying dermis enzymatically, labeled with appropriate antibodies, and then imaged by confocal microscopy, obviating the need to prepare histological sections . BrdU laIn summary, although the rate of cell division turns out not to be a robust marker of stem cells , it is eA different approach to exploring the heterogeneity of basal layer keratinocytes comes from studies of genetic mutations, whether induced by UV light or a manifestation of genetic skin disorders. Sun-exposed human skin contains clonal patches of p53-mutated keratinocytes that can be visualized by antibody staining of epidermal whole-mount preparations . The p532 per donor) of cancer-prone skin than in earlier studies . Up to 36% of EB patients with osaicism . In caseThe conclusion from these studies is that within the epidermal basal layer, lineage relationships between cells can be inferred on the basis of the heterogeneity of genetic mutations. Different basal cells give rise to clones of differing sizes, size being dependent on elements of stochastic behavior , and survival advantages that are potentially conferred by specific mutations or locations within the tissue.In parallel with the in vivo evidence for epidermal basal cell heterogeneity, techniques for culturing human keratinocytes have provided evidence for heterogeneity in vitro. The classic technique of plating human epidermal keratinocytes at clonal density on a feeder layer of 3T3 J2 cells  and subsClonal growth of human keratinocytes has become a well-established method for stem cell quantitation. One assay involves disaggregating apparently uniform clones and then, on replating, scoring them as paraclones, meroclones, or holoclones on the basis of increasing ability to form large secondary clones . AnotherUsing the simple clonal growth assay (rather than the holoclone assay) as a surrogate measure of the number of stem cells, it was possible to screen candidate cell surface markers of stem cells. The first reported marker was a high expression of β1 integrin extracellular matrix (ECM) receptors . ConsistIn addition to the search for markers of clonogenic epidermal stem cells, recent attention has focused on markers of commitment. These are genes that are expressed by basal cells that are no longer stem cells and are destined to differentiate but have yet to express suprabasal markers. The approach that we took was based on the observation that human keratinocytes undergo terminal differentiation when placed as a single-cell suspension in methylcellulose. We found that suspension-induced differentiation could be partially inhibited by β1-integrin ligation with antibodies or ECM proteins. However, after 4 hours in suspension, differentiation could not be inhibited, even though keratinocytes still expressed integrins and involucrin expression did not start to increase until 8 hours . We therBy integrating transcriptomic and proteomic data from keratinocytes held in suspension for different lengths of time, we identified a network of interacting protein phosphatases, including DUSP6, PPTC7, PTPN1, PTPN13, and PPP3CA, which are upregulated at 4 hours in suspension and promote differentiation by negatively regulating extracellular signal‒regulated kinase (ERK) MAPK and positively regulating activator protein 1 transcription factors . The prohi-Pulselo (stem) to Basalhi-Pulsehi were reversible, whereas Basalmid-Pulsehi cells were committed to undergo terminal differentiation. We found that basal ERK activity was regulated by DUSP10, whereas ERK pulses were regulated by DUSP6. This led us to speculate that DUSP6-mediated downregulation of ERK pulses promotes initiation of differentiation, whereas DUSP10-mediated downregulation of mean ERK activity promotes and stabilizes postcommitment differentiation  5 and K14 and as stem or transit-amplifying cells depending on whether or not they expressed the stem cell markers DLL1 and melanoma-associated chondroitin sulfate proteoglycan . The senWith some improvements in sensitivity, we went on to use single-cell global gene expression profiling not only to identify new makers of clonogenic keratinocytes but also to associate them with interacting signaling pathways, including ERK MAPK, which was already known to play a role in stem cell maintenance . We showThese early studies, although technically challenging and limited by sensitivity and by the number of cells analyzed, yielded new stem cell markers and suggested the power of analyzing global gene expression at single-cell resolution.Single-cell RNA-sequencing (scRNA-seq) studies received a major boost through rapidly advancing technology development, combined with the 2016 launch of the global initiative called The Human Cell Atlas (HCA) . The HCAWhereas previous studies focused on cultured keratinocytes , the newSimilar to all experimental approaches, there are limitations to scRNA-seq. In the case of human skin, one of the key concerns is whether all the cell types present in a sample have been isolated and therefore whether their relative abundance in the datasets reflects their relative abundance in the tissue. To illustrate the type of approach that can be taken, CDK1 and MKI67. The relative abundance of different integrin subunits differs across the basal clusters, with ITGA3 and ITGA6 most abundant in basal II and ITGA2 and ITGB1 most abundant in basal III. DLL1 and another stem cell marker that had been characterized in culture, CD46, are most highly expressed in basal II. In culture, CAV1 has been identified as a marker of DLL1 high stem cells  and suprabasal (K10) markers and high levels of the macrophage migration inhibitory factor receptor CD74.As well as obtaining evidence for basal cell heterogeneity, we could identify two clusters as transition states on the basis of the expression of DUSP6 and DUSP10 . DUSP6 iof DUSP6 . We coulCD46 and DLL1  are differentially expressed at the transcript level and may reflect differences in protein turnover rates. For example, in the human breast epithelial cell line MCF10A, the protein half-lives of ITGB1, ITGA6, and CAV1 are approximately 15, 23, and 45 hours, respectively . NotwithIn addition to comparing different keratinocyte states in healthy adult skin, it is possible to use publicly available datasets to examine the changes in cell states associated with skin disease. We have used the The relative abundance of the 13 keratinocyte clusters found in healthy adult skin is altered in lesional and nonlesional epidermis from patients with psoriasis and atopic dermatitis , consistIn recent years, the volume and quality of scRNA-seq datasets have increased considerably, providing new opportunities to explore the nature of epidermal stem cells and test the validity of in vitro experimental models. Overall, there is good agreement between the in vitro and in vivo datasets, and the changes in the relative abundance of different basal clusters suggest that there are changes in the stem cell compartment in psoriasis and atopic dermatitis. Nevertheless, there are many unanswered questions, including whether all skin cells are accounted for. The answer to this question is undoubtedly "no", given the under-representation of hair follicles and other adnexal structures in the existing datasets, the remarkable diversity of hair follicles, and the changes that take place during the hair growth cycle . FurtherOne of the current challenges―and opportunities―is to map the location of the different cell types revealed by scRNA-seq to specific spatial locations within the skin. Integration of high-dimensional multiomics approaches, including spatial transcriptomics and in situ sequencing, is already yielding interesting results . Furtherhttp://orcid.org/0000-0002-9188-1370Victor Augusti Negri: http://orcid.org/0000-0001-9151-5154Fiona M. Watt: FMW receives research funding from Unilever and POLA.


Malignant brain tumors represent approximately 1.5% of all malignant tumors. The survival rate among patients is relatively low and the mortality rate of pediatric brain tumors ranks first among all childhood malignant tumors. At present malignant brain tumors remain incurable. Although some tumors can be treated with surgery and chemotherapy, new treatment strategies are urgent owing to the poor clinical prognosis. Iron is an essential trace element in many biological processes of the human body. Iron transporters play a crucial role in iron absorption and transport. Ferroptosis, an iron-dependent form of nonapoptotic cell death, is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism. Recently, compelling evidence has shown that inducing ferroptosis of tumor cells is a potential therapeutic strategy. In this review, we will briefly describe the significant regulatory factors of ferroptosis, iron, its absorption and transport under physiological conditions, especially the function of iron transporters. Then we will summarize the relevant mechanisms of ferroptosis and its role in malignant brain tumors, wherein the role of transporters is not to be ignored. Finally, we will introduce the current research progress in the treatment of malignant brain tumors by inducing ferroptosis in order to explain the current biological principles of potential treatment targets and treatment strategies for malignant brain tumors. Brain tumors can be categorized as primary malignant types and secondary forms from metastasis . Of thesMalignant brain tumors are commonly intratumoral heterogenic, which likely explains their poor clinical prognosis of malignant brain tumors poor and easy to relapse . DespiteIron is necessary for life . Iron plFerroptosis is an iron-dependent form of regulated cell death . The intStarting from the iron transport in the body under physiological conditions, we further summarize the specific mechanism of iron metabolism disorder and ferroptosis in the pathological condition of malignant brain tumors, in particular, the crucial role of transporters. Finally, we summarized the specific mechanisms and targets for inducing ferroptosis in the treatment of malignant brain tumors and introduced potentially related drugs.Iron is a vital micronutrient for nearly all living organisms due to its significant role in many biological processes such as catalyzing redox reactions and transporting oxygen. In addition, iron is essential for the functions of many enzymes and prosthetic groups , 18.Iron is required across all human life stages, from embryological development, to infancy or old age. Estimated daily average iron requirements are the highest in pregnancy 3rd trimester . DespiteThe absorption site of iron is mainly in the mucosa of duodenum and upper jejunum. In a nutshell, iron absorption can be divided into two steps; first iron in food enters intestinal mucosal cells, second iron in intestinal mucosal cells crosses the cell membrane into capillaries and is transported systemically to the whole body in bloodstream .In humans, a number of proteins have evolved which tightly regulate iron homeostasis since we cannot rapidly excrete iron in the urine and iron must be transported and stored intracellular on a protein carrier due to extremely low free iron levels both systemically and intracellular . These i3+ ions. This iron carrier protein helps maintain iron availability systemically and prevents tissue oxidative damage caused by excessive free radical accumulation (Transferrin (TF) is regulator of free iron levels in body fluids, binding, sequestering, and transporting Femulation .SLC25A37  is a solute carrier localized in the mitochondrial inner membrane. When iron enters cells, Mfrn1 transport iron into mitochondria, which is used to synthesize mitochondrial heme and iron sulfur clusters. Mitoferrin-1 is necessary for neuronal energy metabolism and influences brain function .2+, is involved in systemic iron recycling and cellular iron absorption. DMT1 is located on the parietal membrane of duodenal intestinal epithelial cells, where it brings dietary free iron into cells and promotes iron absorption , is a proton-dependent iron importer of Fesorption . DMT1 issorption .SLC40A1 , is a major iron export protein, is expressed in many cells, such as placental syncytiotrophoblasts, wherein plays a role in transferring maternal iron to the fetus and releasing iron from tissue into the blood. It should be noted that inactivating the murine Fpn1 gene globally is embryonic lethal .Iron in the brain plays a crucial role in maintaining normal physiological function through its participation in many cellular activities such as mitochondrial respiration, myelin synthesis, neurotransmitter synthesis and metabolism . Iron isBlood-brain barrier (BBB) and blood cerebrospinal fluid barrier (BCSFB) are of great significance to maintain the relative stability of physical and chemical factors in the internal environment of brain tissue and prevent harmful substances in blood from entering brain tissue . The BBBHerein we provide a summary of recent literature unveiling the mechanism of iron transport and regulation across the BBB and BCSFB, as well as the characteristics of iron transport and metabolism in different cell types of the central nervous system (CNS) such as neurons, microglia, astrocytes, and oligodendrocytes.CNS is tightly sealed from the changeable milieu of blood by the BBB and the BCSFB . BBB is TF/TFR1 pathway may be the main route of iron transporter across the luminal  membrane of the BBB. Additionally, non-transferrin-bound iron (NTBI) uptake from the blood through luminal DMT1 and H-ferritin uptake may be partly responsible for iron transport across the BBB. Iron transport across the abluminal  membrane is a Fpn1/hephaestin (Fpn1/Heph) and/or Fpn1/ceruloplasmin (CP)-mediated process , 36.TF/TFR1/DMT1 pathway is an important pathway for iron transport across the BCSFB. Furthermore, iron export from the choroid epithelium to the CSF is mediated by the Fpn1/CP or Fpn1/Heph pathways. Beyond restriction of the access of substances from the blood to the CSF, it is possible that the BCSFB has a bigger impact on iron removal from the brain than iron uptake into the brain –37.Iron is essential for neuron development and function . First iThe neuronal expression levels of the TFR1 reflects their need for iron . DMT1 isMicroglia have vital roles in brain development and CNS homeostasis, including programmed cell death, clearance of apoptotic newborn neurons, as well as pruning developing axons and synapses , 48. Micvia the TFR1/DMT1 pathway, and after the release of iron in the acidic milieu of the endosome, this is translocated into the cytosol by DMT1 or other transporters  through Fenton reaction, promoting the oxidation of PUFAs on the cell membrane, greatly accelerating lipid peroxidation and ultimately causing cell damage or death  can transport manganese, iron and zinc Table 3.− on the cell membrane is composed of two core components, SLC7A11  and SLC3A2 , involved in the exchange of extracellular cystine (Cys2) by transporting intracellular glutamate (Glu)  Table 3 te (Glu) . Intracete (Glu) . In factte (Glu) . Ferropt cystine , while R cystine . Cys is  of TP53 , Nrf2  is dependent on SLC1A5 (Solute Carrier Family 1 Member 5) and SLC38A1 (Solute Carrier Family 38 Member 1) Table 3.In 2021, the World Health Organization (WHO) released the fifth edition of the Classification of Tumors of the Central Nervous System (CNS) (WHO CNS5). Among various brain tumors, childhood brain tumors, adult gliomas and meningiomas are currently the most common brain neoplasia. Neuroglioma is one of the common primary central nervous system tumors that originate from glial cells. GBM is the most malignant and deadliest type of neuroglioma . NeuroblRecently increasing numbers of studies have shown that ferroptosis is associated with the pathological process of a variety of neurological diseases, including neurodegenerative diseases, neurotrauma and brain tumors . NeverthSoon after ferroptosis was defined, researchers injected iron-containing water into the rats transplanted with glioma-35 cells and then focused on treating the tumor site with radiotherapy . They foAlthough most ferroptosis-related studies have concentrated on gliomas, neuroblastoma, another malignant brain tumor, is gradually coming into focus. Research suggests that overexpression of Mitochondrial ferritin (FtMt) in dopaminergic neuroblastoma cell line SH-SY5Y cells can significantly inhibit erastin-induced ferroptosis . This isIn a recently published study, researchers evaluated the expression of Merlin/Neurofibromin2 (NF2) and the ferroptosis regulator GPX4 in patients with primary meningioma and found a positive correlation between them. They speculated that the inactivation of NF2 in meningiomas may be more likely to cause ferroptosis. Furthermore, it has been determined that inhibition of NF2 and E-Cadherin can promote ferroptosis-related cytotoxicity and lipid peroxidation in meningioma cell lines. The transcription factor MEF2C has been shown to regulate the transcription of NF2 and E-cadherin genes. Silencing MEF2C, the expression levels of NF2 and E-cadherin in meningiomas decreased, which inhibited the growth of meningiomas mediated by ferroptosis Figure 1Ferroptosis plays a key role in the development of malignant brain tumors. As an important part of ferroptosis, relevant transporters can regulate amino acid metabolism and iron metabolism and are essential for the maintenance of iron homeostasis. Disorders of iron homeostasis in the brain will increase the risk of tumors, which may be one of the factors leading to the increased incidence of brain tumors . In addiThe obvious increase of lipid and cytoplasmic ROS is an important feature of ferroptosis and part of its regulatory factors have been used as small molecule drug targets to induce the death of cancer cells. Fpn1 can inhibit ferroptosis by reducing the accumulation of iron-dependent lipid ROS. Studies have found that in neuroblastoma cells, erastin induces the accumulation of iron and the low expression of Fpn1 involved in iron outflow . Further−/GPX4 pathway, resulting in increased intracellular cystine and enhanced antioxidant protection   or Nox4 Ferroptosis inducers may expand our arsenal of frontline therapeutic agents for combinatory approaches. Temozolomide toxicity operates is boost by ferroptosis . AndrogeAlthough many anticancer compounds that promote ferroptosis have been found, there are still many treasures to be discovered. Drugs targeting other mechanisms of ferroptosis need to be explored, such as targeted iron accumulation. A systematic assessment of the relationship between ferroptosis related genes (FRGs) expression profiles and the occurrence and development of tumors based on the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA) datasets and FerrDb datasets may unveil new targets , 132. InTo find out the potential correlation of GBM with transporters involved in ferroptosis. Here we compared the expression of several ferroptosis related transporters  in normal people and GBM patients based on TCGA data. It is worth mentioning that the differentially expressed genes (DEGs) covered the majority of the transporters that we screened related to ferroptosis. Box-plot shows the expressions of SLC3A2, SLC1A5, SLC40A1, SLC39A14 and TFR1 increased significantly, the expression of SLC38A1 decreased significantly  inhibitors can selectively inhibit ferroptosis in neurons, but promote ferroptosis in tumor cells, which may be due to its different epigenetic regulation on the two cells. The combination of HDAC inhibitors and ferroptosis inducers can not only reduce the dosage of ferroptosis inducers to reduce toxicity, but also protect neurons , 134. Na3O4 nanoparticles selectively and effectively strengthens ferroptosis of tumor cells , the Ministry of Science and Technology of China National Key R&D Programs (2018YFA0506903 to LC), Nation Science and Technology Major Projects for Major New Drugs Innovation and Development (2018ZX09711003-004-002 to LC), Tsinghua University Spring Breeze Fund (2021Z99CFY012 to LC), Tsinghua-Foshan Innovation Special Fund (2020THFS0133 to LC).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.


Historically, the process of epithelial polarity has been primarily described in relation to the localization and function of protein ‘polarity complexes.’ However, a critical and foundational role is emerging for plasma membrane lipids, and in particular phosphoinositide species. Here, we broadly review the evidence for a primary role for membrane lipids in the generation of epithelial polarity and highlight key areas requiring further research. We discuss the complex interchange that exists between lipid species and briefly examine how major membrane lipid constituents are generated and intersect with vesicular trafficking to be preferentially localized to different membrane domains with a focus on some of the key protein-enzyme complexes involved in these processes.The development of cell polarity in epithelia, is critical for tissue morphogenesis and vectorial transport between the environment and the underlying tissue. Epithelial polarity is defined by the development of distinct plasma membrane domains: the apical membrane interfacing with the exterior lumen compartment, and the basolateral membrane directly contacting the underlying tissue. The  Epithelial cells that line mucosal surfaces mediate many of the interactions between biological organisms and the outside environment. In the intestine, this includes a remarkable multi-functional remit, involving nutrient gathering via selective permeability, environmental sensing and surveillance, and defensive barrier function. A critical architectural feature that underlies these functions is the formation of cellular asymmetry or polarity, which consequently allows for vectorial movement of proteins, nutrients, ions and fluid across the epithelium. Epithelial cells contain two distinct plasma membrane domains, organized to direct vectorial transport and partition selective functions within the cell. Basolateral (or organism facing) membrane domains interface with the underlying tissue including the circulatory, lymphatic, immune and nervous systems in higher organisms, with the lateral aspect of this membrane mediating interactions between neighboring epithelial cells. Apical plasma membrane domains face the exterior lumen, and are primarily responsible for fluid, electrolyte and nutrient absorption or secretion, as well sensory and defense functions.The development and maintenance of epithelial cell polarity has been the subject of extensive investigations in a variety of model systems . StudiesLipids are the major constituents of cellular membranes and studies, primarily in cyst models systems, have highlighted their importance as primary drivers in organizing and defining the apical and basolateral membranes in mammalian epithelia. In cells, several different classes of lipids exist that help both define and functionally separate membranes within organelles, endosomal compartments and the plasma membrane as well as between specific nanodomains within membranes . These idrosophila salivary glands, trachea, and hindgut . The AMIS then progresses into a stage termed the pre-apical patch (PAP), where junctional membrane proteins begin to demarcate the separation of the apical and basolateral membrane . Lumen iplicated  as well Despite differences in cellular structure and function, many aspects of the protein machinery involved during polarization in epithelia are highly conserved across species and have been the topic of several extensive reviews . Three mThe initial formation of the apical membrane (AMIS) is characterized by movement and ultimately sequestration of polarity complexes to distinct membrane domains. The Par complex which includes various Par proteins , as well atypical protein kinase C (aPKC) and GTPase CDC42, is found at the early apical membrane before transitioning to its final location at tight junctions by interactions with ZO proteins, and forms the boundary between apical and basolateral membranes in terminally polarized cells . The ParFollowing initial apical membrane specification, the formation of intercellular junctions including tight, adherens and gap junctions are crucial for partitioning of apical and basolateral membrane domains and maintenance of polarity. Tight junctions are belt-like structures that form a selectively permeable barrier separating apical from basolateral surfaces. Tight junctions are composed of a variety of structural and cytoskeletal connecting proteins such as the occludins, claudins, and junction adhesion molecules (JAMs), in addition to zonula occludens (ZO) proteins . FollowiVesicular trafficking is thought to play a major role in correctly localizing proteins to apical and basolateral membrane. The plasma membrane and intracellular organelle membranes are in constant flux with one another via endocytosis, transcytosis, vesicular recycling at apical and basolateral domains, and secretion from the Golgi to the plasma membrane . MultiplFinally, the Ezrin, Radixin and Moesin (ERM) complex of proteins, which link membranes with the cytoskeleton, are important for localization of apical membrane proteins. Evidence for the importance of the ERM proteins in cellular polarity, and tissue morphogenesis come from studies where loss of function in any of the ERM proteins leads to aberrant polarity and lumen formation . PIs havAs briefly outlined above, the protein complexes involved during polarity formation have been extensively studied with a broad set of main players now well established. The regulation of sorting and membrane localization of these protein complexes is thought be directed by the underlying membrane lipid environment, and in particular the presence and interconversion of PIs.Lipids are the main constituents within all plasma membranes, and consist of phosphoinosities, glycosphingolipids, sterols, and phosphatidylserine among others. Phosphoinositides (PIs) consist of less than 1% of the lipids within the cellular membrane, yet have been implicated in a wide variety of cellular processes, including signaling, cytoskeletal and adhesion dynamics, protein complex formation, and cell division . A growiIn contrast to the phosphoinositides, there are relatively few studies of the involvement of glycosphingolipids, cholesterol, and phosphatidylserine in the regulation of cellular polarity. Glycosphingolipids (GSLs) and cholesterol provide membrane structure by forming membrane nanodomains known as lipid rafts , and GSLPIs represent a minor component of plasma membranes yet control a vast array of diverse cellular functions through their recruitment of protein effectors and interaction with various PI binding domains. PIs modulate several processes including actin polymerization, growth and survival signaling and vesicular trafficking . PIs areThe plasma membrane distribution of PIs changes considerably during the process of epithelial cell polarization. In the non-polarized cell state, PIP2 and PIP3 are thought to be equally distributed with areas enriched with PIP2 . As polaThe process of PI species interchange appears to be controlled by the membrane specific localization and trafficking of PI-kinases and phosphatases  within tPhosphoinositide-4-phosphate (PI(4)P) is the most abundant of the monophosphorylated PI species in the cell. PI(4)P can be phosphorylated by both PI-3 kinases and PI-5 kinases, and is often considered an intermediate in the biosynthesis of both PIP2 and PIP2. However, recent studies have shown that PI(4)P itself may be important for cellular function independently of its role in generating downstream PIPs species . PI(4)P Class III PI-4 kinases exhibit a distinct distribution, with PI4KIIIα found in the plasma membrane, ER and nucleus and PI4KIIIβ localized to the Golgi, TGN, nucleus, endosomes and exocytic vesicles  Figure . Class I(where in the cell this may impact PI(4)P, PIP2 or PIP2 biogenesis and subsequent polarity complex formation.PI4KIIIα is thought to be localized and function in membranes by assembly within a multi-protein complex, which includes the putative chaperone proteins, TTC7A/B, and Fam126, and tethered to the plasma membrane by the anchor protein Efr3  In yeast. Emergin and loss. As with and plas. FurtherThe other main monophosphorylated PI that may be involved in cell polarity is PI(3)P. PI(3)P is generated by Class I and III PI3-kinases or by dephosphorylation of PIP2 by INPP4A/B. PI(3)P has been primarily studied for its role in modulating autophagy . There aPIP2 is by far the most well studied PI species in epithelial cell polarization . PIde novo polarity generation, with later studies using the same models amending this hypothesis P2 is only enriched at the gap junctions with an equivalent distribution in the apical and basolateral domains P2 at the apical membrane, during its formation, opinions about its relative importance and position in the process of polarity have varied. Early studies in cyst models proposed PIP2 as the critical PI species during pothesis . Furtherpothesis , with sipothesis . Howeverpothesis , the lospothesis , rather pothesis . Further domains . More wo domains .Despite the lack of clear signaling functions in the cell, PIP2 is emerging as the potential key PI species in the establishment and maintenance of apical and basolateral surfaces. Historically, a role for PIP2 has been implicated in cell motility, and endocytosis . In polaHowever in recent and fascinating studies in epithelial cysts, a primary role for PIP2 in formation of the apical membrane has emerged . These sde novo polarity formation, and causes the presence in cysts of multiple lumens (PI(4P) to PIP2 biosynthesis may also play a role in polarity generation and lumen formation via the class II PI3kinase isoforms PIK3C2A, PIK3C2B and PIK3C2G. Loss of either PIK3C2A or PIK3C2B results in a loss of e lumens . Converse lumens . These de lumens . How PIKThe role of PIP2 in localizing polarity proteins appears to differ from PIP2. Loss of PIP2 generation does not appear to affect aPKC/Par6/Cdc42 or Annexin2 localization in contrast to loss of PIP2 . HoweverP3 is typically excluded from the apical membrane and localized at the basolateral membrane . PI3,4,. After t P3 to the basolateral domain.Overall, the current evidence suggests that the role of PIP3 in C. elegans intestine (Glycosphingolipids (GSL) are a class of glycolipids consisting of a ceramide backbone bound to a complex glycan headgroup. GSL synthesis is complex, with lipid synthesis originating in the ER with glycosylation (attachment of the glycan) occurring within the Golgi , resultintestine . A partintestine . AlthougS cerevisiae), in part due to localized clustering of PS at the apical membrane (Phosphatidylserine (PS) is a negatively charged phospholipid that displays a highly uneven distribution within cellular membranes and is essential for several cellular processes. PS biosynthesis occurs in the endoplasmic reticulum, followed by transport to the plasma membrane. Similar to PIs, phosphatidylserine serves several purposes within the cell, including modulating both protein localization and lipid homeostasis and localization . Phosphamembrane . The polmembrane . Furthermembrane  are essemembrane . The dynmembrane . Given tmembrane , and thamembrane  and PI(4membrane  are requApical-basolateral polarity generation and lumen morphogenesis are fundamental and multifaceted processes that occur across different organs and tissues. The protein complexes involved in this process have been generally studied extensively, while the role of the lipid components of membranes remains an emerging field. Several lipid species, including most notably the PIs have been identified as crucial for the correct sequence of events that underlies polarity generation. The exact proteins-complexes and lipid species that are involved, likely varies between epithelial cell types, and tube formation mechanisms may be subtly, but importantly, different between organs such as the kidney and the intestine. In intestinal epithelia, a variety of mechanisms contribute to the distribution of PIs, GSLs, and PS in the polarizing epithelium, with evidence emerging for a central role for protein-enzyme complexes important for PI species generation such the PI4KIIIα/TTC7, PTEN/CDC42 and Rac/Rho complexes. The relative importance of individual PI species in polarity remains to be fully understood, and further work is needed to investigate this aspect. It is, however, becoming increasingly clear that vesicular trafficking events are critical early in the process of defining the apical and basolateral membrane domains, although exactly how PIs are involved remains to be fully characterized.In summary, there is growing appreciation for the importance of membrane lipids such as the PIs, GSLs and PS in epithelial cell polarity. Future studies focusing on these membrane lipids, including overcoming the considerable technical challenges inherent in studying lipids, will help further illuminate our understanding of the process of polarization in epithelia.


Disbalances between the thyroidal content of these elements challenge the negative feedback regulation of the hypothalamus–pituitary–thyroid periphery axis, causing or facilitating common diseases related to disturbed thyroid hormone status such as autoimmune thyroid disease and metabolic disorders. Iodide is accumulated by the sodium-iodide-symporter NIS, and oxidized and incorporated into thyroglobulin by the hemoprotein thyroperoxidase, which requires local H2O2 as cofactor. The latter is generated by the dual oxidase system organized as ‘thyroxisome’ at the surface of the apical membrane facing the colloidal lumen of the thyroid follicles. Various selenoproteins expressed in thyrocytes defend the follicular structure and function against life-long exposure to H2O2 and reactive oxygen species derived therefrom. The pituitary hormone thyrotropin (TSH) stimulates all processes required for thyroid hormone synthesis and secretion and regulates thyrocyte growth, differentiation and function. Worldwide deficiencies of nutritional iodine, selenium and iron supply and the resulting endemic diseases are preventable with educational, societal and political measures.The adequate availability and metabolism of three essential trace elements, iodine, selenium and iron, provide the basic requirements for the function and action of the thyroid hormone system in humans, vertebrate animals and their evolutionary precursors. Selenocysteine-containing proteins convey both cellular protection along with H Various forms of thyroid cancer are the most frequent malignancies of the endocrine system [TH-related non-contagious disorders, benign and malignant, cover a broad spectrum from common (autoimmunity-related hypothyroidism) to rare diseases (Graves’ disease and thyroid cancer) challenging the global health system and economy due to the necessary diagnostic, therapeutic and monitoring measures. L-Thyroxine  supply are still in their infancy. Only a few years ago the human selenoproteome, encoded by 25 genes, was characterized  status for TH biosynthesis and thyroid function  Figure . An inad2). I2 easily sublimates, is volatile and strongly oxidizing. I2-containing  solutions may be used for drinking water disinfection or as skin and mucosal antiseptics and will oxidize unsaturated lipids under the release of iodide. The cloning, functional characterization and recent identification of the structure of the sodium-iodide symporter (NIS) provides detailed mechanistic insight into the efficient process of iodide accumulation across the basolateral membrane of thyrocytes against an electrochemical gradient [The thyroid accumulates the essential trace element iodine in its inorganic anion form, iodide, but not other iodinated molecules or molecular iodine .2O2-exposed thyroid follicular structure have been identified [Disorders of handling iodide along its path to TH, which impair the functions of TSHR, NIS, TG, TPO, DUOX/DUOXA2 and IYD, are known . Similarentified . Such alentified  and the entified .Most of these observations made in clinical studies and patient care have been substantiated by preclinical studies using dedicated animal models as well as cellular and molecular studies which enable the drawing of solid, intervention-based mechanistic conclusions and the establishment of clearcut cause–effect relationships with high clinical relevance, considering that the whole THS, its regulation and its individual components have been highly conserved along human ontogeny and phylogeny . Such crThe element iodine was more or less simultaneously discovered around 1811 by Bernard Courtois, Louis-Joseph Gay-Lussac and Sir Humphry Davy, and an adult healthy thyroid gland contains around 12–16 mg (0.5–1 mg iodine/g thyroid) . Most foRelationships between iodine supply and disorders of thyroid function, such as the evolution of endemic goiters and the occurrence of congenital hypothyroidism (formerly denominated under various categories of ‘cretinism’) at inadequate iodine intake, were observed especially in mountainous regions where the soil content of trace elements is low due to washouts during glacial periods. Nevertheless, these ideas also met strong opposition from highly influential scientists such as Virchow, who favored the then popular ‘miasm’ hypothesis to explain goitrogenesis and the development of ‘cretinism’. In his view, not iodine deficiency, as proposed in Switzerland and France, but ‘bad odors’, poor nutrition, housing, social status and related adverse environmental factors caused ‘cretinism’ . Obvioushttps://www.ign.org/newsletter/idd_feb16_euthyroid.pdf, accessed on 6 February 2023). While school children still obtain an adequate iodine supply, the situation in the adult population is still inadequate and deficient for pregnant women in several EU countries [3 in table salt has contributed to this situation. According to WHO data, 60% of the European population do not reach the lower limit of urinary iodine excretion (100 μg/L), which corresponds 40 Mio children and more than 430 Mio adults [http://whqlibdoc.who.int/publications/2007/9789241595827_eng.pdf; https://data.unicef.org/topic/nutrition/iodine/, accessed on 6 February 2023). In European countries with the voluntary use of iodinated salt , only in two of the nine countries do pregnant women reach a urinary iodine excretion higher than 100 (μg/L), which indicates a clear risk of impaired brain development and intelligence quotient (IQ) losses of up to 15 points [Recent EU-funded surveys revealed a sobering impression of the European iodine status, indicating that there is still a very long way to go to reach the goal of “Euthyroid: making Europe smarter with iodine”   and nitrogen (NOS) species [Selenoproteins scavenge the excess H species . Such da species . This isAssociations between nutritional Se intake, serum Se status and the prevalence of thyroid-hormone-related diseases had been reported during the last three decades, mainly in small observational or interventional studies in various regions, subpopulations and study groups with different basal Se intakes ,36. OnlyRemarkable associations between dietary Se intake, based on two 24 h dietary recall interviews, and serum thyroid hormone concentrations have recently been reported by a NHANES study with more than 5500 US adult participants. Increased Se intake was negatively correlated with total T4 and the total T4/total T3 ratio, especially in males with adequate iodine intake. Authors discussed that in females, the stronger effect of sex steroid status might obliterate such relationships and that adequate Se intake might stimulate T3 formation by the deiodinase selenoproteins . An inveUnder conditions of inadequate iodine intake, Se supplementation might be counterproductive and iodine deficiency needs to be remediated to an adequate intake before Se compounds are administered. This has been documented by an inadvertent observation during the initial attempts to restore essential trace element status in a population with too-low nutritional iodine and Se intake in Central Africa . Among tA high Se content in mouse thyroids was even found under conditions of very low Se intake (0.2 ppm) . While o2O2-dependent oxidative reactions of iodide oxidation to an iodonium intermediate, followed by (ii) the iodination of selected tyrosyl-residues of TG, the protein enabling synthesis, storage and secretion of TH, and finally, the coupling of selected diiodo-tyrosine (DIT) residues of TG to T4, or of one DIT and one monoiodo-tyrosine (MIT) to T3. The heterodimeric complex of dual oxidase  and its maturation factor, DUOXA2, generates the required H2O2 in a NADPH-dependent reaction maintained by the pentose phosphate cycle [The third essential trace element required for regular TH biosynthesis and function is iron. The body of an adult human contains about 4 g (0.005% body weight) of iron, mostly in hemoglobin and myoglobin, but also in a variety of cytochromes and other hemoproteins containing Fe central atom of the prosthetic groups in their active site, such as thyroperoxidase . TPO, solely expressed by thyrocytes and related to myeloperoxidase and lactoperoxidase, is the multifunctional key enzyme of TH biosynthesis . It catate cycle . These pte cycle  at the ate cycle . The detIron deficiency and anemia are associated with hypothyroidism probably due to the impaired biosynthesis of the hemoprotein TPO, but the central feedback regulation of the HPTP axis is also disturbed . On the −2 or H2Se) in an ATP-dependent process to activated selenophosphate, which phosphorylates seryl-tRNA synthetase Sec using the activated selenophosphate. This Se-containing aminoacyl-tRNA can then occupies a ribosomal free A-site for the cotranslational incorporation of Sec into the nascent polypeptide chain encoded by a selenoprotein mRNA. UGA triplets in these transcripts encode the cotranslational incorporation of Sec if a stable hairpin loop structure, the selenocysteine insertion sequence (SECIS-element), is located downstream of the UGA in the 3′-noncoding region of a selenoprotein mRNA. The SECIS element is recognized by SECIS-binding protein 2, which then recruits elongation factor 2 to steer the incorporation of Sec at the UGA codon position. In the absence of Se or any of these factors, a UGA codon will lead to ribosome pausing and the premature termination of the protein chain [2- or Se2− released from other completely reduced Se-compounds, is available for the regulated biosynthesis of Sec-containing selenoproteins. Altered Se status and the disturbed function of selenoproteins will have a major impact on the homeostasis of various metabolic, structural and regulatory aspects of a living individual, eventually jeopardizing its health and survival [The essential trace element Se is incorporated into proteins either as selenomethionine (SeMet) or as selenoysteine , the 21st proteinogenic amino acid  Figure . The latnthetase . The enzin chain ,61. In cin chain . While Sin chain . The terin chain ,65. Methin chain . One of in chain . In contsurvival .2O2-. DIO1 and DIO2 are highly expressed in a species-dependent pattern, as well as stimulated by TSH- or Graves’-IgG-dependent cAMP-mediated signaling [The human thyroid gland, similar to other endocrine tissue, is characterized by one of the highest Se contents per gram of tissue in a healthy individual consuming a balanced nutrition . This Seignaling ,74. In aignaling . TG is tignaling  typicallignaling . In sectTrsp gene [Scly inactivation [Sbp2 in mice results in the markedly decreased expression and/or activity of several selenoproteins in a tissue-specific manner and a thyroid hormone pattern in serum  mimicking the phenotype of such mutations in humans [Significant insight into the complex network of incorporation, retention and release of Se by specific selenoproteins has been obtained from the systematic manipulation of the expression of selenoproteins using genetic models in mice where specific selenoprotein genes have been inactivated, mutated or transgenically expressed either globally or conditionally in a cell-/tissue-specific manner ,79. The rsp gene , which ctivation  blocks tn humans . Some ofn humans . Neverth2O2, did not result in the expected destructive process of the follicular organization and function of the thyroid [2O2  and ROS derived therefrom compensate  for absent selenoproteins?A complete inactivation of selenoprotein synthesis in mouse thyroid follicular epithelial cells, intended to test their presumed antioxidative function during the life-long production of H thyroid . Even ch thyroid ,86; (ii)Currently, it is not clear how and to what extent Se is transported to the thyroid and which factors contribute to its accumulation, which might solely be caused by the high expression levels of various selenoproteins . The gloSe Status and selenoprotein functions are not only relevant to TH biosynthesis but also essential for TH activation and inactivation as well as for iodine homeostasis and excretion. No information is yet available whether TH distribution in the blood  or TH trThe identification of DIO1 as a selenoprotein, the subsequent cloning of the DIO1 gene, quickly followed by those of DIO2 and DIO3, opened a new era for the better understanding of TH homeostasis and the nutritional impact of trace elements on the TH system. Subsequent to the GPX family, the three DIOs were the second enzyme group whose function and reaction mechanisms critically depend on Sec in their active sites . The TXNAn inadequate Se status impairs DIO function, enhances the formation of TH conjugates  ,95, prevTHRA, THRB) and occurring in various protein isoforms and isotypes depending on the tissue-specific splicing of their transcripts, is sensitive to a redox control similar to the other 49 members of the c-erbA family of ligand-modulated (nuclear) receptors [The T3-receptor protein family, encoded by two different genes  in vitro basis . Even ifWhile cellular and animal experimental data might indicate the major adverse effects of severe Se deficiency and excess on the THS, conditions occurring in human healthy life and diseases might be less extreme and also prevented by multiple compensatory mechanisms. Exceptions obviously will be seen in case of monogenetic diseases affecting components of the Se system , or clin0 bound to various polymeric carriers composed of inorganic or organic (charged and/or coated) building blocks. Whether any elemental Se0, an inert metal, will be bioavailable at all and subsequently incorporated into selenoproteins, which exert most of the biological  effects of the essential trace element, seems to be unclear. If Se0 will not be reduced to Se Se−2, no UGA-codon-dependent incorporation into selenoproteins may occur, and if not oxidized to selenite Se+4 or selenate Se+6, no stochastic incorporation into SeMet and SeMet-containing proteins will occur, resulting in a higher retention of Se in the protein pool of the organism. Some limited information has been reported on microbial reduction of elemental Se0. Whether and to what extent this may be accomplished by the gut microbiome needs to be studied before such (adjuvant) Se supplements can be declared as safe and relevant.While natural nutritional sources of Se intake are mainly based on Sec as a constituent of selenoproteins and SeMet-containing proteins, commercially available Se supplements come in various inorganic and organic forms. This variability is one reason for the divergence in clinical (pilot) studies which mainly are underpowered, short and lack clear information on basal Se status and the detailed speciation of the Se content of the preparations used ,103. Rec2- formed in vivo from such precursors or released by Scly, catalyzing Sec metabolism, rapidly interacted with bivalent heavy metal cations such as Hg, Cd, Pb, etc., forming virtually insoluble selenides deposited at their site of formation, mainly in the kidney, endocrine tissues rich in selenoproteins, and in the brain. The solubility products of these heavy metal selenides is below 10−55 mol2·L−2 and they will probably “never” be redissolved again in a living organism. These also contribute to the high heavy metal content of seafood and sea fish [A similar Se speciation issue is encountered when Se tissue contents were analyzed under regular nutritional intake and after the consumption of Se supplements or Se-containing drugs. Sesea fish ,110, lea2+, soluble ion or “innocent” HgSe or HgS) is contained in a sample!This simple inorganic chemistry is mostly neglected if fancy high-tech labs with expensive machines and methods perform and communicate their  analytics and avoid specifying exactly which chemical species . However, adequate iodine availability and thyroidal processing to TH is not the only bottleneck ensuring a regular thyroid gland performance during fetal development and throughout life. Similarly limiting are the persistent nutritional availabilities of the two other essential trace elements, selenium and iron, both of which are required not only for biosynthesis of the iodine-containing TH by the gland but also for their systemic availability and action. Unlike iodine, which is ‘stockpiled’ for up to three months in the TG-containing colloid of the angiofollicular units of a healthy thyroid gland, both Se and Fe need to be constantly delivered via adequate balanced nutrition [Although the crucial role of the adequate supply of the essential trace element iodine for regular thyroid function and TH biosynthesis has been known for more than a century, no successful worldwide measures have yet been achieved which have resulted in a globally sufficient nutritional iodine intake or the cheap prevention of the simply avoidable fatal medical and societal impact of iodine deficiency and its multiple sequelae . Most ofutrition ,113,114.utrition ,116. ForCurrently, our knowledge about thyroidal uptake, utilization and potential storage mechanisms for Se und Fe, and the interaction of such mechanisms with the thyroid utilization and homeostasis of the iodine system is lacking and thus purposeful basic and clinical research on these relevant interactions is urgently needed. Only limited experimental and clinical evidence for the need of a balanced supply of I and Fe on the one hand ,114,117,More clear are the relationships between I and Se based on animal experimental data and some  clinical observations ,122,123.