Exposure to metals during early pregnancy may affect maternal glucose metabolism. We were aimed to assess the associations between early pregnancy whole blood concentrations of copper (Cu), zinc (Zn), calcium (Ca), iron (Fe), and magnesium (Mg) with GDM later in the second trimester among pregnant women in Northwest China.

This study included 5478 first-trimester pregnant women who participated in the birth cohort of the Northwest Women's and Children's Hospital between July 2018 and December 2023. Metal concentrations, basic demographic characteristics, lifestyle and behavior patterns were collected. An oral glucose tolerance test was performed in the second trimester. A generalized linear model was used to analyze the effects of metal concentrations on GDM. A two-piecewise regression model was adopted to examine the threshold effect and find out the turning point. Weighted Quantile Sum (WQS) regression was conducted using a dataset randomly split into training and validation sets at a 4:6 ratio to investigate the association between metal mixtures and GDM.

Compared to the lowest tertile, the middle (RR = 0.82, 95%CI = 0.71, 0.95) and highest (RR = 0.84, 95%CI = 0.73, 0.97) tertiles of Ca concentrations could decrease the risk of GDM. However, the highest tertile of Cu concentration could increase the risk of GDM (RR = 1.18, 95%CI = 1.01, 1.39). Additionally, a non-linear relationship between Ca concentration with GDM and FPG was observed. The risk of GDM (RR = 0.08, 95%CI: 0.02, 0.31) and FPG (β=-0.56, 95%CI: -0.99, -0.12) decreased with 1 unit increase in ln-transformed Ca concentration below the turning point. However, the WQS index of maternal mixed metals was not correlated with the incidence of GDM (RR = 1.08, 95%CI = 0.98, 1.19).

Higher Cu concentration during early pregnancy may increase the risk of GDM in mothers. Increased Ca concentration may reduce the risk of GDM and lower the concentration of FPG below the turning point. Our findings could provide an early marker for potentially modifiable risk factors associated with maternal glucose dysregulation during pregnancy.

The antidiabetic activity of the novel Buckwheat protein-derived peptide (Ala-Phe-Tyr-Arg-Trp, AFYRW) and its associated protein glycosylation have been verified. Our preliminary study demonstrates the potential of AFYRW as a therapeutic agent for diabetes, but the mechanism needs further investigation. Given the vital role of O-linked N-acetylglucosamine transferase (OGT) in diabetes mellitus and insulin resistance (IR), we focused on the underlying molecular mechanisms of them in ameliorating IR. We found AFYRW protects against hyperglycemia in diabetic mice and improves glucose metabolism in an IR cell model. Mechanistically, we demonstrated that AFYRW decreases glutamine-fructose-6-phosphate amidotransferase (GFAT) expression via X-box binding protein 1 (XBP1) in the hexosamine biosynthesis pathway (HBP), consequently decreasing OGT and stimulating the SIRT1/PGC1α pathway. Of note, the overlapping roles of increased SIRT1 and decreased OGT caused by AFYRW ameliorated IR. The data presented here show that AFYRW contributes to metabolism by directly controlling glucose homeostasis. Taken together, our study unveils that AFYRW protects against both insulin resistance and diabetes mellitus-induced hyperglycemia through OGT to regulate the SIRT1/PGC1α pathway, which provides a mechanistic basis for novel AFYRW to be a potential therapeutic agent.

Studies have shown a strong correlation between excess iron and the development of gestational diabetes mellitus (GDM), though iron is an essential trace element during pregnancy. This study aims to investigate the precise relationship between iron storage levels during late pregnancy and the development of GDM, trying to find out ways to meet pregnant iron storage requirements and reduce GDM risk simultaneously.

A non-anemic population consisting of 9,512 healthy singleton pregnant women were included in this study. Serum ferritin (SF) levels during the second and third trimesters and other clinical information were retrospectively collected. Restricted cubic splines (RCS) were performed to examined the non-linear associations between SF level and the GDM incidence as well as blood glucose related indicators during the second trimester. Moreover, the association between the variation of HbA1c levels and the fluctuation of SF levels throughout the third trimester was also explored with the method of RCS.

Overall, women with GDM had slightly higher median SF level than women without GDM 20.5 (13.3, 32.3) vs. 19.8 (12.9, 30.5), P = 0.017) in the second trimester. A U-shaped relationship between GDM risk and SF levels in the second trimester was established after accounting for other cofounding factors (P < 0.001 for nonlinearity). Both GDM and non-GMD women revealed a significant negative relationship between hemoglobin A1c (HbA1c) and SF levels (P < 0.001 for nonlinearity for both). The 1-hour post-glucose load plasma glucose showed a positive correlation tendency with SF levels (P = 0.748 for nonlinearity) in GDM women, while the relationship between these two variables was not obvious in non-GDM women (P = 0.045 for nonlinearity). Generally, the levels of HbA1c rose in the trimester, however, maintaining a high SF level throughout the third trimester would substantially increase the HbA1c level among GDM women with high SF levels (> 30ng/ml) in the second trimester (P < 0.001 for nonlinearity).

GDM might result from high or low SF levels during the second trimester. Iron supplementation during pregnancy should be administered judiciously based on blood glucose level and iron storage capacity to maintain the SF level within an appropriate range.

Gestational diabetes mellitus (GDM) is a glucose metabolism disorder with an unclear etiology that occurs specifically during pregnancy. While elevated serum ferritin levels have been reported to increase the risk of GDM, these findings lack validation in large-scale studies and have yet to inform clinical practice effectively. This study enrolled 12,434 controls and 3599 GDM patients and employed binary multifactorial logistic regression, restricted cubic spline, propensity score matching, and a random forest algorithm to explore the relationship between serum ferritin and GDM, as well as the effect size of ferritin on GDM. The results indicated that GDM patients have higher serum ferritin levels compared to controls in the second and third trimesters. A weak correlation was found between serum ferritin levels and OGTT 1-hour and 2-hour blood glucose levels in the second trimester. Logistic regression (LR) and restricted cubic spline (RCS) analyses showed a significant positive correlation between serum ferritin levels and GDM in the second and third trimesters. Propensity score matching analysis indicated that the association between second-trimester serum ferritin levels and GDM remained nearly constant before and after matching. The random forest algorithm suggested that among all confounders, serum ferritin had a minimal effect on GDM risk. In conclusion, our study provides further compelling evidence for the association between serum ferritin levels and gestational diabetes mellitus. However, additional research is still needed to clarify the specific mechanisms underlying this association.

Alcohol consumption is associated with reduced expression of hepcidin, a key iron-regulatory hormone, which may lead to accumulation of iron in the body. Although polyphenols from wine may have effects on hepcidin expression and iron absorption contrary to that of alcohol, we recently showed that consumption of 300 ml of red wine for 3 weeks, after an alcohol-free lead-in period of 2 weeks, resulted in decreased serum hepcidin in apparently healthy individuals (n = 13) and subjects with type 2 diabetes (T2D) (n = 18). To determine the mechanism of decrease in hepcidin after wine intervention, additional biochemical analyses of spare serum samples from the same subjects were performed. The decrease in hepcidin was accompanied by increased erythropoietin levels in both groups, while the increase in erythroferrone reached statistical significance only in the T2D group. These results suggest activation of the erythropoietin-erythroferrone-hepcidin pathway by red wine consumption. As an indicator of the activation of the erythropoietin-erythroferrone-hepcidin pathway we observed an increase in the red cell distribution width in both groups and in the reticulocyte count in the T2D group, while serum ferritin decreased. Our study reveals a novel biological effect of wine that may be important in conditions influencing iron homeostasis and functions of hepcidin in general.

Osteoarthritis (OA) is a chronic, degenerative joint disease primarily characterised by damage to the articular cartilage, synovitis and persistent pain, and has become one of the most common diseases worldwide. In OA cartilage, various forms of cell death have been identified, including apoptosis, necroptosis and autophagic cell death. Ever-growing observations indicate that ferroptosis, a newly-discovered iron-dependent form of regulated cell death, is detrimental to OA occurrence and progression. In this review, we first analyse the pathogenetic mechanisms of OA by which iron overload, inflammatory response and mechanical stress contribute to ferroptosis. We then discuss how ferroptosis exacerbates OA progression, focusing on its impact on chondrocyte viability, synoviocyte populations and extracellular matrix integrity. Finally, we highlight several potential therapeutic strategies targeting ferroptosis that could be explored for the treatment of OA.

Iron is known to play a role in glucose homeostasis, and diabetes is highly prevalent in patients with iron overload. Here, we investigated whether ferritin and hepcidin (as parameters of iron status) are associated with the development of post-transplant diabetes in kidney transplant recipients, a population in which around 10 % is known to have high iron status.

Prospective data from the TransplantLines Insulin Resistance and Inflammation Biobank and Cohort Study from the University Medical Center Groningen, the Netherlands were evaluated, involving stable adult kidney transplant recipients > 1 year after transplantation. Associations between ferritin and hepcidin levels, as markers of iron status, and incident post-transplant diabetes were analyzed by multivariable Cox regression models, followed by the exploration of potential clinical cut-offs of ferritin levels related to the risk of post-transplant diabetes.

Of the included 443 kidney transplant recipients (age 50 ± 12 years, 44 % women, median 6.1 [3.0 - 12.1] years after transplantation), 65 kidney transplant recipients (15 %) developed post-transplant diabetes during a median follow-up of 9.6 [6.3 - 10.2] years. In contrast to hepcidin levels, ferritin levels were significantly associated with incident post-transplant diabetes, independent of adjustment for potential confounders (HR per 50 µg/l, 1.08; 95 % CI 1.02 - 1.14). When analyzing specific clinical cut-offs of ferritin levels, kidney transplant recipients with a ferritin > 500 µg/l (n=40) had more than twice the risk of developing post-transplant diabetes, compared to kidney transplant recipients with ferritin < 100 µg/l (HR, 2.81; 95 % CI 1.04 - 7.55).

Increased levels of ferritin are independently associated with a higher risk of post-transplant diabetes in kidney transplant recipients. Especially, kidney transplant recipients with ferritin levels > 500 µg/l, seem susceptible to the development of post-transplant diabetes over time.

Objectives: This study aimed to compare the pancreatic volume between beta-thalassemia major (β-TM) and beta-thalassemia intermedia (β-TI) patients and between thalassemia patients and healthy subjects and to determine the predictors of pancreatic volume and its association with glucose metabolism in β-TM and β-TI patients. Methods: We considered 145 β-TM patients and 19 β-TI patients enrolled in the E-MIOT project and 20 healthy subjects. The pancreatic volume and pancreatic and hepatic iron levels were quantified by magnetic resonance imaging. Results: The pancreatic volume indexed by body surface area (PVI) was significantly lower in both β-TI and β-TM patients compared to healthy subjects and in β-TM patients compared to β-TI patients. The only independent determinants of PVI were pancreatic iron in β-TM and hepatic iron in β-TI. In β-TM, there was an association between alterations of glucose metabolism and PVI, and PVI was a comparable predictor of altered glucose metabolism compared to pancreatic iron. Only one β-TI patient had an altered glucose metabolism and showed a reduced PVI and pancreatic iron overload. Conclusions: Thalassemia syndromes are characterized by a reduced pancreatic volume, associated with iron levels. In β-TM, the pancreatic volume and iron deposition are associated with the development and progression of alterations of glucose metabolism.

Wound healing is a complex biological process involving multiple steps, including hemostasis, inflammation, proliferation, and remodeling. A novel form of regulated cell death, ferroptosis, has garnered attention because of its involvement in these processes. Ferroptosis is characterized by the accumulation of lipid peroxides and is tightly regulated by lipid metabolism, iron metabolism, and the lipid-peroxide repair network, all of which exert a significant influence on wound healing. This review highlights the current findings and emerging concepts regarding the multifaceted roles of ferroptosis throughout the stages of normal and chronic wound healing. Additionally, the potential of targeted interventions aimed at modulating ferroptosis to improve wound-healing outcomes is discussed.

Iron status plays a crucial role in various physiological processes, and its dysregulation is associated with numerous health conditions. However, research on the relationship between iron status and diabetic kidney disease (DKD) is quite limited. Therefore, this study aims to investigate the connection between iron status and DKD.

This population-based cross-sectional survey included adult diabetes patients from five National Health and Nutrition Examination Survey (NHANES) cycles spanning 1999 to 2006 and 2017 to 2018. Regression models were used to assess the impact of iron status on the prevalence of diabetic nephropathy. Restricted cubic spline models further explored potential nonlinear dose-response relationships. Subgroup analyses clarified the effects of other covariates on these associations. Iron and TIBC were negatively correlated with DKD, albuminuria, and low estimated glomerular filtration rate (eGFR). TSAT was negatively correlated with DKD and showed an "L"-shaped nonlinear correlation with albuminuria and low-eGFR. Ferritin exhibited a "J"-shaped nonlinear correlation with DKD, albuminuria, and low-eGFR. Subgroup analysis revealed that the association between TIBC and reduced risk of low eGFR was more pronounced in individuals with hypertension. The associations between iron and TSAT with a reduced risk of DKD were more significant in smokers, while the association between ferritin and an increased risk of albuminuria was also more pronounced in smokers.

In diabetic patients, iron status is closely associated with DKD. Monitoring these iron status markers can help improve the prevention and management of kidney health in diabetic patients.

Intravascular hemolysis releases hemoglobin (Hb) from red blood cells under specific conditions, yet the effect of hemolysis in aquaculture systems remain poorly understood. In this study, a continuous hemolysis model for grass carp was established by injection of phenylhydrazine (PHZ) to investigate the mechanistic impacts of sustained hemolysis. PHZ-induced hemolysis altered liver color, and subsequent hematoxylin and eosin staining revealed substantial Hb accumulation in the head kidney, accompanied by inflammatory cell infiltration and vacuolization in liver tissue. Quantitative real-time PCR and western blotting confirmed that PHZ treatment significantly upregulated Real-time fluorescence quantitative PCR and Western blot confirmed that PHZ treatment significantly up-regulated the expression of iron metabolism-related genes and proteins, including transferrin (Tf), ferritin, ferroportin 1 (FPN1), transferrin receptor 1 (TfR1), nuclear receptor coactivator 4 (NCOA4), divalent metal transporter 1 (DMT1), and six-transmembrane epithelial antigen of prostate 3 (STEAP3). Further investigation of PHZ-induced hemolysis effects on tissues showed that inflammation- and antioxidant enzyme-related genes in the liver and head kidney were significantly upregulated, indicating that hemolysis activated the antioxidant system and intensified inflammatory responses. Perls' staining revealed iron deposition in the head kidney and liver at ten and fourteen days post-PHZ injection. Moreover, β-galactosidase staining and transmission electron microscopy showed increased cellular senescence and mitochondrial damage, respectively, as a result of PHZ-induced hemolysis. In vitro assays with hemin treatment demonstrated increased Fe2+ content in CIK and L8824 cells, which induced oxidative stress, upregulated iron metabolism and inflammatory genes, and ultimately led to cell death. These findings suggest that excessive Hb release during sustained hemolysis leads to iron overload, elevates reactive oxygen species production, disrupts antioxidant balance, and ultimately causes cellular damage.

In this editorial, we have commented on the article that has been published in the recent issue of World Journal of Clinical Cases. The authors have described a case of unilateral thyroid cyst and have opined that the acute onset of infection may be linked to diabetes mellitus (DM). We have focused on the role of nutrition in the association between DM and infection. Patients with DM are at a high risk of infection, which could also be attributed to nutrition-related factors. Nutritional interventions for patients with diabetes are mainly based on a low-calorie diet, which can be achieved by adhering to a low-carbohydrate diet. However, dietary fiber supplementation is recommended to maintain the diversity of the gut microbiota. Furthermore, high-quality protein can prevent the increased risk of infection due to malnutrition. Supplementation of vitamins C, vitamins A, vitamins D, and folic acid improves blood sugar control and facilitates immune regulation. Mineral deficiencies augment the risk of infection, but the relationship with diabetes is mostly U-shaped and a good intake should be maintained.

Review the latest data regarding the intersection of adipose tissue (AT) and iron to meet the needs of AT metabolism and the progression of related diseases.

Iron is involved in fundamental biological metabolic processes and is precisely fine-tuned within the body to maintain cellular, tissue and even systemic iron homeostasis. AT not only serves as an energy storage depot but also represents the largest endocrine organ in the human body, maintaining systemic metabolic homeostasis. It is involved in physiological processes such as energy storage, insulin sensitivity regulation and lipid metabolism. As a unique iron-sensing tissue, AT expresses related regulatory factors, including the classic hepcidin, ferroportin (FPN), iron regulatory protein/iron responsive element (IRP/IRE) and ferritin. Consequently, the interaction between AT and iron is intricately intertwined. Imbalance of iron homeostasis produces the potential risks of steatosis, impaired glucose tolerance and insulin resistance, leading to AT dysfunction diseases, including obesity, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Despite the role of AT iron has garnered increasing attention in recent years, a comprehensive review that systematically organizes the connection between iron and AT remains lacking. Given the necessity of iron homeostasis, emphasizing its potential impact on AT function and metabolism regulation provides valuable insights into physiological effects such as adipocyte differentiation and thermogenesis. Futhermore, regulators including adipokines, mitochondria and macrophages have been mentioned, along with analyzing the novel perspective of iron as a key mediator influencing the fat-gut crosstalk.

The objective of this study was to investigate the potential associations between serum iron levels, dietary iron intake, and iron supplementation, and the prevalence of metabolic syndrome (MetS) in adolescents A cross-sectional analysis was conducted, utilizing data from adolescents participating in the 2003-2018 cycle of the National Health and Nutrition Examination Survey (NHANES). Odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) pertaining to serum iron, dietary iron, and iron supplementation were derived through multivariate logistic regression models. Additionally, a restricted cubic spline (RCS) regression model was applied to explore the nonlinear relationship between dietary iron and serum iron concerning MetS. The study encompassed 4858 American adolescents aged 12 to 19, among whom 413 (8.5%) manifested MetS. The study cohort exhibited an average age of 15.52 years, comprising 2551 males (52.51%) and 2307 females (47.49%). Relative to individuals in the lowest serum iron quartile, those in the highest quartile for serum iron (OR = 0.33, 95% CI 0.21-0.50), the highest quartile for dietary iron (OR = 0.53, 95% CI 0.32-0.89), and those utilizing iron supplements (OR = 0.61, 95% CI 0.37-0.99) evinced a diminished prevalence of MetS, even post adjustment for potential confounding variables. A non-linear relationship was discerned between serum iron and MetS, exhibiting a statistically significant negative correlation when serum iron concentrations exceeded the inflection point (serum iron = 8.66 µmol/L, P for nonlinear < 0.001). This investigation reveals that higher levels of serum iron, increased dietary iron intake, and the use of iron supplements are linked to a lower prevalence of MetS in US adolescents. These findings suggest that dietary modifications could play a role in promoting the health of adolescents.

Thalassemia is a hereditary blood disorder characterized by reduced hemoglobin production, leading to chronic anemia. A major complication of thalassemia is iron overload, primarily due to regular blood transfusions and increased gastrointestinal iron absorption, which can lead to iron overload cardiomyopathy, a significant cause of morbidity and mortality in thalassemia patients. This review aims to provide an in-depth analysis of the pathophysiological mechanisms underlying iron overload cardiomyopathy in thalassemia, examining how excessive iron accumulation disrupts cardiac function through oxidative stress, cellular damage, and altered calcium homeostasis. Clinical manifestations, including fatigue, arrhythmias, and heart failure, are discussed alongside diagnostic strategies such as echocardiography and cardiac MRI for early detection and monitoring. Management approaches focusing on iron chelation therapy, lifestyle modifications, and advanced interventions like gene therapy are explored. The review also highlights the importance of early diagnosis, regular monitoring, and patient adherence to therapy to prevent the progression of cardiomyopathy. Recent advances in treatment and future research directions, including personalized medicine, and gene editing technologies, are presented. Addressing the challenges in managing iron overload in thalassemia patients is crucial for improving outcomes and enhancing quality of life.

Little information is available on iron with diabetes risk among African Americans, a population where both anemia and elevated ferritin are common. We tested whether plasma proteomic measurements of ferritin and transferrin were associated with increased diabetes risk in a cohort of current and former African American (NHB) and Non-Hispanic White (NHW) smokers.

NHB and NHW participants from the COPDGene study who were free of diabetes (n = 4693) at baseline were followed for incident diabetes. The SomaScan was used to determine the relative amounts of natural log-transformed ferritin, transferrin, and hepcidin.

During an average of 5.6 years of follow-up, diabetes incidence was 7.9%. Ferritin at follow-up was higher in NHB than NHW participants (p = <0.0001). Ferritin at follow-up was associated with increased diabetes risk (OR = 1.36, 95% CI = 1.08-1.70), while transferrin was associated with decreased risk (OR = 0.25, 95% CI = 0.08-0.77) controlling for age, sex, BMI, smoking pack-years, hepcidin, CRP, and Il-6. Race-specifically, increased risk associated with higher ferritin levels among NHB (OR = 1.56, 95% CI = 1.13-2.16) but not NHW (OR = 1.22, 95% CI = 0.89-1.68) participants. Sex-specifically, ferritin's relationship was similar among NHB men and women and NHW women (ORs ranging from 1.41-1.59); but not NHW men (OR = 0.98, 95% CI = 0.64-1.49). Similarly, transferrin ORs non-significantly ranged from 0.19-0.30 for NHB men and women and NHW women, but was significant for NHW men (OR = 0.07, 95% CI = 0.01-0.63).

Higher body iron stores is associated with increased diabetes risk among both NHB and NHW people. Unsuspected elevated iron stores may increase diabetes risk in NHB patients and should be monitored.

Excessive iron accumulation in metabolic organs such as the adipose tissue, liver, and skeletal muscle is associated with increased diabetes risk. Tissue-resident macrophages serve multiple roles, including managing inflammatory tone and regulating parenchymal iron homeostasis, thus protecting against metabolic dysfunction upon iron overload. The scavenger receptor CD163 is uniquely present on tissue-resident macrophages and plays a significant role in iron homeostasis by clearing extracellular hemoglobin-haptoglobin complexes, thereby limiting oxidative damage caused by free hemoglobin in metabolic tissues. We show that the absence of CD163 exacerbates glucose intolerance and insulin resistance in male mice with obesity. Additionally, loss of CD163 reduced the expression of iron regulatory genes (Tfr1, Cisd1, Slc40a1) in adipose tissue macrophages and anti-inflammatory (M2-like) bone marrow-derived macrophages (BMDMs). Furthermore, CD163 deficiency mediated a proinflammatory shift and limited hemoglobin scavenging specifically in M2-like BMDMs. To this end, iron buffering was diminished in inguinal white adipose tissue (iWAT) macrophages in vivo, which culminated in iron spillover into adipocytes and CD45+ CD11B- nonmyeloid immune cells in iWAT. These findings show that CD163 on tissue-resident macrophages is critical for their anti-inflammatory and hemoglobin scavenging roles, and its absence results in impaired systemic insulin action in an obese setting.

Apoptosis repressor with caspase recruitment domain (ARC) is a highly potent and multifunctional suppressor of various types of programmed cell death (PCD) (e.g. apoptosis, necroptosis, and pyroptosis) and plays a key role in determining cell fate. Under physiological conditions, ARC is predominantly expressed in terminally differentiated cells, such as cardiomyocytes and skeletal muscle cells. Its expression and activity are tightly controlled by a complicated system consisting of transcription factor (TF), non-coding RNA (ncRNA), and post-translational modification (PTM). ARC dysregulation has been shown to be closely associated with many chronic diseases, including cardiovascular disease, cancer, diabetes, and neurodegenerative disease. However, the detailed mechanisms of ARC involved in the progression of these diseases remain unclear to a large extent. In this review, we mainly focus on the regulatory mechanisms of ARC expression and activity and its role in PCD. We also discuss the underlying mechanisms of ARC in health and disease and highlight the potential implications of ARC in the clinical treatment of patients with chronic diseases. This information may assist in developing ARC-based therapeutic strategies for patients with chronic diseases and expand researchers' understanding of ARC.

Scuba diving is an increasingly popular activity that involves the use of specialized equipment and compressed air to breathe underwater. Scuba divers are subject to the physiological consequences of being immersed in a high-pressure environment, including, but not limited to, increased work of breathing and kinetic energy expenditure, decreased fluid absorption, and alteration of metabolism. Individual response to these environmental stressors may result in a differential risk of decompression sickness, a condition thought to result from excess nitrogen bubbles forming in a diver's tissues. While the mechanisms of decompression sickness are still largely unknown, it has been postulated that this response may further be influenced by the diver's health status. Nutritional intake has direct relevancy to inflammation status and oxidative stress resistance, both of which have been associated with increased decompression stress. While nutritional recommendations have been determined for saturation divers, these recommendations are likely overly robust for recreational divers, considering that the differences in time spent under pressure and the maximum depth could result nonequivalent energetic demands. Specific recommendations for recreational divers remain largely undefined.

This narrative review will summarize existing nutritional recommendations and their justification for recreational divers, as well as identify gaps in research regarding connections between nutritional intake and the health and safety of divers.

Following recommendations made by the Institute of Medicine and the Naval Medical Research Institute of Bethesda, recreational divers are advised to consume ~170-210 kJ·kg-1 (40-50 kcal·kg-1) body mass, depending on their workload underwater, in a day consisting of 3 hours' worth of diving above 46 msw. Recommendations for macronutrient distribution for divers are to derive 50% of joules from carbohydrates and less than 30% of joules from fat. Protein consumption is recommended to reach a minimum of 1 g of protein·kg-1 of body mass a day to mitigate loss of appetite while meeting energetic requirements. All divers should take special care to hydrate themselves with an absolute minimum of 500 ml of fluid per hour for any dive longer than 3 hours, with more recent studies finding 0.69 liters of water two hours prior to diving is most effective to minimize bubble loads. While there is evidence that specialized diets may have specific applications in commercial or military diving, they are not advisable for the general recreational diving population considering the often extreme nature of these diets, and the lack of research on their effectiveness on a recreational diving population.

Established recommendations do not account for changes in temperature, scuba equipment, depth, dive time, work of breathing, breathing gas mix, or individual variation in metabolism. Individual recommendations may be more accurate when accounting for basal metabolic rate and physical activity outside of diving. However, more research is needed to validate these estimates against variation in dive profile and diver demographics.

Diabetic cardiomyopathy (DCM) is defined as structural and functional cardiac abnormalities in diabetes, and cardiomyocyte death is the terminal event of DCM. Ferroptosis is iron-dependent oxidative cell death. Evidence has indicated that iron overload and ferroptosis play important roles in the pathogenesis of DCM. Mitochondria, an important organelle in iron homeostasis and ROS production, play a crucial role in cardiomyocyte ferroptosis in diabetes. Studies have shown some anti-diabetic medicines, plant extracts, and ferroptosis inhibitors might improve DCM by alleviating ferroptosis. In this review, we systematically reviewed the evidence of ferroptosis in DCM. Anti-ferroptosis might be a promising therapeutic strategy for the treatment of DCM.

Dietary factors are well-known modifiable risk factors for type 2 diabetes (T2D), but many studies overlook the interrelationships between these factors, even though foods are often consumed together and contain a variety of nutrients.

In this study, we employed a diet-wide association study approach to investigate the links between various dietary factors and T2D onset, taking into account complex dietary patterns.

We analyzed 16,666 participants without T2D from three Korean population-based cohorts: the Multi-Rural Communities Cohort (n = 8302), the Atherosclerosis Risk of a Rural Area Korean General Population cohort (n = 4990), and the Kanghwa cohort (n = 3374). A two-step approach was employed. In the first step, robust Poisson regression analysis was used for the initial screening (false discovery rate-adjusted p-values < 0.05). In the second step, a hierarchical cluster analysis was conducted of all dietary factors, followed by mutual adjustment of the screened factors within each cluster to account for interrelationships.

The 11 food clusters screened were cooked rice with beans, rice cakes, breads/spreads, bread products, cheese and pizza/hamburger, grain powder, snack/confections, nuts and roasted beans, soy milk, traditional beverages, and non-native fruit. These factors were similarly distributed across three of the seven clusters in each cohort. After mutual adjustment, cooked rice with beans (p-value ≤ 2.00 × 10-7 in all three cohorts) and non-native fruits (p-value ≤ 5.91 × 10-3 in two cohorts) remained significantly associated with lower T2D risk in more than one cohort.

The inverse association of cooked rice with beans, not observed with other types of cooked rice, and that of non-native fruits, suggest that incorporating beans into rice and eating various fruits may be an effective strategy for preventing diabetes.

Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases.

The liver damage caused by Diabetes Mellitus (DM) has attracted increasing attention in recent years. Liver injury in DM can be caused by ferroptosis, a form of cell death caused by iron overload. However, the role of iron transporters in this context is still not clear. Herein, we attempted to shed light on the pathophysiological mechanism of ferroptosis. DM was induced in 8-week-old male rats by streptozotocin (STZ) before assessment of the degree of liver injury. Together with histopathological changes, variations in glutathione peroxidase 4 (GPX4), glutathione (GSH), superoxide dismutase (SOD), transferrin receptor 1 (TFR1), ferritin heavy chain (FTH), ferritin light chain (FTL), ferroportin and Prussian blue staining, were monitored in rat livers before and after treatment with Fer-1. In the liver of STZ-treated rats, GSH and SOD levels decreased, whereas those of malondialdehyde (MDA) increased. Expression of TFR1, FTH and FTL increased whereas that of glutathione peroxidase 4 (GPX4) and ferroportin did not change significantly. Prussian blue staining showed that iron levels increased. Histopathology showed liver fibrosis and decreased glycogen content. Fer-1 treatment reduced iron and MDA levels but GSH and SOD levels were unchanged. Expression of FTH and FTL was reduced whereas that of ferroportin showed a mild decrease. Fer-1 treatment alleviated liver fibrosis, increased glycogen content and mildly improved liver function. Our study demonstrates that ferroptosis is involved in DM-induced liver injury. Regulating the levels of iron transporters may become a new therapeutic strategy in ferroptosis-induced liver injury.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by amyloid plaques, neurofibrillary tangles, and neuronal loss. Early cerebral and body iron dysregulation and accumulation interact with AD pathology, particularly in the precuneus, a crucial functional hub in cognitive functions. Quantitative susceptibility mapping (QSM), a novel post-processing approach, provides insights into tissue iron levels and cerebral oxygen metabolism and reveals abnormal iron accumulation early in AD. Increased iron deposition in the precuneus can lead to oxidative stress, neuroinflammation, and accelerated neurodegeneration. Metabolic disorders (diabetes, non-alcoholic fatty liver disease (NAFLD), and obesity), genetic factors, and small vessel pathology contribute to abnormal iron accumulation in the precuneus. Therefore, in line with the growing body of literature in the precuneus region of patients with AD, QSM as a neuroimaging method could serve as a non-invasive biomarker to track disease progression, complement other imaging modalities, and aid in early AD diagnosis and monitoring.

Ferroportin (Fpn) is the only iron exporter, playing a crucial role in systemic iron homeostasis. Fpn is negatively regulated by its ligand hepcidin, but other potential regulators in physiological and disease conditions remain poorly understood. Diabetes is a metabolic disorder that develops body iron loading with unknown mechanisms. By using diabetic mouse models and human duodenal specimens, we demonstrated that intestinal Fpn expression was increased in diabetes in a hepcidin-independent manner. Protein kinase C (PKC) is hyperactivated in diabetes. We showed that PKCα was required to sustain baseline Fpn expression and diabetes-induced Fpn upregulation in the enterocytes and macrophages. Knockout of PKCα abolished diabetes-associated iron overload. Mechanistically, activation of PKCα increased the exocytotic trafficking of Fpn and decreased the endocytic trafficking of Fpn in the resting state. Hyperactive PKCα also suppressed hepcidin-induced ubiquitination, internalization, and degradation of Fpn. We further observed that iron loading in the enterocytes and macrophages activated PKCα, acting as a novel mechanism to enhance Fpn-dependent iron efflux. Finally, we demonstrated that the loss-of-function of PKCα and pharmacological inhibition of PKC significantly alleviated hereditary hemochromatosis-associated iron overload. Our study has highlighted, to our knowledge, for the first time, that PKCα is an important positive regulator of Fpn and a new target in the control of iron homeostasis.

The liver plays a crucial role in maintaining systemic iron homeostasis by secreting hepcidin, which is essential for coordinating iron levels in the body. Imbalances in iron homeostasis are associated with various clinical disorders related to iron deficiency or iron overload. Despite the clinical significance, the mechanisms underlying how hepatocytes sense extracellular iron levels to regulate hepcidin synthesis and iron storage are not fully understood. In this study, we identified Foxo1, a well-known regulator of macronutrient metabolism, which translocates to the nucleus of hepatocytes in response to high-iron feeding, holo-transferrin, and bone morphogenetic protein 6 (BMP6) treatment. Furthermore, Foxo1 plays a crucial role in mediating hepcidin induction in response to both iron and BMP signals by directly interacting with evolutionally conserved Foxo binding sites within the hepcidin promoter region. These binding sites were found to colocalize with Smad-binding sites. To investigate the physiological relevance of Foxo1 in iron metabolism, we generated mice with hepatocyte-specific deletion of Foxo1. These mice exhibited reduced hepatic hepcidin expression and serum hepcidin levels, accompanied by elevated serum iron and liver nonheme iron concentrations. Moreover, high-iron diet further exacerbated these abnormalities in iron metabolism in mice lacking hepatic Foxo1. Conversely, hepatocyte-specific Foxo1 overexpression increased hepatic hepcidin expression and serum hepcidin levels, thereby ameliorating iron overload in a murine model of hereditary hemochromatosis (Hfe-/- mice). In summary, our study identifies Foxo1 as a critical regulator of hepcidin and systemic iron homeostasis. Targeting Foxo1 may offer therapeutic opportunities for managing conditions associated with aberrant iron metabolism.

The current study investigated the correlation between dietary iron intake and diabetic kidney disease among diabetic adults.

This cross-sectional study enrolled 8118 participants who suffered from diabetes from the National Health and Nutrition Examination Survey (NHANES) 1999-2018. Dietary iron intake was obtained from 24 h recall interviews, and diabetic kidney disease was defined as eGFR < 60 mL/min per 1.73 m2 or albumin creatinine ratio (ACR) ≥ 30 mg/g. Three weighted logistic regression models were utilized to investigate odd ratio (OR) and 95% CIs for diabetic kidney disease. Stratified analyses were performed by gender, age, BMI, HbA1c, hypertension status, and smoking status, and diabetes types.

Among 8118 participants (51.6% male, mean age 61.3 years), 40.7% of participants suffered from diabetic kidney disease. With the adjustment of potential covariates, we found that ≥ 12.59 mg of dietary iron was related to a lower risk of diabetic kidney disease (OR = 0.78, 95% CI: 0.63 to 0.96; OR = 0.79, 95% CI: 0.63 to 0.98). In stratified analyses, higher iron intake was negatively related to diabetic kidney disease, especially among those who were male, < 60 years, those with hypertension, those with HbA1c < 7.0%, and those who were ex-smokers. The result remained robust in sensitivity analyses.

We found that ≥ 12.59 mg of dietary iron is associated with a lower risk of diabetic kidney disease, especially in those who were male, younger, heavier weight, have better blood sugar control, and those who were ex-smokers.

Dietary haem iron intake is linked to an increased risk of type 2 diabetes (T2D), but the underlying plasma biomarkers are not well understood. We analysed data from 204,615 participants (79% females) in three large US cohorts over up to 36 years, examining the associations between iron intake and T2D risk. We also assessed plasma metabolic biomarkers and metabolomic profiles in subsets of 37,544 (82% females) and 9,024 (84% females) participants, respectively. Here we show that haem iron intake but not non-haem iron is associated with a higher T2D risk, with a multivariable-adjusted hazard ratio of 1.26 (95% confidence interval 1.20-1.33; P for trend <0.001) comparing the highest to the lowest quintiles. Haem iron accounts for significant proportions of the T2D risk linked to unprocessed red meat and specific dietary patterns. Increased haem iron intake correlates with unfavourable plasma profiles of insulinaemia, lipids, inflammation and T2D-linked metabolites. We also identify metabolites, including L-valine and uric acid, potentially mediating the haem iron-T2D relationship, highlighting their pivotal role in T2D pathogenesis.

Iron homeostasis is essential for maintaining metabolic health and iron disorder has been linked to chronic metabolic diseases. Increasing thermogenic capacity in adipose tissue has been considered as a potential approach to regulate energy homeostasis. Both mitochondrial biogenesis and mitochondrial function are iron-dependent and essential for adipocyte thermogenic capacity, but the underlying relationships between iron accumulation and adipose thermogenesis is unclear. Firstly, we confirmed that iron homeostasis and the iron regulatory markers (e.g., Tfr1 and Hfe) are involved in cold-induced thermogenesis in subcutaneous adipose tissues using RNA-seq and bioinformatic analysis. Secondly, an Hfe (Hfe-/-)-deficient mouse model, in which tissues become overloaded with iron, was employed. We found iron accumulation caused by Hfe deficiency enhanced mitochondrial respiratory chain expression in subcutaneous white adipose in vivo and resulted in enhanced tissue thermogenesis with upregulation of PGC-1α and adipose triglyceride lipase, mitochondrial biogenesis and lipolysis. To investigate the thermogenic capacity in vitro, stromal vascular fraction from adipose tissues was isolated, followed with adipogenic differentiation. Primary adipocyte from Hfe-/- mice exhibited higher cellular oxygen consumption, associated with enhanced expression of mitochondrial oxidative respiratory chain protein, while primary adipocytes or stromal vascular fractions from WT mice supplemented with iron citrate) exhibited similar effect in thermogenic capacity. Taken together, these findings indicate iron supplementation and iron accumulation (Hfe deficiency) can regulate adipocyte thermogenic capacity, suggesting a potential role for iron homeostasis in adipose tissues.

Atherosclerosis is a chronic inflammatory disease that causes degenerative and productive changes in the arteries. The resulting atherosclerotic plaques restrict the vessel lumen, causing blood flow disturbances. Plaques are formed mainly in large- and medium-sized arteries, usually at bends and forks where there is turbulence in blood flow. Depending on their location, they can lead to various disease states such as myocardial infarction, stroke, renal failure, peripheral vascular diseases, or sudden cardiac death. In this work, we reviewed the literature on the early detection of atherosclerosis markers in the application of photodynamic therapy to atherosclerosis-related diseases. Herein, we described the roles of C-reactive protein, insulin, osteopontin, osteoprotegerin, copeptin, the TGF-β cytokine family, and the amino acid homocysteine. Also, we discuss the role of microelements such as iron, copper, zinc, and Vitamin D in promoting the formation of atherosclerotic plaque. Dysregulation of the administered compounds is associated with an increased risk of atherosclerosis. Additionally, taking into account the pathophysiology of atherosclerotic plaque formation, we believe that maintaining homeostasis in the range of biomarkers mentioned in this article is crucial for slowing down the process of atherosclerotic plaque development and the stability of plaque that is already formed.

Kidney dysfunction is a prevalent complication of diabetes mellitus, contributing significantly to diabetes-related morbidity and mortality. We aim to explore whether platelet-rich plasma administration can modulate iron regulation mechanism within the kidney, thereby mitigating renal dysfunction associated with diabetes. Albino mice with an average body weight of 20 ± 5 g were randomly divided into five groups (N = 50; n = 10): Control Group, PRP Group, diabetic group (DG), treated group A (TA), and treated group B (TB). A single intraperitoneal dose of alloxan (160 mg/kg of body weight) was administered to mice in the DG and in both treated groups. Upon confirmation of diabetes, the DG was left untreated, while PRP treatment (0.5 ml/kg of body weight) was administered to the TA and TB groups for two and four weeks, respectively. Histological examinations of kidney tissues revealed notable signs of damage in DG, which were subsequently improved upon PRP treatment. Likewise, PRP treatment restored the changes in liver enzymes, oxidative stress biomarkers and serum electrolytes in both treated groups. Furthermore, there was an observed upregulation of iron regulatory genes, such as Renin, Epo, Hepc, Kim1, and Hfe, in the DG, accompanied by a downregulation of Tfr1 and Fpn; however, Dmt1 and Dcytb1 expression remained unaltered. Treatment with PRP restored the expression of iron regulatory genes in both treated groups. This study concluded that PRP treatment effectively restored the renal histochemistry and the expression of renal iron regulatory genes in an alloxan-induced diabetic mice model.

Although several studies have found the relationship between essential elements and diabetes, the studies about the association of essential elements with diabetes diagnosed according to an oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) in a sex- and age-specific manner were limited. To investigate the linear and nonlinear relationship of five essential elements including iron (Fe), copper (Cu), Zinc (Zn), magnesium (Mg), and calcium (Ca) with diabetes, fasting plasma glucose (FPG), 2-h postprandial plasma glucose (PPG), and HbA1c and to evaluate the sex- and age-specific heterogeneities in these relationships.

A total of 8392 community-dwelling adults were recruited to complete a questionnaire and undergo checkups of anthropometric parameters and serum levels of five metals (Fe, Cu, Zn, Mg, and Ca). The multivariable logistic and linear regression, the restricted cubic spline (RCS) analysis, and subgroup analysis were applied to find the associations between the essential elements and the prevalence of diabetes as well as FPG, PPG, and HbA1c.

In the multivariable logistic regression and multivariable linear regression, serum Cu was positively associated with FPG, PPG, and HbA1c while serum Mg was significantly inversely correlated with FPG, PPG, HbA1c, and diabetes (all P < 0.001). In the RCS analysis, the non-linear relationship of Cu and diabetes (P < 0.001) was found. In the subgroup analysis, stronger positive associations of Cu with diabetes (P for interaction = 0.027) and PPG (P for interaction = 0.002) were found in younger women.

These findings may lead to more appropriate approaches to essential elements supplementation in people with diabetes of different ages and sexes. However, more prospective cohort and experimental studies are needed to probe the possible mechanism of sex- and age-specific associations between serum essential elements and diabetes.

The relationship between co-exposure to multiple metals and gestational diabetes mellitus (GDM) and the mechanisms involved are poorly understood. In this nested case-control study, 228 GDM cases and 456 matched controls were recruited, and biological samples were collected at 12-14 gestational weeks. The urinary concentrations of 10 metals and 8-hydroxydeoxyguanosine (8-OHdG) as well as the serum levels of malondialdehyde (MDA) and advanced glycation end products (AGEs) were determined to assess the association of metals with GDM risk and the mediating effects of oxidative stress. Urinary Ti concentration was significantly and positively associated with the risk of GDM (odds ratio [OR]:1.45, 95 % confidence interval [CI]: 1.12, 1.88), while Mn and Fe were negatively associated with GDM risk (OR: 0.67, 95 % CI: 0.50, 0.91 or OR: 0.61, 95 % CI: 0.47, 0.80, respectively). A significant negative association was observed between Mo and GDM risk, specifically in overweight and obese pregnant women. Bayesian kernel machine regression showed a significant negative joint effect of the mixture of 10 metals on GDM risk. The adjusted restricted cubic spline showed a protective role of Mn and Fe in GDM risk (P < 0.05). A significant negative association was observed between essential metals and GDM risk in quantile g-computation analysis (P < 0.05). Mediation analyses showed a mediating effect of MDA on the association between Ti and GDM risk, with a proportion of 8.7 % (P < 0.05), and significant direct and total effects on Ti, Mn, and Fe. This study identified Ti as a potential risk factor and Mn, Fe, and Mo as potential protective factors against GDM, as well as the mediating effect of lipid oxidation.

Owing to the increased tissue iron accumulation in patients with diabetes, microorganisms may activate high expression of iron-involved metabolic pathways, leading to the exacerbation of bacterial infections and disruption of systemic glucose metabolism. Therefore, an on-demand transdermal dosing approach that utilizes iron homeostasis regulation to combat antimicrobial resistance is a promising strategy to address the challenges associated with low administration bioavailability and high antibiotic resistance in treating infected diabetic wounds. Here, it is aimed to propose an effective therapy based on hemoglobin bionics to induce disturbances in bacterial iron homeostasis. The preferred "iron cargo" is synthesized by protoporphyrin IX chelated with dopamine and gallium (PDGa), and is delivered via a glucose/pH-responsive microneedle bandage (PDGa@GMB). The PDGa@GMB downregulates the expression levels of the iron uptake regulator (Fur) and the peroxide response regulator (perR) in Staphylococcus aureus, leading to iron nutrient starvation and oxidative stress, ultimately suppressing iron-dependent bacterial activities. Consequently, PDGa@GMB demonstrates insusceptibility to genetic resistance while maintaining sustainable antimicrobial effects (>90%) against resistant strains of both S. aureus and E. coli, and accelerates tissue recovery (<20 d). Overall, PDGa@GMB not only counteracts antibiotic resistance but also holds tremendous potential in mediating microbial-host crosstalk, synergistically attenuating pathogen virulence and pathogenicity.

Major Thalassemia patients suffer from iron overload and organ damage, especially heart and liver damage. Early diagnosis and treatment with a chelator can reduce the complications and mortality of iron overload. Therefore, we aimed to investigate the biochemical and hematological predictors as an alternative and indirect indicator of iron deposition in heart and liver cells in comparison with the MRI T2* method as the gold standard.

MRI T2* was evaluated in the heart and liver tissues of 62 major beta-thalassemia patients undergoing regular transfusion and chelator therapy. Biochemical and hematological factors were also measured, including serum ferritin, serum electrolytes, liver enzymes, hemoglobin, blood glucose, and serum magnesium. The correlation between these factors was assessed using statistical evaluations.

Serum ferritin had a positive and significant correlation with liver siderosis based on MRI T2* (p-value = .015), and no significant association was observed with cardiac siderosis (p-value = .79). However, there was a significant positive correlation between cardiac iron deposition and fasting blood sugar level (p-value = -.049), and plasma level of liver enzymes (alanine aminotransferase (ALT) (p-value = .001), aspartate aminotransferase (AST ((p-value = .01)). Moreover, there was a significant negative correlation between cardiac iron overload and plasma magnesium level (p-value = .014). According to MRI T2*, there was no significant correlation between cardiac and hepatic iron overload (p value = .36).

An increase in blood sugar or liver enzymes and a decrease in serum magnesium was associated with an increase in cardiac iron overload based on MRI T2*. Liver iron overload based on MRI T2* had a significant correlation with serum ferritin.

Non-anaemic iron deficiency (NAID) is a strategic target in cardiovascular medicine because of its association with a range of adverse effects in various conditions. Endeavours to tackle NAID in heart failure have yielded mixed results, exposing knowledge gaps in how best to define 'iron deficiency' and the handling of iron therapies by the body. To address these gaps, we harness the latest understanding of the mechanisms of iron homeostasis outside the erythron and integrate clinical and preclinical lines of evidence. The emerging picture is that current definitions of iron deficiency do not assimilate the multiple influences at play in patients with heart failure and, consequently, fail to identify those with a truly unmet need for iron. Additionally, current iron supplementation therapies benefit only certain patients with heart failure, reflecting differences in the nature of the unmet need for iron and the modifying effects of anaemia and inflammation on the handling of iron therapies by the body. Building on these insights, we identify untapped opportunities in the management of NAID, including the refinement of current approaches and the development of novel strategies. Lessons learned from NAID in cardiovascular disease could ultimately translate into benefits for patients with other chronic conditions such as chronic kidney disease, chronic obstructive pulmonary disease and cancer.

Ferroptosis is a newly discovered form of cell death caused by the peroxidation of fragile fatty acids in cell membranes, which combines with iron to increase reactive oxygen species and disable mitochondria. Ferroptosis has been linked to aging-related conditions, including type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD). Pentadecanoic acid (C15:0), an odd-chain saturated fat, is an essential fatty acid with the primary roles of stabilizing cell membranes and repairing mitochondrial function. By doing so, C15:0 reverses the underpinnings of ferroptosis. Under the proposed "Cellular Stability Hypothesis", evidence is provided to show that cell membranes optimally need >0.4% to 0.64% C15:0 to support long-term health and longevity. A pathophysiology of a newly identified nutritional C15:0 deficiency syndrome ("Cellular Fragility Syndrome") is provided that demonstrates how C15:0 deficiencies (≤0.2% total circulating fatty acids) can increase susceptibilities to ferroptosis, dysmetabolic iron overload syndrome, type 2 diabetes, cardiovascular disease, and NAFLD. Further, evidence is provided that C15:0 supplementation can reverse the described C15:0 deficiency syndrome, including the key components of ferroptosis. Given the declining dietary intake of C15:0, especially among younger generations, there is a need for extensive studies to understand the potential breadth of Cellular Fragility Syndrome across populations.

Hemochromatosis (HC) is the main genetic disorder of iron overload and is regarded as metal-related human toxicosis. HC may result from HFE and rare non-HFE gene mutations, causing hepcidin deficiency or, sporadically, hepcidin resistance. This review focuses on HFE-related HC. The illness presents a strong biochemical penetrance, but its prevalence is low. Unfortunately, the majority of patients with HC remain undiagnosed at their disease-curable stage. The main aim of HC management is to prevent iron overload in its early phase and remove excess iron from the body by phlebotomy in its late stage. Raising global awareness of HC among health staff, teaching them how not to overlook early HC manifestations, and paying attention to careful patient monitoring remain critical management strategies for preventing treatment delays, upgrading its efficacy, and improving patient prognosis.