Iron homeostasis in the heart: Molecular mechanisms and pharmacological implications.

Iron is necessary for the life of practically all living things, yet it may also harm people toxically. Accordingly, humans and other mammals have evolved an effective and tightly regulatory system to maintain iron homeostasis in healthy tissues, including the heart. Iron deficiency is common in patients with heart failure, and is associated with worse prognosis in this population; while the prevalence of iron overload-related cardiovascular disorders is also increasing. Therefore, enhancing the therapy of patients with cardiovascular disorders requires a thorough understanding of iron homeostasis. Here, we give readers an overview of the fundamental mechanisms governing systemic iron homeostasis as well as the most recent knowledge about the intake, storage, use, and export of iron from the heart. Genetic mouse models used for investigation of iron metabolism in various in vivo scenarios are summarized and highlighted. We also go through different clinical conditions and therapeutic approaches that target cardiac iron dyshomeostasis. Finally, we conclude the review by outlining the present knowledge gaps and important open questions in this field in order to guide future research on cardiac iron metabolism.

Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis.

Although the serum-abundant metal-binding protein transferrin (encoded by the Trf gene) is synthesized primarily in the liver, its function in the liver is largely unknown. Here, we generated hepatocyte-specific Trf knockout mice (Trf-LKO), which are viable and fertile but have impaired erythropoiesis and altered iron metabolism. Moreover, feeding Trf-LKO mice a high-iron diet increased their susceptibility to developing ferroptosis-induced liver fibrosis. Importantly, we found that treating Trf-LKO mice with the ferroptosis inhibitor ferrostatin-1 potently rescued liver fibrosis induced by either high dietary iron or carbon tetrachloride (CCl4) injections. In addition, deleting hepatic Slc39a14 expression in Trf-LKO mice significantly reduced hepatic iron accumulation, thereby reducing ferroptosis-mediated liver fibrosis induced by either a high-iron diet or CCl4 injections. Finally, we found that patients with liver cirrhosis have significantly lower levels of serum transferrin and hepatic transferrin, as well as higher levels of hepatic iron and lipid peroxidation, compared with healthy control subjects. Taken together, these data indicate that hepatic transferrin plays a protective role in maintaining liver function, providing a possible therapeutic target for preventing ferroptosis-induced liver fibrosis.

Loss of Cardiac Ferritin H Facilitates Cardiomyopathy via Slc7a11-Mediated Ferroptosis.

RATIONALE: Maintaining iron homeostasis is essential for proper cardiac function. Both iron deficiency and iron overload are associated with cardiomyopathy and heart failure via complex mechanisms. Although ferritin plays a central role in iron metabolism by storing excess cellular iron, the molecular function of ferritin in cardiomyocytes remains unknown. OBJECTIVE: To characterize the functional role of Fth (ferritin H) in mediating cardiac iron homeostasis and heart disease. METHODS AND RESULTS: Mice expressing a conditional Fth knockout allele were crossed with 2 distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack Fth expression specifically in myocytes (MCK-Cre) or cardiomyocytes (Myh6-Cre). Mice lacking Fth in cardiomyocytes had decreased cardiac iron levels and increased oxidative stress, resulting in mild cardiac injury upon aging. However, feeding these mice a high-iron diet caused severe cardiac injury and hypertrophic cardiomyopathy, with molecular features typical of ferroptosis, including reduced glutathione (GSH) levels and increased lipid peroxidation. Ferrostatin-1, a specific inhibitor of ferroptosis, rescued this phenotype, supporting the notion that ferroptosis plays a pathophysiological role in the heart. Finally, we found that Fth-deficient cardiomyocytes have reduced expression of the ferroptosis regulator Slc7a11, and overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis. CONCLUSIONS: Our findings provide compelling evidence that ferritin plays a major role in protecting against cardiac ferroptosis and subsequent heart failure, thereby providing a possible new therapeutic target for patients at risk of developing cardiomyopathy.

Ferroptosis as a target for protection against cardiomyopathy.

Heart disease is the leading cause of death worldwide. A key pathogenic factor in the development of lethal heart failure is loss of terminally differentiated cardiomyocytes. However, mechanisms of cardiomyocyte death remain unclear. Here, we discovered and demonstrated that ferroptosis, a programmed iron-dependent cell death, as a mechanism in murine models of doxorubicin (DOX)- and ischemia/reperfusion (I/R)-induced cardiomyopathy. In canonical apoptosis and/or necroptosis-defective Ripk3-/-, Mlkl-/-, or Fadd-/-Mlkl-/- mice, DOX-treated cardiomyocytes showed features of typical ferroptotic cell death. Consistently, compared with dexrazoxane, the only FDA-approved drug for treating DOX-induced cardiotoxicity, inhibition of ferroptosis by ferrostatin-1 significantly reduced DOX cardiomyopathy. RNA-sequencing results revealed that heme oxygenase-1 (Hmox1) was significantly up-regulated in DOX-treated murine hearts. Administering DOX to mice induced cardiomyopathy with a rapid, systemic accumulation of nonheme iron via heme degradation by Nrf2-mediated up-regulation of Hmox1, which effect was abolished in Nrf2-deficent mice. Conversely, zinc protoporphyrin IX, an Hmox1 antagonist, protected the DOX-treated mice, suggesting free iron released on heme degradation is necessary and sufficient to induce cardiac injury. Given that ferroptosis is driven by damage to lipid membranes, we further investigated and found that excess free iron accumulated in mitochondria and caused lipid peroxidation on its membrane. Mitochondria-targeted antioxidant MitoTEMPO significantly rescued DOX cardiomyopathy, supporting oxidative damage of mitochondria as a major mechanism in ferroptosis-induced heart damage. Importantly, ferrostatin-1 and iron chelation also ameliorated heart failure induced by both acute and chronic I/R in mice. These findings highlight that targeting ferroptosis serves as a cardioprotective strategy for cardiomyopathy prevention.

Causal association of childhood obesity with cancer risk in adulthood: A Mendelian randomization study.

In observational studies of children and adolescents, higher body weight has been associated with distinct disease outcomes, including cancer, in adulthood. Therefore, we performed a two-sample Mendelian randomization (MR) study to evaluate the causal effect of childhood obesity on long-term cancer risk. Single-nucleotide polymorphisms associated with higher childhood body mass index (BMI) from large-scale genome-wide association studies were used as genetic instruments. Summary-level data for 24 site-specific cancers were obtained from UK Biobank. We found that a 1-SD increase in childhood BMI (kg/m2 ) was significantly associated with a 60% increase in risk of pancreatic cancer (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.12-2.28; P < 0.01) and a 47% increase in risk of esophageal cancer (OR: 1.47; 95% CI: 1.09-1.97; P < 0.01) in adults. In contrast, there was an inverse association of genetic predisposition to childhood obesity with throat (OR: 0.46; 95% CI: 0.27-0.79; P < 0.01) and breast cancer (OR: 0.77; 95% CI: 0.64-0.94; P < 0.01) in adult life. For the other 20 cancers studied, no statistically significant association was observed. Our MR analyses found causal effects of childhood obesity on several cancers. Maintaining a healthy weight should be emphasized during childhood and adolescence to prevent cancer risk later in life.

Deletion of ferritin H in neurons counteracts the protective effect of melatonin against traumatic brain injury-induced ferroptosis.

Accumulating evidence demonstrates that ferroptosis may be important in the pathophysiological process of traumatic brain injury (TBI). As a major hormone of the pineal gland, melatonin exerts many beneficial effects on TBI, but there is no information regarding the effects of melatonin on ferroptosis after TBI. As expected, TBI resulted in the time-course changes of ferroptosis-related molecules expression and iron accumulation in the ipsilateral cortex. Importantly, we found that treating with melatonin potently rescued TBI induced the changes mentioned above and improved functional deficits versus vehicle. Similar results were obtained with a ferroptosis inhibitor, liproxstatin-1. Moreover, the protective effect of melatonin is likely dependent on melatonin receptor 1B (MT2). Although ferritin plays a vital role in iron metabolism by storing excess cellular iron, its precise function in the brain, and whether it involves melatonin's neuroprotection remain unexplored. Considering ferritin H (Fth) is expressed predominantly in the neurons and global loss of Fth in mice induces early embryonic lethality, we then generated neuron-specific Fth conditional knockout (Fth-KO) mice, which are viable and fertile but have altered iron metabolism. In addition, Fth-KO mice were more susceptible to ferroptosis after TBI, and the neuroprotection by melatonin was largely abolished in Fth-KO mice. In vitro siFth experiments further confirmed the results mentioned above. Taken together, these data indicate that melatonin produces cerebroprotection, at least partly by inhibiting neuronal Fth-mediated ferroptosis following TBI, supporting the notion that melatonin is an excellent ferroptosis inhibitor and its anti-ferroptosis provides a potential therapeutic target for treating TBI.

[The role of ferroptosis in chronic diseases].

Recently, ferroptosis, an iron-dependent novel type of cell death, has been characterized as an excessive accumulation of lipid peroxides and reactive oxygen species. Emerging studies demonstrate that ferroptosis not only plays an important role in the pathogenesis and progression of chronic diseases, but also functions differently in the different disease context. Notably, it is shown that activation of ferroptosis could potently inhibit tumor growth and increase sensitivity to chemotherapy and immunotherapy in various cancer settings. As a result, the development of more efficacious ferroptosis agonists remains the mainstay of ferroptosis-targeting strategy for cancer therapeutics. By contrast, in non-cancerous chronic diseases, including cardiovascular & cerebrovascular diseases and neurodegenerative diseases, ferroptosis functions as a risk factor to promote these diseases progression through triggering or accelerating tissue injury. As a matter of fact, blocking ferroptosis has been demonstrated to effectively prevent ischemia-reperfusion heart disease in preclinical animal models. Therefore, it is a promising field to develope potent ferroptosis inhibitors for preventing and treating cardiovascular & cerebrovascular diseases and neurodegenerative diseases. In this article, we summarize the most recent progress on ferroptosis in chronic diseases, and draw attention to the possible clinical impact of this recently emerged ferroptosis modalities.

[Progress on epigenetic regulation of iron homeostasis].

Iron homeostasis plays an important role for the maintenance of human health. It is known that iron metabolism is tightly regulated by several key genes, including divalent metal transport-1(DMT1), transferrin receptor 1(TFR1), transferrin receptor 2(TFR2), ferroportin(FPN), hepcidin(HAMP), hemojuvelin(HJV) and Ferritin H. Recently, it is reported that DNA methylation, histone acetylation, and microRNA (miRNA) epigenetically regulated iron homeostasis. Among these epigenetic regulators, DNA hypermethylation of the promoter region of FPN, TFR2, HAMP, HJV and bone morphogenetic protein 6 (BMP6) genes result in inhibitory effect on the expression of these iron-related gene. In addition, histone deacetylase (HADC) suppresses HAMP gene expression. On the contrary, HADC inhibitor upregulates HAMP gene expression. Additional reports showed that miRNA can also modulate iron absorption, transport, storage and utilization via downregulation of DMT1, FPN, TFR1, TFR2, Ferritin H and other genes. It is noteworthy that some key epigenetic regulatory enzymes, such as DNA demethylase TET2 and histone lysine demethylase JmjC KDMs, require iron for the enzymatic activities. In this review, we summarize the recent progress of DNA methylation, histone acetylation and miRNA in regulating iron metabolism and also discuss the future research directions.

Quantitative association between body mass index and the risk of cancer: A global Meta-analysis of prospective cohort studies.

Numerous studies have suggested that excess body weight is associated with increased cancer risk. To examine this putative association, we performed a systematic review and quantitative meta-analysis of cohort studies reporting body mass index (BMI) and the risk of 23 cancer types. PubMed, Embase, and Web of Science were searched for cohort studies, yielding 325 articles with 1,525,052 cases. Strong positive associations were observed between BMI and endometrial cancer (RR: 1.48), esophageal adenocarcinoma (RR: 1.45), and kidney cancer (RR: 1.20); weaker associations (RR < 1.20) were also found for several other cancer types. Interestingly, we found significant inverse associations between BMI and oral cavity (RR: 0.93), lung (RR: 0.91), premenopausal breast (RR: 0.95), and localized prostate (RR: 0.97) cancers. A male-specific association was found for colorectal cancer (p = 0.023), and a female-specific association was found for cancer in brain (p = 0.025) or kidney (p = 0.035). With respect to geography, the strongest positive association was found for total cancer in North America (p = 0.038). This comprehensive meta-analysis provides epidemiological evidence supporting the association between BMI and cancer risk. These findings can be used to drive public policies and to help guide personalized medicine in order to better manage body weight, thereby reducing the risk of developing obesity-related cancer.

Characterization of ferroptosis in murine models of hemochromatosis.

Ferroptosis is a recently identified iron-dependent form of nonapoptotic cell death implicated in brain, kidney, and heart pathology. However, the biological roles of iron and iron metabolism in ferroptosis remain poorly understood. Here, we studied the functional role of iron and iron metabolism in the pathogenesis of ferroptosis. We found that ferric citrate potently induces ferroptosis in murine primary hepatocytes and bone marrow-derived macrophages. Next, we screened for ferroptosis in mice fed a high-iron diet and in mouse models of hereditary hemochromatosis with iron overload. We found that ferroptosis occurred in mice fed a high-iron diet and in two knockout mouse lines that develop severe iron overload (Hjv-/- and Smad4Alb/Alb mice) but not in a third line that develops only mild iron overload (Hfe-/- mice). Moreover, we found that iron overload-induced liver damage was rescued by the ferroptosis inhibitor ferrostatin-1. To identify the genes involved in iron-induced ferroptosis, we performed microarray analyses of iron-treated bone marrow-derived macrophages. Interestingly, solute carrier family 7, member 11 (Slc7a11), a known ferroptosis-related gene, was significantly up-regulated in iron-treated cells compared with untreated cells. However, genetically deleting Slc7a11 expression was not sufficient to induce ferroptosis in mice. Next, we studied iron-treated hepatocytes and bone marrow-derived macrophages isolated from Slc7a11-/- mice fed a high-iron diet. CONCLUSION: We found that iron treatment induced ferroptosis in Slc7a11-/- cells, indicating that deleting Slc7a11 facilitates the onset of ferroptosis specifically under high-iron conditions; these results provide compelling evidence that iron plays a key role in triggering Slc7a11-mediated ferroptosis and suggest that ferroptosis may be a promising target for treating hemochromatosis-related tissue damage. (Hepatology 2017;66:449-465).

Dietary magnesium intake and the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality: a dose-response meta-analysis of prospective cohort studies.

BACKGROUND: Although studies have examined the association between dietary magnesium intake and health outcome, the results are inconclusive. Here, we conducted a dose-response meta-analysis of prospective cohort studies in order to investigate the correlation between magnesium intake and the risk of cardiovascular disease (CVD), type 2 diabetes (T2D), and all-cause mortality. METHODS: PubMed, EMBASE, and Web of Science were searched for articles that contained risk estimates for the outcomes of interest and were published through May 31, 2016. The pooled results were analyzed using a random-effects model. RESULTS: Forty prospective cohort studies totaling more than 1 million participants were included in the analysis. During the follow-up periods (ranging from 4 to 30 years), 7678 cases of CVD, 6845 cases of coronary heart disease (CHD), 701 cases of heart failure, 14,755 cases of stroke, 26,299 cases of T2D, and 10,983 deaths were reported. No significant association was observed between increasing dietary magnesium intake (per 100 mg/day increment) and the risk of total CVD (RR: 0.99; 95% CI, 0.88-1.10) or CHD (RR: 0.92; 95% CI, 0.85-1.01). However, the same incremental increase in magnesium intake was associated with a 22% reduction in the risk of heart failure (RR: 0.78; 95% CI, 0.69-0.89) and a 7% reduction in the risk of stroke (RR: 0.93; 95% CI, 0.89-0.97). Moreover, the summary relative risks of T2D and mortality per 100 mg/day increment in magnesium intake were 0.81 (95% CI, 0.77-0.86) and 0.90 (95% CI, 0.81-0.99), respectively. CONCLUSIONS: Increasing dietary magnesium intake is associated with a reduced risk of stroke, heart failure, diabetes, and all-cause mortality, but not CHD or total CVD. These findings support the notion that increasing dietary magnesium might provide health benefits.

Pleiotropic actions of iron balance in diabetes mellitus.

As an essential element, iron plays a central role in many physiological processes, including redox balance, inflammation, energy metabolism, and environment sensing. Perturbations in iron homeostasis are associated with several conditions, including hyperglycemia and diabetes, both of which have been studied in patients and animal models. To clarify the pleiotropic role of iron homeostasis in diabetes development, the early studies on diseases with iron-overload, studies on clinical iron depletion therapies, associations between iron-related genetic polymorphisms and diabetes, and etiological mechanisms underlying iron perturbations-impaired insulin secretion and insulin sensitivity were carefully reviewed and discussed. Hereditary hemochromatosis, transfusion-dependent thalassemia, and excess heme iron intake can increase the risk of developing diabetes. Genetically modified mice and mice fed a high-iron diet present with discrepant phenotypes due to differences in tissue iron distribution. Moreover, several genetic polymorphisms related to iron homeostasis have been associated with the risk of developing diabetes. Tightly controlled iron metabolism is essential for insulin secretion and insulin sensitivity, and iron overload in pancreatic islets alters reactive oxygen species (ROS) generation, as well as hypoxia-inducible factor-1α (HIF-1α) stability and adenosine triphosphate (ATP) synthesis, thereby impairing the function and viability of ß-cells. Decreased levels of adiponectin, macrophage-mediated inflammation, and ROS-mediated liver kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) activation can contribute to iron overload-induced insulin resistance, whereas iron deficiency could also participate in obesity-related inflammation, hypoxia, and insulin resistance. Because iron homeostasis is closely correlated with many metabolic processes, future studies are needed in order to elucidate the finely tuned network among iron homeostasis, carbohydrate and lipid metabolism, inflammation, and hypoxia.

The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease.

The maintenance of iron homeostasis is essential for proper cardiac function. A growing body of evidence suggests that iron imbalance is the common denominator in many subtypes of cardiovascular disease. In the past 10 years, ferroptosis, an iron-dependent form of regulated cell death, has become increasingly recognized as an important process that mediates the pathogenesis and progression of numerous cardiovascular diseases, including atherosclerosis, drug-induced heart failure, myocardial ischaemia-reperfusion injury, sepsis-induced cardiomyopathy, arrhythmia and diabetic cardiomyopathy. Therefore, a thorough understanding of the mechanisms involved in the regulation of iron metabolism and ferroptosis in cardiomyocytes might lead to improvements in disease management. In this Review, we summarize the relationship between the metabolic and molecular pathways of iron signalling and ferroptosis in the context of cardiovascular disease. We also discuss the potential targets of ferroptosis in the treatment of cardiovascular disease and describe the current limitations and future directions of these novel treatment targets.

Effect of low-glycemic index diet advice on pregnant outcomes in women with elevated risk of gestational diabetes mellitus: A meta-analysis of randomized controlled trails.

BACKGROUND AND AIMS: The beneficial effect of low-glycemic index (GI) diet on gestational diabetes mellitus (GDM) has been suggested in many observational studies; however, results from intervention trials remain inconsistent. This study aims to estimate the effect of interventions with low-GI dietary advice on pregnant outcomes in women with elevated risk of GDM. DESIGN: PubMed, Web of Science, Embase, and Cochrane Library databases were searched for randomized clinical trials (RCTs) through March 2022. Studies reporting the effect of low-GI diet advice intervention on maternal and fetal outcomes in pregnant women with increased risks of GDM were included. Random or fixed effects model was used to calculate combined treatment effects. Publication bias was assessed via Begg's and Egger's tests and funnel plot inspection. RESULTS: Nine RCTs recruiting 3416 participants were included. Low-GI diet advice did not modulate the risk of GDM. Compared with control diets, low-GI diet advice significantly reduced gestational weight gain (GWG) (weighted mean differences, WMD = -0.93 kg, 95% CI: -1.31, -0.55; p < 0.001; n = 7) and the risk of premature birth (RR = 0.55, 95% CI: 0.35, 0.88; p = 0.012; n = 5). In subgroup analyses, the effect of low-GI diet interventions on premature birth was significant only in women with BMI higher than 30 kg/m2 (RR = 0.28, 95% CI: 0.10, 0.77, p = 0.014; n = 3); the significant effect on GWG was not altered by stratification of BMI and the type of GDM risk factors. No significant changes in other maternal and newborn outcomes were found. CONCLUSIONS: Low-GI diet advice interventions during pregnancy decreased GWG and the risk of premature birth in women with elevated GDM risk; however, the interventions did not significantly prevent GDM development in these women.

Malic Enzyme 1 as a Novel Anti-Ferroptotic Regulator in Hepatic Ischemia/Reperfusion Injury.

Ferroptosis has been linked to the pathogenesis of hepatic injury induced by ischemia/reperfusion (I/R). However, the mechanistic basis remains unclear. In this study, by using a mouse model of hepatic I/R injury, it is observed that glutathione (GSH) and cysteine depletion are associated with deficiency of the reducing power of nicotinamide adenine dinucleotide phosphate (NADPH). Genes involved in maintaining NADPH homeostasis are screened, and it is identified that I/R-induced hepatic ferroptosis is significantly associated with reduced expression and activity of NADP+ -dependent malic enzyme 1 (Me1). Mice with hepatocyte-specific Me1 gene deletion exhibit aggravated ferroptosis and liver injury under I/R treatment; while supplementation with L-malate, the substrate of ME1, restores NADPH and GSH levels and eventually inhibits I/R-induced hepatic ferroptosis and injury. A mechanistic study further reveals that downregulation of hepatic Me1 expression is largely mediated by the phosphatase and tensin homologue (PTEN)-dependent suppression of the mechanistic target of rapamycin/sterol regulatory element-binding protein 1 (mTOR/SREBP1) signaling pathway in hepatic I/R model. Finally, PTEN inhibitor, mTOR activator, or SREBP1 over-expression all increase hepatic NADPH, block ferroptosis, and protect liver against I/R injury. Taken together, the findings suggest that targeting ME1 may provide new therapeutic opportunities for I/R injury and other ferroptosis-related hepatic conditions.

Iron status and mental disorders: A Mendelian randomization study.

Background: Mental disorders account for an enormous global burden of disease, and has been associated with disturbed iron metabolism in observational studies. However, such associations are inconsistent and may be attributable to confounding from environmental factors. This study uses a two-sample Mendelian randomization (MR) analysis to investigate whether there is any causal effect of systemic iron status on risk of 24 specific mental disorders. Methods: Genetic variants with concordant relations to 4 biomarkers of iron status (serum iron, ferritin, transferrin saturation, and transferrin) were obtained from a genome-wide association study performed by the Genetics of Iron Status (GIS) consortium. Summary-level data for mental disorders were obtained from the UK Biobank. An inverse-variance weighted (IVW) approach was used for the main analysis, and the simple median, weighted median and MR-Egger methods were used in sensitivity analyses. Results: Genetically predicted serum iron, ferritin, and transferrin saturation were positively associated with depression and psychogenic disorder, and inversely associated with gender identity disorders. A higher transferrin, indicative of lower iron status, was also associated with increased risk of gender identity disorders and decreased risk of psychogenic disorder. Results were broadly consistent when using multiple sensitivity analyses to account for potential genetic pleiotropy. Conclusion: Our findings offer a novel insight into mental health, highlighting a detrimental effect of higher iron status on depression and psychogenic disorder as well as a potential protective role on risk of gender identity disorders. Further studies regarding the underlying mechanisms are warranted for updating preventative strategies.

Citrus Consumption and Risk of Melanoma: A Dose-Response Meta-Analysis of Prospective Cohort Studies.

Background: Epidemiological studies of citrus consumption in relation to melanoma risk have yielded conflicting results. This meta-analysis was performed to investigate the dose-response association between citrus consumption and risk of melanoma. Methods: Relevant prospective cohort studies were identified by searching PubMed, Embase, Scopus, and Web of Science databases up to February 28th, 2022. Results from individual studies were pooled using a random-effects model. Results: Five prospective studies, with 8,836 melanoma cases and 977,558 participants, were included in the meta-analysis. A significantly increased risk of melanoma was associated with the highest categories of either total citrus products (RR: 1.20; 95% CI: 1.01-1.42) or citrus fruit consumption (1.15; 1.04-1.28), but consumption of citrus juice was not associated with melanoma risk (1.08; 0.97-1.21). The dose-response analyses revealed that for per 1 serving/day increase in total citrus or citrus fruit consumption, the risk of melanoma increased by 9 and 12%, respectively. An inverted U-shaped curvilinear relationship, but not linear association, was observed between citrus juice consumption and melanoma risk. Conclusions: Citrus consumption was generally associated with a greater risk of malignant melanoma. Our findings may have important public health implications with respect to preventing melanoma.

The role of type 2 diabetes in the association between habitual glucosamine use and dementia: a prospective cohort study.

BACKGROUND: Growing evidence has showed an association between habitual glucosamine use and type 2 diabetes (T2D). However, the effect of habitual glucosamine use on risk of dementia remains poorly understood. Our study aimed to examine the association between glucosamine use and risk of dementia and further to identify the mediating role of T2D in the association. METHODS: A total of 495,942 participants from UK Biobank who completed a questionnaire on habitual glucosamine use were included at baseline (2006-2010) and then followed up for incidence of dementia until 2020. Cox proportional hazard regressions were performed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident dementia. Markov multi-state models were used to explore the role of incidence of T2D during the follow-up in the association. RESULTS: Overall, 18.80% of the participants reported habitual use of glucosamine at baseline. A total of 6831 dementia events were recorded during a median follow-up of 11 years. In fully adjusted models, habitual glucosamine use was associated with a significantly lower risk of dementia (HR = 0.87, 95% CI: 0.82-0.93). Multi-state models showed that the association between glucosamine use and dementia was mediated by the incidence of T2D during the follow-up (HR of dementia without T2D: 0.92, 95% CI: 0.86-0.99; HR of post-T2D dementia: 0.79, 95% CI: 0.67-0.93). CONCLUSIONS: Our findings reveal that habitual use of glucosamine supplement is associated with a lower risk of dementia, which might be explained by incidence of T2D.

Effects of probiotic supplementation on glucose metabolism in pregnant women without diabetes: a systematic review and meta-analysis.

Background: The preventive effects of probiotic supplementation against gestational diabetes mellitus (GDM) in pregnant women remain unclear. The objective of this review was to investigate the effect of probiotic supplementation on the profiles of glucose metabolism in pregnant women without diabetes. The published literature was retrieved and screened from PubMed, Embase, Web of Science, CNKI (China National Knowledge Infrastructure), Wanfang, and Cochrane Center Register of Controlled Trails up to April 1st, 2021. Random controlled trials (RCTs) of probiotic supplementation on pregnant women without GDM were included. Results: 12 RCTs (2213 participants) were eligible for meta-analyses. Overall, probiotic supplementation significantly reduced GDM incidence (Risk Ratio (RR) = 0.62, 95% CI: 0.39-0.99), serum fasting blood glucose (FBG) (Mean Difference (MD) = -0.14 mmol L-1; 95% CI: -0.26 mmol L-1, -0.01 mmol L-1), insulin concentration (MD = -1.91 pmol L-1, 95% CI: -2.41 to -1.41), the homeostasis model assessment of insulin resistance (HOMA-IR) (MD = -0.32 mmol L-1; 95% CI: -0.42 mmol L-1, -0.22 mmol L-1), and Quantitative Insulin sensitivity Check Index (QUICKI) (MD = 0.02, 95% CI: 0.01,0.03) in pregnant women. Probiotic supplementation had no significant effects on the results of the oral glucose tolerance test (OGTT) (1 h OGTT, MD = -0.10, 95% CI: -0.30, 0.09; 2 h OGTT, MD = -0.06, 95% CI: -0.31, 0.20). Conclusion: This meta-analysis suggested that probiotic supplementation may lead to an improvement in glycemic control and reduction of GDM incidence in pregnant women.