TFPI from erythroblasts drives heme production in central macrophages promoting erythropoiesis in polycythemia.

Bleeding and thrombosis are known as common complications of polycythemia for a long time. However, the role of coagulation system in erythropoiesis is unclear. Here, we discover that an anticoagulant protein tissue factor pathway inhibitor (TFPI) plays an essential role in erythropoiesis via the control of heme biosynthesis in central macrophages. TFPI levels are elevated in erythroblasts of human erythroblastic islands with JAK2V617F mutation and hypoxia condition. Erythroid lineage-specific knockout TFPI results in impaired erythropoiesis through decreasing ferrochelatase expression and heme biosynthesis in central macrophages. Mechanistically, the TFPI interacts with thrombomodulin to promote the downstream ERK1/2-GATA1 signaling pathway to induce heme biosynthesis in central macrophages. Furthermore, TFPI blockade impairs human erythropoiesis in vitro, and normalizes the erythroid compartment in mice with polycythemia. These results show that erythroblast-derived TFPI plays an important role in the regulation of erythropoiesis and reveal an interplay between erythroblasts and central macrophages.

Heme metabolism and HO-1 in the pathogenesis and potential intervention of endometriosis.

Endometriosis (EM) is one of the diseases related to retrograded menstruation and hemoglobin. Heme, released from hemoglobin, is degraded by heme oxygenase-1 (HO-1). In EM lesions, heme metabolites regulate processes such as inflammation, redox balance, autophagy, dysmenorrhea, malignancy, and invasion, where macrophages (Mø) play a fundamental role in their interactions. Regulation occurs at molecular, cellular, and pathological levels. Numerous studies suggest that heme is an indispensable component in EM and may contribute to its pathogenesis. The regulatory role of heme in EM encompasses cytokines, signaling pathways, and kinases that mediate cellular responses to external stimuli. HO-1, a catalytic enzyme in the catabolic phase of heme, mitigates heme's cytotoxicity in EM due to its antioxidant, anti-inflammatory, and anti-proliferative properties. Certain compounds may intervene in EM by targeting heme metabolism, guiding the development of appropriate treatments for all stages of endometriosis.

Causal effects of genetically determined metabolites on androgenetic alopecia: A two-sample Mendelian randomization analysis.

BACKGROUND: Androgenic alopecia (AGA) is the most common non-scarring alopecia disorder. Given its increasing incidence and onset during adolescence, AGA significantly impacts both the physical and psychological well-being of affected individuals. Emerging evidence suggests a pivotal role of metabolites in AGA. This study aims to elucidate the causal relationship between metabolites and AGA using Mendelian randomization (MR) analysis. METHODS: We conducted a two-sample Mendelian randomization (TSMR) analysis based on a genome-wide association study (GWAS) to assess the causality of 452 metabolites on AGA. The main approach employed for inferring causal effects was inverse variance weighted (IVW), which was complemented by MR-Egger regression, weighted median, as well as MR pleiotropy residual sum and outlier (MR-PRESSO) approaches. Additionally, sensitivity analyses were performed to ensure result robustness. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) in GWAS dataset comprising 452 metabolites. RESULTS: Notably, we identified Scyllo-inositol and Alpha-ketoglutarate as the most potent protective factors against AGA, while Heme* and 2-palmitoylglycerophosphocholine* emerged as significant risk factors for AGA. Furthermore, sensitivity analysis revealed no heterogeneity in these findings. CONCLUSIONS: Overall, our research suggests a potential causal link between metabolites and AGA, offering a more comprehensive insight into the pathogenesis of AGA and present additional strategies for prevention and treatment.

Computational Insights into the Catalysis of the pH Dependence of Bromite Decomposition Catalyzed by Chlorite Dismutase from Dechloromonas aromatica (DaCld).

The heme-containing chlorite dismutases catalyze the rapid and efficient decomposition of chlorite (ClO2-) to yield Cl- and O2, and the catalytic efficiency of chlorite dismutase from Dechloromonas aromatica (DaCld) in catalyzing the decomposition of bromite (BrO2-) was dependent on pH, which was supposed to be caused by the conversion of active Cpd I to the inactive Cpd II by proton-coupled electron transfer (PCET) from the pocket Tyr118 to the propionate side chain of heme at high pH. However, the direct evidence of PCET and how the pH affects the efficiency of DaCld, as well as whether Cpd II is really inactive, are still poorly understood. Here, on the basis of the high-resolution crystal structures, the computational models in both acidic (pH 5.0) and alkaline (pH 9.0) environments were constructed, and a series of quantum mechanical/molecular mechanical calculations were performed. On the basis of our calculation results, the O-Br bond cleavage of BrO2- always follows the homolytic mode to generate Cpd II rather than Cpd I. It is different from the O-O cleavage of O2/H2O2 or peracetic acid catalyzed by the other heme-containing enzymes. Thus, in the subsequent O-O rebound reaction, it is the Fe(IV)═O in Cpd II that combines with the O-Br radical. Because the porphyrin ring in Cpd II does not bear an unpaired electron, the previously suggested PCET from Tyr118 to the propionate side chain of heme was not theoretically recognized in an alkaline environment. In addition, the O-O rebound step in an alkaline solution corresponds to an energy barrier that is larger than that in an acidic environment, which can well explain the pH dependence of the activity of DaCld. In addition, the protonation state of the propionic acid side chains of heme and the surrounding hydrogen bond networks were calculated to have a significant impact on the barriers of the O-O rebound step, which is mainly achieved by affecting the reactivity of the Fe(IV)═O group in Cpd II. In an acidic environment, the relatively weaker coordination of the O2 atom to Fe leads to its higher reactivity toward the O-O rebound reaction. These observations may provide useful information for understanding the catalysis of chlorite dismutases.

The clinical relevance of heme detoxification by the macrophage heme oxygenase system.

Heme degradation by the heme oxygenase (HMOX) family of enzymes is critical for maintaining homeostasis and limiting heme-induced tissue damage. Macrophages express HMOX1 and 2 and are critical sites of heme degradation in healthy and diseased states. Here we review the functions of the macrophage heme oxygenase system and its clinical relevance in discrete groups of pathologies where heme has been demonstrated to play a driving role. HMOX1 function in macrophages is essential for limiting oxidative tissue damage in both acute and chronic hemolytic disorders. By degrading pro-inflammatory heme and releasing anti-inflammatory molecules such as carbon monoxide, HMOX1 fine-tunes the acute inflammatory response with consequences for disorders of hyperinflammation such as sepsis. We then discuss divergent beneficial and pathological roles for HMOX1 in disorders such as atherosclerosis and metabolic syndrome, where activation of the HMOX system sits at the crossroads of chronic low-grade inflammation and oxidative stress. Finally, we highlight the emerging role for HMOX1 in regulating macrophage cell death via the iron- and oxidation-dependent form of cell death, ferroptosis. In summary, the importance of heme clearance by macrophages is an active area of investigation with relevance for therapeutic intervention in a diverse array of human diseases.

A hemoprotein with a zinc-mirror heme site ties heme availability to carbon metabolism in cyanobacteria.

Heme has a critical role in the chemical framework of the cell as an essential protein cofactor and signaling molecule that controls diverse processes and molecular interactions. Using a phylogenomics-based approach and complementary structural techniques, we identify a family of dimeric hemoproteins comprising a domain of unknown function DUF2470. The heme iron is axially coordinated by two zinc-bound histidine residues, forming a distinct two-fold symmetric zinc-histidine-iron-histidine-zinc site. Together with structure-guided in vitro and in vivo experiments, we further demonstrate the existence of a functional link between heme binding by Dri1 (Domain related to iron 1, formerly ssr1698) and post-translational regulation of succinate dehydrogenase in the cyanobacterium Synechocystis, suggesting an iron-dependent regulatory link between photosynthesis and respiration. Given the ubiquity of proteins containing homologous domains and connections to heme metabolism across eukaryotes and prokaryotes, we propose that DRI (Domain Related to Iron; formerly DUF2470) functions at the molecular level as a heme-dependent regulatory domain.

Radiolysis of myoglobin concentrated gels by protons: specific changes in secondary structure and production of carbon monoxide.

While particle therapy has been used for decades for cancer treatment, there is still a lack of information on the molecular mechanisms of biomolecules radiolysis by accelerated ions. Here, we examine the effects of accelerated protons on highly concentrated native myoglobin, by means of Fourier transform infrared and UV-Visible spectroscopies. Upon irradiation, the secondary structure of the protein is drastically modified, from mostly alpha helices conformation to mostly beta elements at highest fluence. These changes are accompanied by significant production of carbon monoxide, which was shown to come from heme degradation under irradiation. The radiolytic yields of formation of denatured protein, carbon monoxide, and of heme degradation were determined, and found very close to each other: G+denatured Mb ≈ G+CO ≈ G-heme = 1.6 × 10-8 ± 0.1 × 10-8 mol/J = 0.16 ± 0.01 species/100 eV. The denaturation of the protein to a beta structure and the production of carbon monoxide under ion irradiation are phenomena that may play an important role in the biological effects of ionizing radiation.

Identification of small molecules affecting the interaction between human hemoglobin and Staphylococcus aureus IsdB hemophore.

Human hemoglobin (Hb) is the preferred iron source of Staphylococcus aureus. This pathogenic bacterium exploits a sophisticated protein machinery called Iron-regulated surface determinant (Isd) system to bind Hb, extract and internalize heme, and finally degrade it to complete iron acquisition. IsdB, the surface exposed Hb receptor, is a proven virulence factor of S. aureus and the inhibition of its interaction with Hb can be pursued as a strategy to develop new classes of antimicrobials. To identify small molecules able to disrupt IsdB:Hb protein-protein interactions (PPIs), we carried out a structure-based virtual screening campaign and developed an ad hoc immunoassay to screen the retrieved set of commercially available compounds. Saturation-transfer difference (STD) NMR was applied to verify specific interactions of a sub-set of molecules, chosen based on their efficacy in reducing the amount of Hb bound to IsdB. Among molecules for which direct binding was verified, the best hit was submitted to ITC analysis to measure the binding affinity to Hb, which was found to be in the low micromolar range. The results demonstrate the viability of the proposed in silico/in vitro experimental pipeline to discover and test IsdB:Hb PPI inhibitors. The identified lead compound will be the starting point for future SAR and molecule optimization campaigns.

Structural dynamics of the heme pocket and intersubunit coupling in the dimeric hemoglobin from Scapharca inaequivalvis.

Cooperativity is essential for the proper functioning of numerous proteins by allosteric interactions. Hemoglobin from Scapharca inaequivalvis (HbI) is a homodimeric protein that can serve as a minimal unit for studying cooperativity. We investigated the structural changes in HbI after carbon monoxide dissociation using time-resolved resonance Raman spectroscopy and observed structural rearrangements in the Fe-proximal histidine bond, the position of the heme in the pocket, and the hydrogen bonds between heme and interfacial water upon ligand dissociation. Some of the spectral changes were different from those observed for human adult hemoglobin due to differences in subunit assembly and quaternary changes. The structural rearrangements were similar for the singly and doubly dissociated species but occurred at different rates. The rates of the observed rearrangements indicated that they occurred synchronously with subunit rotation and are influenced by intersubunit coupling, which underlies the positive cooperativity of HbI.

Haem iron versus ferrous iron salts to treat iron deficiency anaemia in Gambian children: protocol for randomised controlled trial {1}.

BACKGROUND: The World Health Organization recommends universal iron supplementation for children aged 6-23 months in countries where anaemia is seen in over 40% of the population. Conventional ferrous salts have low efficacy due to low oral absorption in children with inflammation. Haem iron is more bioavailable, and its absorption may not be decreased by inflammation. This study aims to compare daily supplementation with haem iron versus ferrous sulphate on haemoglobin concentration and serum ferritin concentration after 12 weeks of supplementation. METHODS: This will be a two-arm, randomised controlled trial. Gambian children aged 6-12 months with anaemia will be recruited within a predefined geographical area and recruited by trained field workers. Eligible participants will be individually randomised using a 1:1 ratio within permuted blocks to daily supplementation for 12 weeks with either 10.0 mg of elemental iron as haem or ferrous sulphate. Safety outcomes such as diarrhoea and infection-related adverse events will be assessed daily by the clinical team (see Bah et al. Additional file 4_Adverse event eCRF). Linear regression will be used to analyse continuous outcomes, with log transformation to normalise residuals as needed. Binary outcomes will be analysed by binomial regression or logistic regression, Primary analysis will be by modified intention-to-treat (i.e., those randomised and who ingested at least one supplement dose of iron), with multiple imputations to replace missing data. Effect estimates will be adjusted for baseline covariates (C-reactive protein, alpha-1-acid glycoprotein, haemoglobin, ferritin, soluble transferrin receptor). DISCUSSION: This study will determine if therapeutic supplementation with haem iron is more efficacious than with conventional ferrous sulphate in enhancing haemoglobin and ferritin concentrations in anaemic children aged 6-12 months. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR202210523178727.

The heme binding protein ChuX is a regulator of heme degradation by the ChuS protein in Escherichia coli O157:H7.

Escherichia coli O157:H7 possesses an 8-gene cluster (chu genes) that contains genes involved in heme transport and processing from the human host. Among the chu genes, four encode cytoplasmic proteins (ChuS, ChuX, ChuY and ChuW). ChuX was previously shown to be a heme binding protein and to assist ChuW in heme degradation under anaerobic conditions. The purpose of this work was to investigate if ChuX works in concert with ChuS, which is a protein able to degrade heme by a non-canonical mechanism and release the iron from the porphyrin under aerobic conditions using hydrogen peroxide as the oxidant. We showed that when the heme-bound ChuX and apo-ChuS protein are mixed, heme is efficiently transferred from ChuX to ChuS. Heme-bound ChuX displayed a peroxidase activity with ABTS and H2O2 but not heme-bound ChuS, which is an efficient test to determine the protein to which heme is bound in the ChuS-ChuX complex. We found that ChuX protects heme from chemical oxidation and that it has no heme degradation activity by itself. Unexpectedly, we found that ChuX inhibits heme degradation by ChuS and stops the reaction at an early intermediate. We determined using surface plasmon resonance that ChuX interacts with ChuS and that it forms a relatively stable complex. These results indicate that ChuX in addition to its heme transfer activity is a regulator of ChuS activity, a function that was not described before for any of the heme carrier protein that delivers heme to heme degradation enzymes.

In-depth structure-function profiling of the complex formation between clotting factor VIII and heme.

BACKGROUND AND AIMS: Blood disorders, such as sickle cell disease, and other clinical conditions are often accompanied by intravascular hemolytic events along with the development of severe coagulopathies. Hemolysis, in turn, leads to the accumulation of Fe(II/III)-protoporphyrin IX (heme) in the intravascular compartment, which can trigger a variety of proinflammatory and prothrombotic reactions. As such, heme binding to the blood coagulation proteins factor VIII (FVIII), fibrinogen, and activated protein C with functional consequences has been demonstrated earlier. METHODS: We herein present an in-depth characterization of the FVIII-heme interaction at the molecular level and its (patho-)physiological relevance through the application of biochemical, biophysical, structural biology, bioinformatic, and diagnostic tools. RESULTS: FVIII has a great heme-binding capacity with seven heme molecules associating with the protein. The respective binding sites were identified by investigating heme binding to FVIII-derived peptides in combination with molecular docking and dynamic simulation studies of the complex as well as cryo-electron microscopy, revealing three high-affinity and four moderate heme-binding motifs (HBMs). Furthermore, the relevance of the FVIII-heme complex formation was characterized in physiologically relevant assay systems, revealing a ~ 50 % inhibition of the FVIII cofactor activity even in the protein-rich environment of blood plasma. CONCLUSION: Our study provides not only novel molecular insights into the FVIII-heme interaction and its physiological relevance, but also strongly suggests the reduction of the intrinsic pathway and the accentuation of the final clotting step (by, for example, fibrinogen crosslinking) in hemolytic conditions as well as a future perspective in the context of FVIII substitution therapy of hemorrhagic events in hemophilia A patients.

Dietary Hemin Remodels Gut Microbiota and Mediates Tissue Inflammation and Injury in the Small Intestine.

SCOPE: Epidemiological studies have linked excessive red and processed meat intake to gut disorders. Under laboratory conditions, high heme content is considered the primary health risk factor for red meat. However, heme in meat is present in myoglobin, which is an indigestible protein, suggesting the different functions between myoglobin and heme. This study aims to explore how dietary myoglobin and heme affect gut health and microbiota differently. METHODS AND RESULTS: Histological and biochemical assessments as well as 16S rRNA sequencing are performed. Moderate myoglobin intake (equivalent to the recommended intake of 150 g meat per day for human) has beneficial effects on the duodenal barrier. However, a too high myoglobin diet (equivalent to intake of 3000 g meat per day for human) triggers duodenum injury and alters the microbial community. The hemin diet destroys intestinal tissue and ileal microbiota more significantly. The in vitro experiments further confirm that free heme exhibits high toxicity to beneficial gut bacteria while myoglobin promotes the growth and metabolism of Limosilactobacillus reuteri. CONCLUSION: Moderate intake of myoglobin or hemin is beneficial to intestinal health and microbiota, but too high amounts lead to tissue inflammation and injury in the small intestine by reshaping ileal microbiota.

Identification of histidine residues that affect the T/R-state conformations of human hemoglobin using constant pH molecular dynamics simulations.

Human hemoglobin (Hb) is a tetrameric protein consisting of two α and two ß subunits that can adopt a low-affinity T- and high-affinity R-state conformations. Under physiological pH conditions, histidine (His) residues are the main sites for proton binding or release, and their protonation states can affect the T/R-state conformation of Hb. However, it remains unclear which His residues can effectively affect the Hb conformation. Herein, the impact of the 38 His residues of Hb on its T/R-state conformations was evaluated using constant-pH molecular dynamics (CpHMD) simulations at physiological pH while focusing on the His protonation states. Overall, the protonation states of some His residues were found to be correlated with the Hb conformation state. These residues were mainly located in the proximity of the heme (α87 and ß92), and at the α1ß2 and α2ß1 interfaces (α89 and ß97). This correlation may be partly explained by how easily hydrogen bonds can be formed, which depends on the protonation states of the His residues. Taken together, these CpHMD-based findings provide new insights into the identification of titratable His residues α87, α89, ß92, and ß97 that can affect Hb conformational switching under physiological pH conditions.

TANK Binding Kinase 1 Promotes BACH1 Degradation through Both Phosphorylation-Dependent and -Independent Mechanisms without Relying on Heme and FBXO22.

BTB and CNC homology 1 (BACH1) represses the expression of genes involved in the metabolism of iron, heme and reactive oxygen species. While BACH1 is rapidly degraded when it is bound to heme, it remains unclear how BACH1 degradation is regulated under other conditions. We found that FBXO22, a ubiquitin ligase previously reported to promote BACH1 degradation, polyubiquitinated BACH1 only in the presence of heme in a highly purified reconstitution assay. In parallel to this regulatory mechanism, TANK binding kinase 1 (TBK1), a protein kinase that activates innate immune response and regulates iron metabolism via ferritinophagy, was found to promote BACH1 degradation when overexpressed in 293T cells. While TBK1 phosphorylated BACH1 at multiple serine and threonine residues, BACH1 degradation was observed with not only the wild-type TBK1 but also catalytically impaired TBK1. The BACH1 degradation in response to catalytically impaired TBK1 was not dependent on FBXO22 but involved both autophagy-lysosome and ubiquitin-proteasome pathways judging from its suppression by using inhibitors of lysosome and proteasome. Chemical inhibition of TBK1 in hepatoma Hepa1 cells showed that TBK1 was not required for the heme-induced BACH1 degradation. Its inhibition in Namalwa B lymphoma cells increased endogenous BACH1 protein. These results suggest that TBK1 promotes BACH1 degradation in parallel to the FBXO22- and heme-dependent pathway, placing BACH1 as a downstream effector of TBK1 in iron metabolism or innate immune response.

Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism.

In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]. Our finding revealed that maintaining heme and iron homeostasis is essential to keep naive T cells in a quiescent state. KO naive CD4 T cells exhibited an iron-overloaded phenotype, with increased spontaneous proliferation and hyperactive mitochondria. This was evidenced by reduced IL-7R and IL-15R levels but increased CD5 and Nur77 expression. Upon activation, however, KO CD4 T cells have defects in proliferation, IL-2 production, and mitochondrial functions. Iron-overloaded CD4 T cells failed to induce mitochondrial iron and exhibited more fragmented mitochondria after activation, making them susceptible to ferroptosis. Iron overload also led to inefficient glycolysis and glutaminolysis but heightened activity in the hexosamine biosynthetic pathway. Overall, these findings highlight the essential role of iron in controlling mitochondrial function and cellular metabolism in naive CD4 T cells, critical for maintaining their quiescent state.

Porphyrin overdrive rewires cancer cell metabolism.

All cancer cells reprogram metabolism to support aberrant growth. Here, we report that cancer cells employ and depend on imbalanced and dynamic heme metabolic pathways, to accumulate heme intermediates, that is, porphyrins. We coined this essential metabolic rewiring "porphyrin overdrive" and determined that it is cancer-essential and cancer-specific. Among the major drivers are genes encoding mid-step enzymes governing the production of heme intermediates. CRISPR/Cas9 editing to engineer leukemia cell lines with impaired heme biosynthetic steps confirmed our whole-genome data analyses that porphyrin overdrive is linked to oncogenic states and cellular differentiation. Although porphyrin overdrive is absent in differentiated cells or somatic stem cells, it is present in patient-derived tumor progenitor cells, demonstrated by single-cell RNAseq, and in early embryogenesis. In conclusion, we identified a dependence of cancer cells on non-homeostatic heme metabolism, and we targeted this cancer metabolic vulnerability with a novel "bait-and-kill" strategy to eradicate malignant cells.

Structural basis for the recognition of human hemoglobin by the heme-acquisition protein Shr from Streptococcus pyogenes.

In Gram-positive bacteria, sophisticated machineries to acquire the heme group of hemoglobin (Hb) have evolved to extract the precious iron atom contained in it. In the human pathogen Streptococcus pyogenes, the Shr protein is a key component of this machinery. Herein we present the crystal structure of hemoglobin-interacting domain 2 (HID2) of Shr bound to Hb. HID2 interacts with both, the protein and heme portions of Hb, explaining the specificity of HID2 for the heme-bound form of Hb, but not its heme-depleted form. Further mutational analysis shows little tolerance of HID2 to interfacial mutations, suggesting that its interaction surface with Hb could be a suitable candidate to develop efficient inhibitors abrogating the binding of Shr to Hb.

Associations of dietary iron intake with cardiovascular disease risk and dyslipidemia among Chinese adults.

BACKGROUND: Whether iron intake can affect cardiovascular disease (CVD) and dyslipidemia is controversial. However, few studies have focused on reducing the risk of CVD in people at risk for dyslipidemia. This study explored the linear relationship and possible nonlinear relationship between CVD and dyslipidemia. METHODS: Dietary data were obtained from the China Health and Nutrition Survey between 2004 and 2015. The survey included 8173 participants older than 18 years. CVD risk was estimated by the Framingham risk score (FRS). Logistic regression analysis was used to determine whether iron intake affects CVD incidence and lipid profiles. The nonlinear association was tested with restricted cubic splines (RCSs). RESULTS: For males, higher total iron intake [the fifth quintile (Q) vs. Q1 odds ratio (OR): 0.335, 95% confidence interval (CI): 0.248-0.453], heme iron intake (OR: 0.679, 95% CI: 0.492-0.937) and non-heme iron intake (OR: 0.362, 95% CI: 0.266-0.492) reduced CVD incidence. Heme iron intake increased high low-density lipoprotein cholesterol (LDL-C) (OR: 1.786, 95% CI: 1.226-2.602), high total cholesterol (TC) (OR: 2.404, 95% CI: 1.575-3.669), high triglyceride (TG) (OR: 1.895, 95% CI: 1.423-2.523), and low apolipoprotein A1/apolipoprotein B (ApoA-1/ApoB) risk (OR: 1.514, 95% CI: 1.178-1.945). Moderate non-heme iron intake reduced high-density lipoprotein cholesterol (HDL-C) incidence (Q5 vs. Q1 OR: 0.704, 95% CI: 0.507-0.979). For females, higher total iron intake (Q5 vs. Q1 OR: 0.362, 95% CI: 0.266-0.492) and non-heme iron intake (OR: 0.347, 95% CI: 0.154-0.781) reduced CVD incidence. Heme iron intake increased high LDL-C (OR: 1.587, 95% CI: 1.160-2.170) and high TC incidence (OR: 1.655, 95% CI: 1.187-2.309). CONCLUSIONS: Men, especially those at risk of developing dyslipidemia, should consume non-heme rather than heme iron to reduce CVD incidence. For women, increased heme iron intake did not reduce CVD incidence. Therefore, women should minimize their heme iron intake to prevent dyslipidemia.

Nonlinear optical response of heme solutions.

Heme is the prosthetic group for cytochrome that exists in nearly all living organisms and serves as a vital component of human red blood cells (RBCs). Tunable optical nonlinearity in suspensions of RBCs has been demonstrated previously, however, the nonlinear optical response of a pure heme (without membrane structure) solution has not been studied to our knowledge. In this work, we show optical nonlinearity in two common kinds of heme (i.e., hemin and hematin) solutions by a series of experiments and numerical simulations. We find that the mechanism of nonlinearity in heme solutions is distinct from that observed in the RBC suspensions where the nonlinearity can be easily tuned through optical power, concentration, and the solution properties. In particular, we observe an unusual phenomenon wherein the heme solution exhibits negative optical nonlinearity and render self-collimation of a focused beam at specific optical powers, enabling shape-preserving propagation of light to long distances. Our results may have potential applications in optical imaging and medical diagnosis through blood.