Disruption of monocyte-macrophage differentiation and trafficking by a heme analog during active inflammation.

Heme metabolism is a key regulator of inflammatory responses. Cobalt protoporphyrin IX (CoPP) is a heme analog and mimic that potently activates the NRF2/heme oxygenase-1 (HO-1) pathway, especially in monocytes and macrophages. We investigated the influence of CoPP on inflammatory responses using a murine model of colitis. Surprisingly, conditional deletion of myeloid HO-1 did not impact the colonic inflammatory response or the protective influence of CoPP in the setting of dextran sodium sulfate-induced colitis. Rather, we reveal that CoPP elicits a contradictory shift in blood myeloid populations relative to the colon during active intestinal inflammation. Major population changes include markedly diminished trafficking of CCR2+Ly6Chi monocytes to the inflamed colon, despite significant mobilization of this population into circulation. This resulted in significantly diminished colonic expansion of monocyte-derived macrophages and inflammatory cytokine expression. These findings were linked with significant induction of systemic CCL2 leading to a disrupted CCL2 chemoattractant gradient toward the colon and concentration-dependent suppression of circulating monocyte CCR2 expression. Administration of CoPP also induced macrophage differentiation toward a MarcohiHmox1hi anti-inflammatory erythrophagocytic phenotype, contributing to an overall decreased inflammatory profile. Such findings redefine protective influences of heme metabolism during inflammation, and highlight previously unreported immunosuppressive mechanisms of endogenous CCL2 induction.

Update on the Role of Actovegin in Musculoskeletal Medicine: A Review of the Past 10 Years.

BACKGROUND: Actovegin is a biological drug with a controversial history of use in the treatment of sports injuries during the past 60 years. Particular concerns have been raised about its ergogenic potential to enhance performance, but some of these have been based on little more than anecdote. OBJECTIVES: In this article, we review the most recent scientific evidence to determine the clinical efficacy, safety profile, and legal status of Actovegin. METHODS: We considered all studies directly commenting on experience with Actovegin use as the primary intervention within the past 10 years. Outcomes included mechanisms of action, clinical efficacy in enhancing muscle repair, any report of safety issues, and any evidence for ergogenic effect. RESULTS: Our database search returned 212 articles, abstracts were screened, and after inclusion/exclusion criteria were applied, 25 articles were considered: Publications included 11 primary research articles (7 in vitro studies and 4 clinical trials), 8 review articles, 5 editorials, and a single case report. CONCLUSIONS: Current literature is still yet to define the active compound(s) of Actovegin, but suggests that it shows antioxidant and antiapoptotic properties, and may also upregulate macrophage responses central to muscle repair. Clinical efficacy was supported by one new original research article, and the use of Actovegin to treat muscle injuries remains safe and supported. Two articles argued the ergogenic effect of Actovegin, but in vitro findings did not to translate to the outcomes of a clinical trial. An adequate and meaningful scientific approach remains difficult in a field where there is immense pressure to deliver cutting-edge therapies.

Intravenous Heme Arginate Induces HO-1 (Heme Oxygenase-1) in the Human Heart.

Objective- HO-1 (heme oxygenase-1) induction may prevent or reduce ischemia-reperfusion injury. We previously evaluated its in vivo induction after a single systemic administration of heme arginate in peripheral blood mononuclear cells. The current trial was designed to assess the pharmacological tissue induction of HO-1 in the human heart with heme arginate in vivo. Approach and Results- Patients planned for conventional aortic valve replacement received placebo (n=8), 1 mg/kg (n=7) or 3 mg/kg (n=9) heme arginate infused intravenously 24 hours before surgery. A biopsy of the right ventricle was performed directly before aortic cross-clamping and after cross-clamp release. In addition, the right atrial appendage was partially removed for analysis. HO-1 protein and mRNA concentrations were measured in tissue samples and in peripheral blood mononuclear cells before to and up to 72 hours after surgery. No study medication-related adverse events occurred. A strong, dose-dependent effect on myocardial HO-1 mRNA levels was observed (right ventricle: 7.9±5.0 versus 88.6±49.1 versus 203.6±148.7; P=0.002 and right atrium: 10.8±8.8 versus 229.8±173.1 versus 392.7±195.7; P=0.001). This was paralleled by a profound increase of HO-1 protein concentration in atrial tissue (8401±3889 versus 28 585±10 692 versus 29 022±8583; P<0.001). Surgery and heme arginate infusion significantly increased HO-1 mRNA concentration in peripheral blood mononuclear cells ( P<0.001). HO-1 induction led to a significant increase of postoperative carboxyhemoglobin (1.7% versus 1.4%; P=0.041). No effect on plasma HO-1 protein levels could be detected. Conclusions- Myocardial HO-1 mRNA and protein can be dose-dependently induced by heme arginate. Protective effects of this therapeutic strategy should be evaluated in upcoming clinical trials. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02314780.

Red meat and colon cancer: A review of mechanistic evidence for heme in the context of risk assessment methodology.

On October 26, 2015, IARC published a summary of their findings regarding the association of cancer with consumption of red meat or processed meat (IARC 2015; The Lancet Oncology 2015). The Working Group concluded that there is limited evidence in human beings for carcinogenicity from the consumption of red meat and inadequate evidence in experimental animals for the carcinogenicity of consumption of red meat. Nevertheless, the working group concluded that there is strong mechanistic evidence by which ingestion of red meat can be linked to human colorectal cancer and assigned red meat to Group 2A "probably carcinogenic to humans". The Working Group cited supporting mechanistic evidence for multiple meat components, including those formed from meat processing, such as N-nitroso compounds (NOC) and heterocyclic aromatic amines, and the endogenous compound, heme iron. The mechanism of action for each of these components is different and so it is critical to evaluate the evidence for each component separately. Consequently, this review critically examined studies that investigated mechanistic evidence associated with heme iron to assess the weight of the evidence associating exposure to red meat with colorectal cancer. The evidence from in vitro studies utilized conditions that are not necessarily relevant for a normal dietary intake and thus do not provide sufficient evidence that heme exposure from typical red meat consumption would increase the risk of colon cancer. Animal studies utilized models that tested promotion of preneoplastic conditions utilizing diets low in calcium, high in fat combined with exaggerations of heme exposure that in many instances represented intakes that were orders of magnitude above normal dietary consumption of red meat. Finally, clinical evidence suggests that the type of NOC found after ingestion of red meat in humans consists mainly of nitrosyl iron and nitrosothiols, products that have profoundly different chemistries from certain N-nitroso species which have been shown to be tumorigenic through the formation of DNA adducts. In conclusion, the methodologies employed in current studies of heme have not provided sufficient documentation that the mechanisms studied would contribute to an increased risk of promotion of preneoplasia or colon cancer at usual dietary intakes of red meat in the context of a normal diet.

Meat and haem iron intake in relation to glioma in the European Prospective Investigation into Cancer and Nutrition study.

Diets high in red or processed meat have been associated positively with some cancers, and several possible underlying mechanisms have been proposed, including iron-related pathways. However, the role of meat intake in adult glioma risk has yielded conflicting findings because of small sample sizes and heterogeneous tumour classifications. The aim of this study was to examine red meat, processed meat and iron intake in relation to glioma risk in the European Prospective Investigation into Cancer and Nutrition study. In this prospective cohort study, 408 751 individuals from nine European countries completed demographic and dietary questionnaires at recruitment. Multivariable Cox proportional hazards models were used to examine intake of red meat, processed meat, total dietary iron and haem iron in relation to incident glioma. During an average follow-up of 14.1 years, 688 incident glioma cases were diagnosed. There was no evidence that any of the meat variables (red, processed meat or subtypes of meat) or iron (total or haem) were associated with glioma; results were unchanged when the first 2 years of follow-up were excluded. This study suggests that there is no association between meat or iron intake and adult glioma. This is the largest prospective analysis of meat and iron in relation to glioma and as such provides a substantial contribution to a limited and inconsistent literature.

Association between pre-pregnancy consumption of meat, iron intake, and the risk of gestational diabetes: the SUN project.

PURPOSE: We assessed the association of total meat, processed, and unprocessed red meat and iron intake with the risk of developing gestational diabetes mellitus (GDM) in pregnant women. METHODS: We conducted a prospective study among 3298 disease-free Spanish women participants of the SUN cohort who reported at least one pregnancy between December 1999 and March 2012. Meat consumption and iron intake were assessed at baseline through a validated, 136-item semi-quantitative, food frequency questionnaire. We categorized total, red, and processed meat consumption and iron intake into quartiles. Logistic regression models were used to adjust for potential confounders. RESULTS: We identified 172 incident cases of GDM. In the fully adjusted analysis, total meat consumption was significantly associated with a higher risk of GDM [OR = 1.67 (95% CI 1.06-2.63, p-trend 0.010)] for the highest versus the lowest quartile of consumption. The observed associations were particularly strong for red meat consumption [OR = 2.37 (95% CI 1.49-3.78, p-trend < 0.001)] and processed meat consumption [OR = 2.01 (95% CI 1.26-3.21, p-trend 0.003)]. Heme iron intake was also directly associated with GDM [OR = 2.21 (95% CI 1.37-3.58, p-trend 0.003)], although the association was attenuated and lost its statistical significance when we adjusted for red meat consumption [OR = 1.57 (95% CI 0.91-2.70, p-trend 0.213)]. No association was observed for non-heme and total iron intake, including supplements. CONCLUSIONS: Our overall findings suggest that higher pre-pregnancy consumption of total meat, especially red and processed meat, and heme iron intake, are significantly associated with an increased GDM risk in a Mediterranean cohort of university graduates.

Role of Heme Iron in the Association Between Red Meat Consumption and Colorectal Cancer.

The growing incidence of colorectal cancer (CRC) in the world seems to be related to the spread of Westernized lifestyles, particularly dietary habits. Several studies have found that high consumption of red meat-especially processed red meat, a mainstay of Western diets-is associated with an increased risk of developing CRC. One possible reason for the association are the adverse effects exerted by the heme iron contained in red meat, which has the potential to affect homeostasis and colonic epithelial cell renewal and to promote the formation of mutagenic and carcinogenic agents. A correlation has also emerged between CRC and alterations of the gut microbiota, since the micro-organisms found in the intestinal lumen seem to influence the activation of enterocyte genes involved in the initiation and progression of carcinogenesis. Dietary habits can therefore modify the gut microbiota, affecting gene activation and favoring the development of cancer cells. We review and discuss the most recent literature on the hypothesis that heme iron can exert adverse effects by altering the gut microbiota and colorectal epithelial cell homeostasis.

Dietary Iron and Heme Iron Consumption, Genetic Susceptibility, and Risk of Crohn's Disease and Ulcerative Colitis.

BACKGROUND: Dietary iron and heme, likely through their effect on gut commensal bacteria and colonic barrier function, have been shown to modulate colonic inflammation in animal models of colitis. Nonetheless, the link between dietary total and heme iron and risk of Crohn's disease (CD) and ulcerative colitis (UC) has not been previously explored. METHODS: We conducted a prospective cohort study of 165,331 U.S. women enrolled in the Nurses' Health Study and Nurses' Health Study II. Dietary information was collected using a validated food frequency questionnaire at baseline (1984) and updated every 2 to 4 years. Self-reported CD and UC diagnoses were confirmed through medical records review. We used Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals while adjusting for potential confounders. In a case-control study nested within these cohorts, we evaluated the interaction between single-nucleotide polymorphisms associated with genome-wide susceptibility to CD and UC and dietary total and heme iron intake on risk of CD and UC using logistic regression modeling. RESULTS: Through 2011, over 3,038,049 person-years of follow-up, we documented 261 incident cases of CD and 321 incident cases of UC. Dietary heme iron was nonsignificantly associated with increased risk of UC (Ptrend = 0.12). This association seemed to be modified by the UC susceptibility locus, rs1801274, a coding variant in the FcγRIIA gene (Pinteraction = 7.00E-05). In contrast, there was no association between dietary heme iron and risk of CD (Ptrend = 0.67). We also did not observe an association between total dietary intake of iron and risk of CD or UC (All Ptrend > 0.35). CONCLUSION: In 2 large prospective cohort studies, dietary total and heme iron were not associated with risk of CD or UC. Our suggestive finding that the association between dietary heme iron intake and risk of UC may be modified by a coding variant in FcγRIIA gene warrants additional investigation.

Iron transport proteins: Gateways of cellular and systemic iron homeostasis.

Cellular iron homeostasis is maintained by iron and heme transport proteins that work in concert with ferrireductases, ferroxidases, and chaperones to direct the movement of iron into, within, and out of cells. Systemic iron homeostasis is regulated by the liver-derived peptide hormone, hepcidin. The interface between cellular and systemic iron homeostasis is readily observed in the highly dynamic iron handling of four main cell types: duodenal enterocytes, erythrocyte precursors, macrophages, and hepatocytes. This review provides an overview of how these cell types handle iron, highlighting how iron and heme transporters mediate the exchange and distribution of body iron in health and disease.

Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study.

Objective To determine the association of different types of meat intake and meat associated compounds with overall and cause specific mortality.Design Population based cohort study.Setting Baseline dietary data of the NIH-AARP Diet and Health Study (prospective cohort of the general population from six states and two metropolitan areas in the US) and 16 year follow-up data until 31 December 2011.Participants 536 969 AARP members aged 50-71 at baseline.Exposures Intake of total meat, processed and unprocessed red meat (beef, lamb, and pork) and white meat (poultry and fish), heme iron, and nitrate/nitrite from processed meat based on dietary questionnaire. Adjusted Cox proportional hazards regression models were used with the lowest fifth of calorie adjusted intakes as reference categories.Main outcome measure Mortality from any cause during follow-up.Results An increased risk of all cause mortality (hazard ratio for highest versus lowest fifth 1.26, 95% confidence interval 1.23 to 1.29) and death due to nine different causes associated with red meat intake was observed. Both processed and unprocessed red meat intakes were associated with all cause and cause specific mortality. Heme iron and processed meat nitrate/nitrite were independently associated with increased risk of all cause and cause specific mortality. Mediation models estimated that the increased mortality associated with processed red meat was influenced by nitrate intake (37.0-72.0%) and to a lesser degree by heme iron (20.9-24.1%). When the total meat intake was constant, the highest fifth of white meat intake was associated with a 25% reduction in risk of all cause mortality compared with the lowest intake level. Almost all causes of death showed an inverse association with white meat intake.Conclusions The results show increased risks of all cause mortality and death due to nine different causes associated with both processed and unprocessed red meat, accounted for, in part, by heme iron and nitrate/nitrite from processed meat. They also show reduced risks associated with substituting white meat, particularly unprocessed white meat.

A critical overview on the biological and molecular features of red and processed meat in colorectal carcinogenesis.

A recent investigation by the World Health Organisation (WHO) has found that the consumption of processed meat and potentially red meat promotes carcinogenesis and can increase the risk of colorectal cancer. This literature review aims to summarise both the red and processed meat molecules associated with colorectal carcinogenesis and investigate their relationship with the pathogenic process of colorectal cancer. Literature relating to the carcinogenic effect of red and processed meat molecules was critically reviewed. There are multiple molecules present in red and processed meat with a potential carcinogenic effect on colorectal tissues. Processed meat is more carcinogenic compared to red meat because of the abundance of potent nitrosyl-heme molecules that form N-nitroso compounds. Studies have also noted that other molecules such as polycyclic aromatic hydrocarbons and heterocyclic amines have potential mechanisms for the initiation of colorectal cancer pathogenesis. The non-human sugar molecule N-glycolylneuraminic acid may account for the carcinogenic effects of pork despite its heme content being comparable to that of chicken. Red meat products, especially those that have been processed, have a wide variety of carcinogenic molecules known to increase the risk of colorectal cancer. Thus, the outcome of this review is consistent with the recent findings of WHO.

Heme Iron Intake, Dietary Antioxidant Capacity, and Risk of Colorectal Adenomas in a Large Cohort Study of French Women.

BACKGROUND: Nitrosylated and non-nitrosylated heme iron from red processed and nonprocessed meat have been associated with increased colorectal carcinogenesis. Mechanisms include oxidative processes. It has been hypothesized that dietary antioxidants could counteract the effects of heme iron. We investigated the relationships between heme iron intake and the risk of colorectal adenomas, and a potential interaction with the dietary antioxidant capacity, in the E3N prospective cohort study. METHODS: The study included 17,397 women, who underwent at least one colonoscopy. Among them, 1,409 were diagnosed with at least one first colorectal adenoma during the 103,253 person-years of follow-up. Dietary intake was measured by a semiquantitative food history questionnaire. HR estimates and 95% confidence intervals (CI) were obtained from Cox proportional hazards models, adjusted for potential confounders. RESULTS: Heme iron intake was positively associated with colorectal and colon adenoma risks [HR for the fourth vs. first quartile: HR4 = 1.36 (1.13-1.65), Ptrend = 0.001 and HR4 = 1.49; 95% CI, 1.19-1.87; Ptrend = 0.0003, respectively]. Nonnitrosylated and nitrosylated heme iron intakes were, respectively, associated with advanced distal and proximal adenoma risks. There was a dose-effect relationship between the heme iron to total dietary antioxidant capacity ratio and colorectal adenoma risk. CONCLUSION: In this prospective cohort study, the association between heme iron and colorectal adenoma risk was found to depend on site, nitrosylation or not, and the ratio with the NEAC. IMPACT: These results emphasize the need for a global assessment of diet when considering nutritional prevention of colorectal carcinogenesis. Cancer Epidemiol Biomarkers Prev; 25(4); 640-7. ©2016 AACR.

Long-term risk of type 2 diabetes in relation to habitual iron intake in women with a history of gestational diabetes: a prospective cohort study.

BACKGROUND: An iron overload may induce pancreatic islet damage and increase risk of diabetes. Women with a history of gestational diabetes mellitus (GDM) are at high risk of developing type 2 diabetes mellitus (T2DM) after pregnancy. OBJECTIVE: We aimed to examine the association of habitual iron intake with long-term risk of T2DM in this high-risk population. DESIGN: We included 3976 women with a history of GDM from the Nurses' Health Study II cohort as part of the ongoing Diabetes & Women's Health Study. The women were followed up through 2009. Iron intake was assessed with the use of a validated food-frequency questionnaire in 1991 and every 4 y thereafter. We used Cox proportional hazards models to estimate HRs and 95% CIs. RESULTS: We documented 641 incident T2DM cases during 57,683 person-years of observation. Adjusted HRs for T2DM for the highest quartile compared with the lowest quartile were 1.64 (95% CI: 1.20, 2.25; P-trend = 0.02) for total iron intake and 1.80 (95% CI: 1.18, 2.74; P-trend = 0.005) for dietary heme iron intake. In addition, women who consumed ≥30.0 mg supplemental Fe/d, compared with nonusers, had an adjusted HR of 1.83 (95% CI: 1.25, 2.70; P-trend = 0.002). CONCLUSION: In women with a history of GDM, greater intakes of total iron, dietary heme iron, and supplemental iron were associated with higher risk of T2DM.

Red and processed meat, nitrite, and heme iron intakes and postmenopausal breast cancer risk in the NIH-AARP Diet and Health Study.

Previous studies have shown inconsistent associations between red and processed meat intake and breast cancer risk. N-nitroso compounds and heme iron have been hypothesized as contributing factors. We followed 193,742 postmenopausal women in the NIH-AARP Diet and Health Study and identified 9,305 incident breast cancers (1995-2006). Dietary intake was assessed using a food frequency questionnaire at baseline. We adjusted daily intakes of meat, nitrite and heme iron for energy intake using the nutrient density method. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) by quintiles of dietary exposures for all breast cancer, by stage (in-situ, localized, regional/distant) and by estrogen/progesterone receptor (ER/PR) status using Cox proportional hazards regression. Total red meat intake was positively associated with risk of regional/distant cancer (p-trend = 0.02). The risk was 25% higher in the highest vs. lowest intake quintile (95% CI = 1.03-1.52). Higher processed red meat intake (Q5 vs. Q1) was associated with 27% higher risk of localized breast cancer (95% CI = 1.01-1.27, p-trend = 0.03) and a 19% higher risk of regional/distant cancer (95% CI = 0.98-1.44, p-trend = 0.10). In addition, higher nitrite intake from processed red meat was positively associated with localized cancer (HR for Q5 vs. Q1 = 1.23, 95% CI = 1.09-1.39, p-trend < 0.0001). Heme iron intake was positively associated with breast cancer risk overall and all cancer stages (p-trend = 0.02-0.05). No heterogeneity was observed in risk associations by hormone receptor status. Our findings suggest that high consumption of red meat and processed meat may increase risk of postmenopausal breast cancer. Added nitrite and heme iron may partly contribute to these observed associations.

Are meat and heme iron intake associated with pancreatic cancer? Results from the NIH-AARP diet and health cohort.

Several studies on pancreatic cancer have reported significant positive associations for intake of red meat but null associations for heme iron. We assessed total, red, white and processed meat intake, meat cooking methods and doneness and heme iron and mutagen intake in relation to pancreatic cancer in the NIH-AARP Diet and Health Study cohort. A total of 322,846 participants (187,265 men and 135,581 women) successfully completed and returned the food frequency questionnaire between 1995 and 1996. After a mean follow-up of 9.2 years (up to 10.17 years), 1,417 individuals (895 men and 522 women) developed exocrine pancreatic cancer. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), and trends were calculated using the median value of each quantile. Models incorporated age as the time metric and were adjusted for smoking history, body mass index, self-reported diabetes and energy-adjusted saturated fat. Pancreatic cancer risk significantly increased with intake of total meat (Q5 vs. Q1: HR = 1.20, 95% CI 1.02-1.42, p-trend = 0.03), red meat (HR = 1.22, 95% CI 1.01-1.48, p-trend = 0.02), high-temperature cooked meat (HR = 1.21, 95% CI 1.00-1.45, p-trend = 0.02), grilled/barbequed meat (HR = 1.24, 95% CI 1.03-1.50, p-trend = 0.007), well/very well done meat (HR = 1.32, 95% CI 1.10-1.58, p-trend = 0.005) and heme iron from red meat (Q4 vs. Q1: HR = 1.21, 95% CI 1.01-1.45, p-trend = 0.04). When stratified by sex, these associations remained significant in men but not women except for white meat intake in women (HR = 1.33, 95% CI 1.02-1.74, p-trend = 0.04). Additional studies should confirm our findings that consuming heme iron from red meat increases pancreatic cancer risk.

Consumption of Red/Processed Meat and Colorectal Carcinoma: Possible Mechanisms Underlying the Significant Association.

Epidemiology and experimental studies provide an overwhelming support of the notion that diets high in red or processed meat accompany an elevated risk of developing pre-neoplastic colorectal adenoma and frank colorectal carcinoma (CRC). The underlying mechanisms are disputed; thus several hypotheses have been proposed. A large body of reports converges, however, on haem and nitrosyl haem as major contributors to the CRC development, presumably acting through various mechanisms. Apart from a potentially higher intestinal mutagenic load among consumers on a diet rich in red/processed meat, other mechanisms involving subtle interference with colorectal stem/progenitor cell survival or maturation are likewise at play. From an overarching perspective, suggested candidate mechanisms for red/processed meat-induced CRC appear as three partly overlapping tenets: (i) increased N-nitrosation/oxidative load leading to DNA adducts and lipid peroxidation in the intestinal epithelium, (ii) proliferative stimulation of the epithelium through haem or food-derived metabolites that either act directly or subsequent to conversion, and (iii) higher inflammatory response, which may trigger a wide cascade of pro-malignant processes. In this review, we summarize and discuss major findings of the area in the context of potentially pertinent mechanisms underlying the above-mentioned association between consumption of red/processed meat and increased risk of developing CRC.

Dietary intake of heme iron and risk of cardiovascular disease: a dose-response meta-analysis of prospective cohort studies.

BACKGROUND AND AIMS: Iron is thought to play a fundamentally important role in the development of cardiovascular disease (CVD). This meta-analysis was performed to investigate the dose-response association between dietary intake of iron (including heme and non-heme iron) and the risk of CVD. METHODS AND RESULTS: We performed a search of the PubMed and Embase databases for prospective cohort studies of the association between dietary iron intake and CVD risk. Thirteen articles comprising 252,164 participants and 15,040 CVD cases were eligible for inclusion. Heme iron intake was associated significantly with increased risk of cardiovascular disease, and the pooled relative risk (RR) for each 1 mg/day increment was 1.07 (95% confidence interval: 1.01 to 1.14, I² = 59.7%). We also found evidence of a curvilinear association (P < 0.05 for non-linearity). In contrast, we found no association between CVD risk and dietary non-heme (0.98, 0.96 to 1.01, I² = 15.8%) or total iron (1.00, 0.94 to 1.06, I² = 30.4%). Subgroup analyses revealed that the association between heme iron intake and CVD risk was stronger among non-fatal cases (1.19, 1.07-1.33) and American patients (1.31, 1.11-1.56). CONCLUSIONS: Higher dietary intake of heme iron is associated with an increased risk of cardiovascular disease, whereas no association was found between CVD and non-heme iron intake or total iron intake. These findings may have important public health implications with respect to preventing cardiovascular disease.

Antibiotic suppression of intestinal microbiota reduces heme-induced lipoperoxidation associated with colon carcinogenesis in rats.

Epidemiological studies show that heme iron from red meat is associated with increased colorectal cancer risk. In carcinogen-induced-rats, a heme iron-rich diet increases the number of precancerous lesions and raises associated fecal biomarkers. Heme-induced lipoperoxidation measured by fecal thiobarbituric acid reagents (TBARs) could explain the promotion of colon carcinogenesis by heme. Using a factorial design we studied if microbiota could be involved in heme-induced carcinogenesis, by modulating peroxidation. Rats treated or not with an antibiotic cocktail were given a control or a hemoglobin-diet. Fecal bacteria were counted on agar and TBARs concentration assayed in fecal water. The suppression of microbiota by antibiotics was associated with a reduction of crypt height and proliferation and with a cecum enlargement, which are characteristics of germ-free rats. Rats given hemoglobin diets had increased fecal TBARs, which were suppressed by the antibiotic treatment. A duplicate experiment in rats given dietary hemin yielded similar results. These data show that the intestinal microbiota is involved in enhancement of lipoperoxidation by heme iron. We thus suggest that microbiota could play a role in the heme-induced promotion of colorectal carcinogenesis.

Heme, an essential nutrient from dietary proteins, critically impacts diverse physiological and pathological processes.

Heme constitutes 95% of functional iron in the human body, as well as two-thirds of the average person's iron intake in developed countries. Hence, a wide range of epidemiological studies have focused on examining the association of dietary heme intake, mainly from red meat, with the risks of common diseases. High heme intake is associated with increased risk of several cancers, including colorectal cancer, pancreatic cancer and lung cancer. Likewise, the evidence for increased risks of type-2 diabetes and coronary heart disease associated with high heme intake is compelling. Furthermore, recent comparative metabolic and molecular studies of lung cancer cells showed that cancer cells require increased intracellular heme biosynthesis and uptake to meet the increased demand for oxygen-utilizing hemoproteins. Increased levels of hemoproteins in turn lead to intensified oxygen consumption and cellular energy generation, thereby fueling cancer cell progression. Together, both epidemiological and molecular studies support the idea that heme positively impacts cancer progression. However, it is also worth noting that heme deficiency can cause serious diseases in humans, such as anemia, porphyrias, and Alzheimer's disease. This review attempts to summarize the latest literature in understanding the role of dietary heme intake and heme function in diverse diseases.

Heme iron intake and acute myocardial infarction: a prospective study of men.

BACKGROUND: Epidemiologic studies of heme iron and non-heme iron intake in relation to risk of acute myocardial infarction (AMI) are lacking. Therefore, we examine the associations between heme iron and non-heme iron intake and fatal and nonfatal AMI in men. Moreover, we investigated whether the associations were modified by intake of minerals (calcium, magnesium, and zinc) that decreases iron absorption. METHODS: The population-based prospective cohort of Swedish Men (COSM) included 36882 men, aged 45-79 years, who completed a self-administered questionnaire on diet and had no history of coronary heart disease, stroke, diabetes, or cancer at baseline. RESULTS: During an 11.7 year follow-up, 678 fatal and 2593 nonfatal AMI events were registered. The hazard ratio (HR) of fatal AMI among men in the highest compared with the lowest quintile of heme iron intake was 1.51 (95%CI: 1.07-2.13, P-trend=0.02). The association was confined to men with a low intake of minerals that can decrease iron absorption. Among men with combined intakes of calcium, magnesium, and zinc below the medians, the HR of fatal AMI was 2.89 (95%CI: 1.43-5.82) for the highest vs. the lowest quintile of heme iron intake. There was no association between heme iron intake and nonfatal AMI, or between non-heme iron intake and fatal or nonfatal AMI. CONCLUSIONS: Findings from this prospective study indicate that a high heme iron intake, particularly with simultaneous low intake of minerals that can decrease iron absorption, may increase the risk of fatal AMI.