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Animal models have suggested the carcinogenic effect of iron due to its oxidative potential. The lung is particularly vulnerable to oxidative stress. However, epidemiological studies investigating the association between dietary iron and the risk of lung cancer have reported inconclusive results. In this systematic review and meta-analysis, we aimed to clarify this association. Methods: We searched PubMed, Web of Science, Scopus and Google scholar for eligible articles published through May 2023 reporting the Relative Risk (RR), Hazard Ratio (HR) or Odds Ratio (OR) with 95% confidence interval (95% CI). Case-control and cohort studies that examined the relationship between dietary iron and lung cancer risk were included and review and meta-analyses articles, experimental studies, abstracts, letters to editor and studies with insufficient data were excluded. Finally, three case-control studies and 6 cohort studies were included. Random effect models were used to calculate the pooled results. Results: Nine studies (cases n =21,943, participants n =1,542,993) were included. There were no significant associations between the highest dietary total iron (heme and non-heme) (RR: 1.09, 95% CI: 0.78 to 1.51) or heme iron (RR: 1.01, 95% CI: 0.73 to 1.38) intake compared to the lowest intake with lung cancer risk. Null-associations were also observed in the subgroup analysis based on smoking status and lung cancer histology. However, in the subgroup of women (cases n =5074), heme iron was associated with a 14% increase in the risk of lung cancer (RR: 1.14, 95% CI: 1.01 to 1.29). Conclusions: The current results demonstrated that there is no significant relationship between dietary iron intake and the risk of lung cancer. However, a positive association was observed between dietary heme iron and the risk of lung cancer in women, which may require further investigation.

Photoimaging and phototherapy have become major platforms for the diagnosis and treatment of various health complications. These applications require a photosensitizer (PS) that is capable of absorbing light from a source and converting it into other energy forms for detection and therapy. While synthetic inorganic materials such as quantum dots and gold nanorods have been widely explored for their medical diagnosis and photodynamic (PDT) and photothermal (PTT) therapy capabilities, translation of these technologies has lagged, primarily owing to potential cytotoxicity and immunogenicity issues. Of the various photoreactive molecules, the naturally occurring endogenous compound heme, a constituent of red blood cells, and its derivatives, porphyrin, biliverdin and bilirubin, have shown immense potential as noteworthy candidates for clinically translatable photoreactive agents, as evidenced by previous reports. While porphyrin-based photomedicines have attracted significant attention and are well documented, research on photomedicines based on two other heme-derived compounds, biliverdin and bilirubin, has been relatively lacking. In this review, we summarize the unique photoproperties of heme-derived compounds and outline recent efforts to use them in biomedical imaging and phototherapy applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Purpose: Heme is a red blood cell component released in the brain parenchyma following intracerebral hemorrhage. However, the study of the pathophysiological mechanisms triggered by heme in the brain is hampered by the lack of well-established in vivo models of intracerebral heme injection. This study aims to optimize and characterize a protocol of intrastriatal heme injection in mice, with a focus on the induction of lipid peroxidation, neuroinflammation and, ultimately, sensorimotor deficits. We also evaluated the involvement of NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), an inflammasome sensor, in the behavior deficits induced by heme in this model., Methods: Mice were injected with heme in the striatum for the evaluation of neuroinflammation and brain damage through histological and biochemical techniques. Immunoblot was used to evaluate the expression of proteins involved in heme/iron metabolism and antioxidant responses and the activation of the MAPK (mitogen-activated protein kinase) signaling pathway. For the assessment of neurological function, we followed-up heme-injected mice for 2 weeks using the rotarod, elevated body swing, and cylinder tests. Mice injected with the vehicle (sham), or autologous blood were used as controls., Results: Heme induced lipid peroxidation and inflammation in the brain. Moreover, heme increased the expression of HO-1 (heme oxygenase-1), ferritin, p62, and superoxide dismutase 2, and activated the MAPK signaling pathway promoting pro-IL (interleukin)-1β production and its cleavage to the active form. Heme-injected mice exhibited signs of brain damage and reactive astrogliosis around the injection site. Behavior deficits were observed after heme or autologous blood injection in comparison to sham-operated controls. In addition, behavior deficits and IL-1β production were reduced in Nlrp3 knockout mice in comparison to wild-type mice., Conclusions: Our results show that intracerebral heme injection induces neuroinflammation, and neurological deficits, in an NLRP3-dependent manner, suggesting that this is a feasible model to evaluate the role of heme in neurological disorders.

Emerging data indicate that free heme promotes inflammation in many different disease settings, including in sickle cell disease (SCD). Although free heme, proinflammatory cytokines, and cardiac hypertrophy are co-existing features of SCD, no mechanistic links between these features have been demonstrated. We now report significantly higher levels of IL-6 mRNA and protein in hearts of the Townes sickle cell disease (SS) mice (2.9-fold, p ≤ 0.05) than control mice expressing normal human hemoglobin (AA). We find that experimental administration of heme 50 μmoles/kg body weight induces IL-6 expression directly in vivo and induces gene expression markers of cardiac hypertrophy in SS mice. We administered heme intravenously and found that within three hours plasma IL-6 protein significantly increased in SS mice compared to AA mice (3248 ± 275 vs. 2384 ± 255 pg/ml, p ≤ 0.05). In the heart, heme induced a 15-fold increase in IL-6 transcript in SS mice heart compared to controls. Heme simultaneously induced other markers of cardiac stress and hypertrophy, including atrial natriuretic factor (Nppa; 14-fold, p ≤ 0.05) and beta myosin heavy chain (Myh7; 8-fold, p ≤ 0.05) in SS mice. Our experiments in Nrf2-deficient mice indicate that the cardiac IL-6 response to heme does not require Nrf2, the usual mediator of transcriptional response to heme for heme detoxification by heme oxygenase-1. These data are the first to show heme-induced IL-6 expression in vivo , suggesting that hemolysis may play a role in the elevated IL-6 and cardiac hypertrophy seen in patients and mice with SCD. Our results align with published evidence from rodents and humans without SCD that suggest a causal relationship between IL-6 and cardiac hypertrophy., (Copyright © 2020 Gbotosho, Kapetanaki, Ghosh, Villanueva, Ofori-Acquah and Kato.)

Objective: Excessive iron intake has been linked to diabetes risk. However, the evidence is inconsistent. This study examined the association between dietary heme and nonheme iron intake and diabetes risk in the Chinese population., Research Design and Methods: We included 17,026 adults (8,346 men and 8,680 women) who were part of the China Health and Nutrition Survey (1991-2015) prospective cohort. Dietary intake was measured by three consecutive 24-h dietary recalls combined with a household food inventory. Diabetes cases were identified through a questionnaire. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs., Results: A total of 547 men and 577 women developed diabetes during 202,138 person-years of follow-up. For men, the adjusted HRs (95% CIs) for quintiles of nonheme iron intake were 1.00, 0.77 (0.58-1.02), 0.72 (0.54-0.97), 0.63 (0.46-0.85), and 0.87 (0.64-1.19) ( P -nonlinearity = 0.0015). The corresponding HRs (95% CIs) for women were 1.00, 0.63 (0.48-0.84), 0.57 (0.43-0.76), 0.58 (0.43-0.77), and 0.67 (0.49-0.91) ( P -nonlinearity < 0.0001). The dose-response curves for the association between nonheme iron and total iron intake and diabetes followed a reverse J shape in men and an L shape in women. No significant associations were observed between heme iron intake and diabetes risk., Conclusions: Total iron and nonheme iron intake was associated with diabetes risk, following a reverse J-shaped curve in men and an L-shaped curve in women. Sufficient intake of nonheme or total iron might be protective against diabetes, while excessive iron intake might increase the risk of diabetes among men., (© 2020 by the American Diabetes Association.)

Skeletal muscle injuries in competitive sports cause lengthy absences of athletes from tournaments. This is of tremendous competitive and economic relevance for both the athletes and their respective clubs. Therapy for structural muscle lesions aims to promote regeneration and fast-track return-to-play. A common clinical treatment strategy for muscle injuries is the intramuscular injection of calf blood compound and the homeopathic drug, Tr14. Although the combination of these two agents was reported to reduce recovery time, the regulatory mechanism whereby this occurs remains unknown. In this in vivo study, we selected a rat model of mechanical muscle injury to investigate the effect of this combination therapy on muscle regeneration. Gene expression analysis and histological images revealed that this combined intramuscular injection for muscle lesions can enhance the expression of pro-myogenic genes and proteins and accelerate muscle regeneration. These findings are novel and depict the positive effects of calf blood compound and the homeopathic drug, Tr14, which are utilized in the field of Sports medicine.

In Germany, analyses of clinical and laboratory features of patients with acute porphyrias are only available for hereditary coproporphyria (HCP) but not with other acute porphyrias, acute intermittent porphyria (AIP) and variegate porphyria (VP). The aim of the study was to analyze a large cohort of patients with particular focus upon quality of life aspects. Sixty-two individuals from separate families with acute porphyrias (57 AIP, 5 VP) were included into an observational study collecting biochemical, genetic, and clinical data. A questionnaire was designed to complete anamnestic information and to assess the influence on quality of life. Most frequent signs and symptoms or laboratory abnormalities were abdominal colicky pain, red coloration of urine, and hyponatremia. Depression or anxiety was reported by 61% or 52% individuals, respectively. Fatigue was mentioned as the most quality of life-limiting symptom. In 59/61 patients, mutations could be identified. 44% (20/45) had to be admitted to an intensive care unit. Heme arginate was used in 64% (29/45) of patients for treatment of acute attacks at least once and in 33% for long-term treatment with high frequency of administration. Serum creatinine values increased in 47% (7/17) of the patients with recurrent attacks. Our analysis confirms a substantial influence of the diseases on the quality of life on patients. Percentages of urine discoloration and intensive care unit admissions were much higher than in other reports. Long-term treatment with heme arginate requires careful monitoring of iron status and renal values.

Background: Epidemiological studies suggest that haem iron, which is found predominantly in red meat and increases endogenous formation of carcinogenic N-nitroso compounds, may be positively associated with lung cancer. The objective was to examine the relationship between haem iron intake and lung cancer risk using detailed smoking history data and serum cotinine to control for potential confounding., Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 416,746 individuals from 10 countries completed demographic and dietary questionnaires at recruitment. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident lung cancer (n = 3731) risk relative to haem iron, non-haem iron, and total dietary iron intake. A corresponding analysis was conducted among a nested subset of 800 lung cancer cases and 1489 matched controls for whom serum cotinine was available., Results: Haem iron was associated with lung cancer risk, including after adjustment for details of smoking history (time since quitting, number of cigarettes per day): as a continuous variable (HR per 0.3 mg/1000 kcal 1.03, 95% CI 1.00-1.07), and in the highest versus lowest quintile (HR 1.16, 95% CI 1.02-1.32; trend across quintiles: P = 0.035). In contrast, non-haem iron intake was related inversely with lung cancer risk; however, this association attenuated after adjustment for smoking history. Additional adjustment for serum cotinine did not considerably alter the associations detected in the nested case-control subset., Conclusions: Greater haem iron intake may be modestly associated with lung cancer risk.

Background: The World Health Organization classified processed and red meat consumption as "carcinogenic" and "probably carcinogenic", respectively, to humans. Haem iron from meat plays a role in the promotion of colorectal cancer in rodent models, in association with enhanced luminal lipoperoxidation and subsequent formation of aldehydes. Here, we investigated the short-term effects of this haem-induced lipoperoxidation on mucosal and luminal gut homeostasis including microbiome in F344 male rats fed with a haem-enriched diet (1.5 μmol/g) 14-21 days., Results: Changes in permeability, inflammation, and genotoxicity observed in the mucosal colonic barrier correlated with luminal haem and lipoperoxidation markers. Trapping of luminal haem-induced aldehydes normalised cellular genotoxicity, permeability, and ROS formation on a colon epithelial cell line. Addition of calcium carbonate (2%) to the haem-enriched diet allowed the luminal haem to be trapped in vivo and counteracted these haem-induced physiological traits. Similar covariations of faecal metabolites and bacterial taxa according to haem-induced lipoperoxidation were identified., Conclusions: This integrated approach provides an overview of haem-induced modulations of the main actors in the colonic barrier. All alterations were closely linked to haem-induced lipoperoxidation, which is associated with red meat-induced colorectal cancer risk.

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.

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.

Iron is an essential micronutrient for human health and inadequate intake may result in iron deficiency (ID) or iron deficiency anaemia (IDA). Unlike other recent studies investigating iron status in young women, this cross-sectional study analysed dietary intake and biochemical data from healthy young (18-35 years) women ( n = 299) to determine the association between both haem iron (HI) and non-haem iron (NHI) intakes and serum ferritin (SF). Dietary restraint and possible inflammation secondary to obesity were also measured and accounted for, and energy intake was adjusted for using the residuals method. Independent samples t -tests and chi-squared tests were performed, and factors found to be significantly different between iron replete (IR) and ID/IDA participants were analysed using general linear modelling. ID/IDA participants consumed significantly lower total energy than iron replete (IR) ( p = 0.003). Lower energy intake was also associated with higher levels of dietary restraint ( p = 0.001). Both HI and NHI were positively associated with SF with HI was found to be a stronger predictor ( β = 0.128, p = 0.009) than NHI ( β = 0.037, p = 0.028). The study demonstrates that intake of both HI and NHI, as well as adequate dietary energy, are associated with normal iron status levels in young women, and that restrained eaters may be at greater risk of low iron status., Competing Interests: The authors declare no conflict of interest.

The main function of the microcirculatory bed consists in maintaining tissue homeostasis at an optimal level irrespective of the effect of various external and internal factors. Of all types of metabolism (diffusive, filtration-reabsorption and vesicular), directly dependent on the haemodynamic parameters is filtration-reabsorption metabolism which provides exchange of water, low-molecular-weight and water-soluble substances at the opposite to the heart «pole» of the cardiovascular system. The present study was aimed at testing a hypothesis that activation of metabolic processes in man would be accompanied by alterations in haemodynamic parameters which may be registered by means of modern non-invasive methods of examination, i. e., laser Doppler flowmetry (LDF) and computer-assisted capillaroscopy (CCS). We used actovegin as an activator of metabolic processes. The study included acute pharmacological testing in apparently healthy volunteers (n=28), a course of taking actovegin in patients with cognitive dysfunctions on the background of arterial hypertension (n=60) and in patients with chronic ischaemia of the lower limbs (n=80). The obtained findings of LDF and CCS demonstrated that the known metabolic effects of actovegin (improved utilization of oxygen and glucose by tissues) were accompanied by an increase in the number of functioning capillaries, increased velocity of capillary blood flow with a decrease in the degree of hydration of the interstitial space, thus reducing the «blood-cell» distance for nutrients and products of tissue metabolism. Improvement of capillary blood flow was determined by a decrease in the tonicity of the capillary sphincters, thus leading to reduced arteriolar-venular shunting of blood with predominant supply to the capillary bed, improved NO-mediated regulation of the value of the lumen of the precapillary arterioles by the microvascular endothelium, improved reaction of resistant microvessels to various dilatation stimuli. The obtained results make it possible to draw a conclusion that modern non-invasive methods of study of human microcirculation (LDF and CCS) are informative not only for assessment of the functional state of the microcirculatory bed of the skin but make it possible to evaluate efficacy of the filtration-reabsorption mechanism of metabolism.

We evaluated the relationships of red meat, poultry, fish, and shellfish intakes, as well as heme iron intake, with the risk of type 2 diabetes mellitus (T2D).The Singapore Chinese Health Study is a population-based cohort study that recruited 63,257 Chinese adults aged 45-74 years from 1993 to 1998. Usual diet was evaluated using a validated 165-item semiquantitative food frequency questionnaire at recruitment. Physician-diagnosed T2D was self-reported during 2 follow-up interviews in 1999-2004 and 2006-2010. During a mean follow-up of 10.9 years, 5,207 incident cases of T2D were reported. When comparing persons in the highest intake quartiles with those in the lowest, the multivariate-adjusted hazard ratio for T2D was 1.23 (95% confidence interval (CI): 1.14, 1.33) for red meat intake (P for trend < 0.001), 1.15 (95% CI: 1.06, 1.24) for poultry intake (P for trend = 0.004), and 1.07 (95% CI: 0.99, 1.16) for fish/shellfish intake (P for trend = 0.12). After additional adjustment for heme iron, only red meat intake remained significantly associated with T2D risk (multivariate-adjusted hazard ratio = 1.13, 95% CI: 1.01, 1.25; P for trend = 0.02). Heme iron was associated with a higher risk of T2D even after additional adjustment for red meat intake (multivariate-adjusted hazard ratio = 1.14, 95% CI: 1.02, 1.28; P for trend = 0.03). In conclusion, red meat and poultry intakes were associated with a higher risk of T2D. These associations were mediated completely for poultry and partially for red meat by heme iron intake., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Animal by-products can be recycled and used as sources of essential nutrients. Water-soluble heme iron (WSHI), a functional food additive for supplementing iron, is produced by processing animal blood. In this study, we investigated the effects of dietary supplementation of 3% WSHI and exercise training for 4 weeks on the accumulation of abdominal fat and lipid metabolism in mice fed high-fat diet. Exercise-trained mice had significantly less perirenal adipose tissue, whereas WSHI-fed mice tended to have less epididymal adipose tissue. In addition, total weight of abdominal adipose tissues was significantly decreased in the Exercise + WSHI group. Dietary WSHI significantly increased the messenger RNA (mRNA) levels of lipoprotein lipase and hormone-sensitive lipase. WSHI-fed mice also tended to show increased mRNA levels of adipose triglyceride lipase in their epididymal adipose tissue. Dietary WSHI also significantly decreased the mRNA levels of fatty acid oxidation-related enzymes in the liver, but did not influence levels in the Gastrocnemius muscle. Exercise training did not influence the mRNA levels of lipid metabolism-related enzymes in the epididymal adipose tissue, liver or the Gastrocnemius muscle. These findings suggest that the accumulation of abdominal fat can be efficiently decreased by the combination of dietary WSHI and exercise training in mice fed high-fat diet., (© 2016 Japanese Society of Animal Science.)

Heme is an efficient source of iron in the diet, and heme preparations are used to prevent and cure iron deficiency anemia in humans and animals. However, the molecular mechanisms responsible for heme absorption remain only partially characterized. Here, we employed young iron-deficient piglets as a convenient animal model to determine the efficacy of oral heme iron supplementation and investigate the pathways of heme iron absorption. The use of bovine hemoglobin as a dietary source of heme iron was found to efficiently counteract the development of iron deficiency anemia in piglets, although it did not fully rebalance their iron status. Our results revealed a concerted increase in the expression of genes responsible for apical and basolateral heme transport in the duodenum of piglets fed a heme-enriched diet. In these animals the catalytic activity of heme oxygenase 1 contributed to the release of elemental iron from the protoporphyrin ring of heme within enterocytes, which may then be transported by the strongly expressed ferroportin across the basolateral membrane to the circulation. We hypothesize that the well-recognized high bioavailability of heme iron may depend on a split pathway mediating the transport of heme-derived elemental iron and intact heme from the interior of duodenal enterocytes to the bloodstream.

Aims: To evaluate two definitions of response and the predictive value of baseline covariates for response to actovegin treatment in type 2 diabetic patients with symptomatic diabetic sensorimotor polyneuropathy (DSPN)., Methods: Response to 6-months treatment with actovegin or placebo was defined as a clinically meaningful decline from baseline to 6months in (1) both Neuropathy Impairment Score of Lower Limbs (NIS-LL) ≥2 points and Total Symptom Score (TSS) >50% and (2) NIS-LL ≥2 points only. Nineteen baseline covariates were evaluated using separate logistic regression models and either both NIS-LL and TSS or NIS-LL response definitions., Results: Intention-to-treat analysis included 567 patients. Actovegin treatment compared to placebo was associated with better odds of response (OR [95% CI] of 1.73 [1.21-2.48] for definition 1 and 1.94 [1.33-2.84] for definition 2). Significant interaction with actovegin treatment was noted only for baseline use of angiotensin receptor blockers (ARBs)/angiotensinogen converting enzyme inhibitors (ACEIs), resulting in a reduced treatment response (P=0.03)., Conclusions: Actovegin treatment was associated with a clinically meaningful response in neuropathic symptoms and/or impairments in patients with symptomatic DSPN. Since only one predictor of response to actovegin treatment was identified, this drug seems an appropriate therapy for the majority of patients with DSPN., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Total iron intake is not strongly associated with iron stores, but haem iron intake may be more predictive. Haem iron is not available in most nutrient databases, so experimentally determined haem contents were applied to an Australian Food Frequency Questionnaire (FFQ) to estimate haem iron intake in a representative sample of young women (25-30 years). The association between dietary haem iron intakes and incident self-reported diagnosed iron deficiency over six years of follow-up was examined. Haem iron contents for Australian red meats, fish, and poultry were applied to haem-containing foods in the Dietary Questionnaire for Epidemiological Studies V2 (DQESv2) FFQ. Haem iron intakes were calculated for 9076 women from the Australian Longitudinal Study on Women's Health (ALSWH) using the DQESv2 dietary data from 2003. Logistic regression was used to examine the association between haem iron intake (2003) and the incidence of iron deficiency in 2006 and 2009. Multiple logistic regression showed baseline haem iron intake was a statistically significant predictor of iron deficiency in 2006 (Odds Ratio (OR): 0.91; 95% Confidence Interval (CI): 0.84-0.99; p -value: 0.020) and 2009 (OR: 0.89; 95% CI: 0.82-0.99; p -value: 0.007). Using the energy-adjusted haem intake made little difference to the associations. Higher haem iron intake is associated with reduced odds of iron deficiency developing in young adult Australian women., Competing Interests: The authors declare no conflict of interest.

Background and Purpose: Poststroke cognitive impairment is a debilitating consequence of stroke. The aim of this study was to assess whether Actovegin confers cognitive benefit in patients who have had an ischemic stroke., Methods: This was a 12-month, parallel-group, randomized, multicenter, double-blind, placebo-controlled study. Eligible patients were ≥60 years of age with a Montreal Cognitive Assessment test score of ≤25 points. Patients were randomized into 2 groups within 1 week of acute supratentorial ischemic stroke in a 1:1 ratio: Actovegin (a deproteinized hemoderivative of calf blood, 2000 mg/d for ≤20 intravenous infusions followed by 1200 mg/d orally) or placebo for 6 months. Patients were treated in accordance with standard clinical practice for a further 6 months. The primary end point was the change from baseline in Alzheimer's Disease Assessment Scale, cognitive subscale, extended version at 6 months., Results: Two-hundred forty-eight patients were randomized to Actovegin and 255 patients to placebo. At month 6, the least squares mean change from baseline in Alzheimer's Disease Assessment Scale, cognitive subscale, extended version was -6.8 for Actovegin and -4.6 for placebo; the estimated treatment difference was -2.3 (95% confidence interval, -3.9, -0.7; P =0.005). Recurrent ischemic stroke was the most frequently reported serious adverse event, with a nonsignificantly higher number for Actovegin versus placebo., Conclusions: Actovegin had a beneficial effect on cognitive outcomes in patients with poststroke cognitive impairment. The safety experience was consistent with the known safety and tolerability profile of the drug. These results warrant confirmation in additional robustly designed studies., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01582854., (© 2017 The Authors.)

Iron deficiency anemia (IDA) is the most common nutritional deficiency worldwide. This deficiency could be solved by preparing stable, edible, and absorbable iron food ingredients using environmentally friendly methods. This study investigated enzymatic hydrolysis and microencapsulation process of goose blood. The physicochemical properties, stabilities of the microencapsulated goose blood hydrolysate (MGBH) and a supplement for rats with IDA were also evaluated. The results showed that the synergetic hydrolytic action of neutrase and alkaline protease significantly increased the heme-releasing efficiency. The heme was then microencapsulated using sodium caseinate, maltodextrin and carboxymethyl cellulose (CMC) as the edible wall material, and the encapsulation efficiency of the product reached 98.64%. Meanwhile, favorable thermal, storage and light stabilities were observed for the microencapsulation. It was found that MGBH can significantly improve the body weight and hematological parameters of IDA Wistar rat., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background and Objectives: Some potential role of iron overload in the development of diabetes mellitus have been suggested. Our study aimed to systematically assess the association between the risk of gestational diabetes mellitus (GDM) and iron intakes/body iron status., Methods and Study Design: PubMed and Web of Science were searched for relevant articles. Relative risks (RR) of GDM in relation to dietary iron intakes and body iron stores were pooled with the random-effects model. Weighted mean differences of iron blood markers between GDM and non-GDM individuals were also analyzed., Results: Twenty-five studies were included in the qualitative analysis, and 23 studies with 29,378 participants and 3,034 GDM patients were included in the quantitative analysis. Dietary intake of heme iron was significantly associated with GDM risk (RR=1.65, 95% CI: 1.28 to 2.12), and the pooled RR for each 1mg/day increment of heme iron intake was 1.38 (95% CI: 1.19 to 1.61). No association between GDM and the intakes of nonheme iron, total iron, or supplemental iron was detected. Body iron stores, as represented by serum ferritin level, were correlated with GDM risk (RR=1.64, 95% CI: 1.27 to 2.11). Moreover, the concentrations of both serum ferritin and serum iron were increased in GDM patients, compared with non-GDM individuals., Conclusions: Increased dietary intake of heme iron and body iron status are positively associated with the risk of GDM development in pregnant women. Future studies are warranted to better understand the role of iron in GDM development.

The authors examined the effect of actovegin and solcoseryl on microcirculation parameters in treatment of experimental critical lower limb ischaemia. The study included a total of 130 male Wistar albino rats divided into four groups: intact, control, first and second study groups. The intact group consisted of 10 animals used for assessment of the normal indices of microcirculation, with the remaining three groups comprising 40 rats each. All animals, except the intact ones, were subjected to modelled critical ischaemia of a hind limb. The control group animals received no treatment, with the rats of the first and second study groups given intraperitoneal actovegin and solcoseryl, respectively, at a dose of 50 μg/kg first injected 3 hours after the operation and then once daily for five days. The level of microcirculation in the murine crural muscles was assessed by means of laser Doppler flowmetry on postoperative days 5, 10, 21 and 28. At the same time intervals, we performed histological examination of the ischaemized muscles, determining the level of microcirculation, the level of arteriovenular shunting, the area of necrosis and capillary network density. It was determined that actovegin and solcoseryl exerted a positive effect on formation of new capillaries in the ischaemized muscles, increasing density of the capillary network, decreasing arteriovenular shunting, increasing the level of microcirculation, decreasing the specific area of muscular tissue necrosis. The obtained findings showed advantages of actovegin over solcoseryl by the dynamics of the parameters of microcirculation, arteriovenular shunting, and capillary network density.

Aim: To provide a rationale for and to evaluate the therapeutic efficiency of the combined use of pancreatic enzymes and actovegin in the combination therapy of patients with metabolic syndrome (MS) on the basis of comprehensive clinical and functional studies of the small bowel (SB)., Subjects and Methods: In the course of treatment, 120 patients with MS (verified using the diagnostic criteria elaborated by the All-Russian Research Society of Cardiology (2009)) underwent a comprehensive study of SB function: an isolated study of resorptive processes; evaluation of parietal and cavitary digestion, motor-evacuation function. The peripheral blood levels of gastrin, insulin, cortisol, thyroxine and thyrotropin were determined., Results: The combined use of pancreatic enzymes and actovegin has a positive impact on the clinical and functional state of SB, which was manifested as restoration of its hydrolysis and absorption, as well as motor-evacuation function in the patients with MS. The treatment resulted in reductions in the levels of triglycerides from 2.85±0.34 to 1.53±0.18 mmol/l (p<0.01), total cholesterol from 6.08±0.16 to 5.19±0.21 mmol/l (p<0.05), and atherogenic factor from 5.21±0.28 to 2.93±0.34 (p<0.05). Posttreatment HOMA-IR decreased from 4.22±0.8 to 2.12±0.8. There were no substantial changes in insulin levels and insulin resistance index in the patients on standard therapy., Conclusion: The combined use of pancreatic enzymes and actovegin is pathogenetically sound in correcting SB dysfunctions and may be one of the most effective directions for the treatment of patients with MS.

Cerebral malaria is the deadliest complication of Plasmodium falciparum infection. Its pathophysiology is associated with a strong pro-inflammatory reaction and the activation of glial cells. Among modulators released during the infection, heme seems to play a controversial role in the pathophysiology of malaria. Herein, we first investigated the phenotype of glial cells during cerebral malaria in C57BL/6 mice infected with P. berghei ANKA. Given the fact that high levels of heme were associated with cerebral malaria, we then investigated its impact on microglial, astrocyte, and T cell responses to further clarify its contribution in the neuropathophysiology. Surprisingly, we found that administration of heme twice a day from day three of infection induced the expression of the Heme oxygenase-1 (Hmox1) gene and prevented brain damages. More specifically, heme inhibited the M1 phenotype of microglia, hampered the activation of astrocytes, and decreased the cerebral expression of Ifng, Tnfa and Ip10. Heme might that way alter the migration of pathogenic CD4 and CD8 T lymphocytes within the brain observed during cerebral malaria. Taking into account that cerebral malaria results from a complex interplay between host- and parasite-derived factors, it is possible that genetic polymorphisms of Hmox1, which could be associated with the control of systemic levels of heme during P. falciparum infection, might explain its dual role and its contribution to the resistance to cerebral malaria., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Actovegin, a deproteinized haemodialysate of calf blood, is suggested to have ergogenic properties, but this potential effect has never been investigated in human skeletal muscle. To investigate this purported ergogenic effect, we measured the mitochondrial respiratory capacity in permeabilized human skeletal muscle fibres acutely exposed to Actovegin in a low and in a high dose. We found that Actovegin, in the presence of complex I-linked substrates increased the oxidative phosphorylation (OXPHOS) capacity significantly in a concentration-dependent manner (19 ± 3, 31 ± 4 and 45 ± 4 pmol/mg/s). Maximal OXPHOS capacity with complex I and II-linked substrate was increased when the fibres were exposed to the high dose of Actovegin (62 ± 6 and 77 ± 6 pmol/mg/s) (p < .05). The respiratory capacity of the electron transfer system as well as Vmax and Km were also increased in a concentration-dependent manner after Actovegin exposure (70 ± 6, 79 ± 6 and 88 ± 7 pmol/mg/s; 13 ± 2, 25 ± 3 and 37 ± 4 pmol/mg/s; 0.08 ± 0.02, 0.21 ± 0.03 and 0.36 ± 0.03 mM, respectively) (p < .05). In summary, we report for the first time that Actovegin has a marked effect on mitochondrial oxidative function in human skeletal muscle. Mitochondrial adaptations like this are also seen after a training program in human subjects. Whether this improvement translates into an ergogenic effect in athletes and thus reiterates the need to include Actovegin on the World Anti-Doping Agency's active list remains to be investigated.

Acute intermittent porphyria (AIP) is a rare metabolic disease involving a defect in haem biosynthesis resulting in the accumulation and excessive secretion of porphyrins and its precursors. Acute attacks present with episodes of severe abdominal pain, nausea, confusion and severe life-threatening seizures. A high index of suspicion is required for the initial diagnosis of AIP., (© The Author(s) 2015.)

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., (© 2015 UICC.)

Background: The enzyme heme oxygenase-1 (HO-1) degrades heme and protects against ischemia-reperfusion injury. Monocytes/macrophages are the major source of HO-1 and higher levels improve renal transplant outcomes. Heme arginate (HA) safely induces HO-1 in humans., Methods: The Heme Oxygenase-1 in renal Transplantation study was a randomized, placebo-controlled, IIb trial to evaluate HA effect on HO-1 upregulation after deceased donor kidney transplantation. 40 recipients were randomized to either 3 mg kg HA or placebo (0.9% NaCl), given preoperatively (day 0) and again on day 2. Recipient blood and urine were collected daily. Graft biopsies were taken preoperatively and on day 5. Primary outcome was HO-1 upregulation in peripheral blood mononuclear cells (PBMCs). Secondary outcomes were graft HO-1 upregulation and injury, urinary biomarkers, and renal function., Results: The HA upregulated PBMC HO-1 protein more than placebo at 24 hours: HA 11.1 ng/mL versus placebo 0.14 ng/mL (P = < 0.0001). The PBMC HO-1 messenger RNA also increased: HA 2.73-fold versus placebo 1.41-fold (P = 0.02). Heme arginate increased day 5 tissue HO-1 protein immunopositivity compared with placebo: HA 0.21 versus placebo -0.03 (P = 0.02) and % HO-1-positive renal macrophage also increased: HA 50.8 cells per high power field versus placebo 22.3 (P = 0.012). Urinary biomarkers were reduced after HA but not significantly. Histological injury and renal function were similar but the study was not powered for this. Adverse events were equivalent between groups., Conclusions: The primary outcome was achieved and demonstrated for the first time that HA safely induces HO-1 in transplant recipients. Planned larger studies will determine the impact of HO-1 upregulation on clinical outcomes and evaluate the benefit to patients at risk of ischemia-reperfusion injury.

In patients with chronic cerebral ischemia on the background of hypertension grade 2, stage 2, our investigation revealed a significant decrease (by 30.1%) in the level of phospholipids in the erythrocyte membrane and cholesterol esters (by 44.2%), increase in lizofosfa-tidilholina, free cholesterol, triacylglycerides, and free fatty acids (by 23.2 - 46.2%), and change in the ratio of lipid fractions responsible for the structure formation and stabilization of erythrocyte membranes. It was found that the most effective correction of lipid profile in erythrocyte membranes was produced by 10-day injection of a combination of actovegin (200 mg intravenous bolus) and cereton (1000 mg choline alfoscerate intravenous drip in 200.0 mL of 0.9% sodium chloride solution), while the minimum ef- fect was produced by a combination of cerebrolysin (2152 mg concentrated complex of peptides from pig brain, intravenous drip in 100.0 mL of 0.9% sodium chloride solution) and mexidol (250 mg of 2-ethyl-6-methyl-3-hydroxypyridine succinate intravenous bolus). The combination of emoxypine (40 mg of 3-hydroxy-6-methyl-2-ethylpyridine, intramuscularly) and piracetam (1000 mg of 2-oxo-I-pyrrolidine-acetamide intravenous bolus) gave intermediate results.

Objective: To assess the efficacy of pharmacological preconditioning with actovegin in carotid endarterectomy., Material and Methods: The study was based on the results of surgical treatment of 80 patients with hemodynamically significant uni- and bilateral lesions of carotid arteries. Half of the patients was operated immediately and others after pharmacological preconditioning with actovegin in dose of 1200 mg/daily during 1,5 months., Results: Pharmacological preconditioning with actovegin increased the cerebral perfusion determined with one-photon emission computed tomography that improved significantly results of the surgery. There were significant changes in patient's state 7 days and 6 months after surgery. The improvement was correlated with the less number of asymptotic post-surgery ischemic strokes in different brain areas., Conclusion: A positive role of pharmacological preconditioning with actovegin in surgical treatment of carotid artery stenosis has been demonstrated.

Geographical expansion and re-emerging new genotypes of the Japanese encephalitis virus (JEV) require the development of novel therapeutic approaches. Here, we studied a non-conventional approach for antibody therapy and show that, upon exposure to heme, a fraction of natural human immunoglobulins acquires high-affinity reactivity with the antigenic domain-III of JEV E glycoprotein. These JEV-reactive antibodies exhibited neutralizing activity against recently dominant JEV genotypes. This study opens new therapeutic options for Japanese encephalitis.

An excess of free heme is present in the blood during many types of hemolytic anemia. This has been linked to organ damage caused by heme-mediated oxidative stress and vascular inflammation. We investigated the mechanism of heme-induced coagulation activation in vivo. Heme caused coagulation activation in wild-type mice that was attenuated by an anti-tissue factor antibody and in mice expressing low levels of tissue factor. In contrast, neither factor XI deletion nor inhibition of factor XIIa-mediated factor XI activation reduced heme-induced coagulation activation, suggesting that the intrinsic coagulation pathway is not involved. We investigated the source of tissue factor in heme-induced coagulation activation. Heme increased the procoagulant activity of mouse macrophages and human PBMCs. Tissue factor-positive staining was observed on leukocytes isolated from the blood of heme-treated mice but not on endothelial cells in the lungs. Furthermore, heme increased vascular permeability in the mouse lungs, kidney and heart. Deletion of tissue factor from either myeloid cells, hematopoietic or endothelial cells, or inhibition of tissue factor expressed by non-hematopoietic cells did not reduce heme-induced coagulation activation. However, heme-induced activation of coagulation was abolished when both non-hematopoietic and hematopoietic cell tissue factor was inhibited. Finally, we demonstrated that coagulation activation was partially attenuated in sickle cell mice treated with recombinant hemopexin to neutralize free heme. Our results indicate that heme promotes tissue factor-dependent coagulation activation and induces tissue factor expression on leukocytes in vivo. We also demonstrated that free heme may contribute to thrombin generation in a mouse model of sickle cell disease., (Copyright© Ferrata Storti Foundation.)

Unlabelled: The problem of distal occlusion of the lower limbs cannot be currently considered solved due to too large number (40%) of postoperative amputations. Only surgical way of disease management seems impossible. Thus multidisciplinary approach is necessary., Aim: To determine the effectiveness of actovegin in treatment of critical ischemia of lower extremities., Material and Methods: The study included 60 patients (34 men, 26 women, mean age - 69.5 ± 7.2 years) with confirmed atherosclerosis obliterans (critical limb ischemia stage III-IV with necrotic processes within the toes). Patients in the control group (n=30) received standard medical therapy including pentoxifylline (15 ml), rheopolyglukin (400.0 ml), antiplatelet agents (in some cases with dual antiplatelet therapy), low molecular weight heparins in prophylactic doses, statins. In the main group (n=30) actovegin in a daily dose of 1200 mg intravenously for 15 days, followed by 1200 mg in tablet form (2 tablets 3 times per day) for 15 days was added. Primary, 15-, 30- and 60-day pain-free walking distance and microcirculation using polarography and laser Doppler imaging were assessed in all patients. Cytological and histological studies were applied for double control of therapy's effectiveness. The reliability of the results of microcirculation investigation was achieved using an index of regional tissue perfusion., Results and Discussion: Statistically significant improvement of transcutaneous oxygen tension has not been received in the control group. In the main group therapy with actovegin improved skin perfusion 35% by the 15th day and activated microcirculation 12.8% followed by increased tissue oxygenation., Conclusions: Positive effect of actovegin on the development of collateral blood flow in patients with distal occlusion of the lower limbs is convincingly proven.

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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The study was aimed at examining efficacy of preoperative preparation (pharmacological preconditioning) for carotid endarterectomy in patients with chronic cerebrovascular insufficiency. For this purpose, we analysed the outcomes of surgical treatment in a total of 80 patients presenting with haemodynamically significant unilateral and bilateral lesions of carotid arteries. Of these, 40 patients were operated on immediately and a further 40 patients underwent surgery after pharmacological preconditioning with Actovegin taken at a daily dose of 1,200 mg for 1.5 months. It was demonstrated that preoperative preparation prior to surgery increases cerebral perfusion which is determined by means of single-photon emission computed tomography, thus substantially improving the outcomes of surgical treatment. Statistically significant differences in cognitive function of these groups of patients were revealed 7 days and 6 months after the operation. Improvement of cognitive functions was associated with fewer symptom-free postoperative cerebral ischaemic foci in various regions of the brain. A conclusion was made on a positive role of pharmacological preconditioning with Actovegin in surgical management of cerebrovascular insufficiency, first of all in relation to more complete restoration of cognitive functions.

Background: Injection therapies are widely used for muscle injuries. As there is only limited evidence of their efficacy, physicians should be aware of the potential harmful effects of these injected preparations., Objectives: The purpose of this review was to systematically review the literature on the myotoxic effects of intramuscular injection preparations commonly used for acute muscle injuries., Data Sources: The databases of PubMed, Embase, Web of Science, Cochrane Library, CINAHL and SportDiscus were searched in March 2013., Study Eligibility Criteria: Studies reporting histological evaluation or creatine kinase activity after intramuscular injection with local anaesthetics, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), platelet-rich plasma (PRP), Traumeel(®) and Actovegin(®), or combination preparations were eligible for inclusion., Data Analysis: Two authors independently screened the search results and assessed the risk of bias. A best-evidence synthesis was used to identify the level of evidence., Results: Forty-nine studies were included in this systematic review. There is strong to moderate evidence that intramuscularly injected local anaesthetics and NSAIDs are myotoxic, and there is conflicting evidence of the myotoxicity of PRP. There is limited evidence that single corticosteroid injections are not myotoxic but have a synergistic myotoxic effect when used together with local anaesthetics. There is no information to assess whether Actovegin(®) and Traumeel(®) are myotoxic., Conclusion: Local anaesthetics and NSAID injections are not recommended for the treatment of muscle injuries in athletes, as they are myotoxic. The possible myotoxic effects of corticosteroids, PRP, Traumeel(®) and Actovegin(®) should be assessed in future research.

Results of treatment of 43 patients, suffering varicose disease, complicated by trophic disorders, were analyzed. To the patients a complex was prescribed, including sorpents, angioprotectors, locally - ointments. There were operated 14 patients.

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.

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., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The present study aims to investigate whether a daily intake of heme iron enriched peptide obtained from bovine hemoglobin is effective in alleviating iron deficiency anemia (IDA). Wistar rats were randomly divided into six groups: a control group, an anemic group not treated, and anemic groups treated with FeSO4 or with the heme iron enriched peptide at low, moderate or high doses. The rats in the anemic groups were fed on a low-iron diet to establish the iron deficiency anemia model. After the model had been established, different doses of heme iron enriched peptide were given to the rats once a day via intragastric administration. After the iron supplement administration, it was observed that heme iron enriched peptide had effective restorative action returning the hemoglobin, red blood cells, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration and serum iron in IDA animals to normal values or better. In addition, compared with FeSO4, higher Fe bioavailability and fewer side effects were observed. The rats in the moderate dose group had the highest apparent Fe absorption. Moreover, in vivo antioxidant activity was also observed, enhancing the activities of antioxidant enzymes and reduced malondialdehyde levels in IDA rats. Furthermore, the heme iron enriched peptide also exhibited strong in vitro antioxidant activities. In conclusion, heme iron enriched peptide significantly alleviated iron deficiency anemia, and exhibited strong in vitro and in vivo antioxidant activities. This suggests that heme iron enriched peptide might be exploited as a safe, efficient new iron supplement.

Unlabelled: Search for an optimal method of conservative treatment of patients presenting with chronic obliterating disease of lower limb arteries (CODLLA) still remains an important and hitherto unsolved problem. Comparative studies of different drugs and objective assessment of their efficacy may be carried out using the method of laser Doppler flowmetry (LDF) with wavelet analysis of fluctuations in blood flow., Objective: The study was aimed at assessing efficacy of using Actovegin in conservative treatment of patients presenting with chronic obliterating disease of the lower extremities induced by occlusive and stenotic lesions of the arterial bed., Material and Methods: The study included a total of 80 patients with stage 2B chronic ischaemia of the lower limbs. The patients were subdivided into two groups. Group One comprised 40 patients undergoing a course of intravenous infusions of Actovegin (at a dose of 250 ml, 4 mg/ml) as monotherapy for 10 days. Group Two comprised 40 patients receiving intravenous infusion of dextranes, as well as pentoxyphyllin at a dose of 100 mg/day. The state of microcirculation before and after the course of the infusion therapy was assessed by means of LDF with wavelet analysis of blood follow fluctuations. The basal blood flow was registered at a temperature of + 32° C for 10 minutes followed by a thermal test, i. e., heating to + 42oC for 30-40 minutes., Results: The course of infusion therapy in Group One patients was followed by an increase of the amplitude of myogenic fluctuation by 56% (p=0.006) and a decrease in the index of blood flow shunting (p=0.1) with basal perfusion, as well as an increase in the maximum level of perfusion (p=0.006). Group Two patients showed were found to have only statistically significant shortening of the time of reaching the maximum level of thermal hyperaemia. The increase of the pain-free walking distance averagely amounted to 58.8% in Group One patients and 60.7% in Group Two (p=0.068). Patients of the both groups showed satisfactory tolerance of the carried out therapy. No undesirable adverse events were observed., Conclusion: LDF with wavelet analysis of fluctuations of blood flow makes it possible to thoroughly study the mechanisms of action of therapeutic agents on microcirculation in patients with CODLLA . The use of Actovegin as monotherapy in CODLLA patients leads to a decrease in the myogenic tonus of precapillary arterioles and capillary sphincters, to a decrease in the arteriolar-venular shunting of blood flow with predominant supply of blood to the capillary bed, to an increase in the oxide-synthase function of the endothelium of microvessels (endothelioprotective effect), as well as to an increase in the maximum level of thermal vasodilatation. Hence, Actovegin may be considered as a promising therapeutic agent for pharmacotherapy of CODLLA.

Actovegin was used in complex conservative and surgical treatment of lower limb chronic ischemia and diabetic foot syndrome in 200 patients. In 120 patients Actovegin was used in combination with reconstructive operations, angioplasty and stenting for preparation for surgery. In 80 patients Actovegin was used as independent method of treatment. In severe cases the medicine was injected intravenously 1000-2000 mg №10-15, and in mild degrees (IIA-IIB) - 400-800 mg intramuscularly with conversion on the tablet form in the future. Clinical picture, dopplerographic and microcirculatory data evidence about absolute safety, efficiency and comparative cheapness of the parenteral and enteral forms of Actovegine.

Intake of different types of protein may be associated with differences in biomarkers among various populations. This work investigated the influence of protein intake from haem and non-haem animals as well as protein from plants on haematological and biochemical parameters in inflammation among apparently-healthy adults living in Greece, a Mediterranean country. Four hundred and ninety apparently-healthy subjects (46 +/- 16 years, 40% men), who consecutively visited Polykliniki General Hospital for routine examinations, voluntarily agreed to participate in the study (participation rate 85%). Demographic, anthropometric and lifestyle characteristics were recorded. Participants completed a valid, semi-quantitative food frequency questionnaire. Protein intake was classified into three sources: protein from haem animals, protein from non-haem animals, and protein from plant origin. Fasting blood samples were taken from all participants; uric acid, creatinine, lipids, cystatin C, haptoglobin, haemoglobin, haematocrit, iron, ferritin, white blood cells, monocytes, platelets, and C-reactive protein were measured. Protein intake from only haem animals was associated with increased haemoglobin and haematocrit levels (p < 0.05) whereas intake of protein from non-haem animals and plant origin was not associated with the investigated haematological and biochemical markers of low-grade chronic inflammation when lifestyle factors and overall dietary habits were taken into account. Intake of protein from only haem animals seems to be consistently associated with haematological markers. The confounding role of dietary habits and lifestyle variables on the tested parameters deserves further attention in future research.

Background: Several epidemiological studies have observed an increased risk of type 2 diabetes mellitus (T2DM) among subjects with a higher consumption of red and processed meat. Heme iron intake has been directly associated with a higher risk of T2DM in healthy adult Chinese and U.S populations. The objective of the present study was to evaluate the association between heme iron intake and the incidence of T2DM in a Mediterranean population at high cardiovascular risk., Methods: We assessed a subset of participants in the PREDIMED trial as an observational cohort, followed up for a maximum of eight years. We initially included 1073 non-diabetic subjects (57.1% women) aged 67.3 ± 6.0 years, at high cardiovascular risk. Diet was assessed at the study baseline using a validated, semi-quantitative food frequency questionnaire., Results: During the follow-up period 131 diabetics were newly diagnosed. The risk of developing T2DM was assessed using baseline heme iron intake and proportional hazard models, first unadjusted, then adjusted for energy, and finally adjusted for dietary, anthropometric, socio-demographic and lifestyle variables. Significant direct associations with the incidence of T2DM were found for heme iron (Hazard Ratio [HR] 1.30, 95% confidence interval [CI], 1.02 to 1.66). Secondarily, we have also observed that coffee (HR:0.93, 95% CI, 0.89 to 0.98) and alcoholic beverages (HR: 1.02, 95% CI, 1.01 to 1.04) were also found to reduce and increase the risk of T2DM, respectively., Conclusion: High dietary intake of heme iron was associated with an increased risk of developing T2DM in a Mediterranean population at high cardiovascular risk., Trial Registration: Identifier: ISRCTN35739639.

Amelioration of rodent type 2 diabetes by hemin has been linked to increased heme oxygenase (HO) activity, however alternative mechanisms have recently been proposed for its anti-diabetic effect. We sought to determine the anti-diabetic efficacy of heme arginate (HA), a clinically licensed preparation of heme, and whether its predominant mode of action is via increased HO activity. Intravenous administration of HA reduced hyperglycemia in diabetic (db/db) mice. Co-administration of the HO inhibitor stannous (IV) mesoporphyrin IX dichloride (SM) resulted unexpectedly in a further improvement in glycaemic control despite restoring HO activity to baseline levels. The anti-diabetic effects of HA±SM were associated with increased adiposity, increased serum adiponectin levels, reduced adipose tissue and islet inflammation and preservation of islet β-cell function. HO activity independent effects of HA on adipogenesis and β-cell inflammation were further confirmed in cell culture models using the 3T3-L1 pre-adipocyte and MIN6 β-cell lines, respectively. In conclusion, our work demonstrates that the heme component of HA ameliorates experimental type 2 diabetes by promoting metabolically favourable adipogenesis and preserving islet β-cell function, but this is not mediated via increased HO activity.

Supplementation with iron-fortified foods is an effective method for treating iron deficiency diseases. However, traditional iron agents used to treat anemia of inflammation (AI) have little effect. In this study, two types of iron liposomes, heme liposomes (HEME-LIP) and ferric citrate liposomes (FAC-LIP), were prepared by the rotary-evaporated film-ultrasonication method, and the encapsulation efficiencies, microstructures, size distributions and zeta potentials were assessed. Both types of iron liposomes showed stable physical characteristics. When used to treat rat models of AI, FAC-LIP and HEME-LIP could increase serum iron levels by 119% and 54% higher than did ferric citrate (FAC) and heme, respectively. Furthermore, the hepcidin, a key regulator of iron homeostasis was up-regulated by these iron liposomes, especially by HEME-LIP. These results indicate that the absorption of iron liposomes was improved over that of unencapsulated iron agents. Thus, iron liposomes may be used to fortify food in treating iron deficiency diseases, especially AI., (Copyright © 2013 Elsevier B.V. All rights reserved.)