Iron Out-of-Balance: A Risk Factor for Acute and Chronic Diseases

Weinberg, Eugene D.

doi:10.1080/03630260701680805

Cited by 19 publications

(12 citation statements)

References 46 publications

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“…This characteristic increase in low‐grade inflammation is typical of the aging brain with higher levels of pro‐inflammatory cytokines and lower levels of anti‐inflammatory cytokines detected in aged brains (Sparkman and Johnson ). Microglia have been found to be very long‐lived cells in a study that monitored them over the mouse lifespan (Weinberg ). This puts microglia forward as ideal candidates for chronic senescence and explains how microglial senescence can potentially have a major effect in neurodegenerative diseases.…”

Section: Dystrophic and Senescent Microgliamentioning

confidence: 99%

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

Angelova

Brown

2019

Journal of Neurochemistry

187

125

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The single largest risk factor for etiology of neurodegenerative diseases like Alzheimer’s disease is increased age. Therefore, understanding the changes that occur as a result of aging is central to any possible prevention or cure for such conditions. Microglia, the resident brain glial population most associated with both protection of neurons in health and their destruction is disease, could be a significant player in age related changes. Microglia can adopt an aberrant phenotype sometimes referred to either as dystrophic or senescent. While aged microglia have been frequently identified in neurodegenerative diseases such as Alzheimer’s disease, there is no conclusive evidence that proves a causal role. This has been hampered by a lack of models of aged microglia. We have recently generated a model of senescent microglia based on the observation that all dystrophic microglia show iron overload. Iron‐overloading cultured microglia causes them to take on a senescent phenotype and can cause changes in models of neurodegeneration similar to those observed in patients. This review considers how this model could be used to determine the role of senescent microglia in neurodegenerative diseases.

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Section: Dystrophic and Senescent Microgliamentioning

confidence: 99%

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

Angelova

Brown

2019

Journal of Neurochemistry

187

125

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“…Hereditary hemochromatosis, a common genetic iron overload disease (Ganz and Nemeth, 2011), increases susceptibility to infections with Vibrio vulnificus and Yersinia enterocolitica (Khan et al, 2007), gram-negative bacteria classified as “siderophilic” because their pathogenicity is enhanced by excess iron (Weinberg, 2008, 2009). Vibrio vulnificus causes fulminant sepsis with mortality higher than 50% in susceptible patients including those with hereditary hemochromatosis and other iron overload conditions (Horseman and Surani, 2011) but it does not cause severe illness in healthy individuals.…”

Section: Introductionmentioning

confidence: 99%

Hepcidin-Induced Hypoferremia Is a Critical Host Defense Mechanism against the Siderophilic Bacterium Vibrio vulnificus

Arezes

Jung

Gabayan

et al. 2015

Cell Host & Microbe

202

182

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SUMMARY Hereditary hemochromatosis, an iron overload disease caused by a deficiency in the iron-regulatory hormone hepcidin, is associated with lethal infections by siderophilic bacteria. To elucidate the mechanisms of this susceptibility, we infected wild-type and hepcidin-deficient mice with the siderophilic bacterium Vibrio vulnificus, and found that hepcidin deficiency results in increased bacteremia and decreased survival of infected mice, which can be partially ameliorated by dietary iron depletion. Additionally, timely administration of hepcidin agonists to hepcidin-deficient mice induces hypoferremia that decreases bacterial loads and rescues these mice from death, regardless of initial iron levels. Studies of Vibrio vulnificus growth ex vivo show that high iron sera from hepcidin-deficient mice support extraordinarily rapid bacterial growth, and that this is inhibited in hypoferremic sera. Our findings demonstrate that hepcidin-mediated hypoferremia is a host defense mechanism against siderophilic pathogens and suggest that hepcidin agonists may improve infection outcomes in patients with hereditary hemochromatosis or thalassemia.

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“…Recently, the EPIC-Norfolk prospective study has clinically demonstrated the prediction of diabetes (of recent onset) with elevated serum ferritin levels; thus, as we said before, but now in healthy women, the greater the body deposits of ferritin, the greater the risk of suffering from the disease [179,180]. And excessive body ferritin is the link between diabetes, obesity (especially androidabdominal) and cancer.…”

Section: Diabetes and Cancer: The Murderous Intermediation Of Ironmentioning

confidence: 87%

“…Several epidemiological studies have reported a positive association between high ferric body deposits and the increased risk of type 2 diabetes and other insulin resistance states, from the metabolic syndrome and polycystic ovarian disease to gestational diabetes; all of them with a higher incidence of cancer; and it is that a greater oral intake of heme iron increases the risk of DM2 in healthy populations due to drastically elevating hyperinsulinemia and tissue resistance to insulin (particularly at the adipose, hepatic and muscular levels) [102,180]. By elevating insulin, but, most importantly, directly, free iron (not linked to transferrin) amplifies the action of genes carcinogenic (beta-catenin) and promotes the deletion of genes (1) protectors and inhibitors of malignant neoplasia such as protein P-53 [139].…”

Section: Diabetes and Cancer: The Murderous Intermediation Of Ironmentioning

confidence: 99%

Iron in the Promotion and Initiation of Cancer How Free Iron Accelerates Predisposing Insulin Resistance

2018

AHOR

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Iron is physiologically essential to life, but biochemically it is harmful because of its evident -but unappreciated- oxidative and inflammatory tissue power when it accumulates, is dosed in excess, or is free; and that because, after entering the body, unlike any other metal, its elimination is almost non-existent in man; thus, metal is a powerful promoter of chronic degenerative diseases, from diabetes, neurodegeneration to cancer, through extensive coronary and cardio-cerebrovascular disease; modifying its clinical expressivity and accelerating its severity. Iron is a powerful oxidizing and inflammatory agent, and its accumulation causes and promotes the proliferation of cancer cells in particular, both in animals and in humans. Free and accumulated iron triggers a powerful uncontrolled Cell Proliferation, permanently feeding the survival of the neoplastic cell. After more than 50 years of experimental and preclinical studies, it is clearly demonstrating the carcinogenicity of iron; and this is also proven in humans, from breast cancer and endometrium, in women, to cancer of the colon-rectum, prostate, and pancreas in men. In Western men and women, the reductions in iron deposits have an important anti-tumor and preventive effect for the development of cancer or diabetes, two entities biologically interrelated by the states of Resistance to Insulin, an inflammatory state that favors the development of malignant neoplasms, and can accelerate its aggressiveness. It is the chronic excess of insulin or its Tissue Resistance, the biological event and the clinical syndrome that increases the cancerous power of excess iron, both silent epidemics in modern man. Moderate increases in body iron levels increase the risk of acquiring cancer, and raise the level of their mortality. And its deficiency or chelation in vivo decreases the Tumor growth (Wang F, Elliott RL, Head JF: Inhibitory effect of deferoxamine mesylate and low iron diet on the 13762NF rat mammary adenocarcinoma Anticancer Res. 1999 Jan-Feb; 19 (1A): 445-50). If excess iron mediates and increases the risk of cancer associated with Insulin resistance, any subject with this syndrome can minimize any associated health risks (and their increased risk of cancer), avoiding iron-rich diets and donating blood with regularity; Iron is the metal that causes “exponential” and punctual mutations and fusion of genes through chromosomal translocations, constituting the greatest risk factor for human carcinogenesis. Iron is physiologically essential for life but biochemically dangerous. Chronic accumulation of iron causes pantropic organ damage and excess body iron play an important role in carcinogenesis, coronary artery disease, neurodegenerative disease, stroke and inflammatory disorders. Iron is very slowly excreted from humans once it is absorbed into the body. The significance of iron excess has been markedly underestimated, despite the fact that iron overloading disorders are as common place in the US white population. Iron-overload and catalytic iron promotes activation of oxidative responsive transcription factors and pro-inflammatory cytokines that increase cancer extension and aggravate them. There is accumulative evidence for iron as a carcinogenic metal in epidemiological, clinical, animal, and cell culture studies. The role of iron in various cancers, such as colorectal and liver cancer was demonstrated. Recent advancements on the molecular mechanisms of iron carcinogenesis evolved the Insulin-resistance generation and promotion, fisiopatologic condition that is not only permissive, but may be generated cancer and promoting it. Unlike other nutritional metals, iron is highly conserved: toxicity due to excess iron can occur either acutely after a single dose or chronically due to excessive accumulation in the body from diet. In vivo studies have demonstrated that an iron deficiency induced by either feeding a low iron diet injecting the iron chelator deferoxamine mesylate decreases tumor growth (Wang F, Elliott RL, Head JF: Inhibitory effect of deferoxamine mesylate and low iron diet on the 13762NF rat mammary adenocarcinoma Anticancer Res. 1999 Jan-Feb;19(1A):445-50). Iron supplementation has at times proven ineffective and even detrimental to health. Thus, iron excess may mediate the increased cancer risk associated with insulin resistance and heme-rich diets, and subjects who are insulin resistant can minimize any health risk associated with iron overload by avoiding heme-rich flesh foods and donating blood regularly. The energy that sustains cancer cells derived preferentially from glycolysis depends on the gene p53 deficiency-iron induced. This nutrient is postulated to contribute to the initiation of cancer in vivo, but iron overload initiates and sustain cancer development if chronic infection or insulin resistance conditions are present. Cancer cells require considerably more iron than normal cells. Since iron catalytic can induce driver point mutation and create fusion genes through chromosomal translocations, iron overload is one of the most important risk factors in human carcinogenesis. Because free iron may play a catalytic role in “spontaneous” mutagenesis, moderately elevated iron stores increased overall risk for cáncer.

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Iron Out-of-Balance: A Risk Factor for Acute and Chronic Diseases

Cited by 19 publications

References 46 publications

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

Hepcidin-Induced Hypoferremia Is a Critical Host Defense Mechanism against the Siderophilic Bacterium Vibrio vulnificus

Iron in the Promotion and Initiation of Cancer How Free Iron Accelerates Predisposing Insulin Resistance

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