Sustained Submicromolar H2O2 Levels Induce Hepcidin via Signal Transducer and Activator of Transcription 3 (STAT3)

Millonig, Gunda; Ganzleben, Ingo; Peccerella, Teresa; Casanovas, Guillem; Brodziak-Jarosz, Lidia; Breitkopf‐Heinlein, Katja; Dick, Tobias P.; Seitz, Helmut K.; Muckenthaler, Martina U.; Mueller, Sebastian

doi:10.1074/jbc.m112.358911

Cited by 70 publications

(92 citation statements)

References 47 publications

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“…A recent study demonstrated in vitro that sustained levels of H 2 O 2 , similar to inflammatory conditions, are sufficient to activate hepcidin transcription in hepatocytes via increased STAT-3 phosphorylation. 48 The authors further found that H 2 O 2 acts synergistically with IL-6 in inducing hepcidin, thus suggesting another mechanism through which oxidative stress contributes to the anemia of chronic disease. 48 To strengthen our results we compared anemic and nonanemic patients, confirming that anemia was significantly associated with the highest levels of CRP, inflammatory cytokines, EPO, ferritin, hepcidin and ROS levels, and with the lowest levels of serum iron, transferrin, leptin, albumin, lipid profile parameters and antioxidant Role of inflammation and malnutrition in CRA haematologica | 2015; 100 (1) 129 enzymes.…”

Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 95%

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The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study

Macciò

Madeddu

Gramignano³

et al. 2014

Haematologica

211

150

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ABSTRACTfore, essential to analyze all these factors that cause anemia, particularly before beginning any form of therapy that may worsen anemia.The aim of this work was to document the prevalence of anemia in a large cohort of patients with solid tumors before any exposure to antineoplastic treatment, and to assess the possible correlation between Hb levels and the commonly used indices of inflammation, malnutrition, and metabolic stress. We hypothesized that inflammation and malnutrition are independent predictors of the development and severity of anemia and that a better knowledge of CRA may enable its more adequate treatment. MethodsThis study was a prospective, observational trial performed in accordance with the Helsinki declaration after approval by the Local Institutional Ethics Committee. Between May 2011 and January 2014, 888 consecutive patients with histologically confirmed solid cancer at different sites referred to the Departments of Obstetrics and Gynecology, Sirai Hospital, Carbonia, Medical Oncology at "N.S. Bonaria" Hospital, San Gavino, "Nuova Casa di Cura", Decimomannu, and "A. Businco" Hospital, Cagliari, Italy, were enrolled. Table 1 reports the participants' clinical characteristics. Patients were assessed at diagnosis before receiving any cancer treatment. Exclusion criteria were: evidence of infections, chronic inflammatory disease, active bleeding, hemolysis, renal insufficiency, or hypothyroidism; known history of hematologic disorders (including hemoglobinopathies), family history of thalassemia or hemocromatosis; treatment with EPO, i.v. iron or blood transfusion in the preceding 12 weeks; current iron, vitamin B12 or folate supplementation.Anemia was defined according to our laboratory populationbased normal ranges as Hb <13.0 g/dL for males and <12.0 g/dL for females. Karnofsky PS was categorized into four prognostic classes. 17 Blood samples were obtained at 8 a.m. after overnight fasting since serum hepcidin and iron levels show similar circadian changes. In accordance with Ganz et al., 18 the 8 a.m. fasting hepcidin concentrations were more consistent than those at other times of the day. After centrifugation of the blood samples, serum was stored at -80°C until analysis.In all patients Hb levels and parameters of chronic inflammation [CRP, fibrinogen, IL-6, IL-1β, tumor necrosis factor-α (TNFα)], iron metabolism (iron, ferritin, transferrin, hepcidin), EPO, nutritional status (albumin, leptin, cholesterol, HDL, LDL, triglycerides) and oxidative stress [ROS, glutathione peroxidase (GPx), superoxide dismutase (SOD)] were measured. The formula for expected EPO was: 2.5 x (140-Hb g/L). 19 Since leptin is highly dependent on body mass index (BMI), the leptin/BMI ratio was reported. The modified Glasgow prognostic score (mGPS) was calculated as follows: 2, both elevated CRP (≥10 mg/L) and low albumin (<3.5 g/dL); 1, elevated CRP only; 0, normal CRP (<10 mg/L). 20 Laboratory assaysRoutine analyses of Hb, CRP, fibrinogen, serum iron, transferrin, ferritin, triglycerides, cholesterol...

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 95%

The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study

Macciò

Madeddu

Gramignano³

et al. 2014

Haematologica

211

150

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“…Finally, upon infection, activated inflammatory cells undergo an oxidative burst that results in the release of large amounts of reactive oxygen species, which help to kill invading microbes. Neutrophils generate H 2 O 2 when activated, and work in cell culture has shown that low levels of H 2 O 2 stimulation contribute to hepatic hepcidin induction through STAT3 (55).…”

Section: Regulation Of Hepcidin By Inflammationmentioning

confidence: 99%

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Schmidt

2015

Journal of Biological Chemistry

139

105

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Iron is a redox-active metal required as a cofactor in multiple metalloproteins essential for a host of life processes. The metal is highly toxic when present in excess and must be strictly regulated to prevent tissue and organ damage. Hepcidin, a molecule first characterized as an antimicrobial peptide, plays a critical role in the regulation of iron homeostasis. Multiple stimuli positively influence the expression of hepcidin, including iron, inflammation, and infection by pathogens. In this Minireview, I will discuss how inflammation regulates hepcidin transcription, allowing for sufficient concentrations of iron for organismal needs while sequestering the metal from infectious pathogens.Iron is crucial for many life functions in both eukaryotic hosts and prokaryotic pathogens. Due to its ability to readily accept or donate electrons, iron is a valuable cofactor in proteins essential in metabolic processes. However, when left unsupervised, iron can also react with oxygen to generate radical oxygen species that can damage all facets of a cell, leading to tissue damage and eventual organ failure. Therefore, it is crucial for organisms to maintain strict control over iron uptake and distribution to assure appropriate amounts for life requirements, yet regulate and sequester it tightly to prevent oxidative stress or microbial proliferation during infection. Herein, I will present an overview of how iron balance is maintained in vertebrate organisms and discuss the role of hepcidin, the master regulator of iron metabolism, in iron regulation during inflammation and infection. General Iron HomeostasisEach day the average human must absorb 1-2 mg of iron from the diet to offset unregulated losses from general bleeding, menstruation, or the sloughing of epithelial cells. Iron is a critical cofactor required for DNA synthesis, mitochondrial respiration, and various signaling pathways. Most crucially, almost 25 mg of iron per day is required for hemoglobin synthesis and the replacement of an estimated 200 billion RBCs. The vast majority of this iron pool is acquired through the recycling of senescent erythrocytes by macrophages of the reticuloendothelial compartment. Whole body iron homeostasis is thought to occur completely at the level of iron absorption, as no physiologically regulated means of iron excretion has been elucidated. Hence, influx of iron from the diet, and recycling of iron from aged or damaged RBCs, must be closely regulated to prevent iron-restricted erythropoiesis resulting in anemia or excess iron loading and subsequent tissue damage caused by the generation of radical oxygen species. Proper distribution of circulating iron to tissues such as the brain, heart, and skeletal muscle is crucial for the prevention of human disease states.Non-heme dietary reduced iron is admitted into the body through divalent metal transporter 1 (DMT1, Slc11a2) (1, 2), an iron transporter located on the apical membrane of duodenal enterocytes located in the first section of the small intestine ( Fig. 1). After uptake in...

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“…Авторами были про-ведены эксперименты с использованием двух способов доступа к окислительному стрессу: лечение клеток с Н2О2 или Ар-42 пептида в его олигомерной форме. Оба вида лечения вызвали накопление маркеров окислительного стресса, такие как окис-ленные белки и липиды, а также измене-ния в ДНК, что также отмечали Millonig G., Gansleben I., Peccerella T. et al [11]. Что ка-сается микроэлементов, клетки, обработан-ные Н2О2, показали более высокие уров-ни Zn и более низких уровней Са в ядрах по сравнению с контрольными клетками, без каких-либо окислительных обработок.…”

Section: международный журнал прикладныхunclassified

“…В астроцитах интерлейкин-lfl повышает генерацию Н 2 О 2 , что приводит к снижению фосфатазной ак-тивности и активации МАР-киназы. ФНО-а через повышение образования АФК активи-рует факторы транскрипции NF-kp и АР-1, процессы апоптоза [11,23].…”

Section: заключениеunclassified

Biological and Chemical Effects by Endo- And Exogenous Hydrogen Peroxide in Human Body Cells Structures

Reva¹,

Yamamoto²,

Gulkov³

et al. 2017

IJAFR (МЖПФИ)

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Учитывая возрастающую антибиотикорезистентность микроорганизмов, появление новых устойчивых к антибиотикам штаммов смертельно опасных инфекционных патогенов, поиск альтернативных медицин-ских препаратов приобретает особую актуальность на современном этапе. В работе представлен анализ собственных и данных литературы о роли экзогенного и эндогенного hydrogen peroxide в условиях нормы и патологии, на фоне микробной контаминации и при острой и хронической ишемии тканей. Показано, что наряду с отрицательной ролью внутриклеточного hydrogen peroxide, при парентеральном введении, он оказывает благоприятное лечебное действие при инфекциях, ишемических повреждениях нервной ткани, а также онкологической и эндокринной патологии. Отмечено, что в то время, как наружное применение пре-паратов hydrogen peroxide не вызывает никаких сомнений в необходимости его использования, применение его в качестве внутреннего лечебного препарата требует глубоких исследований вследствие многочислен-ных противоречивых данных. Vladivostok, e-mail: tiltiltil@yandex.ru) Given the increasing antibiotic resistance of microorganisms, the emergence of new antibiotic-resistant strains of deadly infectious pathogens, the search for alternative medicines is the particular relevance at the present stage. The paper presents an analysis of its own data and literature on the role of exogenous and endogenous hydrogen peroxide under normal and pathological conditions, against microbial contamination and acute and chronic tissue ischemia. It is shown that in addition to the negative role endogenous hydrogen peroxide entered in the blood, or parenteral, it has a beneficial and healing effect in infections, ischemic damage to the nervous tissue, as well as oncology and endocrine pathology. It is noted that while the external application of preparations hydrogen peroxide no doubt the necessity of its use, its application as an internal curative preparation requires numerous deep researches conflicting data.

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Sustained Submicromolar H2O2 Levels Induce Hepcidin via Signal Transducer and Activator of Transcription 3 (STAT3)

Cited by 70 publications

References 47 publications

The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study

The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Biological and Chemical Effects by Endo- And Exogenous Hydrogen Peroxide in Human Body Cells Structures

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