Iron promotes ovarian cancer malignancy and advances platinum resistance by enhancing DNA repair via FTH1/FTL/POLQ/RAD51 axis.

Iron is crucial for cell DNA synthesis and repair, but an excess of free iron can lead to oxidative stress and subsequent cell death. Although several studies suggest that cancer cells display characteristics of 'Iron addiction', an ongoing debate surrounds the question of whether iron can influence the malignant properties of ovarian cancer. In the current study, we initially found iron levels increase during spheroid formation. Furthermore, iron supplementation can promote cancer cell survival, cancer spheroid growth, and migration; vice versa, iron chelators inhibit this process. Notably, iron reduces the sensitivity of ovarian cancer cells to platinum as well. Mechanistically, iron downregulates DNA homologous recombination (HR) inhibitor polymerase theta (POLQ) and relieves its antagonism against the HR repair enzyme RAD51, thereby promoting DNA damage repair to resist chemotherapy-induced damage. Additionally, iron tightly regulated by ferritin (FTH1/FTL) which is indispensable for iron-triggered DNA repair. Finally, we discovered that iron chelators combined with platinum exhibit a synergistic inhibitory effect on ovarian cancer in vitro and in vivo. Our findings affirm the pro-cancer role of iron in ovarian cancer and reveal that iron advances platinum resistance by promoting DNA damage repair through FTH1/FTL/POLQ/RAD51 pathway. Our findings highlight the significance of iron depletion therapy, revealing a promising avenue for advancing ovarian cancer treatment.

The effects of oral ferrous bisglycinate supplementation on hemoglobin and ferritin concentrations in adults and children: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT: Iron deficiency and anemia have serious consequences, especially for children and pregnant women. Iron salts are commonly provided as oral supplements to prevent and treat iron deficiency, despite poor bioavailability and frequently reported adverse side effects. Ferrous bisglycinate is a novel amino acid iron chelate that is thought to be more bioavailable and associated with fewer gastrointestinal (GI) adverse events as compared with iron salts. OBJECTIVE: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the effects of ferrous bisglycinate supplementation compared with other iron supplements on hemoglobin and ferritin concentrations and GI adverse events. DATA SOURCES: A systematic search of electronic databases and grey literature was performed up to July 17, 2020, yielding 17 RCTs that reported hemoglobin or ferritin concentrations following at least 4 weeks' supplementation of ferrous bisglycinate compared with other iron supplements in any dose or frequency. DATA EXTRACTION: Random-effects meta-analyses were conducted among trials of pregnant women (n = 9) and children (n = 4); pooled estimates were expressed as standardized mean differences (SMDs). Incidence rate ratios (IRRs) were estimated for GI adverse events, using Poisson generalized linear mixed-effects models. The remaining trials in other populations (n = 4; men and nonpregnant women) were qualitatively evaluated. DATA ANALYSIS: Compared with other iron supplements, supplementation with ferrous bisglycinate for 4-20 weeks resulted in higher hemoglobin concentrations in pregnant women (SMD, 0.54 g/dL; 95% confidence interval [CI], 0.15-0.94; P < 0.01) and fewer reported GI adverse events (IRR, 0.36; 95%CI, 0.17-0.76; P < 0.01). We observed a non-significant trend for higher ferritin concentrations in pregnant women supplemented with ferrous bisglycinate. No significant differences in hemoglobin or ferritin concentrations were detected among children. CONCLUSION: Ferrous bisglycinate shows some benefit over other iron supplements in increasing hemoglobin concentration and reducing GI adverse events among pregnant women. More trials are needed to assess the efficacy of ferrous bisglycinate against other iron supplements in other populations. PROSPERO REGISTRATION NO: CRD42020196984.

Therapeutic potential of iron modulating drugs in a mouse model of multiple system atrophy.

Multiple System Atrophy (MSA) is a rare neurodegenerative synucleinopathy which leads to severe disability followed by death within 6-9 years of symptom onset. There is compelling evidence suggesting that biological trace metals like iron and copper play an important role in synucleinopathies like Parkinson's disease and removing excess brain iron using chelators could slow down the disease progression. In human MSA, there is evidence of increased iron in affected brain regions, but role of iron and therapeutic efficacy of iron-lowering drugs in pre-clinical models of MSA have not been studied. We studied age-related changes in iron metabolism in different brain regions of the PLP-αsyn mice and tested whether iron-lowering drugs could alleviate disease phenotype in aged PLP-αsyn mice. Iron content, iron-ferritin association, ferritin protein levels and copper-ceruloplasmin association were measured in prefrontal cortex, putamen, substantia nigra and cerebellum of 3, 8, and 20-month-old PLP-αsyn and age-matched non-transgenic mice. Moreover, 12-month-old PLP-αsyn mice were administered deferiprone or ceruloplasmin or vehicle for 2 months. At the end of treatment period, motor testing and stereological analyses were performed. We found iron accumulation and perturbed iron-ferritin interaction in substantia nigra, putamen and cerebellum of aged PLP-αsyn mice. Furthermore, we found significant reduction in ceruloplasmin-bound copper in substantia nigra and cerebellum of the PLP-αsyn mice. Both deferiprone and ceruloplasmin prevented decline in motor performance in aged PLP-αsyn mice and were associated with higher neuronal survival and reduced density of α-synuclein aggregates in substantia nigra. This is the first study to report brain iron accumulation in a mouse model of MSA. Our results indicate that elevated iron in MSA mice may result from ceruloplasmin dysfunction and provide evidence that targeting iron in MSA could be a viable therapeutic option.

Long-term efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in anaemia of chronic kidney disease: A meta-analysis including 13,146 patients.

WHAT IS KNOWN AND OBJECTIVE: Previous studies based on small-sample clinical data proved that short-term use of hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors increased haemoglobin levels in anaemic patients with chronic kidney disease (CKD). However, these studies reached conflicting conclusions on iron parameters and adverse event profiles. Our meta-analysis aimed to evaluate the long-term efficacy and safety of HIF-PHD inhibitors in renal anaemia. METHODS: Randomized controlled trials comparing treatment with HIF-PHD inhibitors versus placebo or erythropoiesis-stimulating agents (ESAs) were thoroughly searched in the PubMed, Embase, Cochrane Library and international clinical trial registries. Meta-analysis was performed on main outcomes with random effects models. RESULTS AND DISCUSSION: A total of 30 studies comprising 13,146 patients were included. The HIF-PHD inhibitors used included roxadustat, daprodustat, vadadustat, molidustat, desidustat and enarodustat. HIF-PHD inhibitors significantly increased haemoglobin levels in comparison with placebo [weighted mean difference (WMD) 1.53, 95% confidence interval (CI) 1.39 to 1.67] or ESAs (WMD 0.13, 95% CI 0.03 to 0.22). Hepcidin, ferritin and serum iron levels were decreased, while total iron binding capacity and transferrin levels were increased in the HIF-PHD inhibitor group versus those in placebo or ESAs group. Additionally, HIF-PHD inhibitors medication was associated with cholesterol-lowering effects. As for safety, the risk of serious adverse events in the HIF-PHD inhibitor group was increased in comparison with placebo group [risk ratio (RR) 1.07, 95% CI 1.01 to 1.13], but comparable to the ESAs group (RR 1.02, 95% CI 0.94 to 1.10). Compared with placebo, the agents increased the risk of diarrhoea (1.21, 1.00 to 1.47), nausea (1.46, 1.09 to 1.97), oedema peripheral (1.32, 1.01 to 1.59), hyperkalemia (1.27, 1.05 to 1.54) and hypertension (1.34, 1.02 to 1.76). Compared with ESAs, the drugs increased the risk of vomiting (1.30, 1.02 to 1.65), headache (1.27, 1.05 to 1.53) and thrombosis events (1.31, 1.05 to 1.63). WHAT IS NEW AND CONCLUSION: HIF-PHD inhibitors treatment effectively increased haemoglobin levels and promoted iron utilization in anaemic patients with CKD, and they were well tolerated for long-term use. In order to avoid unfavourable effects of excessive iron consumption, it was appropriate to administer HIF-PHD inhibitors in combination with iron supplements for long-term treatment.

Tratamiento y evolución del síndrome de tormenta de citoquinas asociados a infección por SARS-CoV-2 en pacientes octogenarios / Evolution and treatment of storm cytoquine syndrome associated to SARS-CoV-2 infection among octogenarians

INTRODUCCIÓN: El síndrome de tormenta de citoquinas (STC) es una complicación muy grave de los pacientes con infección por SARS-CoV-2. El tratamiento y la evolución no están bien definidos. Nuestro objetivo es describir sus características clínicas, los tratamientos empleados y su evolución clínica. PACIENTES Y MÉTODO: Estudio retrospectivo observacional de pacientes consecutivos ingresados en el período comprendido entre el 23 de marzo y el 12 de abril de 2020 con infección por SARS-CoV-2 confirmada, con neumonía por estudio radiológico o tomografía de tórax, que cumplían criterios de STC y que recibieron tratamiento. Clasificamos a los pacientes en los que recibieron solo pulsos de glucocorticoides (GC), o pulsos de GC y tocilizumab. Determinamos niveles séricos de ferritina, PCR y dímeros-D. La variable final fue la supervivencia. RESULTADOS: Veintiún pacientes con una edad de 83 años (80-88 años). La ferritina media fue de 1.056 microg/L (317-3.553), la PCR de 115,8mg/dL (22-306) y los dímeros-D de 2,9mg/L (0,45-17,5). Todos los pacientes recibieron pulsos de GC y en 2 casos simultáneamente tocilizumab. El tiempo medio de seguimiento fue de 13,7 días (8-21). La mortalidad global fue del 38,1% (8/21pacientes). Los 2 pacientes que recibieron tocilizumab fallecieron. Los fallecidos presentaron niveles significativamente más elevados de ferritina (1.254 vs. 925microg/L; p = 0,045) y PCR (197,6 vs. 76mg/dL; p = 0,007). Al final del seguimiento se observó una disminución en los parámetros bioquímicos con ferritina de 727microg/L, PCR de 27mg/dl y dímeros-D de 1,18mg/L. En 13/21 pacientes (61,9%) el STC se controló sin necesidad de añadir otros tratamientos. CONCLUSIONES: La mortalidad del STC por SARS-CoV-2 es alta a pesar del tratamiento. Una mayor respuesta inflamatoria se asoció con una mayor mortalidad. Aunque parece que el uso precoz de pulsos de GC puede controlarlo, pudiendo disminuir la necesidad de uso de otros tratamientos, con el diseño del estudio y sus limitaciones, no se puede establecer esta conclusión

INTRODUCTION: Cytokine storm syndrome (CTS) is a serious complication of patients with SARS-CoV-2 infection. Treatment and evolution in octogenarians are not well defiREVned. Our objective is to describe its clinical characteristics, the treatments and its clinical evolution. PATIENTS AND METHOD: Retrospective observational study of consecutive patients admitted in the period between March 23 and April 12, 2020 with confirmed SARS-CoV-2 infection, with pneumonia by radiological study or chest tomography, whith STC criteria and who received treatment. We classified patients as those who received only glucocorticoid (GC) pulses, or GC and tocilizumab pulses. We determined serum levels of ferritin, CRP and D-dimers. The final variable was survival. RESULTS: 21 patients, (80-88 years). The mean ferritin was 1056 microg/L (317-3,553), CRP 115.8mg/dL (22-306) and D-dimers 2.9m/L (0.45-17.5). All patients received GC pulses and in 2 cases simultaneously tocilizumab. The mean follow-up time was 13.7 days (8-21). The overall mortality was 38.1% (8/21 patients). The 2 patients who received tocilizumab died. The deceased had significantly higher levels of ferritin (1,254 vs. 925microg/L; P=.045) and CRP (197.6 vs. 76mg / dL; P=.007). At the end of the follow-up, a decrease in the biochemical parameters was observed with ferritin of 727microg/L, CRP of 27mg/dl and D-dimers of 1.18mg/L. In 13/21 patients (61.9%), the CTS was controlled without the need to add other treatments. CONCLUSIONS: STC mortality from SARS-CoV-2 is high despite treatment. A greater inflammatory response was associated with a higher mortality. Although it seems that the early use of GC pulses could control it, and the use of other treatments such as tocilizumab shouldo be, with the study design and its limitations, this conclusion cannot be stablished

Quantification of Iron Release from Native Ferritin and Magnetoferritin Induced by Vitamins B2 and C.

Various pathological processes in humans are associated with biogenic iron accumulation and the mineralization of iron oxide nanoparticles, especially magnetite. Ferritin has been proposed as a precursor to pathological magnetite mineralization. This study quantifies spectroscopically the release of ferrous ions from native ferritin and magnetoferritin as a model system for pathological ferritin in the presence of potent natural reducing agents (vitamins C and B2) over time. Ferrous cations are required for the transformation of ferrihydrite (physiological) into a magnetite (pathological) mineral core and are considered toxic at elevated levels. The study shows a significant difference in the reduction and iron release from native ferritin compared to magnetoferritin for both vitamins. The amount of reduced iron formed from a magnetoferritin mineral core is two to five times higher than from native ferritin. Surprisingly, increasing the concentration of the reducing agent affects only iron release from native ferritin. Magnetoferritin cores with different loading factors seem to be insensitive to different concentrations of vitamins. An alternative hypothesis of human tissue magnetite mineralization and the process of iron-induced pathology is proposed. The results could contribute to evidence of the molecular mechanisms of various iron-related pathologies, including neurodegeneration.

Exercise Training and Vitamin C Supplementation Affects Ferritin mRNA in Leukocytes without Affecting Prooxidative/Antioxidative Balance in Elderly Women.

Physical training and antioxidant supplementation may influence iron metabolism through reduced oxidative stress and subsequent lowering of mRNA levels of genes that are easily induced by this stress, including those responsible for iron homeostasis. Fifteen elderly women participated in our 12-week experiment, involving six weeks of training without supplementation and six weeks of training supported by oral supplementation of 1000 mg of vitamin C daily. The participants were divided into two groups (n = 7 in group 1 and n = 8 in group 2). In group 1, we applied vitamin C supplementation in the first six weeks of training, while in group 2 during the remaining six weeks of training. In both phases, the health-related training occurred three times per week. Training accompanied by vitamin C supplementation did not affect prooxidative/antioxidative balance but significantly decreased ferritin heavy chain (FTH) and ferritin light chain (FTL) mRNA in leukocytes (for FTH mRNA from 2^64.24 to 2^11.06, p = 0.03 in group 1 and from 2^60.54 to 2^16.03, p = 0.01 in group 2, for FTL mRNA from 2^20.22 to 2^4.53, p = 0.01 in group 2). We concluded that vitamin C supplementation might have caused a decrease in gene expression of two important antioxidative genes (FTH, FTL) and had no effect on plasma prooxidative/antioxidative balance.

Iron-responsive-like elements and neurodegenerative ferroptosis.

A set of common-acting iron-responsive 5'untranslated region (5'UTR) motifs can fold into RNA stem loops that appear significant to the biology of cognitive declines of Parkinson's disease dementia (PDD), Lewy body dementia (LDD), and Alzheimer's disease (AD). Neurodegenerative diseases exhibit perturbations of iron homeostasis in defined brain subregions over characteristic time intervals of progression. While misfolding of Aß from the amyloid-precursor-protein (APP), alpha-synuclein, prion protein (PrP) each cause neuropathic protein inclusions in the brain subregions, iron-responsive-like element (IRE-like) RNA stem-loops reside in their transcripts. APP and αsyn have a role in iron transport while gene duplications elevate the expression of their products to cause rare familial cases of AD and PDD. Of note, IRE-like sequences are responsive to excesses of brain iron in a potential feedback loop to accelerate neuronal ferroptosis and cognitive declines as well as amyloidosis. This pathogenic feedback is consistent with the translational control of the iron storage protein ferritin. We discuss how the IRE-like RNA motifs in the 5'UTRs of APP, alpha-synuclein and PrP mRNAs represent uniquely folded drug targets for therapies to prevent perturbed iron homeostasis that accelerates AD, PD, PD dementia (PDD) and Lewy body dementia, thus preventing cognitive deficits. Inhibition of alpha-synuclein translation is an option to block manganese toxicity associated with early childhood cognitive problems and manganism while Pb toxicity is epigenetically associated with attention deficit and later-stage AD. Pathologies of heavy metal toxicity centered on an embargo of iron export may be treated with activators of APP and ferritin and inhibitors of alpha-synuclein translation.

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis.

The current chemotherapeutical treatment against alveolar echinococcosis relies exclusively on benzimidazoles, which are not parasiticidal and can induce severe toxicity. There are no alternative treatment options. To identify novel drugs with activity against Echinococcus multilocularis metacestodes, researchers have studied potentially interesting drug targets (e.g. the parasite's energy metabolism), and/or adopted drug repurposing approaches by undertaking whole organism screenings. We here focus on drug screening approaches, which utilize an in vitro screening cascade that includes assessment of the drug-induced physical damage of metacestodes, the impact on metacestode viability and the viability of isolated parasite stem cells, structure-activity relationship (SAR) analysis of compound derivatives, and the mode of action. Finally, once in vitro data are indicative for a therapeutic window, the efficacy of selected compounds is assessed in experimentally infected mice. Using this screening cascade, we found that the anti-malarial mefloquine was active against E. multilocularis metacestodes in vitro and in vivo. To shed more light into the mode of action of mefloquine, SAR analysis on mefloquine analogues was performed. E. multilocularis ferritin was identified as a mefloquine-binding protein, but its precise role as a drug target remains to be elucidated. In mice that were infected either intraperitoneally with metacestodes or orally with eggs, oral treatment with mefloquine led to a significant reduction of parasite growth compared to the standard treatment with albendazole. However, mefloquine was not acting parasiticidally. Assessment of mefloquine plasma concentrations in treated mice showed that levels were reached which are close to serum concentrations that are achieved in humans during long-term malaria prophylaxis. Mefloquine might be applied in human AE patients as a salvage treatment. Future studies should focus on other repurposed anti-infective compounds (MMV665807, niclosamide, atovaquone), which showed stronger in vitro activity against E. multilocularis than mefloquine.

Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had ß-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.

Chronic Exposure to Low-Dose Carbon Monoxide Alters Hemoglobin Mass and V˙O2max.

By blocking the oxygen binding sites on the hemoglobin molecule, chronic low-dose carbon monoxide (CO) administration may produce similar effects to those of exposure to altitude. PURPOSE: This study aimed to determine the effect of chronic low-dose CO application on hemoglobin mass (Hbmass) and V˙O2max. METHODS: For 3 wk, 11 healthy and moderately trained male subjects inhaled a CO bolus five times per day to increase their HbCO concentration by ~5%. Another 11 subjects received a placebo. Hbmass, serum erythropoietin concentration, ferritin, and basic hematological parameters were determined before and weekly during and until 3 wk after the CO inhalation period. V˙O2max tests on a cycle ergometer were performed before and after the CO administration period. RESULTS: In the CO group, Hbmass increased from 919 ± 69 to 962 ± 78 g in week 3 (P < 0.001) and was maintained for the following 3 wk. Reticulocytes (%) and immature reticulocyte fraction significantly increased after 1 wk. Serum erythropoietin concentration tended to increase after 1 wk (P = 0.07) and was suppressed in the postperiod (P < 0.01). Ferritin decreased during the inhalation period (from 106 ± 37 to 72 ± 37 ng·mL, P < 0.001). V˙O2max tended to increase from 4230 ± 280 to 4350 ± 350 mL·min (P < 0.1) immediately after the inhalation period and showed a significant relationship to the change in Hbmass (y = 4.1x - 73.4, r = 0.70, P < 0.001). CONCLUSIONS: Chronic continuous exposure to low-dose CO enhances erythropoietic processes resulting in a 4.8% increase in Hbmass. The individual changes in Hbmass were correlated to the corresponding changes in V˙O2max. Examination of ethical and safety concerns is warranted before the implementation of low-dose CO inhalation in the clinical/athletic setting as a tool for modifying Hbmass.

The effect of vitamin D supplementation on hemoglobin concentration: a systematic review and meta-analysis.

AIMS: The purpose of this review was to investigate the effect of vitamin D supplements on hemoglobin concentration in subjects aged 17.5-68 years old; using randomized controlled trials (RCTs). METHODS: Relevant RCT studies were identified from January 2000 to January 2019 by using MeSH terms in PubMed, Embase, Cochrane Library, Clinical trials, Scopus databases and gray literature. The studies were reviewed systematically, and quality assessments were evaluated by the guidelines of the Cochrane risk of bias. The effect of vitamin D supplements (n = 14) on hemoglobin concentration was considered as primary outcome, while its effects on the levels of ferritin, transferrin saturation and iron status were derived as secondary outcomes. In total, 1385 subjects with age range of 17.5 to 68 years old were examined for 3 h to 6 months; Mean (standard deviation) or median interquartile changes in the hemoglobin concentration in each treatment group was recorded for meta-analysis. RESULTS: Fourteen RCTs met the inclusion criteria. Current study findings propose that vitamin D supplementation leads to a non-significant reduction in hemoglobin levels in subjects (17.5-68 years old) [std. mean difference (SMD): 0.01; 95% CI: - 0.28, 0.29; P = 0.95], also it has no significant effect on ferritin concentrations [std. mean difference (SMD): -0.01; 95% CI: [- 0.20, 0.18; P = 0.91]. However, vitamin D supplementation demonstrated positive effects on transferrin saturation [mean difference (MD): 1.54; 95% CI: 0.31, 2.76; P = 0.01] and iron status [std. mean difference (SMD): 0.24; 95% CI: - 0.09, 0.39; P = 0.002]. CONCLUSION: Current review concluded that supplementation with vitamin D had no significant effect on hemoglobin and ferritin levels while positive effects on transferrin saturation and iron status were observed. Further clinical studies are required to determine the actual effect of this intervention on hemoglobin levels.

Comparison of the effects of nimodipine and deferoxamine on brain injury in rat with subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) may lead to brain atrophy and cognitive dysfunction. This study aimed to compare the efficacy of nimodipine and deferoxamine on these sequelae of SAH. A rat model of SAH was established by the double-hemorrhage method. These rats were injected with saline (intraperitoneal, IP), nimodipine (IP), or deferoxamine (IP and intranasal) every 12 h for 5 days after SAH. The MRI scanning, including magnetic resonance angiography, diffusion tensor imaging, T2-weighted imaging, was performed to detect the brain structure. The levels of iron metabolism-related proteins were examined by Western blot analysis. The Morris water maze (MWM) test was used to assess the cognitive function. Then, then neurons in the cortex and hippocampus were counted on hematoxylin and eosin-stained brain sections. Significant cerebral vasospasm (CVS) was found in the saline and deferoxamine groups, but not in the nimodipine group. Cerebral peduncle injury was detected in the saline and nimodipine groups, but not significantly in the deferoxamine group. Compared with nimodipine, deferoxamine reduced transferrin (Tf), Tf receptor, and ferritin levels after SAH. The MWM performances were significantly worse in the saline and nimodipine groups than that in the deferoxamine group. Brain atrophy and neuronal losses were more significant in the saline and nimodipine groups than in the deferoxamine group. Nimodipine significantly ameliorated CVS, but it did not improve the late changes in brain structure and cognitive function. Deferoxamine effectively reduced neuronal cell death and ameliorated cognitive function after SAH.

Caspse-11-GSDMD pathway is required for serum ferritin secretion in sepsis.

Ferritin is the major iron storage molecule of vertebrates, which can be detected in serum under numerous conditions, including inflammatory, neurodegenerative, and malignant diseases. Given this character, serum ferritin is frequently used as a biomarker in clinical settings. How the ferritin secreted to the serum has attracted much attention. Although some studies have found ferritin was mediated via the endoplasmic reticulum (ER)-Golgi secretion pathway or secretory lysosomes trafficking pathway under normal conditions, the secretion pathway of ferritin under pathological conditions, especially in sepsis is not very clear. In this report, we adopt a murine sepsis model to study the secretion pathway of ferritin in sepsis. We demonstrated caspase-11-GSDMD pathway and associated pyroptosis are required for secretion of ferritin in vitro and in vivo in sepsis. Moreover, our work connects pyroptosis to serum ferritin secretion and suggests a passive release process of ferritin, enhancing our understanding of the mechanism of ferritin secretion.

Effects of Coenzyme Q10 Supplementation on Serum Values of Gamma-glutamyl transferase, Pseudocholinesterase, Bilirubin, Ferritin, and High-Sensitivity C-Reactive Protein in Women with Type 2 Diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a disease associated with increased oxidative stress which results from mitochondrial dysfunction. Coenzyme Q10 (CoQ10) is an essential antioxidant for energy production in mitochondria. The purpose of this randomized double-blind clinical trial study was to evaluate the effects of CoQ10 supplementation on serum values of gamma-glutamyl transferase (GGT), pseudocholinesterase (PchE), bilirubin, ferritin, and high-sensitivity c-reactive protein (hs-CRP) and metabolic syndrome biomarkers in women with T2DM. MATERIAL & METHODS: Eighty women with T2DM enrolled in this study. Thirty six of them were randomized in the drug group (receiving 100 mg/day of CoQ10) and 44 women were randomized in placebo group. Intervention was continued for 12 weeks. In both groups 35 subjects finished the study and were included in the analysis. Serum levels of the variables were measured before and after supplementation. RESULTS: Serum values of FBS (P=0.039), HOMA-IR (P=0.01), ferritin (P<0.001), total cholesterol (TC) (P=0.006), LDL-C (P=0.007) decreased and HDL-C (P=0.02) increased significantly in the drug group after intervention. Serum levels of triglyceride (P=0.09) decreased marginally in CoQ10 group. CONCLUSIONS: The results of the current study had shown that after supplementation with 100 mg/day of CoQ10 for 12 weeks, serum values of FBS, HOMA-IR, TC, LDL-C and ferritin were decreased and values of HDL-C were increased in women with T2DM.

Phosphoinositide-3-kinase inhibition elevates ferritin level resulting depletion of labile iron pool and blocking of glioma cell proliferation.

BACKGROUND: Elevated endogenous phosphoinositide-3-kinase (PI3K) activity is critical for cell proliferation in gliomas. Iron availability is one of the essential factors for cell growth and proliferation. However, any relation between PI3K and cellular iron homeostasis has not been understood so far. METHODS: Glioma cells and human primary astrocytes were treated with class I PI3K inhibitors to examine regulation of iron homeostasis components. Regulation of ferritin was detected at mRNA and translational level. Labile iron pool (LIP) and cell proliferation were examined in glioma cells and human primary astrocytes. RESULTS: Blocking of PI3K activity elevated ferritin level by 6-10 folds in glioma cells by augmenting mRNA expression of ferritin subunits and also by influencing ferritin translation. IRE-IRP interaction was affected due to conversion of IRP1 to cytosolic aconitase that was influenced by increased iron-sulfur scaffold protein iron-sulfur cluster assembly enzyme (ISCU) level. Elevated ferritin sequestered LIP to affect cell proliferation that was reversed in silencing ferritin by siRNAs of ferritin-H and ISCU. Human primary astrocyte with little PI3K activity did not show any change in ferritin level, LIP and cell proliferation by PI3K inhibitors. CONCLUSIONS: PI3K inhibition promotes ferritin synthesis by dual mechanism resulting sequestration of iron to limit its availability for cell proliferation in glioma cells but not in primary astrocytes. GENERAL SIGNIFICANCE: This observation establishes a relation between PI3K signalling and iron homeostasis in glioma cells. It also implies that activated PI3K controls ferritin expression to ensure availability of adequate iron required for cell proliferation.

Cold plasma effect on the proteome of Pseudomonas aeruginosa - Role for bacterioferritin.

Cold atmospheric-pressure plasma (CAP) is a relatively new method used for bacterial inactivation. CAP is ionized gas that can be generated by applying an electric current to air or a feeding gas. It contains reactive species and emits UV radiation, which have antibacterial activity. Previous data suggests that CAP is effective in microbial inactivation and can decontaminate and sterilize surfaces, but its exact mode of action is still under debate. This study demonstrates the effect of CAP on the whole proteome of Pseudomonas aeruginosa PAO1 biofilms, which is a dominant pathogen in cystic fibrosis and medical device-related infections. Liquid chromatography-mass spectrometry (LC-MS) was used to identify differentially regulated proteins of whole cell P. aeruginosa extracts. A total of 16 proteins were identified to be affected by plasma treatment compared to the control. Eight of the identified proteins have functions in transcription and translation and their expression changes are likely to be part of a general physiological response instead of a CAP-specific adaptation. However, CAP also affected bacterioferritin (Bfr), Isocitrate dehydrogenase (Idh), Trigger factor (Tig) and a chemotaxis protein, which may be involved in P. aeruginosa's specific response to CAP. We confirm that bacterioferritin B plays a role in the bacterial response to CAP because ΔbfrB mutants of both PAO1 and PA14 are more susceptible to plasma-induced cell-death than their corresponding wild-type strains. To our knowledge, this is the first study showing the effect of plasma on the whole proteome of a pathogenic microorganism. It will help our understanding of the mode of action of CAP-mediated bacterial inactivation and thus support a safe and effective routine use of CAP in clinical and industrial settings.

Recurrence of anti-MDA5 antibody-positive clinically amyopathic dermatomyositis after long-term remission: A case report.

RATIONALE: Among all dermatomyositis (DM) patients, antimelanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) positive patients have significantly poor short-term mortality, whereas they experience less relapses over the long term after the remission. We report the case of a patient with anti-MDA5 Ab-positive clinically amyopathic dermatomyositis (CADM) with the recurrence of interstitial lung disease (ILD) after 7 years of remission. There has been no case report of an anti-MDA5 Ab-positive DM patient with the recurrence of ILD after 7 years of long-term remission. PATIENT CONCERNS: A 70-year-old Japanese woman was diagnosed with anti-MDA5 Ab-positive CADM and ILD. After achieving 7 years long-term remission, she was admitted to our department with erythema on the fingers and interstitial pneumonia. Her anti-MDA5 Ab titer was elevated. DIAGNOSES: We diagnosed recurrent CADM complicated with ILD. INTERVENTIONS: We successfully treated her with 1,000 mg of methyl-prednisolone pulse and intravenous cyclophosphamide therapy followed by prednisolone 50 mg/day and an increase of cyclosporine. OUTCOMES: After that treatment, the patient's skin symptoms and interstitial pneumonia were relieved. All laboratory investigations such as ferritin, the serum markers of interstitial pneumonia (i.e., SP-A, SP-D), and the titer of anti-MDA5 Ab showed signs of improvement. LESSONS: Her case suggests that careful physical examinations and monitoring the serum markers are important even after long-term remission is achieved.

Minocycline Effects on Intracerebral Hemorrhage-Induced Iron Overload in Aged Rats: Brain Iron Quantification With Magnetic Resonance Imaging.

BACKGROUND AND PURPOSE: Brain iron overload is a key factor causing brain injury after intracerebral hemorrhage (ICH). This study quantified brain iron levels after ICH with magnetic resonance imaging R2* mapping. The effect of minocycline on iron overload and ICH-induced brain injury in aged rats was also determined. METHODS: Aged (18 months old) male Fischer 344 rats had an intracerebral injection of autologous blood or saline, and brain iron levels were measured by magnetic resonance imaging R2* mapping. Some ICH rats were treated with minocycline or vehicle. The rats were euthanized at days 7 and 28 after ICH, and brains were used for immunohistochemistry and Western blot analyses. Magnetic resonance imaging (T2-weighted, T2* gradient-echo, and R2* mapping) sequences were performed at different time points. RESULTS: ICH-induced brain iron overload in the perihematomal area could be quantified by R2* mapping. Minocycline treatment reduced brain iron accumulation, T2* lesion volume, iron-handling protein upregulation, neuronal cell death, and neurological deficits (P<0.05). CONCLUSIONS: Magnetic resonance imaging R2* mapping is a reliable and noninvasive method, which can quantitatively measure brain iron levels after ICH. Minocycline reduced ICH-related perihematomal iron accumulation and brain injury in aged rats.

The Improvement of the Hepatic Histological Findings in a Patient with Non-alcoholic Steatohepatitis with Type 2 Diabetes after the Administration of the Sodium-glucose Cotransporter 2 Inhibitor Ipragliflozin.

The patient was a 67-year-old woman with type 2 diabetes and non-alcoholic steatohepatitis (NASH). The administration of the sodium-glucose cotransporter 2 (SGLT2) inhibitor, ipragliflozin improved her liver dysfunction clinically and histologically. The serum alanine aminotransferase (ALT) and ferritin levels decreased to normal limits after treatment for four months. Type IV collagen and hyaluronic acid, both of which were serum fibrotic markers, decreased after treatment. Ultrasonography and computed tomography showed a decrease in the fat deposits in her liver. Her liver sample showed marked improvement, especially in steatosis, inflammation, and ballooning. The SGLT2 inhibitor ipragliflozin may be useful as a specific therapeutic drug for NASH.