Eff ects of continuous renal replacement therapy on infl ammation-related anemia, iron metabolism and prognosis in sepsis patients with acute kidney injury

BACKGROUND:This study aims to evaluate the eff ect of continuous renal replacement therapy(CRRT)on inflammation-related anemia,iron metabolism,and the prognosis in sepsis patients with acute kidney injury(AKI).METHODS:Sepsis patients with AKI were prospectively enrolled and randomized into the CRRT and control groups.The clinical and laboratory data on days 1,3 and 7 after intensive care unit(ICU)admission were collected.The serum interleukin(IL)-6,hepcidin,erythropoietin,ferritin,and soluble transferrin receptor(sTfR)were determined by enzyme-linked immunosorbent assay.The Sequential Organ Failure Assessment(SOFA)score and 28-day mortality were recorded.Data were analyzed using Pearson’s Chi-square test or Fisher’s exact test(categorical variables),and Mann-Whitney U-test or t-test(continuous variables).RESULTS:The hemoglobin and serum erythropoietin levels did not signifi cantly diff er between the CRRT and control groups though gradually decreased within the first week of ICU admission.On days 3 and 7,the serum IL-6,hepcidin,ferritin,and red blood cell distribution width significantly decreased in the CRRT group compared to the control group(all P<0.05).On day 7,the serum iron was significantly elevated in the CRRT group compared to the control group(P<0.05).However,the serum sTfR did not signifi cantly diff er between the groups over time.In addition,the SOFA scores were signifi cantly lower in the CRRT group compared to the control group on day 7.The 28-day mortality did not signifi cantly diff er between the control and CRRT groups(38.0%vs.28.2%,P=0.332).CONCLUSION:CRRT might have beneficial effects on the improvement in inflammationrelated iron metabolism and disease severity during the fi rst week of ICU admission but not anemia and 28-day mortality in sepsis patients with AKI.

Iron metabolism, oxidative stress, and neonatal brain injury

The brain injury associated with neonatal hypoxia ischemia（HI）is a major contributor to neonatal mortality and neurodevelopment retardation.Approximately 30-40%of infants with brain injury will die and 20-40%of survivors will develop significant neurological disorders and lifelong disability.

Hepcidin and Iron Metabolism in Non-diabetic Obese and Type 2 Diabetic Rats

Summary： The aim of this study was to investigate the changes of iron levels and hepatic regulatory molecules expression involved in iron metabolism in non-diabetic obese/type 2 diabetic rat models. Male Wistar rats were divided into 3 groups： control group, non-diabetic obese group and type 2 dia- betic group （n=20 each）. The rats were evaluated physiologically and biochemically. The hepatic histo- pathological changes were observed using haematoxylin and eosin （HE） staining. The mRNA expres- sion patterns of hepcidin, interleukin-6 （IL-6）, hypoxia-inducible factor （HIF） and ferroportin （Fpn） in the rat liver in control group, non-diabetic obese group and type 2 diabetic group were analyzed by real-time RT-PCR. The protein expression patterns of hepcidin in liver of each group were further ana- lyzed by immunohistochemistry and Western blotting. As compared with control group, the ferritin in non-diabetic obese group and type 2 diabetic group was increased significantly （P〈0.001）. However, there was no significant difference in soluble transferring receptor （sTfR）：ferritin ratio among the three groups （P〉0.05）. The real-time RT-PCR, immunohistochemistry and Western blotting results all re- vealed that the expression levels of hepcidin in non-diabetic obese group and type 2 diabetic group were elevated significantly as compared with those in control group （P〈0.001）. The expression levels of hep- cidin mRNA between non-diabetic obese group and type 2 diabetic group showed no significant differ- ence （P〉0.05）. However, the protein expression levels of hepcidin in type 2 diabetic group were sig- nificantly higher than those in non-diabetic obese group （P〈0.05）. Compared to control group, the ex- pression levels of IL-6 mRNA in non-diabetic obese group and type 2 diabetic group were increased significantly and the expression levels ofFpn mRNA decreased （P〈0.05）. However, the expression lev- els ofHIF mRNA had no significant difference among three groups. It is suggested that iron metabolism is substantially disturbed in non-diabetic obese and type 2 diabetic rats probably by the abnormal ex- pression of hepcidin in chronic inflammatory status. The increased hepcidin may restrain the iron re- lease from the cells by affecting the expression of Fpn, which probably associates with the development of diabetic complication.

Effects of Lujingyiqishengxue Pill on Iron Metabolism in Rats with Iron Deficiency Anemia

[Objectives]This study was conducted to observe the effect of Lujingyiqishengxue Pill on iron metabolism in rats with iron deficiency anemia. [Methods] The iron-deficiency anemia rat model was established by feeding low-iron diet. Meanwhile, the rats were given oral gavage of ferrous succinate(0.036 g/kg, positive drug group) and Lujingyiqishengxue Pill(4.4, 2.2, 1.1 g/kg, high, middle and low dose groups), once daily for 42 consecutive days. The body weight of the rats was observed every week, and the peripheral blood[red blood cells(RBC), hemoglobin(HGB), and hematocrit(HCT)]and the iron contents in tissues(the liver, spleen, small intestine, kidney) of the rats were detected after modeling;and serum iron(SI), serum total iron binding capacity(TIBC), transferrin saturation(TSAT), serum ferritin(SF) and serum transferrin receptor 1(TFR1) and other iron metabolism indexes were determined. [Results] Compared with the model group, the high-dose Lujingyiqishengxue Pill significantly reversed the peripheral blood(HGB, HCT) and iron contents of various tissues(the liver, spleen, small intestine, kidney) in rats(P<0.01), and significantly increased SI, TSAT, SF(P<0.01), while the contents of TIBC and TFR1 were significantly decreased(P<0.01). [Conclusions] Lujingyiqishengxue Pill can significantly improve anemia and regulate iron metabolism in rats with iron-deficiency anemia, which provides a pharmacological reference for the clinical application of Lujingyiqishengxue Pill.

The effect of iron metabolism on anxiety disorder

Anxiety disorder is one of the most common emotional disorders,but its pathogenesis re-mains unclear.Research has shown that iron deficiency is more common in people with emotional disorders and that these disorders can improve after taking iron supple-ments.Many factors can cause anxiety disorders,includ-ing external stress,genetic factors,impaired neurodevel-opment,and abnormal monoamine metabolism.Studies have shown that abnormal monoamine metabolism and impaired neurodevelopment can contribute to the severity of emotional disorders.The synthesis of serotonin(5-HT)and dopamine(DA)require iron as a cofactor in the syn-thesis of monoamine metabolism,and the release of epi-nephrine(E)was potentially associated with labile iron in plasma.At the same time,iron is also directly involved in myelin synthesis as a cofactor in neural development.Therefore,iron maybe involved some of the main causes of the onset of anxiety disorders.

Research progress of iron metabolism in retinal diseases

Background:Retinal diseases can lead to severe visual impairment and even blindness,but current treatments are limited.For precise targeted therapy,the pathophysiological mechanisms of the diseases still need to be further explored.Iron serves an essential role in many biological activities and helps maintain the function and morphology of the retina.The vision problems caused by retinal diseases are affecting more and more people,the study of iron metabolism in retinal diseases possesses great potential for clinical application.Main text:Iron maintains a dynamic balance in the retina but in excess is toxic to the retina.Iron overload can lead to various pathological changes in the retina through oxidative stress,inflammation,cell death,angiogenesis and other pathways.It is therefore involved in the progression of retinal diseases such as age-related macular degeneration,glaucoma,diabetic retinopathy,retinitis pigmentosa,and hereditary iron overload.In recent years,iron chelators have been shown to be effective in the treatment of retinal diseases,but the exact mechanism is not yet fully understood.This question prompted further investigation into the specific mechanisms by which iron metabolism is involved in retinal disease.Conclusions:This review summarizes iron metabolism processes in the retina and mechanistic studies of iron metabolism in the progression of retinal disease.It also highlights the therapeutic potential of iron chelators in retinal diseases.

Caveolin‑1 is critical for hepatic iron storage capacity in the development of nonalcoholic fatty liver disease

Background:Nonalcoholic fatty liver disease(NAFLD)is associated with disordered lipid and iron metabolism.Our previous study has substantiated the pivotal role of Caveolin-1(Cav-1)in protecting hepatocytes and mediating iron metabolism in the liver.This study aimed to explore the specific mechanisms underlying the regulation of iron metabolism by Cav-1 in NAFLD.Methods:Hepatocyte-specific Cav-1 overexpression mice and knockout mice were used in this study.Cav-1-knockdown of RAW264.7 cells and mouse primary hepatocytes were performed to verify the changes in vitro.Moreover,a high-fat diet and palmitic acid plus oleic acid treatment were utilized to construct a NAFLD model in vivo and in vitro,respectively,while a high-iron diet was used to construct an in vivo iron overload model.Besides,iron concentration,the expression of Cav-1 and iron metabolism-related proteins in liver tissue or serum were detected using iron assay kit,Prussian blue staining,Western blotting,immunofluorescence staining,immunohistochemical staining and ELISA.The related indicators of lipid metabolism and oxidative stress were evaluated by the corresponding reagent kit and staining.Results:Significant disorder of lipid and iron metabolism occurred in NAFLD.The expression of Cav-1 was decreased in NAFLD hepatocytes(P<0.05),accompanied by iron metabolism disorder.Cav-1 enhanced the iron storage capacity of hepatocytes by activating the ferritin light chain/ferritin heavy chain pathway in NAFLD,subsequently alleviating the oxidative stress induced by excess ferrous ions in the liver.Further,CD68^(+) CD163^(+) macrophages expressing Cav-1 were found to accelerate iron accumulation in the liver,which was contrary to the effect of Cav-1 in hepatocytes.Positive correlations were also observed between the serum Cav-1 concentration and the serum iron-related protein levels in NAFLD patients and healthy volunteers(P<0.05).Conclusions:These findings confirm that Cav-1 is an essential target protein that regulates iron and lipid metabolic homeostasis.It is a pivotal molecule for predicting and protecting against the development of NAFLD.

Iron metabolism,ferroptosis,and lncRNA in cancer: knowns and unknowns

Cancer cells undergo substantial metabolic alterations to sustain increased energy supply and uncontrolled proliferation.As an essential trace element,iron is vital for many biological processes.Evidence has revealed that cancer cells deploy various mechanisms to elevate the cellular iron concentration to accelerate proliferation.Ferroptosis,a form of cell death caused by iron-catalyzed excessive peroxidation of polyunsaturated fatty acids(PUFAs),is a promising therapeutic target for therapyresistant cancers.Previous studies have reported that long noncoding RNA(lncRNA)is a group of critical regulators involved in modulating cell metabolism,proliferation,apoptosis,and ferroptosis.In this review,we summarize the associations among iron metabolism,ferroptosis,and ferroptosis-related lncRNA in tumorigenesis.This information will help deepen understanding of the role of lncRNA in iron metabolism and raise the possibility of targeting lncRNA and ferroptosis in cancer combination therapy.

Targeting iron metabolism using gallium nanoparticles to suppress ferroptosis and effectively mitigate acute kidney injury

Ferroptosis plays a critical pathophysiological role in several types of acute kidney injury(AKI).The development of nanomaterials targeting iron metabolism and ferroptosis is a promising approach for AKI treatment.Herein,we synthesized gallic acid-gallium polyvinyl pyrrolidone nanoparticles(GGP NPs)as a potential iron-scavenging agent because of their nearly ionic radius and chemical similarity with iron.The results indicated that GGP NPs accumulated in tubular epithelial cells and showed good biocompatibility.GGP NPs significantly inhibited cisplatin(CP)-induced ferroptosis in HK-2 cells by reducing the accumulation of intracellular free iron and mitochondrial dysfunction,and suppressing the perturbations of ferroptosis processes,including lipid peroxidation,nicotinamide adenine dinucleotide phosphate(NADPH)and glutathione(GSH)levels,glutathione peroxidase 4(GPX4)activity,and ferritinophagy.An in vivo study demonstrated that treatment with GGP NPs significantly ameliorated the renal tubular injury and mitochondrial damage induced by CP treatment or ischemia-reperfusion injury.Our study suggests that GGP NPs may be an effective and promising candidate for AKI treatment and enable potential clinical translation.

A Static Magnetic Field Improves Iron Metabolism and Prevents High-Fat-Diet/Streptozocin-Induced Diabetes

Type 2 diabetes(T2D)is a metabolic disorder with high prevalence and severe complications that has recently been indicated to be treatable by a combined static magnetic field(SMF)and electric field.We systematically compared four types of SMFs and found that a downward SMF of
100 mT could effectively reduce the development of hyperglycemia,fatty liver,weight gain,and tissue injury in high-fat-diet(HFD)/streptozocin-induced T2D mice,but not the upward SMF.The downward SMF markedly restored the Bacteroidetes population and reversed the iron complex outer membrane receptor gene reduction in the mice gut microbiota,and reduced iron deposition in the pancreas.SMF also reduced the labile iron and reactive oxygen species level in pancreatic Min6 cells in vitro and prevented palmitate-induced Min6 cell number reduction.Therefore,this simple SMF setting could partially prevent HFD-induced T2D development and ameliorate related symptoms,which could provide a low-cost and non-invasive physical method to prevent and/or treat T2D in the future.

A correlative study of iron metabolism based on q-Dixon MRI in benign prostatic hyperplasia and prostate cancer

Clinical staging,Gleason score,and prostate-specific antigen(PSA)have been accepted as factors for evaluating the prognosis of prostate cancer(PCa).With the in-depth study of iron metabolism and the development of multiparametric magnetic resonance imaging technology,we used q-Dixon magnetic resonance imaging(MRI)to measure the iron content of the PCa patients'lesions,and used enzyme-linked immunosorbent assay(ELISA)to measure the iron metabolism indicators in the patients'serum samples,combined with the patients'postoperative clinical data for analysis.We found that the serum indexes were correlated with the T2 star values,International Society of Urological Pathology(ISUP)grade,and pathological classification in PCa patients(all P<O.001)but not in benign prostatic hyperplasia(BPH)patients(all P>O.05).The utilization of q-Dixon-based MRI and serum indexes allows the noninvasive measurement of iron content in prostate lesions and the assessment of differential iron metabolism between PCa and BPH,which may be helpful for evaluating the prognosis of PCa.

Effect of Qingjin Huatan Decoction on transferrin and Iron regulatory protein in COPD rats

Objective:To explore the mechanism of Qingjin Huatan Decoction in regulating iron metabolism by regulating inflammatory factors in the inflammatory environment of chronic obstructive pulmonary disease.Methods:The COPD model was prepared by tracheal drops of lipopolysaccharide(LPS)combined with smoke.40 rats were randomly divided into normal group,COPD group,roxithromycin western medicine group and Qingjin Huatan Decoction traditional Chinese medicine group(n=10).Post-molding drug administration intervention,Qingjin Huatan Decoction Chinese medicine group was given 14.62 g/kg(Qingjin Huatan Decoction),roxithromycin western medicine group was given 0.01575 g/kg(roxithromycin),COPD group and normal group were given normal saline 10 mL/kg,twice a day.The expressions of Hepcidin,IL-1β,IL-10 and TGF-β1 in serum of rats in each group were detected by ELISA.WesternBlot and qRT-PCR were used to detect the expression of TF and IREB2 protein and mRNA in lung tissues of each group.Results:Compared with the normal group,the contents of serum Hepcidin and IL-10 in COPD group were significantly decreased(P<0.01),while the contents of serum IL-1βand TGF-β1 were significantly increased(P<0.01,P<0.05).Compared with COPD group,the contents of serum Hepcidin and IL-10 were significantly increased in the two drug groups(P<0.01),while the contents of serum IL-1βand TGF-β1 were significantly decreased in the two drug groups(P<0.05).Compared with normal group,TF mRNA and protein expression in COPD group were increased(P<0.01),while IREB2 mRNA and protein expression were decreased(P<0.01).Compared with COPD group,TF mRNA and protein expressions in lung tissues of the two-drug group were decreased(P<0.01,P<0.05),while IREB2 mRNA and protein expressions were increased(P<0.01).Conclusion:Iron metabolism is related to inflammation.Qingjin Huatan Decoction can regulate iron metabolism in inflammatory environment to treat COPD.

Iron Status of a People Living with HIV in Sub-Saharan Africa Using a Multi-Criteria Approach Based on the Determination of Blood Ferritin, sTfR, CRP and sTfR-F Index

Background: The assessment of iron status using a single biomarker of iron metabolism is not enough sensitive and specific to reliably diagnose iron deficiency associated with multiple comorbidities. The objective of this study was to describe the iron status of people living with HIV in sub-Saharan Africa using a multi-criteria approach based on the determination of blood ferritin, sTfR, CRP and the calculation of sTfR-F index. Methods: This study was conducted using a retrospective panel of 933 sera/plasmas. We determined serum ferritin concentration, serum sTfR concentration, and C-reactive protein (CRP) by immunoturbidimetry for each subject. The sTfR-F index was determined by calculating the sTfR/log ferritin ratio. The statistical test used was Chi2. Results: Regardless of the inflammatory syndrome, we determined 3.80%, 30.29%, and 42.70% iron deficiency based on the separate interpretation of ferritin concentration, sTfR, and sTfR-F calculation, respectively. We used those biomarkers in addition to CRP in an algorithm for the diagnosis of iron deficiency. Subjects without inflammatory syndrome, had iron deficiency of 2.89% (n = 26). Taking into account the presence of an inflammatory syndrome, the frequency obtained was n = 88 (9.78%). Overall, iron deficiency was diagnosed in 114 (12.67%) patients when we used the diagnostic algorithm. Conclusion: The use of diagnostic algorithms combining several biomarkers of iron metabolism and taking into account the presence or absence of an inflammatory syndrome is a good approach to detect a large number of iron deficiencies in a population. Therefore, an assessment of the effectiveness of different diagnostic algorithms is necessary.

Research progress on the anti-colorectal cancer effect of traditional Chinese medicine active ingredients based on ferroptosis

Ferroptosis is defined as an iron-dependent form of regulated cell death that is initiated by the toxic accumulation of lipid peroxides on cellular membranes.In the past decade,ferroptosis has aroused considerable interest in comprehensive treatment of colorectal cancer,mainly as it is a specific cell death mode that is mechanistically and morphologically differ from other forms of cell death such as autophagy,apoptosis,and pyroptosis,following by holding a giant potential for the therapy of colorectal cancer.Research has found that various active ingredients in traditional Chinese medicine possess the ability of inducing ferroptosis in colorectal cancer cells through pathways such as lipid metabolism,iron metabolism,or cysteine/glutamate transporter system,which demonstrating enormous clinical therapeutic potential.In this review,the metabolic regulatory network of ferroptosis is introduced from the perspective of ferroptosis mechanism,and the information on the induction of ferroptosis in colorectal cancer cells by active ingredients of traditional Chinese medicine is also be retrospected,which the purpose is to provide novel strategies for the anti-colorectal cancer therapy of active ingredients in traditional Chinese medicine.

Reabsorption of iron into acutely damaged rat liver:A role for ferritins

AIM To studied iron metabolism in liver, spleen, and serum after acute liver-damage, in relation to surrogate markers for liver-damage and repair.METHODS Rats received intraperitoneal injection of the hepatotoxin thioacetamide(TAA), and were sacrificed regularly between 1 and 96 h thereafter. Serum levels of transaminases and iron were measured using conventional laboratory assays. Liver tissue was used for conventional histology, immunohistology, and iron staining. The expression of acute-phase cytokines, ferritin light chain(FTL), and ferritin heavy chain(FTH)was investigated in the liver by q RT-PCR. Western blotting was used to investigate FTL and FTH in liver tissue and serum. Liver and spleen tissue was also used to determine iron concentrations.RESULTS After a short initial decrease, iron serum concentrations increased in parallel with serum transaminase(aspartate aminotransferase and alanine aminotransferase) levels, which reached a maximum at 48 h, and decreased thereafter. Similarly, after 48 h a significant increase in FTL, and after 72 h in FTH was detected in serum. While earliest morphological signs of inflammation in liver were visible after 6 h, increased expression of the two acute-phase cytokines IFN-γ(1 h) and IL-1β(3 h) was detectable earlier, with maximum values after 12-24 h. Iron concentrations in liver tissue increased steadily between 1 h and 48 h, and remained high at 96 h. In contrast, spleen iron concentrations remained unchanged until 48 h, and increased mildly thereafter(96 h). Although tissue iron staining was negative, hepatic FTL and FTH protein levels were strongly elevated. Our results reveal effects on hepatic iron concentrations after direct liver injury by TAA. The increase of liver iron concentrations may be due to the uptake of a significant proportion of the metal by healthy hepatocytes, and only to a minor extent by macrophages, as spleen iron concentrations do not increase in parallel. The temporary increase of iron, FTH and transaminases in serum is obviously due to their release by damaged hepatocytes.CONCLUSION Increased liver iron levels may be the consequence of hepatocyte damage. Iron released into serum by damaged hepatocytes is obviously transported back and stored via ferritins.

Direct modulation of hepatocyte hepcidin signaling by iron

BACKGROUND Liver-secreted hepcidin is the systemic master switch of iron homeostasis and decreased levels of hepcidin are considered to cause iron overload not only in hereditary hemochromatosis but also in hemolytic anemia and chronic liver diseases.The regulation of hepcidin is complex and its response to iron is still not completely understood.AIM To study the direct effect of iron on various established hepcidin signaling pathways in hepatoma cells or primary hepatocytes.METHODS Hepcidin mRNA expression was studied by quantitative real-time(qRT)-PCR in the presence of various forms of iron including ferric ammonium citrate(FAC)in hepatoma cells(Huh7),murine primary hepatocytes and an established co-culture model of phorbol myristate acetate-differentiated THP-1 monocytes and Huh7 cells.To analyze hepcidin signaling,the response to bone morphogenetic protein 6(BMP6),interleukin(IL)-6,IL-1β,hypoxia and lipopolysaccharide(LPS)were studied.Hepcidin and small mothers against decapentaplegic 6(SMAD6)mRNA levels were assessed by qRT-PCR and the expression of phosphorylated signal transducer and activator of transcription 3(phospho-STAT3),STAT3,phospho-SMAD1/5/8 and SMAD1 proteins were analyzed by western blot.RESULTS All iron III forms including FAC efficiently blocked hepcidin mRNA expression at non-toxic dosages in Huh7 cells or primary hepatocytes in a time and dosedependent manner(P<0.001;P<0.05).Hepcidin blockage could be efficiently blunted by iron chelators salicylaldehyde isonicotinoyl hydrazone(SIH)and Desferal(P<0.001).FAC also inhibited BMP6,hypoxia,IL-1βand IL-6-mediated hepcidin induction(P<0.001;P<0.001;P<0.05;P<0.001),and FAC also inhibited LPS-mediated hepatic hepcidin induction in co-culture model(P<0.001).Moreover,FAC reduced SMAD6 mRNA and p-SMAD1/5/8 protein expression at basal or upon stimulation by BMP6(P<0.05;P<0.01),and FAC also reduced SMAD6 and p-SMAD1/5/8 expression under hypoxia(P<0.01;P<0.05).However,FAC has no significant effect on p-STAT3 protein expression at basal or upon stimulation by various stimuli.Notably,in the presence of the BMP/SMAD signaling pathway inhibitor LDN193189 Hydrochloride(LDN),FAC was unable to further decrease hepcidin,SMAD6 and p-SMAD1/5/8 expression compared with LDN alone.CONCLUSION Iron directly blocks hepatocellular hepcidin signaling through the BMP/SMAD pathway but independent of STAT3.This mechanism may contribute to continued iron overload in many pathophysiological conditions ultimately causing a vicious cycle of continued hepcidin suppression.

AB038. Pathological neovascularization in retinopathy of prematurity is regulated by heme-derived iron trafficking

Background:Retinopathy of prematurity(ROP)is an eye disease of the immature newborn characterized by pathological neovascularization(NV).ROP classically arises due to changes in oxygen availability in the retina.However,other factors,such as red blood cell(RBC)transfusion,independently contribute to disease severity.Heme molecules,rich in RBC,are the primary source of endogenous iron.Heme is metabolized by heme oxygenase(HO)into biliverdin,carbon monoxide,and ferrous ions.Low iron levels stabilize hypoxia-inducible factor 1α(HIF1α),the main transcription factor of vascular endothelial growth factor(VEGF)that drives angiogenesis.Here we investigate the role of heme metabolism in pathological NV.Methods:ROP was studied using the well-characterized oxygen-induced retinopathy(OIR)mouse model.Wild-type(WT)pups are exposed to high oxygen concentrations(FiO275%)for 5 days,from the post-natal day(P)7 to 12,and subsequently returned to room air until retinal collection at P12,P14,&P17.Retinas are then analyzed via single-cell RNAseq,RT-qPCR,western blot,Prussian blue staining,and immunostaining techniques to elucidate the effect of OIR on iron metabolism and Hmox1.In OIR,we quantified vaso-obliteration(VO)and pathologic neovascular(NV)areas at P17 to assess the effects of1 Hmox1 competitive inhibition,and2Hmox1 allosteric inhibition.Results:Iron trafficking genes across different retinal cell-types were upregulated in OIR,including CP,FTH1,IREB2,TF,and Hmox1.Moreover,Prussian blue staining suggests iron accumulation in retinal vessels exposed to OIR.Hmox1 mRNA(n=7,P<0.01 at P17)and protein expression(n=3,P<0.05)were increased 3.8-fold from P12 to 19.Immunostaining and single-cell RNAseq confirmed that Hmox1 predominantly resides in retinal microglial cells.Competitively and allosterically Hmox1 inhibition decreased NV by 15%(n=15,P=0.02)and 60%(n=5,P<0.01)respectively.Conclusions:Iron metabolism has seldom been explored in the context of ROP.Perhaps microglial heme metabolism by Hmox1 contributes to HIF1αstabilization and pathological NV.

The Potential Clinical Significance of the Serum Iron and Ferritin Status in Lung Cancer Patients

Background An increasing number of studies have shown that iron,one of the indispensable trace elements in the human body,is closely related to the occurrence and development of cancer.However,few studies have clearly demonstrated the role of the iron levels in lung cancer patients,or the potential effects of inflammation on iron levels.Methods The clinical data for lung cancer patients and non-lung cancer participants were retrospectively analyzed.The serum iron and ferritin levels were measured and compared using a rank-sum test.The correlation between the serum iron/ferritin and C-reactive protein(CRP)was analyzed by rank correlation.The cut-off values for continuous variables were obtained by the receiver operating characteristic curve(ROC)method.An analysis of potential prognostic factors in lung cancer patients was conducted by univariate and multivariate survival analyses.Results The serum iron levels in patients with extensive small-cell lung cancer(SCLC)were lower than those with limited-stage SCLC,and the levels of serum ferritin and CRP in those with extensive SCLC were higher than those with limited-stage SCLC.Similarly,the serum iron levels in patients with stage IV non-small cell lung cancer(NSCLC)were lower than those of patients with stageⅠ-Ⅲdisease,and the levels of serum ferritin and CRP in those with stage IV NSCLC were higher than those in stagesⅠ-Ⅲ.The serum iron level was negatively correlated with the level of CRP,while the serum ferritin level was positively correlated with CRP.The stage of lung cancer,but not the serum iron/ferritin level,was an independent prognostic factor in lung cancer patients.Conclusions The serum iron and ferritin levels are associated with the staging of lung cancer.The later stages of lung cancer are associated with a lower serum iron level,a higher serum ferritin level,and a higher CRP level.Inflammation may play an important role in regulating the serum iron and ferritin levels in lung cancer patients.

Chronic administration of triclosan leads to liver fibrosis through hepcidin-ferroportin axis-mediated iron overload

Triclosan(TCS)has been manufactured as an antibacterial compound for half a century.Currently,it is widely used in various personal care products;however,its potential adverse effects raise a lot of attention.Here,we create a long-term oral administration mouse model and identify the corresponding hepatotoxicity of TCS.We discover that daily intragastric administration of 10 mg/kg TCS to mice for 12 weeks results in severe hepatic fibrosis.Further study displays that hepatic iron increased 18%,23%and 29%upon oral TCS treatment for4,8 and 12 weeks,respectively.Accompanied by hepatic iron variation,splenic and duodenal iron are increased,which indicates systemic iron disorder.Not only excessive iron accumulated in the liver,abnormal hepatic malondialdehyde,prostaglandin synthase 2 and glutathione peroxidase 4 are pointed to ferroptosis.Additional study uncovers that hepcidin expression increases 7%,10%,4%in serum and 2.4-,4.8-,and 2.3-fold on transcriptional levels upon TCS exposure for 4,8 and 12 weeks,individually.Taken together,the mice in the TCS-treated group show disordered systemic iron homeostasis via the upregulated hepatic hepcidin-ferroportin axis.Meanwhile,both hepatic iron overload(systemic level)and hepatocyte ferroptosis(cellular level)are accused of TCS-induced liver fibrosis.Ferriprox■,an iron scavenger,significantly ameliorates TCS-induced liver fibrosis.In summary,this study confirms the impact of TCS on liver fibrosis;a critical signal pathway is also displayed.The significance of the current study is to prompt us to reevaluate the“pros and cons”of TCS applications.

Ferroptosis-based nano delivery systems targeted therapy for colorectal cancer:Insights and future perspectives

There are limited options for patients who develop liver metastasis from colorectal cancer(CRC),the leading cause of cancer-related mortality worldwide.Emerging evidence has provided insights into iron deficiency and excess in CRC.Ferroptosis is an iron-dependent form of programmed cell death characterized by aberrant iron and lipid metabolism,which play crucial roles in tumorigenesis,tumor progression,and treatment options.A better understanding of the underlying molecular mechanism of ferroptosis has shed light on the current findings of ferroptosis-based nanodrug targeting strategies,such as driving ferroptosis in tumor cells and the tumor microenvironment,emerging combination therapy and against multidrug resistance.Furthermore,this review highlights the challenge and perspective of a ferroptosis-driven nanodrug delivery system for CRC-targeted therapy.