Disruption Of Iron Metabolism Research Articles

Ferroptosis at the crossroads of manganese-induced neurotoxicity: A retrospective study

Manganese is an essential trace element, but overexposure can cause neurotoxicity and subsequent neurodegenerative diseases. Ferroptosis is a form of cell death characterized by lipid peroxidation and iron overload inside cells, which is closely related to manganese neurotoxicity. Manganese can induce ferroptosis through multiple pathways: causing oxidative stress and increased cellular reactive oxygen species (ROS), resulting in lipid peroxidation; depleting glutathione (GSH) and weakening the antioxidant capacity of cells; disrupting iron metabolism and increasing iron-dependent lipid peroxidation; damaging mitochondrial function and disrupting the electron transport chain, leading to increased ROS production. Oxidative stress, iron metabolism disorders, lipid peroxidation, GSH depletion, and mitochondrial dysfunction, typical features of ferroptosis, have been observed in animal and cell models after manganese exposure. In summary, manganese can participate in the pathogenesis of neurodegenerative diseases by inducing events related to ferroptosis. This provides new insights into studying the mechanism of manganese neurotoxicity and developing therapeutic drugs.

Atomistic modelling and NMR studies reveal that gallium can target the ferric PQS uptake system in P. aeruginosa biofilms.

Intravenous gallium nitrate therapy is a novel therapeutic strategy deployed to combat chronic Pseudomonas aeruginosa biofilm infections in the lungs of cystic fibrosis (CF) patients by interfering with iron (Fe3+) uptake. The therapy is a source of Ga3+, which competes with Fe3+ for siderophore binding, subsequently disrupting iron metabolism and inhibiting biofilm proliferation in vivo. It was recently demonstrated that the Pseudomonas quinolone signal (PQS) can chelate Fe3+ to assist in bacterial iron uptake. However, it is unknown whether exogenous gallium also targets [Fe(PQS)3] uptake, which, in turn, would extend the mechanism of gallium therapy beyond siderophore competition, potentially supporting use of the therapy against P. aeruginosa mutants deficient in siderophore uptake proteins. To that end, the thermodynamic feasibility of iron-for-gallium cation exchange into [Fe(PQS)3] was evaluated using quantum chemical density functional theory (DFT) modelling and verified experimentally using 1H nuclear magnetic resonance (NMR). We demonstrate here that Ga3+ can strongly bind to three PQS molecules and, furthermore, displace and substitute Fe3+ from the native chelate pocket within PQS complexes, through a Trojan horse mechanism, retaining the key structural features present within the native ferric complex. As such, [Fe(PQS)3] complexes, in addition to ferric-siderophore complexes, represent another target for gallium therapy.

PM2.5 exposure exacerbates seizure symptoms and cognitive dysfunction by disrupting iron metabolism and the Nrf2-mediated ferroptosis pathway

In recent years, air pollution has garnered global attention due to its ability to traverse borders and regions, thereby impacting areas far removed from the emission sources. While prior studies predominantly focused on the deleterious effects of PM2.5 on the respiratory and cardiovascular systems, emerging evidence has highlighted the potential risks of PM2.5 exposure to the central nervous system. Nonetheless, research elucidating the potential influences of PM2.5 exposure on seizures, specifically in relation to neuronal ferroptosis, remains limited. In this study, we investigated the potential effects of PM2.5 exposure on seizure symptoms and seizures-induced hippocampal neuronal ferroptosis. Our findings suggest that seizure patients residing in regions with high PM2.5 levels are more likely to disturb iron homeostasis and the Nrf2 dependent ferroptosis pathway compared to those living in areas with lower PM2.5 levels. The Morris Water Maze test, Racine scores, and EEG recordings in epileptic mice suggest that PM2.5 exposure can exacerbate seizure symptoms and cognitive dysfunction. Neurotoxic effects of PM2.5 exposure were demonstrated via Nissl staining and CCK-8 assays. Direct evidence of PM2.5-induced hippocampal neuronal ferroptosis was provided through TEM images. Additionally, increased Fe2+ and lipid ROS levels indirectly supported the notion of PM2.5-induced hippocampal ferroptosis. Therefore, our study underscores the necessity of preventing and controlling PM2.5 levels, particularly for patients with seizures.

The effect of chronic intermittent hypobaric hypoxia improving liver damage in metabolic syndrome rats through ferritinophagy.

Studies have confirmed that hepatic iron overload is one of the important factors causing liver damage in the metabolic syndrome (MS). As a special form of autophagy, ferritinophagy is involved in the regulation of iron metabolism. Our previous studies have shown that chronic intermittent hypobaric hypoxia (CIHH) can improve the iron metabolism disorder. The aim of this study was to investigate how CIHH improves liver damage through ferritinophagy in MS rats. Male Sprague-Dawley rats aged 8-10weeks were randomly divided into four groups: control (CON), CIHH (exposed to hypoxia at a simulated altitude of 5000m for 28days, 6h daily), MS model (induced by a 16-week high-fat diet and 10% fructose water feeding), and MS + CIHH (exposed to CIHH after a 16-week MS inducement) groups. Liver index, liver function, iron content, tissue morphology, oxidative stress, ferritinophagy, ferroptosis, and iron metabolism-related protein expression were measured, and the ferritinophagy flux in the liver was further analyzed. Compared with CON rats, MS rats had an increased liver index, damaged liver tissue and function, increased iron content and iron deposition, disrupted iron metabolism, significantly increased oxidative stress indicators in the liver, significantly upregulated expression of ferroptosis-related proteins, and downregulated expression of nuclear receptor coactivator 4 (NCOA4) and ferritinophagy flux. After CIHH treatment, the degree of liver damage and various abnormal indicators in MS rats were significantly improved. CIHH may improve liver damage by promoting NCOA4-mediated ferritinophagy, reducing iron overload and oxidative stress, and thereby alleviating ferroptosis in MS rats.

Gemfibrozil Alleviates Cognitive Impairment by Inhibiting Ferroptosis of Astrocytes via Restoring the Iron Metabolism and Promoting Antioxidant Capacity in Type 2 Diabetes.

Diabetes-associated cognitive dysfunction (DACD) is considered a significant complication of diabetes and manifests as cognitive impairment. Astrocytes are vital to the brain energy metabolism and cerebral antioxidant status. Ferroptosis has been implicated in cognitive impairment, but it is unclear whether the ferroptosis of astrocytes is involved in the progression of DACD. PPARA/PPARα (peroxisome proliferator-activated receptor alpha) is a transcription factor that regulates glucose and lipid metabolism in the brain. In this study, we demonstrated that high glucose promoted ferroptosis of astrocytes by disrupting iron metabolism and suppressing the xCT/GPX4-regulated pathway in diabetic mice and astrocytes cultured in high glucose. Administration of gemfibrozil, a known PPARα agonist, inhibited ferroptosis and improved memory impairment in db/db mice. Gemfibrozil also prevented the accumulation of lipid peroxidation products and lethal reactive oxygen species induced by iron deposition in astrocytes and substantially reduced neuronal and synaptic loss. Our findings demonstrated that ferroptosis of astrocytes is a novel mechanism in the development of DACD. Additionally, our study revealed the therapeutic effect of gemfibrozil in preventing and treating DACD by inhibiting ferroptosis.

Abstract 3898: Synergistic combination of the iron chelator deferasirox with cisplatin and doxorubicin chemotherapies against nonsmall cell lung carcinoma

Abstract Lung cancer is the second most common and leading cause of cancer-related deaths worldwide with 85% of these cases being non-small cell lung carcinoma (NSCLC). Unfortunately, despite improvements in NSCLC outcomes, many of these tumors develop resistance against principal chemotherapies (e.g., cisplatin (CisPt) and doxorubicin (Doxo)), inducing abysmally low survival prognosis. Deferasirox (Def), an FDA-approved iron chelation therapy, is a drug under study for cancer therapy due to iron plays a key role in cell growth and energy production. Herein, we determined the effect of Def alone and in combination with CisPt and Doxo on NSCLC A549 cells. Viability assays results showed that Def has synergistic cytotoxic effects in combination with CisPt and Doxo at low uM concentrations after 24 h of incubation using the Chou Talalay method. In addition, qPCR gene expression studies showed that Def induced a significant downregulation of EGFR, VEGF, MMP9, MMP2, CHD4 genes related to resistance and metastatic process. In addition, we determined the overexpression of NDRG1 gene mediated by Def confirming the chelation of iron and disruption of iron metabolism. Overall, this work will set the basis for adjuvant therapies against chemoresistance and metastasis processes using an iron chelator. Citation Format: Natalia I. Ortiz Alvelo, Grace Torres, Sthephanie Estrada, Daraishka Pérez, Yancy Ferrer, Yamixa Delgado. Synergistic combination of the iron chelator deferasirox with cisplatin and doxorubicin chemotherapies against nonsmall cell lung carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3898.

Total Marrow Irradiation Reduces Organ Damage in a Bone Marrow Transplant Model of Sickle Cell Disease

Sickle cell disease (SCD) is associated with significant organ pathology. Currently, the only curative option is bone marrow transplantation (BMT) after myeloablative conditioning. However, significant organ damage from myeloablative total body irradiation (TBI) remains one of the major side effects of BMT. To reduce exposure to vital organs, but efficient enough to maintain engraftment, we developed 3D image guided-total marrow irradiation (TMI) for targeted delivery to the bone marrow (BM) and spleen of humanized BERK sickle mice while sparing the vital organs. We hypothesized that TMI will prevent organ damage compared to that induced by TBI during BMT. Sickle mice were treated with: [i] TBI (4:4), 4 Gy to the BM & 4 Gy to the whole body; [ii] TMI (4:0), 4 Gy to BM, 0 Gy to the body, and [iii] TMI (8:2), 8 Gy to BM & 2 Gy to the whole body. After 24h of irradiation, SS mice were transplanted with 5 million donor BM cells from HbAA BERK mice expressing normal human hemoglobin A (n=3/group). Thirty days after BMT mice were euthanized, and organs were necropsied for histopathology. Formalin-fixed paraffin-embedded sections of the lung, liver, kidney, spleen, and bone marrow (femur & tibia) were stained with H&E and Prussian blue (iron deposits). Morphologic findings of vascular congestion, inflammatory infiltrate, and iron deposits were scored from '0' for no lesion up to '6' for severe lesions occupying 90-100% of the field (Manci et al., Blood 2006). Tubular brush border thickness was assessed on periodic acid Schiff's (PAS)-hematoxylin-stained kidney sections using a 0-4 grading scale: no changes ='0'; lesion area <25%=1; 25%-50% = 2; >50% = 3 and 100% = 4 (Kasztan et al. J Am Soc Nephrol. 2017). We observed significantly increased vascular congestion in the liver (p=0.003), and spleen (p=0.013), and inflammatory infiltrates in the lungs (p=0.031) of TBI-treated mice compared to TMI (8:2). Total body irradiation has been shown to induce inflammation with granulocyte infiltration into tissues in association with endothelial damage, vascular dilatation, and congestion. Moreover, increase iron content in BM and serum and disrupted iron metabolism is another known sequala of total body irradiation, which contributes to hemosiderin formation in tissues. We found significant increase in iron deposits in TBI (4:4) vs TMI (8:2) in liver (p=0.001), spleen (p=0.014), and kidney (p=0.043). TBI (4:4) led to more renal tubular lesions (p=0.003) marked by a significant loss in the tubular brush border on PAS-stained kidney sections compared to TMI (8:2). Thus, TMI shows lesser damaging effect on vital organs compared to TBI, while TMI (8:2) showed donor chimerism similar to TBI on days 7 and 14 but higher than TMI (4:0) treated mice. However, the engraftment failed (less than 10% chimerism) in all groups by day 30. To improve engraftment, we transplanted 10- and 25-million donor HbAA BERK BM cells into TMI (4:0) and TMI (8:2) treated sickle mice. TMI (8:2) showed sustained donor chimerism but TMI (4:0) did not. Histopathological analysis 90 days post-BMT showed that TMI (8:2) treatment (n=3) results in significantly lesser organ pathology Vs untreated sickle mice (n=2), as evinced by reduction in: vascular congestion (lung, p=0.014; liver, p=0.014; spleen p= 0.014), inflammatory infiltrate (lung, p= 0.031; liver p= 0.005), liver infarctions (p=0.003) and liver and kidney iron deposits (p=0.041 & 0.021, respectively). Untreated mice showed a significant loss in the tubular brush border compared to TMI (8:2) treatment (p=0.008). BM in TMI (8:2) (cellularity~70%) showed improvement in cellular differentiation and topography in comparison to the untreated (cellularity ~90% ) that were packed with minimal fat spaces, thin trabeculae, and marked erythroid hyperplasia. These data suggest recovery from sickle cell phenotype with TMI-8:2 without significant organ pathology. Additionally, toluidine blue stained skin sections showed that the number (~45 Vs ~15) and % degranulating mast cells (~85 % Vs 50 %) were significantly lower in TMI (8:2) Vs untreated sickle mice (p<0.05), suggesting that TMI (8:2) treatment and successful engraftment of healthy donor cells may reduce inflammation and pain phenotype. We show that dose escalated TMI (8:2) is well tolerated with reduced organ pathology. Therefore, TMI has the potential to improve BMT-related outcomes without an adverse effect on organ damage.

Pathologically high intraocular pressure disturbs normal iron homeostasis and leads to retinal ganglion cell ferroptosis in glaucoma

Glaucoma can result in retinal ganglion cell (RGC) death and permanently damaged vision. Pathologically high intraocular pressure (ph-IOP) is the leading cause of damaged vision during glaucoma; however, controlling ph-IOP alone does not entirely prevent the loss of glaucomatous RGCs, and the underlying mechanism remains elusive. In this study, we reported an increase in ferric iron in patients with acute primary angle-closure glaucoma (the most typical glaucoma with ph-IOP damage) compared with the average population by analyzing free iron levels in peripheral serum. Thus, iron metabolism might be involved in regulating the injury of RGCs under ph-IOP. In vitro and in vivo studies confirmed that ph-IOP led to abnormal accumulation of ferrous iron in cells and retinas at 1–8 h post-injury and elevation of ferric iron in serum at 8 h post-injury. Nuclear receptor coactivator 4 (NCOA4)-mediated degradation of ferritin heavy polypeptide 1(FTH1) is essential to disrupt iron metabolism in the retina after ph-IOP injury. Furthermore, knockdown of Ncoa4 in vivo inhibited FTH1 degradation and reduced the retinal ferrous iron level. Elevated ferrous iron induced by ph-IOP led to a marked accumulation of pro-ferroptotic factors (lipid peroxidation and acyl CoA synthetase long-chain family member 4) and a depletion of anti-ferroptotic factors (glutathione, glutathione peroxidase 4, and nicotinamide adenine dinucleotide phosphate). These biochemical changes resulted in RGC ferroptosis. Deferiprone can pass through the blood-retinal barrier after oral administration and chelated abnormally elevated ferrous iron in the retina after ph-IOP injury, thus inhibiting RGC ferroptosis and protecting visual function. In conclusion, this study revealed the role of NCOA4-FTH1-mediated disturbance of iron metabolism and ferroptosis in RGCs during glaucoma. We demonstrate the protective effect of Deferiprone on RGCs via inhibition of ferroptosis, providing a research direction to understand and treat glaucoma via the iron homeostasis and ferroptosis pathways.

Ferroptosis in sepsis: The mechanism, the role and the therapeutic potential

Sepsis is a common critical illness in the Intensive care unit(ICU) and its management and treatment has always been a major challenge in critical care medicine. The dysregulated host response to infection, causing systemic multi-organ and multi-system damage is the main pathogenesis. Notably, intense stress during sepsis can lead to metabolic disturbances of ions, lipids and energy in the organism. Ferroptosis is an iron-dependent, non-apoptotic cell death distinguished by a disruption of iron metabolism and iron-dependent accumulation of lipid peroxides. Mounting researches have established that ferroptosis has an essential part in anti-inflammatory and sepsis, and drugs targeting ferroptosis-related molecules, such as ferroptosis inhibitors, are gradually proving their effectiveness in sepsis. This paper summarizes and reviews the pathogenesis of ferroptosis, its regulatory network, and its vital involvement in the initiation of sepsis and related organ damage, and finally discusses the possible target drugs provided by the above mechanisms, describes the dilemmas as well as the outlook, in the hope of finding more links between ferroptosis and sepsis and providing new perspectives for the future treatment of sepsis.

Iron Overload and Breast Cancer: Iron Chelation as a Potential Therapeutic Approach.

Breast cancer has historically been one of the leading causes of death for women worldwide. As of 2020, breast cancer was reported to have overtaken lung cancer as the most common type of cancer globally, representing an estimated 11.3% of all cancer diagnoses. A multidisciplinary approach is taken for the diagnosis and treatment of breast cancer that includes conventional and targeted treatments. However, current therapeutic approaches to treating breast cancer have limitations, necessitating the search for new treatment options. Cancer cells require adequate iron for their continuous and rapid proliferation. Excess iron saturates the iron-binding capacity of transferrin, resulting in non-transferrin-bound iron (NTBI) that can catalyze free-radical reactions and may lead to oxidant-mediated breast carcinogenesis. Moreover, excess iron and the disruption of iron metabolism by local estrogen in the breast leads to the generation of reactive oxygen species (ROS). Therefore, iron concentration reduction using an iron chelator can be a novel therapeutic strategy for countering breast cancer development and progression. This review focuses on the use of iron chelators to deplete iron levels in tumor cells, specifically in the breast, thereby preventing the generation of free radicals. The inhibition of DNA synthesis and promotion of cancer cell apoptosis are the targets of breast cancer treatment, which can be achieved by restricting the iron environment in the body. We hypothesize that the usage of iron chelators has the therapeutic potential to control intracellular iron levels and inhibit the breast tumor growth. In clinical settings, iron chelators can be used to reduce cancer cell growth and thus reduce the morbidity and mortality in breast cancer patients.

HO-1 Contributes to Luteolin-Triggered Ferroptosis in Clear Cell Renal Cell Carcinoma via Increasing the Labile Iron Pool and Promoting Lipid Peroxidation.

Ferroptosis, a novel form of regulated cell death characterized by disrupted iron metabolism and the accumulation of lipid peroxides, has exhibited enormous potential in the therapy of cancer particularly clear cell renal cell carcinoma (ccRCC). Luteolin (Lut), a natural flavonoid widely existing in various fruits and vegetables, has been proven to exert potent anticancer activity in vitro and in vivo. However, previous studies on the anticancer mechanism of Lut have been shown in apoptosis but not ferroptosis. In the present study, we identified that Lut substantially inhibited the survival of ccRCC in vitro and in vivo, and this phenomenon was accompanied by excessively increased intracellular Fe2+ and abnormal depletion of GSH. In addition, Lut induced the imbalance of mitochondrial membrane potential, classical morphological alterations of mitochondrial ferroptosis, generation of ROS, and occurrence of lipid peroxidation in an iron-dependent manner in ccRCC cells. However, these alterations induced by Lut could be reversed to some extent by the iron ion chelator deferiprone or the ferroptosis inhibitor ferrostatin-1, indicating that ccRCC cells treated with Lut underwent ferroptosis. Mechanistically, molecular docking further established that Lut probably promoted the heme degradation and accumulation of labile iron pool (LIP) by excessively upregulating the HO-1 expression, which led to the Fenton reaction, GSH depletion, and lipid peroxidation in ccRCC, whereas blocking this signaling pathway evidently rescued the Lut-induced cell death of ccRCC by inhibiting ferroptosis. Altogether, the current study shows that the natural compound monomer Lut exerted anticancer efficacy by excessively upregulating HO-1 expression and activating LIP to trigger ferroptosis in ccRCC and could be a promising and potent drug candidate for ccRCC treatment.

Selenotranscriptome Network in Non-alcoholic Fatty Liver Disease.

Observational studies indicate that selenium may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Transcriptomic exploration of the aetiology and progression of NAFLD may offer insight into the role selenium plays in this disease. This study compared gene expression levels of known selenoprotein pathways between individuals with a healthy liver to those with NAFLD. Publicly available gene expression databases were searched for studies that measured global gene expression in liver samples from patients with steatosis and non-alcoholic steatohepatitis (NASH) and healthy controls (with [HOC] or without [HC] obesity). A subset of five selenoprotein-related pathways (164 genes) were assessed in the four datasets included in this analysis. The gene TXNRD3 was less expressed in both disease groups when compared with HOC. SCLY and SELENOO were less expressed in NASH when compared with HC. SELENOM, DIO1, GPX2, and GPX3 were highly expressed in NASH when compared to HOC. Disease groups had lower expression of iron-associated transporters and higher expression of ferritin-encoding sub-units, consistent with dysregulation of iron metabolism often observed in NAFLD. Our bioinformatics analysis suggests that the NAFLD liver may have lower selenium levels than a disease-free liver, which may be associated with a disrupted iron metabolism. Our findings indicate that gene expression variation may be associated with the progressive risk of NAFLD.

Lipophilic Ga Complex with Broad-Spectrum Antimicrobial Activity and the Ability to Overcome Gallium Resistance in both Pseudomonas aeruginosa and Staphylococcus aureus.

Antibiotic resistance (AR) necessitates the discovery of new antimicrobials with alternative mechanisms of action to those employed by conventional antibiotics. One such strategy utilizes Ga3+ to target iron metabolism, a critical process for survival. Still, Ga-based therapies are generally ineffective against Gram-positive bacteria and promote Ga resistance. In response to these drawbacks, we report a lipophilic Ga complex, [Ga2L3(bpy)2] (L = 2,2'-bis(3-hydroxy-1,4-naphthoquinone; bpy = 2,2'-bipyridine)), effective against drug-resistant Pseudomonas aeruginosa (DRPA; minimum inhibitory concentration, MIC = 10 μM = 14.8 μg/mL) and methicillin-resistant Staphylococcus aureus (MRSA, MIC = 100 μM = 148 μg/mL) without iron-limited conditions. Importantly, [Ga2L3(bpy)2] shows noticeably delayed and decreased resistance in both MRSA and DRPA, with only 8× MIC in DRPA and none in MRSA after 30 passages. This is likely due to the dual mode of action afforded by Ga (disruption of iron metabolism) and the ligand (reactive oxygen species production). Overall, [Ga2L3(bpy)2] demonstrates the utility of lipophilic metal complexes with multiple modes of action in combatting AR in Gram-positive and Gram-negative bacteria.

Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways

Disruption of iron metabolism is closely related to metabolic diseases. Iron deficiency is frequently associated with obesity and hepatic steatosis. However, the effects of iron supplementation on obesity and energy metabolism remain unclear. Here we show that a high-fat diet supplemented with iron reduces body weight gain and hepatic lipid accumulation in mice. Iron supplementation was found to reduce mitochondrial morphological abnormalities and upregulate gene transcription involved in mitochondrial function and beta oxidation in the liver and skeletal muscle. In both these tissues, iron supplementation increased the expression of genes involved in heme or iron–sulfur (Fe–S) cluster synthesis. Heme and Fe–S cluster, which are iron prosthetic groups contained in electron transport chain complex subunits, are essential for mitochondrial respiration. The findings of this study demonstrated that iron regulates mitochondrial signaling pathways—gene transcription of mitochondrial component molecules synthesis and their energy metabolism. Overall, the study elucidates the molecular basis underlying the relationship between iron supplementation and obesity and hepatic steatosis progression, and the role of iron as a signaling molecule.

Disrupted Iron Metabolism and Mortality during Co-infection with Malaria and an Intestinal Gram-Negative Extracellular Pathogen

SummaryIndividuals with malaria exhibit increased morbidity and mortality when infected with Gram-negative (Gr−) bacteria. To explore this experimentally, we performed co-infection of mice with Plasmodium chabaudi and Citrobacter rodentium, an extracellular Gr− bacterial pathogen that infects the large intestine. While single infections are controlled effectively, co-infection results in enhanced virulence that is characterized by prolonged systemic bacterial persistence and high mortality. Mortality in co-infected mice is associated with disrupted iron metabolism, elevated levels of plasma heme, and increased mitochondrial reactive oxygen species (ROS) production by phagocytes. In addition, iron acquisition by the bacterium plays a key role in pathogenesis because co-infection with a mutant C. rodentium strain lacking a critical iron acquisition pathway does not cause mortality. These results indicate that disrupted iron metabolism may drive mortality during co-infection with C. rodentium and P. chabaudi by both altering host immune responses and facilitating bacterial persistence.

C-reactive Protein and Hepcidin in Non-Dialysis Chronic Kidney Disease

Complications such as anemia and its clinical consequences arise as chronic kidney diseases progress,. One renal anemia pathophysiology is a disruption of iron metabolism, regulated by the main iron exporter hormone, hepcidin. Chronic kidney disease patients were constantly in an inflammatory state, represented by an increased in C-reactive protein. This inflammatory state would facilitate the liver to secrete hepcidin, which would subsequently follow a decrease of iron circulation, thus resulting in functional iron deficiency. Both acute phase reactants which used thoroughly as markers in tropical and infectious diseases, had their own roles in chronic kidney disease. The correlation of c-reactive protein and hepcidin in chronic kidney disease patients was still controversial. To analyse the relationship between c-reactive protein and hepcidin in non-dialysis chronic kidney disease patients. We conducted an observational cross-sectional study with 40 non-dialysis chronic kidney disease patients who met the inclusion and exclusion criteria. Patients were enrolled with consecutive sampling and were examined for serum c-reactive protein and hepcidin levels.A total of forty subjects (67.5% male with mean age of 50.23 ± 1.04 years) were eligible for enrolment in this study. The most comorbid factor was hypertension (62.5%). The common stage for chronic kidney disease was stage 3 (40%). The mean hemoglobin value was 10.74 ± 0.36 g/dL, mean blood urea nitrogen was 39.98 ± 29.59 mg/dL, and serum creatinine of 4.12 ± 3.39 mg/dL. Mean serum c-reactive protein levels were 3.52 ± 5.13 mg/l. Mean hepcidin level were 94,03 ± 95,39 ng/ml. Serum C-reactive protein levels correlated positively (r=0.487) and significantly (p-value=0.001) with serum hepcidin value. C-reactive protein and hepcidin was significantly correlated in non-dialysis chronic kidney disease patients.

A high-fructose diet in rats induces systemic iron deficiency and hepatic iron overload by an inflammation mechanism.

Nonalcoholic fatty liver disease (NAFLD) correlates with the high intake of fructose-rich soft drinks. Both inflammation and dysregulated iron metabolism are pathogenic factors in the development of NAFLD. The present investigation assessed the effects of a high-fructose diet (HF diet) on inflammation and iron metabolism. In this study, rats were fed a control or HF diet for 4, 8, or 12weeks, after which insulin resistance, transaminases levels, serum and liver lipid profiles, inflammatory factors, and iron metabolism-related molecules were evaluated. The activities of the hepatic inflammation-associated pathways, IKKβ/NF-κB, and JAK2/STAT3, were detected by western blot. Result showed that the HF diet-fed animals developed a time-dependent serum lipid increase and hepatic lipid accumulation as well as insulin resistance. Serum iron (SI), serum ferritin (SF), and transferrin saturation (TS) decreased while total iron-binding capacity (TIBC) and serum transferrin (s-TF) increased at 8 and 12weeks in the HF diet group. The HF diet led to increased transaminases levels at 8 and 12weeks, and iron deposition was observed in the liver, accompanied by an upregulation of ferritin light chain (FTL), hepcidin (HEPC), transferrin (TF), transferrin receptor 1 (TfR1), iron regulatory protein 1 (IRP1), hemojuvelin (HJV), and divalent metal transporter 1 (DMT1). Moreover, ferroportin (FPN1) levels were downregulated, as expected from the increased HEPC. A progressive inflammation phenotype was apparent, with increased inflammatory factors, MDA, IL-1β, IL-6, and TNF-α, in the serum and liver tissue. Concomitantly, the hepatic IKKβ/NF-κB and JAK2/STAT3 pathways were activated. In summary, we verified that HF diet induces systemic iron deficiency and hepatic iron accumulation, likely due to the activation of inflammation via the NF-κB and JAK2/STAT3 pathways. PRACTICAL APPLICATIONS: As increasing numbers of individuals consume HF diets, the health implications of this type of over nutrition become globally relevant. Using a high-fructose diet rat model, our present study reveals inflammation as the link between a HF diet and dysregulated iron metabolism. Importantly, both inflammation and disrupted iron metabolism have been shown to be pathogenic factors in nonalcoholic fatty liver disease (NAFLD). The iron regulatory hormone, HEPC, is a link between the liver, inflammation, and iron metabolism. As fructose-rich foods become increasingly abundant and people's fructose intake increases, the impact of high fructose on health requires increased attention. Little research has been conducted on the effects of fructose on iron metabolism. Our study provides useful insights into the prevention and treatment of iron metabolism disorders arising from metabolic syndrome.

Correlation between blood lead level and anemia in hemodialysis patients

Introduction: Studies show that blood lead level (BLL) is higher in hemodialysis patients than in healthy people. Lead can disrupt iron metabolism and hemoglobin synthesis and therefore it is regarded as a cause of anemia. Objectives: This study investigated the relationship between BLL and anemia in end-stage renal disease (ESRD) undergoing maintenance hemodialysis Patients and Methods: This case-control study was conducted on 70 patients who had received hemodialysis at least for three months. The participants were selected randomly among eligible patients considering the inclusion and exclusion criteria. Based on their hemoglobin levels, the participants were divided into two groups, namely patients with anemia (case) and those without anemia (control). Results: The mean age of the participants in the case and control groups were 63.8±11.02 and 55.4±13.34 years, respectively. There were significant differences between two groups regarding hemoglobin, C-reactive protein (CRP) and erythropoietin (EPo) levels (P &lt; 0.05). There was a significant correlation between hemoglobin and ferritin levels in the case group and between the length of dialysis and serum iron level in the control group without anemia (P &lt; 0.001). Conclusion: Our results showed no correlation between BLL and anemia, however the BLL was higher in those undergoing long-term maintenance hemodialysis. Our findings require further investigation with larger studies.

BCc1 Nanomedicine Therapeutic Effects in Streptozotocin and High-Fat Diet Induced Diabetic Kidney Disease.

BackgroundOne common feature of chronic diseases, such as cancer, diabetes and chronic kidney disease (CKD), is the disruption of iron metabolism and increase in labile iron pool, which can result in excessive production of harmful oxidative stress. The proper management of iron metabolism in this situation can be a valuable tool to ameliorate pathological events.Materials and MethodsIn the previous studies, the anti-neoplastic effects of BCc1, a nanochelating-based nanomedicine with iron-chelating property, were demonstrated in cell culture, animal models and clinical trials. In the present study, the therapeutic effects of BCc1 in animal model of diabetic kidney disease (DKD), induced by streptozotocin injection (35 mg/kg) and high-fat diet consumption, were evaluated.ResultsThe results showed that BCc1 significantly decreased HOMA-IR index, uric acid, blood urea nitrogen, malondialdehyde and 8-isoprostane. In addition, it reduced urinary albumin excretion rate and albumin-to-creatinine ratio in comparison to DKD control rats. This nanomedicine had no negative impact on liver iron content, hemoglobin level, red blood cell count, hematocrit and mean corpuscular volume, while it significantly decreased aspartate aminotransferase and alanine aminotransferase compared to DKD control group. Moreover, the histopathological assessment indicated that lesser glomerular basement membrane and wrinkling, mesangial matrix expansion and pathological changes in proximal cortical tubules were seen in the kidney samples of BCc1-treated rats.ConclusionIn conclusion, BCc1 as an iron-chelating agent shows promising impacts in DKD animal model, which can ameliorate biochemical and pathological events of this disease.

Potential of Gallium as an Antifungal Agent.

There are only few drugs available to treat fungal infections, and the lack of new antifungals, along with the emergence of drug-resistant strains, results in millions of deaths/year. An unconventional approach to fight microbial infection is to exploit nutritional vulnerabilities of microorganism metabolism. The metal gallium can disrupt iron metabolism in bacteria and cancer cells, but it has not been tested against fungal pathogens such as Aspergillus and Candida. Here, we investigate in vitro activity of gallium nitrate III [Ga(NO3)3] against these human pathogens, to reveal the gallium mechanism of action and understand the interaction between gallium and clinical antifungal drugs. Ga(NO3)3 presented a fungistatic effect against azole-sensitive and -resistant A. fumigatus strains (MIC50/90 = 32.0 mg/L) and also had a synergistic effect with caspofungin, but not with azoles and amphotericin B. Its antifungal activity seems to be reliant on iron-limiting conditions, as the presence of iron increases its MIC value and because we observed a synergistic interaction between gallium and iron chelators against A. fumigatus. We also show that an A. fumigatus mutant (ΔhapX) unable to grow in the absence of iron is more susceptible to gallium, reinforcing that gallium could act by disrupting iron homeostasis. Furthermore, we demonstrate that gallium has a fungistatic effect against different species of Candida ranging from 16.0 to 256.0 mg/L, including multidrug-resistant Candida auris, C. haemulonii, C. duobushaemulonii, and C. glabrata. Our findings indicate that gallium can inhibit fungal pathogens in vitro under iron-limiting conditions, showing that Ga(NO3)3 could be a potential therapy not only against bacteria but also as an antifungal drug.