Iron Proteins, Transferrins and Iron Transport

AbstractOral iron promotes intestinal tumourigenesis in animal models. In humans, expression of iron transport proteins are altered in colorectal cancer. This study examined whether the route of iron therapy alters iron transport and tumour growth. Colorectal adenocarcinoma patients with pre-operative iron deficiency anaemia received oral ferrous sulphate (n = 15), or intravenous ferric carboxymaltose (n = 15). Paired (normal and tumour tissues) samples were compared for expression of iron loading, iron transporters, proliferation, apoptosis and Wnt signalling using immunohistochemistry and RT-PCR. Iron loading was increased in tumour and distributed to the stroma in intravenous treatment and to the epithelium in oral treatment. Protein and mRNA expression of proliferation and iron transporters were increased in tumours compared to normal tissues but there were no significant differences between the treatment groups. However, intravenous iron treatment reduced ferritin mRNA levels in tumours and replenished body iron stores. Iron distribution to non-epithelial cells in intravenous iron suggests that iron is less bioavailable to tumour cells. Therefore, intravenous iron may be a better option in the treatment of colorectal cancer patients with iron deficiency anaemia due to its efficiency in replenishing iron levels while its effect on proliferation and iron metabolism is similar to that of oral iron treatment.

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1455. Potential Mechanisms of Cefiderocol MIC Increase in Enterobacterales in In Vitro Resistance Acquisition Studies

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1636 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S730-S730

Author(s):

Yoshinori Yamano ◽

Rio Nakamura ◽

Miki Takemura ◽

Roger Echols

Keyword(s):

Iron Transport ◽

Resistance Mechanisms ◽

Altered Expression ◽

Carbapenem Resistant ◽

Mueller Hinton ◽

Two Component ◽

Mueller Hinton Agar ◽

Related Proteins

Abstract Background Cefiderocol (CFDC) is a novel siderophore, iron-chelating cephalosporin, which is transported into bacteria via iron transporters. CFDC has potent in vitro and in vivo activity against all aerobic Gram-negative bacteria, including carbapenem-resistant strains. To date, clinical isolates with cefiderocol MIC >4 µg/mL have been found infrequently, in which the presence of a few β-lactamases or altered iron transport was found. We investigated potential new mechanisms causing CFDC MIC increases in non-clinical studies. Methods The mutation positions were determined by whole genome sequencing using four K. pneumoniae mutants including two KPC producers and one NDM producer that had shown CFDC MIC increases in previous in vitro resistance-acquisition studies. The mutant strains were obtained at the frequency of 10-7 to < 10-8 by spreading bacteria on standard Mueller‒Hinton agar medium containing CFDC at concentrations of 10× MIC, with or without apo-transferrin (20 μg/mL). CFDC MIC was determined by broth microdilution using iron-depleted cation-adjusted Mueller-Hinton broth based on Clinical and Laboratory Standards Institute guidelines. The emergence of MIC increase mutants was also assessed by in vitro chemostat models under humanized plasma pharmacokinetic exposures of CFDC. Results The possible resistance mechanisms were investigated. Mutation of baeS or envZ, sensors of two-component regulation systems, were found in three or two mutants among the tested four isolates, respectively, and caused the MIC to increase by 4–32-fold. The altered expression level of specific genes by the baeS or envZ mutation could affect CFDC susceptibility, but the specific genes have not been identified. In addition, the mutation of exbD, an accessory protein related to iron transport, was identified in one case and caused the MIC to increase by >8-fold. In vitro chemostat studies using two isolates (one NDM producer and one KPC producer) showed no resistance acquisition during 24-hour exposure. Table. Overview of mutation emergence in five isolates of K. pneumoniae Conclusion The mutation of two-component regulation systems (BaeSR and OmpR/EnvZ) and iron transport-related proteins were shown to be possible mechanisms causing CFDC MIC increases, but these mutants did not appear under human exposures. Disclosures Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi & Co., Ltd. (Employee) Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant)

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Effect of iron deficiency on placental transfer of iron and expression of iron transport proteins in vivo and in vitro

Biochemical Journal ◽

10.1042/bj3560883 ◽

2001 ◽

Vol 356 (3) ◽

pp. 883-889 ◽

Cited By ~ 68

Author(s):

Lorraine GAMBLING ◽

Ruth DANZEISEN ◽

Susan GAIR ◽

Richard G. LEA ◽

Zehane CHARANIA ◽

...

Keyword(s):

Iron Deficiency ◽

Transferrin Receptor ◽

Iron Transport ◽

Receptor Expression ◽

Mrna Levels ◽

Iron Transfer ◽

Metal Transporter ◽

Protein Levels ◽

Copper Oxidase ◽

Maternal Iron

Maternal iron deficiency during pregnancy induces anaemia in the developing fetus; however, the severity tends to be less than in the mother. The mechanism underlying this resistance has not been determined. We have measured placental expression of proteins involved in iron transfer in pregnant rats given diets with decreasing levels of iron and examined the effect of iron deficiency on iron transfer across BeWo cell layers, a model for placental iron transfer. Transferrin receptor expression was increased at both mRNA and protein levels. Similarly, expression of the iron-responsive element (IRE)-regulated form of the divalent metal transporter 1 (DMT1) was also increased. In contrast, the non-IRE regulated isoform showed no change in mRNA levels. Protein levels of DMT1 increased significantly. Iron efflux is thought to be mediated by the metal transporter protein, IREG1/ferroportin1/MTP1, and oxidation of Fe(II) to Fe(III) prior to incorporation into fetal transferrin is carried out by the placental copper oxidase. Expression of IREG1 was not altered by iron deficiency, whereas copper oxidase activity was increased. In BeWo cells made iron deficient by treatment with desferrioxamine (‘deferioxamine’), iron accumulation from iron-transferrin increased, in parallel with increased expression of the transferrin receptor. At the same time, iron efflux also increased, showing a higher flux of iron from the apical to the basolateral side. The data show that expression of placental proteins of iron transport are up-regulated in maternal iron deficiency, resulting in an increased efficiency of iron flux and a consequent minimization of the severity of fetal anaemia.

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Chimeric Protein IPath® with Chelating Activity Improves Atlantic Salmon’s Immunity against Infectious Diseases

Vaccines ◽

10.3390/vaccines9040361 ◽

2021 ◽

Vol 9 (4) ◽

pp. 361

Author(s):

Valentina Valenzuela-Muñoz ◽

Bárbara P. Benavente ◽

Antonio Casuso ◽

Yeny Leal ◽

Cristian Gallardo-Escárate

Keyword(s):

Immune Response ◽

Atlantic Salmon ◽

Iron Metabolism ◽

Iron Transport ◽

Aeromonas Salmonicida ◽

Transcriptional Analysis ◽

Control Fish ◽

Control Group ◽

Commercial Fish ◽

Chelating Activity

Infection processes displayed by pathogens require the acquisition of essential inorganic nutrients and trace elements from the host to survive and proliferate. Without a doubt, iron is a crucial trace metal for all living organisms and also a pivotal component in the host–parasite interactions. In particular, the host reduces the iron available to face the infectious disease, increasing iron transport proteins’ expression and activating the heme synthesis and degradation pathways. Moreover, recent findings have suggested that iron metabolism modulation in fish promotes the immune response by reducing cellular iron toxicity. We hypothesized that recombinant proteins related to iron metabolism could modulate the fish’s immune system through iron metabolism and iron-responsive genes. Here a chimeric iron transport protein (IPath®) was bioinformatically designed and then expressed in a recombinant bacterial system. The IPath® protein showed a significant chelating activity under in vitro conditions and biological activity. Taking this evidence, a vaccine candidate based on IPath® was evaluated in Atlantic salmon challenged with three different fish pathogens. Experimental trials were conducted using two fish groups: one immunized with IPath® and another injected with adjutant as the control group. After 400 accumulated thermal units (ATUs), two different infection trials were performed. In the first one, fish were infected with the bacterium Aeromonas salmonicida, and in a second trial, fish were exposed to the ectoparasite Caligus rogercresseyi and subsequently infected with the intracellular bacterium Piscirickettsia salmonis. Fish immunized with IPath® showed a significant delay in the mortality curve in response to A. salmonicida and P. salmonis infections. However, no significant differences between infected and control fish groups were observed at the end of the experiment. Notably, sea lice burden reduction was observed in vaccinated Atlantic salmon. Transcriptional analysis evidenced a high modulation of iron-homeostasis-related genes in fish vaccinated with IPath® compared to the control group during the infection. Moreover, increasing expression of Atlantic salmon IgT was associated with IPath® immunization. This study provides evidence that the IPath® protein could be used as an antigen or booster in commercial fish vaccines, improving the immune response against relevant pathogens for salmon aquaculture.

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Alteration of Iron Concentration in Alzheimer’s Disease as a Possible Diagnostic Biomarker Unveiling Ferroptosis

International Journal of Molecular Sciences ◽

10.3390/ijms22094479 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4479

Author(s):

Eleonora Ficiarà ◽

Zunaira Munir ◽

Silvia Boschi ◽

Maria Eugenia Caligiuri ◽

Caterina Guiot

Keyword(s):

Iron Transport ◽

Biological Fluids ◽

Iron Status ◽

Iron Concentration ◽

Diagnostic Biomarker ◽

Resonance Imaging ◽

Brain Iron ◽

Indirect Measurements ◽

Brain Iron Metabolism ◽

The Brain

Proper functioning of all organs, including the brain, requires iron. It is present in different forms in biological fluids, and alterations in its distribution can induce oxidative stress and neurodegeneration. However, the clinical parameters normally used for monitoring iron concentration in biological fluids (i.e., serum and cerebrospinal fluid) can hardly detect the quantity of circulating iron, while indirect measurements, e.g., magnetic resonance imaging, require further validation. This review summarizes the mechanisms involved in brain iron metabolism, homeostasis, and iron imbalance caused by alterations detectable by standard and non-standard indicators of iron status. These indicators for iron transport, storage, and metabolism can help to understand which biomarkers can better detect iron imbalances responsible for neurodegenerative diseases.

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Meta-analysis cum machine learning approaches address the structure and biogeochemical potential of marine copepod associated bacteriobiomes

Scientific Reports ◽

10.1038/s41598-021-82482-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Balamurugan Sadaiappan ◽

Chinnamani PrasannaKumar ◽

V. Uthara Nambiar ◽

Mahendran Subramanian ◽

Manguesh U. Gauns

Keyword(s):

Machine Learning ◽

Iron Transport ◽

Meta Analysis ◽

Zooplankton Community ◽

Gradient Boosting ◽

Learning Approaches ◽

16S Rdna Gene ◽

Marine Copepod ◽

Form Of Life ◽

First Time

AbstractCopepods are the dominant members of the zooplankton community and the most abundant form of life. It is imperative to obtain insights into the copepod-associated bacteriobiomes (CAB) in order to identify specific bacterial taxa associated within a copepod, and to understand how they vary between different copepods. Analysing the potential genes within the CAB may reveal their intrinsic role in biogeochemical cycles. For this, machine-learning models and PICRUSt2 analysis were deployed to analyse 16S rDNA gene sequences (approximately 16 million reads) of CAB belonging to five different copepod genera viz., Acartia spp., Calanus spp., Centropages sp., Pleuromamma spp., and Temora spp.. Overall, we predict 50 sub-OTUs (s-OTUs) (gradient boosting classifiers) to be important in five copepod genera. Among these, 15 s-OTUs were predicted to be important in Calanus spp. and 20 s-OTUs as important in Pleuromamma spp.. Four bacterial s-OTUs Acinetobacter johnsonii, Phaeobacter, Vibrio shilonii and Piscirickettsiaceae were identified as important s-OTUs in Calanus spp., and the s-OTUs Marinobacter, Alteromonas, Desulfovibrio, Limnobacter, Sphingomonas, Methyloversatilis, Enhydrobacter and Coriobacteriaceae were predicted as important s-OTUs in Pleuromamma spp., for the first time. Our meta-analysis revealed that the CAB of Pleuromamma spp. had a high proportion of potential genes responsible for methanogenesis and nitrogen fixation, whereas the CAB of Temora spp. had a high proportion of potential genes involved in assimilatory sulphate reduction, and cyanocobalamin synthesis. The CAB of Pleuromamma spp. and Temora spp. have potential genes accountable for iron transport.

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Non-heme Iron Proteins

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)94486-8 ◽

1968 ◽

Vol 243 (23) ◽

pp. 6262-6272 ◽

Cited By ~ 5

Author(s):

J N Tsunoda ◽

K T Yasunobu ◽

H R Whiteley

Keyword(s):

Heme Iron ◽

Iron Proteins ◽

Non Heme Iron

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