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Molecules (Basel, Switzerland) Nov 2023The diagnosis of iron disturbances usually includes the evaluation of serum parameters. Serum iron is assumed to be entirely bound to transferrin, and transferrin... (Review)
Review
The diagnosis of iron disturbances usually includes the evaluation of serum parameters. Serum iron is assumed to be entirely bound to transferrin, and transferrin saturation-the ratio between the serum iron concentration and serum transferrin-usually reflects iron availability. Additionally, serum ferritin is commonly used as a surrogate of tissue iron levels. Low serum ferritin values are interpreted as a sign of iron deficiency, and high values are the main indicator of pathological iron overload. However, in situations of inflammation, serum ferritin levels may be very high, independently of tissue iron levels. This presents a particularly puzzling challenge for the clinician evaluating the overall iron status of the patient in the presence of an inflammatory condition. The increase in serum ferritin during inflammation is one of the enigmas regarding iron metabolism. Neither the origin, the mechanism of release, nor the effects of serum ferritin are known. The use of serum ferritin as a biomarker of disease has been rising, and it has become increasingly diverse, but whether or not it contributes to controlling the disease or host pathology, and how it would do it, are important, open questions. These will be discussed here, where we spotlight circulating ferritin and revise the recent clinical and preclinical data regarding its role in health and disease.
Topics: Humans; Ferritins; Iron; Transferrin; Iron Overload; Inflammation
PubMed: 38067440
DOI: 10.3390/molecules28237707 -
Journal of Neurochemistry Oct 2023Copper is an essential enzyme cofactor in oxidative metabolism, anti-oxidant defenses, and neurotransmitter synthesis. However, intracellular copper, when improperly...
Copper is an essential enzyme cofactor in oxidative metabolism, anti-oxidant defenses, and neurotransmitter synthesis. However, intracellular copper, when improperly buffered, can also lead to cell death. Given the growing interest in the use of copper in the presence of the ionophore elesclomol (CuES) for the treatment of gliomas, we investigated the effect of this compound on the surround parenchyma-namely neurons and astrocytes in vitro. Here, we show that astrocytes were highly sensitive to CuES toxicity while neurons were surprisingly resistant, a vulnerability profile that is opposite of what has been described for zinc and other toxins. Bolstering these findings, a human astrocytic cell line was similarly sensitive to CuES. Modifications of cellular metabolic pathways implicated in cuproptosis, a form of copper-regulated cell death, such as inhibition of mitochondrial respiration or knock-down of ferredoxin 1 (FDX1), did not block CuES toxicity to astrocytes. CuES toxicity was also unaffected by inhibitors of apoptosis, necrosis or ferroptosis. However, we did detect the presence of lipid peroxidation products in CuES-treated astrocytes, indicating that oxidative stress is a mediator of CuES-induced glial toxicity. Indeed, treatment with anti-oxidants mitigated CuES-induced cell death in astrocytes indicating that oxidative stress is a mediator of CuES-induced glial toxicity. Lastly, prior induction of metallothioneins 1 and 2 in astrocytes with zinc plus pyrithione was strikingly protective against CuES toxicity. As neurons express high levels of metallothioneins basally, these results may partially account for their resistance to CuES toxicity. These results demonstrate a unique toxic response to copper in glial cells which contrasts with the cell selectivity profile of zinc, another biologically relevant metal.
Topics: Humans; Copper; Ferredoxins; Astrocytes; Oxidative Stress; Antioxidants; Zinc; Neurons; Cells, Cultured
PubMed: 37702109
DOI: 10.1111/jnc.15961 -
Journal of Molecular Cell Biology Apr 2024Nonalcoholic steatohepatitis (NASH) is a condition that progresses from nonalcoholic fatty liver disease (NAFLD) and is characterized by hepatic fat accumulation,...
Nonalcoholic steatohepatitis (NASH) is a condition that progresses from nonalcoholic fatty liver disease (NAFLD) and is characterized by hepatic fat accumulation, inflammation, and fibrosis. It has the potential to develop into cirrhosis and liver cancer, and currently no effective pharmacological treatment is available. In this study, we investigate the therapeutic potential of targeting ceruloplasmin (Cp), a copper-containing protein predominantly secreted by hepatocytes, for treating NASH. Our result show that hepatic Cp is remarkedly upregulated in individuals with NASH and the mouse NASH model. Hepatocyte-specific Cp ablation effectively attenuates the onset of dietary-induced NASH by decreasing lipid accumulation, curbing inflammation, mitigating fibrosis, and ameliorating liver damage. By employing transcriptomics and metabolomics approaches, we have discovered that hepatic deletion of Cp brings about remarkable restoration of bile acid (BA) metabolism during NASH. Hepatic deletion of Cp effectively remodels BA metabolism by upregulating Cyp7a1 and Cyp8b1, which subsequently leads to enhanced BA synthesis and notable alterations in BA profiles. In conclusion, our studies elucidate the crucial involvement of Cp in NASH, highlighting its significance as a promising therapeutic target for the treatment of this disease.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Ceruloplasmin; Liver; Inflammation; Fibrosis; Bile Acids and Salts
PubMed: 37771074
DOI: 10.1093/jmcb/mjad060 -
Free Radical Biology & Medicine Nov 2023Ferroptosis is a regulated form of cell death, the mechanism of which is still to be understood. 15-lipoxygenase (15LOX) complex with phosphatidylethanolamine...
Ferroptosis is a regulated form of cell death, the mechanism of which is still to be understood. 15-lipoxygenase (15LOX) complex with phosphatidylethanolamine (PE)-binding protein 1 (PEBP1) catalyzes the generation of pro-ferroptotic cell death signals, hydroperoxy-polyunsaturated PE. We focused on gaining new insights into the molecular basis of these pro-ferroptotic interactions using computational modeling and liquid chromatography-mass spectrometry experiments. Simulations of 15LOX-1/PEBP1 complex dynamics and interactions with lipids revealed that association with the membrane triggers a conformational change in the complex. This conformational change facilitates the access of stearoyl/arachidonoyl-PE (SAPE) substrates to the catalytic site. Furthermore, the binding of SAPE promotes tight interactions within the complex and induces further conformational changes that facilitate the oxidation reaction. The reaction yields two hydroperoxides as products, 15-HpETE-PE and 12-HpETE-PE, at a ratio of 5:1. A significant effect of PEBP1 is observed only on the predominant product. Moreover, combined experiments and simulations consistently demonstrate the significance of PEBP1 P112E mutation in generating ferroptotic cell death signals.
Topics: Cell Death; Ferroptosis; Oxidation-Reduction; Arachidonate 15-Lipoxygenase; Phosphatidylethanolamine Binding Protein; Phosphatidylethanolamines; Humans; Animals; Swine
PubMed: 37678654
DOI: 10.1016/j.freeradbiomed.2023.09.001 -
Journal of Inorganic Biochemistry Dec 2023The flexibility of mammalian metallothioneins (MTs) has contributed to the difficulty in obtaining structural information for this family of metalloproteins that bind...
The flexibility of mammalian metallothioneins (MTs) has contributed to the difficulty in obtaining structural information for this family of metalloproteins that bind divalent metals with its twenty cysteines. While the two-domain structure for CdMT is well-established as a CdS and CdS, a third structure has been reported when 8 Cd(II) ions bind to MT1. Isoform 3 of the MT family, MT3, has been of interest to the research community since its isolation as a growth inhibitory factor isolated in brain tissue, and has since been noted as a prominent participant in the mediation of neurodegenerative diseases and regular brain development. The differences between MT3 and the other isoforms of MT include an additional hexapeptide insertion of acidic residues in the α domain as well as the introduction of two prolines in the β domain. It is unclear whether these changes impact the metalation properties of MT3. We report the formation of a CdMT3 species is characterized by electrospray ionization mass spectrometry and UV-visible absorption spectroscopy. We report that the spectroscopic properties of this supermetalated CdMT3 are similar to those of the supermetalated CdMT1, with a clear indication of changes in structure from "fully-metalated" CdMT3 to supermetalated CdMT3 from circular dichroism spectra and both 1D Cd and 2D H-Cd HSQC NMR spectra. We conclude that the metalation properties are not impacted significantly due to the amino acid changes in MT3, and that the cysteinyl thiols are the key players in determining the capacity of metal-binding and the structure of metal-thiolate clusters.
Topics: Humans; Animals; Metallothionein 3; Cadmium; Metals; Metallothionein; Circular Dichroism; Mammals
PubMed: 37832463
DOI: 10.1016/j.jinorgbio.2023.112392 -
Free Radical Biology & Medicine Feb 2024Exposure to bisphenol A (BPA) during gestation leads to fetal growth restriction (FGR), whereby the underlying mechanisms remain unknown. Here, we found that FGR...
Exposure to bisphenol A (BPA) during gestation leads to fetal growth restriction (FGR), whereby the underlying mechanisms remain unknown. Here, we found that FGR patients showed higher levels of BPA in the urine, serum, and placenta; meanwhile, trophoblast ferroptosis was observed in FGR placentas, as indicated by accumulated intracellular iron, impaired antioxidant molecules, and increased lipid peroxidation products. To investigate the role of ferroptosis in placental and fetal growth, BPA stimulation was performed both in vivo and in vitro. BPA exposure during gestation was associated with FGR in mice; also, it induces ferroptosis in mouse placentas and human placental trophoblast. Pretreatment with ferroptosis inhibitor ferritin-1 (Fer-1) alleviated BPA-induced oxidative damage and cell death. Notably, BPA reduced the trophoblastic expression of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which regulated tissue growth and organ size. YAP or TAZ siRNA enhanced BPA-induced ferroptosis, suggesting that trophoblast ferroptosis is dependent on YAP/TAZ downregulation after BPA stimulation. Consistently, the protein levels of YAP/TAZ were also reduced in FGR placentas. Further results revealed that silencing YAP/TAZ promoted BPA-induced ferroptosis through autophagy. Pretreatment with autophagy inhibitor chloroquine (CQ) attenuated BPA-induced trophoblast ferroptosis. Ferritinophagy, an autophagic degradation of ferritin (FTH1), was observed in FGR placentas. Similarly, BPA reduced the protein level of FTH1 in placental trophoblast. Pretreatment with iron chelator desferrioxamine (DFO) and NCOA4 (an autophagy cargo receptor) siRNA weakened the ferroptosis of trophoblast after exposure to BPA, indicating that autophagy mediates ferroptosis in BPA-stimulated trophoblast by degrading ferritin. In summary, ferroptosis was featured in BPA-associated FGR and trophoblast injury; the regulation of ferroptosis involved the YAP/TAZ-autophagy-ferritin axis.
Topics: Humans; Pregnancy; Female; Animals; Mice; Placenta; Fetal Growth Retardation; Ferroptosis; Ferritins; RNA, Small Interfering
PubMed: 38103660
DOI: 10.1016/j.freeradbiomed.2023.12.013 -
Frontiers in Endocrinology 2023To explore the correlations between diabetic nephropathy (DN) and serum levels of glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4...
OBJECTIVE
To explore the correlations between diabetic nephropathy (DN) and serum levels of glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), iron, transferrin (Tf), and ferritin in patients with type 2 diabetes mellitus (T2DM).
METHODS
According to the urinary albumin excretion rate(UAER) or estimated glomerular filtration rate (eGFR) levels, a total of 123 patients with T2DM were separately divided into normoalbuminuria (NO), microalbuminuria (MI), macroalbuminuria (MA) groups, and G1 (eGFR ≥ 90 mL/min), G2 (eGFR ≤ 60 mL/min to < 90 mL/min), and G3 groups (eGFR< 60 mL/min), with 33 healthy participants as the control (HC). The differences in serum GPX4, ACSL4, iron, Tf, and ferritin levels between groups were compared, and the relationships between these levels were analysed. The independent correlations between UAER or DN severity and serum GPX4, ACSL4, iron, Tf, and ferritin levels were analysed by multiple linear and multinomial logistic regression, respectively.
RESULTS
To the patients with T2DM, with the increase in UAER levels, GPX4, iron, and Tf levels gradually decreased, whereas ACSL4 levels increased, meanwhile with the decrease in eGFR levels, GPX4 and Tf levels gradually decreased, whereas ACSL4 levels increased. UAER were independently and positively correlated with ACSL4 [β = 17.53, 95% confidence interval (CI; 11.94, 23.13)] and negatively correlated with GPX4 [β = -1.633, 95% CI (-2.77, -0.496)] and Tf [β = -52.94, 95% CI (-95.78, -10.11)].The NO and MI groups were considered as reference groups, respectively. The severity of DN was negatively correlated with serum GPX4 [odds ratio (OR) = 0.925 and 0.902, 0.015 and 0.001], and Tf (OR = 0.109 and 0.119, 0.043 and 0.034), and positively correlated with ACSL4 (OR = 1.952 and 1.865, both 0.001) in the MA group.
CONCLUSION
DN severity was negatively correlated with serum GPX4 and Tf levels and positively correlated with serum ACSL4 levels in patients with T2DM.
Topics: Humans; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Ferroptosis; Diabetic Nephropathies; Iron; Transferrin; Ferritins; Albuminuria
PubMed: 38189040
DOI: 10.3389/fendo.2023.1297166 -
Methods in Enzymology 2024Among the important questions in supramolecular peptide self-assemblies are their interactions with metallic compounds and ions. In the last decade, intensive efforts...
Among the important questions in supramolecular peptide self-assemblies are their interactions with metallic compounds and ions. In the last decade, intensive efforts have been devoted to understanding the structural properties of these interactions including their dynamical and catalytic impact in natural and de novo systems. Since structural insights from experimental approaches could be particularly challenging, computational chemistry methods are interesting complementary tools. Here, we present the general multiscale strategies we developed and applied for the study of metallopeptide assemblies. These strategies include prediction of metal binding site, docking of metallic moieties, classical and accelerated molecular dynamics and finally QM/MM calculations. The systems of choice for this chapter are, on one side, peptides involved in neurodegenerative diseases and, on the other, de novo fibrillar systems with catalytic properties. Both successes and remaining challenges are highlighted so that the protocol could be apply to other system of this kind.
Topics: Molecular Dynamics Simulation; Peptides; Metalloproteins; Binding Sites; Humans; Molecular Docking Simulation; Metals; Quantum Theory
PubMed: 38816124
DOI: 10.1016/bs.mie.2024.03.021 -
Journal of Trace Elements in Medicine... Jul 2023Evidence on the link between iron metabolism markers and endometriosis is limited. We aimed to investigate the associations of iron metabolism markers, including serum...
BACKGROUND
Evidence on the link between iron metabolism markers and endometriosis is limited. We aimed to investigate the associations of iron metabolism markers, including serum ferritin level and transferrin saturation, with endometriosis.
METHODS
This study involved 6551 participants from the National Health and Nutrition Examination Survey (NHANES). Univariable and multivariable logistic regression analyses were used to examine the linear relationships between iron metabolism markers and endometriosis. Furthermore, restricted cubic splines were used to identify the non-linear dose-response associations.
RESULTS
Univariable analysis showed that the factors associated with endometriosis included age, race, education level, and smoking status. In multivariable model, compared with lowest quartile, highest quartile of serum ferritin level was positively associated with endometriosis (OR: 2.11, 95% confidence intervals [CI]: 1.31, 3.40, P = 0.004), and third quartile of transferrin saturation positively associated with endometriosis (OR: 1.55, 95% CI: 1.05, 2.29, P = 0.033). The restricted cubic splines showed the non-linear (inverted U-shape) associations between serum ferritin level and transferrin saturation and endometriosis (all P for non-linear<0.01), indicating that the ORs of endometriosis increased with serum ferritin level and transferrin saturation up to the turning point and thereafter the ORs of endometriosis did not significantly increase with the increasing serum ferritin and transferrin saturation.
CONCLUSIONS
Our findings suggests that serum ferritin level and transferrin saturation were positively associated with endometriosis. Serum ferritin and transferrin saturation may be an important marker for endometriosis. Future prospective and longitudinal studies are necessary to better understand these findings.
Topics: Female; Humans; Ferritins; Transferrin; Cross-Sectional Studies; Nutrition Surveys; Endometriosis; Biomarkers; Iron; Life Style; Socioeconomic Factors
PubMed: 37075566
DOI: 10.1016/j.jtemb.2023.127175 -
Journal of Inorganic Biochemistry Sep 2023Heme proteins perform diverse biochemical functions using a single iron porphyrin cofactor. This versatility makes them attractive platforms for the development of new... (Review)
Review
Heme proteins perform diverse biochemical functions using a single iron porphyrin cofactor. This versatility makes them attractive platforms for the development of new functional proteins. While directed evolution and metal substitution have expanded the properties, reactivity, and applications of heme proteins, the incorporation of porphyrin analogs remains an underexplored approach. This review discusses the replacement of heme with non-porphyrin cofactors, such as porphycene, corrole, tetradehydrocorrin, phthalocyanine, and salophen, and the attendant properties of these conjugates. While structurally similar, each ligand exhibits distinct optical and redox properties, as well as unique chemical reactivity. These hybrids serve as model systems to elucidate the effects of the protein environment on the electronic structure, redox potentials, optical properties, or other features of the porphyrin analog. Protein encapsulation can confer distinct chemical reactivity or selectivity of artificial metalloenzymes that cannot be achieved with the small molecule catalyst alone. Additionally, these conjugates can interfere with heme acquisition and uptake in pathogenic bacteria, providing an inroad to innovative antibiotic strategies. Together, these examples illustrate the diverse functionality that can be achieved by cofactor substitution. The further expansion of this approach will access unexplored chemical space, enabling the development of superior catalysts and the creation of heme proteins with emergent properties.
Topics: Hemeproteins; Metalloproteins; Heme; Oxidation-Reduction; Metals
PubMed: 37320889
DOI: 10.1016/j.jinorgbio.2023.112282