A Review on Lactoferrin and Central Nervous System Diseases

Li, Yu-Qi; Guo, Chuangxin

doi:10.3390/cells10071810

Cited by 52 publications

(33 citation statements)

References 166 publications

(260 reference statements)

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“…Indeed, we cannot exclude the effect of hepcidin on FP, but since there is no complete internalisation, the hepcidin may act in an internalisation-independent way, by inhibiting iron release via the iron exporter contributing iron retention of the cells [ 68 , 69 ]. Moreover, the mRNA level of LF, a multipurpose glycoprotein, significantly decreased suggesting the deterioration of iron transport between neurons and glial cells, as well as the decreasing rate of ROS scavenging [ 70 ]. Normally, the TfR1 protein level should be downregulated by IRP by binding to the IRE element on the 3’end of the mRNA, upon intracellular iron accumulation but there are several reasons for the deregulation of iron metabolism.…”

Section: Discussionmentioning

confidence: 99%

Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model

Pandur

Szabó

Hormay

et al. 2022

Diabetol Metab Syndr

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Background The hypothalamus of the central nervous system is implicated in the development of diabetes due to its glucose-sensing function. Dysregulation of the hypothalamic glucose-sensing neurons leads to abnormal glucose metabolism. It has been described that fractalkine (FKN) is involved in the development of hypothalamic inflammation, which may be one of the underlying causes of a diabetic condition. Moreover, iron may play a role in the pathogenesis of diabetes via the regulation of hepcidin, the iron regulatory hormone synthesis. MicroRNAs (miRNAs) are short non-coding molecules working as key regulators of gene expression, usually by inhibiting translation. Hypothalamic miRNAs are supposed to have a role in the control of energy balance by acting as regulators of hypothalamic glucose metabolism via influencing translation. Methods Using a miRNA array, we analysed the expression of diabetes, inflammation, and iron metabolism related miRNAs in the hypothalamus of a streptozotocin-induced rat type 1 diabetes model. Determination of the effect of miRNAs altered by STZ treatment on the target genes was carried out at protein level. Results We found 18 miRNAs with altered expression levels in the hypothalamus of the STZ-treated animals, which act as the regulators of mRNAs involved in glucose metabolism, pro-inflammatory cytokine synthesis, and iron homeostasis suggesting a link between these processes in diabetes. The alterations in the expression level of these miRNAs could modify hypothalamic glucose sensing, tolerance, uptake, and phosphorylation by affecting the stability of hexokinase-2, insulin receptor, leptin receptor, glucokinase, GLUT4, insulin-like growth factor receptor 1, and phosphoenolpyruvate carboxykinase mRNA molecules. Additional miRNAs were found to be altered resulting in the elevation of FKN protein. The miRNA, mRNA, and protein analyses of the diabetic hypothalamus revealed that the iron import, export, and iron storage were all influenced by miRNAs suggesting the disturbance of hypothalamic iron homeostasis. Conclusion It can be supposed that glucose metabolism, inflammation, and iron homeostasis of the hypothalamus are linked via the altered expression of common miRNAs as well as the increased expression of FKN, which contribute to the imbalance of energy homeostasis, the synthesis of pro-inflammatory cytokines, and the iron accumulation of the hypothalamus. The results raise the possibility that FKN could be a potential target of new therapies targeting both inflammation and iron disturbances in diabetic conditions. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model

Pandur

Szabó

Hormay

et al. 2022

Diabetol Metab Syndr

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“…61 – 63 LF regulates iron homeostasis 64 and also presents anti-inflammatory, antibacterial, reactive oxygen species modulator, antiviral, and antitumor immunity effects. 65 This protein has been previously proposed as a candidate biomarker of dry eye disease, 66 in which oral LF administration preserves lacrimal gland function in aged mice, reducing the oxidative damage and inflammation. 67 The administration of LF also reduces the choroidal neovascularization in a laser-induced mouse model that mimics the AMD wet form through the inhibition of hypoxia-inducible factors.…”

Section: Discussionmentioning

confidence: 99%

Targeted Analysis of Tears Revealed Specific Altered Metal Homeostasis in Age-Related Macular Degeneration

Valencia

García

Fernández‐Vega

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Specific altered metal homeostasis has been investigated in the tear film of age-related macular degeneration (AMD) patients considering that metal dyshomeostasis contributes to the production of free radicals, inflammation, and apoptosis and results in conformational changes of proteins. Methods A multitargeted approach based on spectrophotometry and mass spectrometry techniques has been implemented to the multiplexed quantitation of lactoferrin (LF), S100 calcium binding protein A6 (S100A6), metallothionein 1A (MT1A), complement factor H (CFH), clusterin (CLU), amyloid precursor protein (APP), Mg, P, Na, Fe, Cu, Zn, and Ca, in the tear film from 60 subjects, 31 patients diagnosed with the dry form of AMD, and 29 healthy individuals Results Significant up-regulations of MT1A (1.9-fold) and S100A6 (1.4-fold) and down-regulations of LF (0.7-fold), Fe (0.6-fold), Mg (0.7-fold), and Cu (0.7-fold) were observed in AMD patients, when compared to control subjects. Of all the studied variables, only APP showed negative correlation with age in the AMD group. Also, positive correlations were observed for the variables Mg and Na, Cu and Mg, and P and Mg in both the AMD and control groups, whereas positive correlations were exclusively determined in the AMD group for Cu and LF, Na and Ca, and Mg and Ca. The panel constituted of MT1A, Na, and Mg predicts AMD disease in 73% of cases. Conclusions The different levels of target metals and (metallo-)proteins in the tear film suggest altered metal homeostasis in AMD patients. These observed pathophysiological changes may be related with the anomalous protein aggregation in the macula.

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“…This effect was confirmed by the histological analysis, in which the HILf10 group presented decreased corpus callosum length and MBP expression evidencing white matter damage. Interestingly, patients suffering from gelatinous drop corneal dystrophy (an autosomal recessive genetic disease that can occur at an early age and cause growth delays) exhibit high levels of Lf gene expression in their corneal tissue, which can correlate excess Lf to developmental delays and might help explain the detrimental effects of Lf [81,82].…”

Section: Discussionmentioning

confidence: 99%

Dose-Dependent Neuroprotective Effects of Bovine Lactoferrin Following Neonatal Hypoxia–Ischemia in the Immature Rat Brain

et al. 2021

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Injuries to the developing brain due to hypoxia–ischemia (HI) are common causes of neurological disabilities in preterm babies. HI, with oxygen deprivation to the brain or reduced cerebral blood perfusion due to birth asphyxia, often leads to severe brain damage and sequelae. Injury mechanisms include glutamate excitotoxicity, oxidative stress, blood–brain barrier dysfunction, and exacerbated inflammation. Nutritional intervention is emerging as a therapeutic alternative to prevent and rescue brain from HI injury. Lactoferrin (Lf) is an iron-binding protein present in saliva, tears, and breast milk, which has been shown to have antioxidant, anti-inflammatory and anti-apoptotic properties when administered to mothers as a dietary supplement during pregnancy and/or lactation in preclinical studies of developmental brain injuries. However, despite Lf’s promising neuroprotective effects, there is no established dose. Here, we tested three different doses of dietary maternal Lf supplementation using the postnatal day 3 HI model and evaluated the acute neurochemical damage profile using 1H Magnetic Resonance Spectroscopy (MRS) and long-term microstructure alterations using advanced diffusion imaging (DTI/NODDI) allied to protein expression and histological analysis. Pregnant Wistar rats were fed either control diet or bovine Lf supplemented chow at 0.1, 1, or 10 g/kg/body weight concentration from the last day of pregnancy (embryonic day 21–E21) to weaning. At postnatal day 3 (P3), pups from both sexes had their right common carotid artery permanently occluded and were exposed to 6% oxygen for 30 min. Sham rats had the incision but neither surgery nor hypoxia episode. At P4, MRS was performed on a 9.4 T scanner to obtain the neurochemical profile in the cortex. At P4 and P25, histological analysis and protein expression were assessed in the cortex and hippocampus. Brain volumes and ex vivo microstructural analysis using DTI/NODDI parameters were performed at P25. Acute metabolic disturbance induced in cortical tissue by HIP3 was reversed with all three doses of Lf. However, data obtained from MRS show that Lf neuroprotective effects were modulated by the dose. Through western blotting analysis, we observed that HI pups supplemented with Lf at 0.1 and 1 g/kg were able to counteract glutamatergic excitotoxicity and prevent metabolic failure. When 10 g/kg was administered, we observed reduced brain volumes, increased astrogliosis, and hypomyelination, pointing to detrimental effects of high Lf dose. In conclusion, Lf supplementation attenuates, in a dose-dependent manner, the acute and long-term cerebral injury caused by HI. Lf reached its optimal effects at a dose of 1 g/kg, which pinpoints the need to better understand effects of Lf, the pathways involved and possible harmful effects. These new data reinforce our knowledge regarding neuroprotection in developmental brain injury using Lf through lactation and provide new insights into lactoferrin’s neuroprotection capacities and limitation for immature brains.

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A Review on Lactoferrin and Central Nervous System Diseases

Cited by 52 publications

References 166 publications

Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model

Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model

Targeted Analysis of Tears Revealed Specific Altered Metal Homeostasis in Age-Related Macular Degeneration

Dose-Dependent Neuroprotective Effects of Bovine Lactoferrin Following Neonatal Hypoxia–Ischemia in the Immature Rat Brain

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