Generic placeholder image

Current Gene Therapy

Editor-in-Chief

ISSN (Print): 1566-5232
ISSN (Online): 1875-5631

Research Article

Effect of Bovine Lactoferrin Treatment on Iron Homeostasis and Gene Expression Changes in Multiple Organ Dysfunctions During Wound Healing Process in Rats

Author(s): Ahmet Sarper Bozkurt* and Şenay Görücü Yılmaz

Volume 24, Issue 5, 2024

Published on: 21 February, 2024

Page: [410 - 421] Pages: 12

DOI: 10.2174/0115665232279426240217174738

Price: $65

Abstract

Background: Injury systemically disrupts the homeostatic balance and can cause organ failure. LF mediates both iron-dependent and iron-independent mechanisms, and the role of LF in regulating iron homeostasis is vital in terms of metabolism.

Objectives: In this study, we evaluated the organ-level effect and gene expression change of bLf in the cutaneous repair process.

Materials and Methods: An excisional full-thickness skin defect (FTSD) wound model was created in male Sprague Dawley rats (180-250 g) (n = 48) fed a high-fat diet (HFD) and the PHGPx, SLC7A11 and SLC40A1 genes and iron metabolism were evaluated. The animals were randomly divided into 6 groups: 1- Control, 2- bLf (200 mg/kg/day, oral), 3- FTSD (12 mm in diameter, dorsal), 4- HFD + bLf, 5- HFD + FTSD, 6- HFD + FTSD + bLf. Histologically, iron accumulation was demonstrated by Prussian blue staining in the liver, kidney, and intestinal tissues. Gene expression analysis was performed with qPCR.

Results: Histologically, iron accumulation was demonstrated by Prussian blue staining in the liver, kidney, and intestinal tissues. Prussian blue reactions were detected in the kidney. PHPGx and SLC7A11 genes in kidney and liver tissue were statistically significant (P < 0.05) except for the SLC40A1 gene (P > 0.05). Expression changes of the three genes were not statistically significant in analyses of rat intestinal tissue (P = 0.057).

Conclusion: In the organ-level ferroptotic damage mechanism triggered by wound formation. BLf controls the expression of three genes and manages iron deposition in these three tissues. In addition, it suppressed the increase in iron that would drive the cell to ferroptosis and anemia caused by inflammation, thereby eliminating iron deposition in the tissues.

Keywords: Bovine lactoferrin, wound healing, PHGPx, SLC7A11, SLC40A1, FSTD.

Graphical Abstract
[1]
Tavakoli S, Kisiel MA, Biedermann T, Klar AS. Immunomodulation of skin repair: Cell-based therapeutic strategies for skin replacement. Biomedicines 2022; 10(1): 118.
[http://dx.doi.org/10.3390/biomedicines10010118] [PMID: 35052797]
[2]
Esmaeili Y, Bidram E, Bigham A, et al. Exploring the evolution of tissue engineering strategies over the past decade: From cell-based strategies to gene-activated matrix. Alex Eng J 2023; 81: 137-69.
[http://dx.doi.org/10.1016/j.aej.2023.08.080]
[3]
Rascón-Cruz Q, Espinoza-Sánchez EA, Siqueiros-Cendón TS, Nakamura-Bencomo SI, Arévalo-Gallegos S, Iglesias-Figueroa BF. Lactoferrin: A glycoprotein involved in immunomodulation, anticancer, and antimicrobial processes. Molecules 2021; 26(1): 205.
[http://dx.doi.org/10.3390/molecules26010205] [PMID: 33401580]
[4]
Mouritzen MV, Petkovic M, Qvist K, et al. Improved diabetic wound healing by LFcinB is associated with relevant changes in the skin immune response and microbiota. Mol Ther Methods Clin Dev 2021; 20: 726-39.
[http://dx.doi.org/10.1016/j.omtm.2021.02.008] [PMID: 33738327]
[5]
Aschemeyer S, Qiao B, Stefanova D, et al. Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin. Blood 2018; 131(8): 899-910.
[http://dx.doi.org/10.1182/blood-2017-05-786590] [PMID: 29237594]
[6]
Jyotsana N, Ta KT, DelGiorno KE. The role of cystine/glutamate antiporter SLC7A11/xCT in the pathophysiology of cancer. Front Oncol 2022; 12: 858462.
[http://dx.doi.org/10.3389/fonc.2022.858462] [PMID: 35280777]
[7]
Sakai O, Ueta T, Yanagi Y, Amano S. Role of glutathione peroxidase 4 in maintaining homeostasis of corneal epithelial cells. Invest Ophthalmol Vis Sci 2013; 54: 539-9.
[8]
Hessin A, Hegazy R, Hassan A, Yassin N, Kenawy S. Lactoferrin enhanced apoptosis and protected against thioacetamide-induced liver fibrosis in rats. Open Access Maced J Med Sci 2015; 3(2): 195-201.
[http://dx.doi.org/10.3889/oamjms.2015.038] [PMID: 27275221]
[9]
Qiu Z, Kwon AH, Kamiyama Y. Effects of plasma fibronectin on the healing of full-thickness skin wounds in streptozotocin-induced diabetic rats. J Surg Res 2007; 138(1): 64-70.
[http://dx.doi.org/10.1016/j.jss.2006.06.034] [PMID: 17161431]
[10]
Reeves PG, Nielsen FH, Fahey GC Jr. AIN-93 purified diets for laboratory rodents: Final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 1993; 123(11): 1939-51.
[http://dx.doi.org/10.1093/jn/123.11.1939] [PMID: 8229312]
[11]
Shapiro A, Mu W, Roncal C, Cheng KY, Johnson RJ, Scarpace PJ. Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding. Am J Physiol Regul Integr Comp Physiol 2008; 295(5): R1370-5.
[http://dx.doi.org/10.1152/ajpregu.00195.2008] [PMID: 18703413]
[12]
Fang S, Xu C, Zhang Y, et al. Umbilical cord-derived mesenchymal stem cell-derived exosomal microRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-β/SMAD2 pathway during wound healing. Stem Cells Transl Med 2016; 5(10): 1425-39.
[http://dx.doi.org/10.5966/sctm.2015-0367] [PMID: 27388239]
[13]
Flecknell PA, Roughan JV, Stewart R. Use of oral buprenorphine (‘buprenorphine jello’) for postoperative analgesia in rats - A clinical trial. Lab Anim 1999; 33(2): 169-74.
[http://dx.doi.org/10.1258/002367799780578381] [PMID: 10780821]
[14]
Kasahara T, Miyazaki T, Nitta H, et al. Evaluation of methods for duration of preservation of RNA quality in rat liver used for transcriptome analysis. J Toxicol Sci 2006; 31(5): 509-19.
[http://dx.doi.org/10.2131/jts.31.509] [PMID: 17202763]
[15]
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Δ Δ C(T)) Method. Methods 2001; 25(4): 402-8.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[16]
Corp I. IBM SPSS statistics for windows, version 220. Armonk, NY: IBM Corp 2013.
[17]
Takayama Y, Aoki R. Roles of lactoferrin on skin wound healing. Biochem Cell Biol 2012; 90(3): 497-503.
[http://dx.doi.org/10.1139/o11-054] [PMID: 22332789]
[18]
Deonarine K, Panelli MC, Stashower ME, et al. Gene expression profiling of cutaneous wound healing. J Transl Med 2007; 5(1): 11.
[http://dx.doi.org/10.1186/1479-5876-5-11] [PMID: 17313672]
[19]
Xiao Z, Shen D, Lan T, et al. Reduction of lactoferrin aggravates neuronal ferroptosis after intracerebral hemorrhagic stroke in hyperglycemic mice. Redox Biol 2022; 50: 102256.
[http://dx.doi.org/10.1016/j.redox.2022.102256] [PMID: 35131600]
[20]
Recalcati S, Gammella E, Buratti P, et al. Macrophage ferroportin is essential for stromal cell proliferation in wound healing. Haematologica 2019; 104(1): 47-58.
[http://dx.doi.org/10.3324/haematol.2018.197517] [PMID: 30115660]
[21]
Wang G, Shen G, Jiang X, Chen Z, Yin T. Assessment of para‑inflammation in a wound healing model. Exp Ther Med 2020; 20(1): 655-61.
[http://dx.doi.org/10.3892/etm.2020.8666] [PMID: 32509025]
[22]
Kell DB, Heyden EL, Pretorius E. The biology of lactoferrin, an iron-binding protein that can help defend against viruses and bacteria. Front Immunol 2020; 11: 1221.
[http://dx.doi.org/10.3389/fimmu.2020.01221] [PMID: 32574271]
[23]
Superti F. Lactoferrin from bovine milk: A protective companion for life. Nutrients 2020; 12(9): 2562.
[http://dx.doi.org/10.3390/nu12092562] [PMID: 32847014]
[24]
Žarković N, Stipančić I, Hrženjak M, et al. The influence of liver regeneration on skin wound healing and lymphocyte growth features. Host Defense Dysfunction in Trauma, Shock and Sepsis. Berlin, Heidelberg: Springer 1993.
[25]
Maras JS, Maiwall R, Harsha HC, et al. Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute-on-chronic liver failure. Hepatology 2015; 61(4): 1306-20.
[http://dx.doi.org/10.1002/hep.27636] [PMID: 25475192]
[26]
Alkhatib B, Al-Domi H, Irmaileh BA. Effect of high-fat-diets on iron homeostasis and tissue iron deposition in female sprague-dawley rats. J Res Diabetes Metab 2017; 3(1): 024028.
[27]
Ni L, Yuan C, Wu X. Targeting ferroptosis in acute kidney injury. Cell Death Dis 2022; 13(2): 182.
[http://dx.doi.org/10.1038/s41419-022-04628-9] [PMID: 35210424]
[28]
Bukowska-Ośko I, Sulejczak D, Kaczyńska K, et al. Lactoferrin as a human genome “guardian” - An overall point of view. Int J Mol Sci 2022; 23(9): 5248.
[http://dx.doi.org/10.3390/ijms23095248] [PMID: 35563638]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy