Relationship between Iron-Related Parameters and Soluble Tumor Necrosis Factor-Like Weak Inducer of Apoptosis in Obese Children
Iron is physiologically essential. However, it also participates in the catalysis of free radical formation reactions. Its deficiency is associated with amplified health risks. This trace element establishes some links with another physiological process related to cell death, apoptosis. Both iron deficiency and iron overload are closely associated with apoptosis. Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) has the ability to trigger apoptosis and plays a dual role in the physiological versus pathological inflammatory responses of tissues. The aim of this study was to investigate the status of these parameters as well as the associations among them in children with obesity, a low-grade inflammatory state. The study was performed on groups of children with normal body mass index (N-BMI) and obesity. 43 children were included in each group. Based upon age- and sex-adjusted BMI percentile tables prepared by the World Health Organization, children whose values varied between 85 and 15 were included in N-BMI group. Children, whose BMI percentile values were between 99 and 95, comprised obese (OB) group. Institutional ethical committee approval and informed consent forms were taken prior to the study. Anthropometric measurements (weight, height, waist circumference, hip circumference, head circumference, neck circumference) and blood pressure values (systolic blood pressure and diastolic blood pressure) were recorded. Routine biochemical analyses, including serum iron, total iron binding capacity (TIBC), transferrin saturation percent (Tf Sat %) and ferritin, were performed. sTWEAK levels were determined by enzyme-linked immunosorbent assay. study data were evaluated using appropriate statistical tests performed by the statistical program SPSS. Serum iron levels were 91 ± 34 mcrg/dl and 75 ± 31 mcrg/dl in N-BMI and OB children, respectively. The corresponding values for TIBC, Tf Sat %, ferritin were 265 mcrg/dl vs. 299 mcrg/dl, 37.2 ± 19.1% vs. 26.7 ± 14.6%, and 41 ± 25 ng/ml vs 44 ± 26 ng/ml. In N-BMI and OB groups, sTWEAK concentrations were measured as 351 ng/L and 325 ng/L, respectively (p > 0.05). Correlation analysis revealed significant associations between sTWEAK levels and iron related parameters (p < 0.05) except ferritin. In conclusion, iron contributes to apoptosis. Children with iron deficiency have decreased apoptosis rate in comparison with that of healthy children. sTWEAK is an inducer of apoptosis. OB children had lower levels of both iron and sTWEAK. Low levels of sTWEAK are associated with several types of cancers and poor survival. Although iron deficiency state was not observed in this study, the correlations detected between decreased sTWEAK and decreased iron as well as Tf Sat % values were valuable findings, which point out decreased apoptosis. This may induce a proinflammatory state, potentially leading to malignancies in the future lives of OB children.
[1] R. De, K. U. Prakash, and E. S. Edison, “Complex interactions in regulation of haematopoiesis-An unexplored iron mine,” Genes (Basel), vol.12, no.8, pp.1270, Aug. 2021.
[2] J. L. Miller, “Iron deficiency anemia: a common and curable disease,” Cold Spring Harb. Perspect. Med., vol.3, no.7, pp.a011866, Jul. 2013.
[3] M. Ortíz Pérez, M. A. Vázquez López, M. Ibáñez Alcalde, R. Galera Martínez, M. Martín González, F. Lendínez Molinos, and A. Bonillo Perales, “Relationship between obesity and iron deficiency in healthy adolescents,” Child. Obes., vol.16, no.6, pp.440-447, Sep. 2020.
[4] Á. González-Domínguez, F. M. Visiedo-García, J. Domínguez-Riscart, R. González-Domínguez, R. M. Mateos, and A. M. Lechuga-Sancho, “Iron metabolism in obesity and metabolic syndrome,” Int. J. Mol. Sci., vol.21, no.15, pp.5529, Aug 2020.
[5] A. C. Cepeda-Lopez, I. Aeberli, and M. B. Zimmermann, “Does obesity increase risk for iron deficiency? A review of the literature and the potential mechanisms,” Int. J. Vitam. Nutr. Res., vol.80, no.4-5, pp.263-270, Oct. 2010.
[6] D. Siyaram, P. Bhatia, D. Dayal, A. K. Bhalla, and R. Marathe, “Hypoferremic state in overweight and obese children,” Indian Pediatr., vol.55, no.1, pp.72-73, Jan. 2018.
[7] M. L. Muzzio, E. S. Lozano Chiappe, L. Kabakian, F. Ferraro, I. Landó, E. Alonso, J. Fernández, S. Peredo, L. Brovarone, M. Pia Santucci, and T. Meroño, “Effects of pubertal status and inflammation on the use of ferritin to define iron deficiency in children with overweight or obesity,” Nutr. Metab. Insights, vol.12, pp.1178638819839064, Apr.2019.
[8] N. M. Alshwaiyat, A. Ahmad, W. M. R. Wan Hassan, and H. A. N. Al-Jamal, “Association between obesity and iron deficiency (Review),” Exp. Ther. Med., vol. 22, no.5, pp. 1268, Nov. 2021.
[9] D. Prá, S. I. Franke, J. A. Henriques, and M. Fenech, “Iron and genome stability: an update,” Mutat. Res., vol.733, no.1-2, pp.92-99. May 2012.
[10] E. Luporsi, A. Turpin, V. Massard, S. Morin, B. Chauffert, A. Carnot, P. Cacoub; Behalf of the CARENFER Study Group, “Iron deficiency in patients with cancer: a prospective cross-sectional study,” BMJ Support. Palliat. Care, 2021 Jul 30:bmjspcare-2021-002913. Epub ahead of print.
[11] Z. Levi, J. D. Kark, L H. Katz, G. Twig, E. Derazne, D. Tzur, Y. Leibovici Weissman, A. Leiba, I. Lipshiez, L. Keinan Boker, and A. Afek,“Adolescent body mass index and risk of colon and rectal cancer in a cohort of 1.79 million Israeli men and women: A population-based study,” Cancer, vol.123, pp. 204022-204030, Oct. 2017.
[12] H. Scherübl, “Excess body weight and gastrointestinal cancer risk,” Visc. Med., vol.37, no.4, pp.261-266, Aug. 2021.
[13] X. Wang, Z. Guo, Z. Ding, and J. L. Mehta, “Inflammation, autophagy, and apoptosis after myocardial infarction,” J. Am. Heart Assoc., vol.7, no.9, pp.e008024, 2018.
[14] R. S. Y. Wong, “Apoptosis in cancer: from pathogenesis to treatment,” J. Exp. Clin. Cancer Res., vol.30, no.1, pp.87, 2011.
[15] E. O. Melin, J. Dereke, and M. Hillman, “Low levels of soluble TWEAK, indicating on-going inflammation, were associated with depression in type 1 diabetes: a cross-sectional study,” BMC Psychiatry, vol.20, no.1, pp.574, Dec. 2020.
[16] A. Díaz-López, M. R. Chacón, M. Bulló, E. Maymó-Masip, M. A. Martínez-González, R. Estruch, J. Vendrell, J. Basora, J. Díez-Espino, M-I. Covas, and J. Salas-Salvadó, “Serum sTWEAK concentrations and risk of developing Type 2 diabetes in a high cardiovascular risk population: A nested case-control study,” J. Clin. Endocrinol. Metab., vol. 98, no. 8, pp.3482-3490, Aug. 2013.
[17] A. Díaz-López, M. Bulló, M. R. Chacón, R. Estruch, J. Vendrell, J. Díez-Espino, M. Fitó, D. Corella, and J. Salas-Salvadó, “Reduced circulating sTWEAK levels are associated with metabolic syndrome in elderly individuals at high cardiovascular risk,” Cardiovasc. Diabetol., vol. 13, pp.51, Feb. 2014.
[18] F. X. Avilés-Jurado, X. Terra, D. Gómez, J. C. Flores, A. Raventós, E. Maymó-Masip, X. León, V. Serrano-Gonzalvo, J. Vendrell, E. Figuerola, and M. R. Chacón, “Low blood levels of sTWEAK are related to locoregional failure in head and neck cancer,” Eur. Arch. Otorhinolaryngol., vol.272, no.7, pp.1733-1741, Jul. 2015.
[19] A. Altuna-Coy, X. Ruiz-Plazas, M. Alves-Santiago, J. Segarra-Tomás, and M. R. Chacón, “Serum levels of the cytokine TWEAK are associated with metabolic status in patients with prostate cancer and modulate cancer cell lipid metabolism in vitro,” Cancers (Basel), vol.13, no.18, pp.4688, Sep. 2021.
[20] J. M. Gómez-Martin, E. Aracil, M. Insenser, G. de la Peña, M. A. Lasunción, J. Galindo, H. F. Escobar-Morreale, J. A. Balsa, and J. I. Botella-Carretero, “Changes in soluble TWEAK concentrations, but not those in amyloid-β(1-40), are associated with a decrease in carotid intima-media thickness after bariatric surgery in obese women,” Obes. Facts, vol.13, no.3, pp.321-330, 2020.
[21] Ö. Yıldırım, T. Demircan, Ö. Tüfekçi, Ö. Kızılca, P. Kuyum, M. Kır, A. Abacı, N. Ünal, N. Arslan, E. Böber, Ş. Yılmaz, and H. Ören, “Anemia and its effect on cardiovascular findings in obese adolescents,” Turk. J. Haematol., vol.35, no.3, pp.192-196, Aug. 2018.
[22] L. M. Blanco-Colio, J. L. Martín-Ventura, B. Muñóz-García, J. Orbe, J. A. Páramo, J. B. Michel, A. Ortiz, O. Meilhac, and J. Egido, “Identification of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) as a possible biomarker of subclinical atherosclerosis,” Arterioscler. Thromb. Vasc. Biol., vol.27, no.4, pp.916-922, Apr. 2007.
[23] World Health Organization (WHO). The WHO Child Growth Standards. 2016 June. Access: http://www.who.int/childgrowth/en/
[24] O. Suteerojntrakool, T. Khongcharoensombat, S. Chomtho, C. Bongsebandhu-Phubhakdi, T. Tempark, and M. Fewtrell, “Anthropometric markers and iron status of 6-12-year-old Thai children: Associations and predictors,” J. Nutr. Metab., vol.2021, pp.9629718, Apr. 2021.
[25] R. Bridges, “Iron metabolism and sideroblastic anemia,” in Hematology of Infancy and Childhood, D.G. Nathan, F. A. Oski, Eds. Philadelphia, PA: W.B. Saunders Company, 1992, pp.391.
[26] C. J. Thiele, M. Kastan, “Biology of childhood cancer,” in Principles and Practice of Pediatric Oncology, P. A. Pizzo, D. G. Poplack, Eds. Philadelphia, PA: Lippincott Williams & Wilkins, 2002, pp.89.
[27] A. L. Fisher, D. N. Srole, N. J. Palaskas, D. Meriwether, S. T. Reddy, T. Ganz, and E. Nemeth, “Iron loading induces cholesterol synthesis and sensitizes endothelial cells to TNFα-mediated apoptosis,” J. Biol. Chem., vol.297, no.4, pp.101156, Sep 2021.
[28] Y. Feng, P. Y. He, W. D. Kong, W. J. Cen, P. L. Wang, C. Liu, W. Zhang, S. S. Li, and J. W. Jiang, “Apoptosis-promoting properties of miR-3074-5p in MC3T3-E1 cells under iron overload conditions,” Cell Mol. Biol. Lett.,vol. 26, no. 1, pp.37, Aug. 2021.
[29] D. D. Im, C. H. Ho, and R. Y. Chan, “Hypersegmented neutrophils in an adolescent male with heatstroke,” J. Pediatr. Hematol. Oncol., vol.37, pp.488, 2015.
[30] S. G. Berrak, M. Angaji, E. Turkkan, C. Canpolat, C. Timur, and E. Eksioglu-Demiralp, “The effects of iron deficiency on neutrophil/monocyte apoptosis in children,” Cell Prolif., vol. 40, no.5, pp.741-754, Oct. 2007.
[1] R. De, K. U. Prakash, and E. S. Edison, “Complex interactions in regulation of haematopoiesis-An unexplored iron mine,” Genes (Basel), vol.12, no.8, pp.1270, Aug. 2021.
[2] J. L. Miller, “Iron deficiency anemia: a common and curable disease,” Cold Spring Harb. Perspect. Med., vol.3, no.7, pp.a011866, Jul. 2013.
[3] M. Ortíz Pérez, M. A. Vázquez López, M. Ibáñez Alcalde, R. Galera Martínez, M. Martín González, F. Lendínez Molinos, and A. Bonillo Perales, “Relationship between obesity and iron deficiency in healthy adolescents,” Child. Obes., vol.16, no.6, pp.440-447, Sep. 2020.
[4] Á. González-Domínguez, F. M. Visiedo-García, J. Domínguez-Riscart, R. González-Domínguez, R. M. Mateos, and A. M. Lechuga-Sancho, “Iron metabolism in obesity and metabolic syndrome,” Int. J. Mol. Sci., vol.21, no.15, pp.5529, Aug 2020.
[5] A. C. Cepeda-Lopez, I. Aeberli, and M. B. Zimmermann, “Does obesity increase risk for iron deficiency? A review of the literature and the potential mechanisms,” Int. J. Vitam. Nutr. Res., vol.80, no.4-5, pp.263-270, Oct. 2010.
[6] D. Siyaram, P. Bhatia, D. Dayal, A. K. Bhalla, and R. Marathe, “Hypoferremic state in overweight and obese children,” Indian Pediatr., vol.55, no.1, pp.72-73, Jan. 2018.
[7] M. L. Muzzio, E. S. Lozano Chiappe, L. Kabakian, F. Ferraro, I. Landó, E. Alonso, J. Fernández, S. Peredo, L. Brovarone, M. Pia Santucci, and T. Meroño, “Effects of pubertal status and inflammation on the use of ferritin to define iron deficiency in children with overweight or obesity,” Nutr. Metab. Insights, vol.12, pp.1178638819839064, Apr.2019.
[8] N. M. Alshwaiyat, A. Ahmad, W. M. R. Wan Hassan, and H. A. N. Al-Jamal, “Association between obesity and iron deficiency (Review),” Exp. Ther. Med., vol. 22, no.5, pp. 1268, Nov. 2021.
[9] D. Prá, S. I. Franke, J. A. Henriques, and M. Fenech, “Iron and genome stability: an update,” Mutat. Res., vol.733, no.1-2, pp.92-99. May 2012.
[10] E. Luporsi, A. Turpin, V. Massard, S. Morin, B. Chauffert, A. Carnot, P. Cacoub; Behalf of the CARENFER Study Group, “Iron deficiency in patients with cancer: a prospective cross-sectional study,” BMJ Support. Palliat. Care, 2021 Jul 30:bmjspcare-2021-002913. Epub ahead of print.
[11] Z. Levi, J. D. Kark, L H. Katz, G. Twig, E. Derazne, D. Tzur, Y. Leibovici Weissman, A. Leiba, I. Lipshiez, L. Keinan Boker, and A. Afek,“Adolescent body mass index and risk of colon and rectal cancer in a cohort of 1.79 million Israeli men and women: A population-based study,” Cancer, vol.123, pp. 204022-204030, Oct. 2017.
[12] H. Scherübl, “Excess body weight and gastrointestinal cancer risk,” Visc. Med., vol.37, no.4, pp.261-266, Aug. 2021.
[13] X. Wang, Z. Guo, Z. Ding, and J. L. Mehta, “Inflammation, autophagy, and apoptosis after myocardial infarction,” J. Am. Heart Assoc., vol.7, no.9, pp.e008024, 2018.
[14] R. S. Y. Wong, “Apoptosis in cancer: from pathogenesis to treatment,” J. Exp. Clin. Cancer Res., vol.30, no.1, pp.87, 2011.
[15] E. O. Melin, J. Dereke, and M. Hillman, “Low levels of soluble TWEAK, indicating on-going inflammation, were associated with depression in type 1 diabetes: a cross-sectional study,” BMC Psychiatry, vol.20, no.1, pp.574, Dec. 2020.
[16] A. Díaz-López, M. R. Chacón, M. Bulló, E. Maymó-Masip, M. A. Martínez-González, R. Estruch, J. Vendrell, J. Basora, J. Díez-Espino, M-I. Covas, and J. Salas-Salvadó, “Serum sTWEAK concentrations and risk of developing Type 2 diabetes in a high cardiovascular risk population: A nested case-control study,” J. Clin. Endocrinol. Metab., vol. 98, no. 8, pp.3482-3490, Aug. 2013.
[17] A. Díaz-López, M. Bulló, M. R. Chacón, R. Estruch, J. Vendrell, J. Díez-Espino, M. Fitó, D. Corella, and J. Salas-Salvadó, “Reduced circulating sTWEAK levels are associated with metabolic syndrome in elderly individuals at high cardiovascular risk,” Cardiovasc. Diabetol., vol. 13, pp.51, Feb. 2014.
[18] F. X. Avilés-Jurado, X. Terra, D. Gómez, J. C. Flores, A. Raventós, E. Maymó-Masip, X. León, V. Serrano-Gonzalvo, J. Vendrell, E. Figuerola, and M. R. Chacón, “Low blood levels of sTWEAK are related to locoregional failure in head and neck cancer,” Eur. Arch. Otorhinolaryngol., vol.272, no.7, pp.1733-1741, Jul. 2015.
[19] A. Altuna-Coy, X. Ruiz-Plazas, M. Alves-Santiago, J. Segarra-Tomás, and M. R. Chacón, “Serum levels of the cytokine TWEAK are associated with metabolic status in patients with prostate cancer and modulate cancer cell lipid metabolism in vitro,” Cancers (Basel), vol.13, no.18, pp.4688, Sep. 2021.
[20] J. M. Gómez-Martin, E. Aracil, M. Insenser, G. de la Peña, M. A. Lasunción, J. Galindo, H. F. Escobar-Morreale, J. A. Balsa, and J. I. Botella-Carretero, “Changes in soluble TWEAK concentrations, but not those in amyloid-β(1-40), are associated with a decrease in carotid intima-media thickness after bariatric surgery in obese women,” Obes. Facts, vol.13, no.3, pp.321-330, 2020.
[21] Ö. Yıldırım, T. Demircan, Ö. Tüfekçi, Ö. Kızılca, P. Kuyum, M. Kır, A. Abacı, N. Ünal, N. Arslan, E. Böber, Ş. Yılmaz, and H. Ören, “Anemia and its effect on cardiovascular findings in obese adolescents,” Turk. J. Haematol., vol.35, no.3, pp.192-196, Aug. 2018.
[22] L. M. Blanco-Colio, J. L. Martín-Ventura, B. Muñóz-García, J. Orbe, J. A. Páramo, J. B. Michel, A. Ortiz, O. Meilhac, and J. Egido, “Identification of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) as a possible biomarker of subclinical atherosclerosis,” Arterioscler. Thromb. Vasc. Biol., vol.27, no.4, pp.916-922, Apr. 2007.
[23] World Health Organization (WHO). The WHO Child Growth Standards. 2016 June. Access: http://www.who.int/childgrowth/en/
[24] O. Suteerojntrakool, T. Khongcharoensombat, S. Chomtho, C. Bongsebandhu-Phubhakdi, T. Tempark, and M. Fewtrell, “Anthropometric markers and iron status of 6-12-year-old Thai children: Associations and predictors,” J. Nutr. Metab., vol.2021, pp.9629718, Apr. 2021.
[25] R. Bridges, “Iron metabolism and sideroblastic anemia,” in Hematology of Infancy and Childhood, D.G. Nathan, F. A. Oski, Eds. Philadelphia, PA: W.B. Saunders Company, 1992, pp.391.
[26] C. J. Thiele, M. Kastan, “Biology of childhood cancer,” in Principles and Practice of Pediatric Oncology, P. A. Pizzo, D. G. Poplack, Eds. Philadelphia, PA: Lippincott Williams & Wilkins, 2002, pp.89.
[27] A. L. Fisher, D. N. Srole, N. J. Palaskas, D. Meriwether, S. T. Reddy, T. Ganz, and E. Nemeth, “Iron loading induces cholesterol synthesis and sensitizes endothelial cells to TNFα-mediated apoptosis,” J. Biol. Chem., vol.297, no.4, pp.101156, Sep 2021.
[28] Y. Feng, P. Y. He, W. D. Kong, W. J. Cen, P. L. Wang, C. Liu, W. Zhang, S. S. Li, and J. W. Jiang, “Apoptosis-promoting properties of miR-3074-5p in MC3T3-E1 cells under iron overload conditions,” Cell Mol. Biol. Lett.,vol. 26, no. 1, pp.37, Aug. 2021.
[29] D. D. Im, C. H. Ho, and R. Y. Chan, “Hypersegmented neutrophils in an adolescent male with heatstroke,” J. Pediatr. Hematol. Oncol., vol.37, pp.488, 2015.
[30] S. G. Berrak, M. Angaji, E. Turkkan, C. Canpolat, C. Timur, and E. Eksioglu-Demiralp, “The effects of iron deficiency on neutrophil/monocyte apoptosis in children,” Cell Prolif., vol. 40, no.5, pp.741-754, Oct. 2007.
@article{"International Journal of Medical, Medicine and Health Sciences:80860", author = "Mustafa M. Donma and Orkide Donma and Savas Guzel", title = "Relationship between Iron-Related Parameters and Soluble Tumor Necrosis Factor-Like Weak Inducer of Apoptosis in Obese Children", abstract = "Iron is physiologically essential. However, it also participates in the catalysis of free radical formation reactions. Its deficiency is associated with amplified health risks. This trace element establishes some links with another physiological process related to cell death, apoptosis. Both iron deficiency and iron overload are closely associated with apoptosis. Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) has the ability to trigger apoptosis and plays a dual role in the physiological versus pathological inflammatory responses of tissues. The aim of this study was to investigate the status of these parameters as well as the associations among them in children with obesity, a low-grade inflammatory state. The study was performed on groups of children with normal body mass index (N-BMI) and obesity. 43 children were included in each group. Based upon age- and sex-adjusted BMI percentile tables prepared by the World Health Organization, children whose values varied between 85 and 15 were included in N-BMI group. Children, whose BMI percentile values were between 99 and 95, comprised obese (OB) group. Institutional ethical committee approval and informed consent forms were taken prior to the study. Anthropometric measurements (weight, height, waist circumference, hip circumference, head circumference, neck circumference) and blood pressure values (systolic blood pressure and diastolic blood pressure) were recorded. Routine biochemical analyses, including serum iron, total iron binding capacity (TIBC), transferrin saturation percent (Tf Sat %) and ferritin, were performed. sTWEAK levels were determined by enzyme-linked immunosorbent assay. study data were evaluated using appropriate statistical tests performed by the statistical program SPSS. Serum iron levels were 91 ± 34 mcrg/dl and 75 ± 31 mcrg/dl in N-BMI and OB children, respectively. The corresponding values for TIBC, Tf Sat %, ferritin were 265 mcrg/dl vs. 299 mcrg/dl, 37.2 ± 19.1% vs. 26.7 ± 14.6%, and 41 ± 25 ng/ml vs 44 ± 26 ng/ml. In N-BMI and OB groups, sTWEAK concentrations were measured as 351 ng/L and 325 ng/L, respectively (p > 0.05). Correlation analysis revealed significant associations between sTWEAK levels and iron related parameters (p < 0.05) except ferritin. In conclusion, iron contributes to apoptosis. Children with iron deficiency have decreased apoptosis rate in comparison with that of healthy children. sTWEAK is an inducer of apoptosis. OB children had lower levels of both iron and sTWEAK. Low levels of sTWEAK are associated with several types of cancers and poor survival. Although iron deficiency state was not observed in this study, the correlations detected between decreased sTWEAK and decreased iron as well as Tf Sat % values were valuable findings, which point out decreased apoptosis. This may induce a proinflammatory state, potentially leading to malignancies in the future lives of OB children.", keywords = "Apoptosis, children, iron-related parameters, obesity, soluble tumor necrosis factor-like weak inducer of apoptosis.", volume = "16", number = "7", pages = "90-4", }
