DOWNLOAD PDF

Hepcidin: The Gatekeeper of Iron in Malaria Resistance

*Emmanuel Ifeanyi Obeagu1, Esther U. Alum2,3 and Okechukwu P.C. Ugwu3

1Department of Medical Laboratory Science, Kampala International University, Uganda.

2Department of Biochemistry, Ebonyi State University, Abakaliki, Ebonyi State, Nigeria.

3Department of Publication and Extension, Kampala International University, Uganda.

*Corresponding authour: Emmanuel Ifeanyi Obeagu, Department of Medical Laboratory Science, Kampala International University, Uganda, emmanuelobeagu@yahoo.com, ORCID: 0000-0002-4538-0161

ABSTRACT

Malaria, a life-threatening disease caused by Plasmodium parasites, remains a global health challenge. Understanding the intricate dynamics between the host’s iron regulation and the survival strategies of the parasites is crucial for the development of innovative antimalarial strategies. Hepcidin, a central regulator of iron homeostasis, has emerged as a key player in the host’s defense against malaria. This comprehensive review explores the multifaceted roles of hepcidin in safeguarding the host from malaria infection. We delve into the molecular mechanisms of hepcidin regulation, its impact on iron availability, and its influence on the immune response. Furthermore, we discuss the complex interplay between hepcidin and Plasmodium species, revealing how the host’s iron management influences the parasites’ survival and pathogenicity. Additionally, we explore the therapeutic potential of targeting hepcidin and iron regulation in the context of malaria treatment. By unraveling the intricate web of hepcidin’s functions as the “gatekeeper” of iron in malaria resistance, this review contributes to the development of novel strategies for combating this deadly disease.

Keywords: hepcidin, iron, malaria, inflammation

INTRODUCTION

Malaria, a formidable global health challenge, continues to exact a heavy toll on human lives, particularly in regions with limited resources and inadequate healthcare infrastructure. Plasmodium parasites, the causative agents of malaria, wield a cunning ability to adapt and persist within their human hosts [1-5]. Understanding the mechanisms that underpin the host’s defense against these relentless invaders is a matter of paramount importance in the quest to develop effective strategies for preventing and treating malaria [4-9].

At the heart of this battle is hepcidin, a small peptide hormone with a monumental role in regulating iron homeostasis. While hepcidin’s involvement in maintaining the body’s iron balance is well-documented, its multifaceted roles in the context of malaria resistance have recently come to the forefront of scientific inquiry. Hepcidin can be aptly described as the “gatekeeper of iron” in the host’s response to Plasmodium infection [10]. The battle against malaria is ongoing, but with the insights provided by hepcidin’s pivotal role, we find hope for more effective prevention and treatment strategies. As we embark on this journey through the intricate world of hepcidin, the gatekeeper of iron in malaria resistance, we aim to uncover the key to safeguarding the host from this relentless adversary [11].

Top of Form

Bottom of Form

Hepcidin: Molecular Pathways and Regulation

Hepcidin, a critical regulator of iron homeostasis, plays a central role in governing the body’s iron balance. Its intricate regulation is influenced by a myriad of factors and pathways, ensuring that iron levels are maintained within the narrow range required for normal physiological functions. In this section, we will explore the molecular pathways and regulatory mechanisms that govern hepcidin production and its role in maintaining systemic and local iron homeostasis [12-20]. The synthesis of hepcidin is predominantly regulated at the transcriptional level through the HAMP gene. The HAMP gene is located on chromosome 19 and encodes prohepcidin, a precursor protein that is cleaved to produce the biologically active hepcidin peptide [21]. Prohepcidin undergoes proteolytic processing to generate mature hepcidin, which is subsequently secreted into the bloodstream. This mature peptide plays a pivotal role in regulating iron metabolism by controlling the expression and activity of the iron exporter, ferroportin [22].

The Role of Iron Status, Erythropoiesis, and Inflammation in Hepcidin Regulation

Hepcidin production is exquisitely sensitive to iron levels in the body. High iron levels stimulate the production of bone morphogenetic proteins (BMPs), particularly BMP6 and BMP2, which activate the SMAD signaling pathway. This pathway culminates in the transcription of the HAMP gene, leading to increased hepcidin synthesis [23].Erythropoiesis, the process of red blood cell production, is another key regulator of hepcidin. Erythropoietin (EPO), a hormone produced by the kidneys in response to tissue hypoxia, suppresses hepcidin production, allowing increased iron absorption to support red blood cell formation during anemia [24-31].Inflammatory signals, such as interleukin-6 (IL-6), play a pivotal role in hepcidin regulation. During inflammation, IL-6 induces hepcidin production via the JAK-STAT signaling pathway. This inflammatory response is part of the innate immune system’s strategy to sequester iron away from pathogens, thereby limiting their growth [32-39].

The Impact of Hepcidin on Systemic and Local Iron Homeostasis

Hepcidin’s ability to modulate systemic iron homeostasis ensures that the body can maintain iron levels within a narrow and physiologically relevant range. When iron is in excess, hepcidin levels increase, limiting dietary iron absorption and iron release from macrophages and hepatocytes into the bloodstream. Conversely, during iron deficiency, hepcidin production decreases, allowing for increased iron absorption to replenish iron stores [40]. Hepcidin also plays a crucial role in the regulation of iron within specific tissues. In the context of malaria, where iron sequestration can be a host defense strategy, local iron control in macrophages and other cells is essential to prevent Plasmodium access to iron sources [41]. Hepcidin’s molecular pathways and regulatory mechanisms ensure the fine-tuned control of iron levels, enabling the host to respond to variations in iron status, erythropoietic demands, and inflammatory states. This dynamic regulation is a cornerstone of the host’s defense against malaria and other pathogens, as it influences the availability of an essential nutrient to both host and parasite [42].Top of FormBottom of Form Hepcidin, a central regulator of iron homeostasis, exerts a significant influence on the host’s immune response. Its role in modulating iron levels and the complex interplay between iron and immunity make hepcidin a key player in the host’s defense against various pathogens, including Plasmodium species responsible for malaria.

Hepcidin’s Effect on Innate Immune Cells

Macrophages and neutrophils are essential components of the innate immune system, actively participating in the defense against pathogens. Hepcidin’s ability to regulate iron availability can influence the function of these cells. Elevated hepcidin levels can restrict iron availability, potentially impairing the antimicrobial activity of macrophages and neutrophils [43]. While iron is crucial for microbial growth, excessive iron can also be toxic due to the generation of reactive oxygen species (ROS). Hepcidin-mediated iron restriction may have dual effects on immune cells, limiting iron availability for pathogens while potentially protecting host cells from iron-induced oxidative damage [44].

The Influence of Hepcidin on Adaptive Immune Responses

T lymphocytes, including CD4+ and CD8+ T cells, play a central role in the adaptive immune response. Proper T cell responses are critical for the development of protective immunity against Plasmodium parasites. Hepcidin-mediated iron restriction may affect T cell proliferation, differentiation, and function, potentially influencing the host’s ability to mount an effective antimalarial response [45].

Hepcidin’s regulation of iron levels can also impact the production of antibodies, a key component of adaptive immunity. Antibodies play a vital role in the host’s defense against malaria by targeting Plasmodium antigens and preventing parasite invasion of host cells. Hepcidin-mediated iron restriction may affect the humoral immune response [46].

Implications of Hepcidin-Mediated Iron Regulation for Host Immunity during Malaria Infection

In the context of malaria, iron’s dual role as a nutrient for the parasite and a potential driver of oxidative stress in the host creates a delicate balance. Hepcidin’s role in iron regulation is central in maintaining this balance and optimizing the host’s defense mechanisms [47]. Anemia, a common outcome of chronic inflammation, can compromise the host’s ability to mount an effective immune response against malaria [48-52]. Excessive hepcidin production during inflammation, while serving as a defense mechanism to limit iron availability to pathogens, can also result in anemia of inflammation. This condition, characterized by decreased hemoglobin levels, can negatively impact the host’s immune cells and overall resistance to the disease [53].Understanding the complex interactions between hepcidin, iron regulation, and the host’s immune response is pivotal in the context of malaria resistance. Hepcidin’s ability to restrict iron availability to both pathogens and the host’s immune cells represents a double-edged sword that demands a delicate balance. The host’s response to Plasmodium infection, influenced by hepcidin-mediated iron regulation, holds the key to more effective strategies for combatting malaria [54-58].

The Complex Interplay: Hepcidin and Plasmodium Species

The interaction between hepcidin, the master regulator of iron homeostasis, and Plasmodium species, the causative agents of malaria, is a multifaceted and intricate process. Hepcidin’s role in governing iron levels within the host’s body has significant implications for the survival strategies of the parasites. In this section, we delve into the complex interplay between hepcidin and Plasmodium species, shedding light on how hepcidin influences the pathogenesis of malaria and the strategies employed by the parasites for survival [59].Plasmodium parasites, particularly during the intraerythrocytic phase, depend on host iron stores for their survival and replication. Iron is a crucial nutrient for various physiological processes, including heme detoxification, DNA synthesis, and the production of proteins essential for the parasites’ growth [60-64].Plasmodium parasites digest host hemoglobin to obtain heme, an essential source of iron. However, excess heme can be toxic to the parasites. To counteract this toxicity, Plasmodium has evolved detoxification mechanisms, allowing them to manage heme and utilize it as a source of iron [65-69].

Host Defense Mechanisms and Hepcidin’s Role

Hepcidin, as the master regulator of iron homeostasis, can influence the host’s iron management. By binding to ferroportin, the sole known cellular iron exporter, hepcidin triggers its internalization and degradation. This action effectively limits the export of iron from cells such as macrophages, hepatocytes, and enterocytes, reducing the availability of iron in the bloodstream [70]. Hepcidin-mediated iron sequestration creates a hostile environment for Plasmodium by restricting iron availability. By limiting iron access, the host can potentially inhibit the growth and survival of the parasites, thwarting their ability to propagate within the host [71]. Plasmodium parasites have evolved various mechanisms to counteract host defenses, including those related to hepcidin-mediated iron restriction. These adaptation strategies allow the parasites to circumvent the host’s attempts to limit iron availability, ensuring their survival and propagation within the host’s bloodstream [72]. Plasmodium species have evolved efficient antioxidant systems to cope with the oxidative stress associated with heme detoxification. These systems enable the parasites to neutralize reactive oxygen species (ROS) generated during heme catabolism [73].

Top of Form

Bottom of Form

Therapeutic Implications and Antimalarial Strategies

The intricate interplay between hepcidin, iron regulation, and Plasmodium species has unveiled potential therapeutic implications and antimalarial strategies. By targeting hepcidin and the host’s iron management, researchers aim to develop innovative approaches to enhance the host’s ability to combat malaria. In this section, we explore various therapeutic implications and strategies for malaria, leveraging the role of hepcidin as a central player in the host’s defense [74].

Strategies to Target Hepcidin for Antimalarial Defense

One potential strategy is to develop therapeutics or vaccines that can induce the host to increase hepcidin expression in response to Plasmodium infection [75-78]. This would lead to a temporary reduction in serum iron levels, limiting iron availability to the parasites and potentially hindering their growth [78-82]. Hepcidin mimetics, synthetic molecules that mimic the actions of endogenous hepcidin, can be explored as potential antimalarial agents [75-78]. These mimetics could be administered to directly target ferroportin and limit iron export, effectively starving the parasites of this vital nutrient [78-82]. Iron chelation therapies, which involve the administration of iron-binding molecules, can help sequester iron within the host, making it less accessible to Plasmodium parasites. By limiting the parasites’ access to iron, these therapies can inhibit their growth and replication [76-79].

Combining iron chelation therapies with conventional antimalarial drugs may offer a multi-pronged approach to treating malaria. Such combinations could target both the parasites directly and their iron acquisition strategies, potentially improving treatment outcomes.

 

Vaccine Development and Hepcidin-Modulating Interventions

Strategies aimed at enhancing the host’s immune responses, particularly those affected by hepcidin-mediated iron regulation, can be explored. This includes interventions to improve the function of immune cells, such as T cells and macrophages, by mitigating the impact of hepcidin-induced iron restriction. Vaccines that target Plasmodium antigens and enhance the host’s immune response can be used in combination with hepcidin-modulating therapies. By bolstering the host’s immunity, these vaccines may lead to improved antimalarial defense [77].Top of FormBottom of Form

CONCLUSION

Hepcidin, the “gatekeeper of iron” in the host’s defense against malaria, emerges as a pivotal player in the intricate battle against Plasmodium parasites. Hepcidin’s multifaceted roles in regulating iron homeostasis, influencing the immune response, and shaping the host’s defense strategies against malaria offer valuable insights and potential solutions in the battle against this devastating disease. As we continue to unravel the intricate host-parasite dynamics and refine our understanding of hepcidin’s functions, we move closer to the development of more effective strategies for malaria prevention and treatment.

REFERENCES

  1. Obeagu, E. I., Chijioke, U. O., & Ekelozie, I. S. (2018). Malaria rapid diagnostic test (RDTs). Ann Clin Lab Res, 6(4), 275.
  2. Obeagu, E. I., Obeagu, G. U., Chukwueze, C. M., Ikpenwa, J. N., & Ramos, G. F. (2022). EVALUATION OF PROTEIN C, PROTEIN S AND FIBRINOGEN OF PREGNANT WOMEN WITH MALARIA IN OWERRI METROPOLIS. Madonna University journal of Medicine and Health Sciences ISSN: 2814-3035, 2(2), 1-9.
  3. Obeagu, E. I., Ibeh, N. C., Nwobodo, H. A., Ochei, K. C., & Iwegbulam, C. P. (2017). Haematological indices of malaria patients coinfected with HIV in Umuahia. J. Curr. Res. Med. Sci, 3(5), 100-104.
  4. Hassan, A. O., Oso, O. V., Obeagu, E. I., & Adeyemo, A. T. (2022). Malaria Vaccine: Prospects and Challenges. Madonna University journal of Medicine and Health Sciences ISSN: 2814-3035, 2(2), 22-40.
  5. Ezeoru, V. C., Enweani, I. B., Ochiabuto, O., Nwachukwu, A. C., Ogbonna, U. S., & Obeagu, E. I. (2021). Prevalence of Malaria with Anaemia and HIV status in women of reproductive age in Onitsha, Nigeria. Journal of Pharmaceutical Research International, 33(4), 10-19.
  6. Ogomaka, I. A., & Obeagu, E. I. (2019). Methods of Breast Feeding as Determinants of Malaria Infections among Babies in IMO State, Nigeria. International Journal of Medical Science and Dental Research, 2(01), 17-24.
  7. Okorie, H. M., Obeagu, E. I., Obarezi, H. C., & Anyiam, A. F. (2019). Assessment of some inflammatory cytokines in malaria infected pregnant women in Imo State Nigeria. International Journal of Medical Science and Dental Research, 2(1), 25-36.
  8. Obeagu, E. I., Ogbonna, U. S., Nwachukwu, A. C., Ochiabuto, O., Enweani, I. B., & Ezeoru, V. C. (2021). Prevalence of Malaria with Anaemia and HIV status in women of reproductive age in Onitsha, Nigeria. Journal of Pharmaceutical Research International, 33(4), 10-19.
  9. Obeagu, E. I., Busari, A. I., Uduchi, I. O., Ogomaka, I. A., Ibekwe, A. M., Vincent, C. C. N., … & Adike, C. N. (2021). Age-Related Haematological Variations in Patients with Asymptomatic Malaria in Akure, Ondo State, Nigeria. Journal of Pharmaceutical Research International, 33(42B), 218-224.
  10. Swift, J. (2018). Iron Deficiency and Endurance Athletes (Doctoral dissertation, William Woods University).
  11. da Silva-Nunes, M., Moreno, M., Conn, J. E., Gamboa, D., Abeles, S., Vinetz, J. M., & Ferreira, M. U. (2012). Amazonian malaria: asymptomatic human reservoirs, diagnostic challenges, environmentally driven changes in mosquito vector populations, and the mandate for sustainable control strategies. Acta tropica, 121(3), 281-291.
  12. Sangkhae, V., & Nemeth, E. (2017). Regulation of the iron homeostatic hormone hepcidin. Advances in nutrition, 8(1), 126-136.
  13. Obeagu, E., Felix, C. E., MTB, O., Chikodili, U. M., Nchekwubedi, C. S., & Chinedum, O. K. (2021). Studies on some cytokines, CD4, iron status, hepcidin and some haematological parameters in pulmonary tuberculosis patients based on duration of treatment in Southeast, Nigeria. African Journal of Biological Sciences, 3(1), 146-156.
  14. Ifeanyi, O. E. (2020). Studies on Some Cytokines, Hepcidin, Iron Status and Haematological Parameters of Patients with Pulmonary Tuberculosis in Southeast, Nigeria. EC Pulmonology and Respiratory Medicine, 9, 12-23.
  15. Obeagu Emmanuel, I., Chukwurah Ejike, F., Ochiabuto, M. T. B., Ugwuja Mabel, C., Chukwu Stella, N., & Ochei Kingley, C. (2021). Studies on some cytokines, CD4, iron status, hepcidin and some haematological parameters in pulmonary tuberculosis patients based on duration of treatment in Southeast, Nigeria.
  16. Obeagu, E. I., Okoroiwu, I. L., & Azuonwu, O. (2018). An update on hypoxic regulation of iron homeostasis and bone marrow environment. J. Curr. Res. Med. Sci, 4(10), 42-48.
  17. Ifeanyi, O., Ochie, K., Nonyelum, E., Chikodili, U., Chinemerem, O., & Ijego, A. (2020). Evaluation of Some Cytokines, CD4, Hepcidin, Iron, and Some Haematological Parameters of Patients Living with Human Immunodeficiency Virus in Southeastern Part of Nigeria. Journal of Pharmaceutical Research International, 32(14), 6-14.
  18. Nnodim, J., Uche, U., Ifeoma, U., Chidozie, N., Ifeanyi, O., & Oluchi, A. A. (2015). Hepcidin and erythropoietin level in sickle cell disease. British Journal of Medicine and Medical Research, 8(3), 261-265.
  19. Ifeanyi, O., Uzoma, O., Nonyelum, E., Amaeze, A. A., Ngozi, A., & Ijego, A. (2020). Studies on some cytokines, CD4, hepcidin, iron, and some haematological parameters of patients with pulmonary tuberculosis and human immunodeficiency virus in Southeast, Nigeria. Journal of Pharmaceutical Research International, 32(21), 149-159.
  20. Ifeanyi, O., Uzoma, O., Nonyelum, E., Amaeze, A., Ngozi, A., Stella, E., & Chukwu, O. (2020). Studies on Some Cytokines, CD4, Hepcidin, Iron, and Some Haematological Parameters of Pulmonary Tuberculosis Patients Co-infected with Human Immunodeficiency Virus on Chemotherapy for 60 Days in Southeast, Nigeria. Journal of Pharmaceutical Research International, 32(22), 11-22.
  21. Reichert, C. O., da Cunha, J., Levy, D., Maselli, L. M. F., Bydlowski, S. P., & Spada, C. (2017). Hepcidin: homeostasis and diseases related to iron metabolism. Acta haematologica, 137(4), 220-236.
  22. Wang, J., & Pantopoulos, K. (2011). Regulation of cellular iron metabolism. Biochemical Journal, 434(3), 365-381.
  23. Xiao, X., Alfaro-Magallanes, V. M., & Babitt, J. L. (2020). Bone morphogenic proteins in iron homeostasis. Bone, 138, 115495.
  24. Obeagu, E. I. (2020). Erythropoeitin in Sickle Cell Anaemia: A Review. International Journal of Research Studies in Medical and Health Sciences, 5(2), 22-8.
  25. Obeagu, E. I., Obeagu, G. U., Nchuma, B. O., & Amazue, P. O. (2015). A Review on erythropoietin receptor (EpoR). J. Adv. Res. Biol. Sci, 2(8), 80-84.
  26. Obeagu, E. I., Okoroiwu, I. L., & Obeagu, G. (2015). Molecular mechanism and systemic response of erythropoietin: A Review. J. Adv. Res. Biol. Sci, 2(7), 58-62.
  27. Obeagu, E. I., Ezimah, A. C., & Obeagu, G. U. (2016). Erythropoietin in the anaemias of pregnancy: a review. Int J Curr Res Chem Pharm Sci, 3(3), 10-8.
  28. Ifeanyi, O. E. (2015). A review on erythropoietin. Int J Adv Res Biol Sci, 2(4), 35-47.
  29. Obeagu, E. I., Okoroiwu, I. I., & Ezimah, A. C. U. (2016). Evaluation of serum erythropoietin levels in chronic kidney disease patients in Federal Medical centre, Umuahia, Nigeria. J. Curr. Res. Biol. Med, 1(4), 15-21.
  30. Obeagu, E. I. (2016). Erythrocyte enumeration and serum erythropoietin in chronic kidney disease patients: A study in Federal Medical Centre, Umuahia, Nigeria. International Journal of Advanced Research in Biological Sciences, 3(7), 163-170.
  31. Ifeanyi, O. E., & Uzoma, O. G. (2018). A review on erythropietin in pregnancy. Gynecol. Womens Health, 8(3), 1-4.
  32. Obeagu, E. I., Muhimbura, E., Kagenderezo, B. P., Nakyeyune, S., & Obeagu, G. U. (2022). An Insight of Interleukin-6 and Fibrinogen: In Regulating the Immune System. J Biomed Sci, 11(10), 83.
  33. Obeagu, E. I., Nwosu, D. C., & Obeagu, G. U. Interleukin-6 (IL-6): A Major target for quick recovery of COVID-19 patients.
  34. Obeagu, E. I., Okoroiwu, I. L., Nwanjo, H. U., & Nwosu, D. C. (2019). Evaluation of interferon-gamma, interleukin 6 and interleukin 10 in tuberculosis patients in Umuahia. Ann Clin Lab Res, 7(2), 307.
  35. Obeagu, E. I., Nwazu, M. E., & Obeagu, G. U. (2022). Evaluation of plasma levels of interleukin 6 and iron status based on sleeping patterns of students in a Nigerian University. J. Curr. Res. Med. Sci, 8(9), 1-6.
  36. Obeagu, E. I. (2022). Gender-based assessment of tumour necrosis factor–alpha and interleukin–6 of patients with Schizophrenia in Nigeria. J. Adv. Res. Biol. Sci, 9(9), 29-35.
  37. Obeagu, E. I., Amedu, G. O., Okoroiwu, I. L., Okafor, C. J., Okun, O., Ochiabuto, O. M., & Ukeekwe, C. O. (2021). Evaluation of plasma levels of interleukin 6 and iron status of football players in a Nigerian university. Journal of Pharmaceutical Research International, 33(59B), 383-388.
  38. Obeagu, E. I., Anierobi, C. C., Eze, G. C., Chukwueze, C. M., Makonyonga, R. D., Amadi, N. M., & Hassan, R. (2022). Evaluation of Plasma Levels of Interleukin 6 and Iron Status of Volleyball Players in a Nigerian University. Journal of Advances in Medical and Pharmaceutical Sciences, 24(6), 18-23.
  39. Obeagu, E. I., Obeagu, G. U., Guevara, M. E. C., Okafor, C. J., Bot, Y. S., Eze, G. C., … & Uwakwe, O. S. (2022). Evaluation of Plasma Levels of Interleukin 6 and Iron of Volleyball Players Based on Heights and Weight of a Nigerian University Students. Asian Journal of Medicine and Health, 20(10), 147-152.
  40. Muñoz, M., Villar, I., & García-Erce, J. A. (2009). An update on iron physiology. World journal of gastroenterology: WJG, 15(37), 4617.
  41. Ganz, T., & Nemeth, E. (2012). Hepcidin and iron homeostasis. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1823(9), 1434-1443.
  42. Winn, N. C., Volk, K. M., & Hasty, A. H. (2020). Regulation of tissue iron homeostasis: the macrophage “ferrostat”. JCI insight, 5(2).
  43. Nairz, M., Dichtl, S., Schroll, A., Haschka, D., Tymoszuk, P., Theurl, I., & Weiss, G. (2018). Iron and innate antimicrobial immunity—depriving the pathogen, defending the host. Journal of Trace Elements in Medicine and Biology, 48, 118-133.
  44. Michels, K., Nemeth, E., Ganz, T., & Mehrad, B. (2015). Hepcidin and host defense against infectious diseases. PLoS pathogens, 11(8), e1004998.
  45. Overstreet, M. G., Cockburn, I. A., Chen, Y. C., & Zavala, F. (2008). Protective CD8+ T cells against Plasmodium liver stages: immunobiology of an ‘unnatural’immune response. Immunological reviews, 225(1), 272-283.
  46. Aitken, E. H., Mahanty, S., & Rogerson, S. J. (2020). Antibody effector functions in malaria and other parasitic diseases: a few needles and many haystacks. Immunology and Cell Biology, 98(4), 264-275.
  47. Camaschella, C., Nai, A., & Silvestri, L. (2020). Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica, 105(2), 260.
  48. Ogomaka, I. A., & Obeagu, E. I. (2021). Malaria in Pregnancy Amidst Possession of Insecticide Treated Bed Nets (ITNs) in Orlu LGA of Imo State, Nigeria. Journal of Pharmaceutical Research International, 33(41B), 380-386.
  49. Ogbonna, C. O., Obeagu, E. I., Ufelle, S. A., & Ogbonna, L. N. (2021). Evaluation of haematological alterations in children infected by Plasmodium falciparum Species in Enugu, Enugu State, Nigeria. Journal of Pharmaceutical Research International, 33(1), 38-45.
  50. Nwosu, D. C., Obeagu, E. I., Ezenwuba, C., Agu, G. C., Amah, H., Ozims, S. J., … & Emesowum, A. C. (2016). Antioxidant status of children with Plasmodium falciparum malaria in Owerri municipal council of Imo state. J. Curr. Res. Chem. Pharm. Sci, 3(8), 40-46.
  51. Okamgba, O. C., Nwosu, D. C., Nwobodo, E. I., Agu, G. C., Ozims, S. J., Obeagu, E. I., … & Ifeanyichukwu, M. O. (2017). Iron Status of Pregnant and Post-Partum Women with Malaria Parasitaemia in Aba Abia State, Nigeria. Annals of Clinical and Laboratory Research, 5(4), 206.
  52. Madekwe, C. C., Madekwe, C. C., & Obeagu, E. I. (2022). Inequality of monitoring in Human Immunodeficiency Virus, Tuberculosis and Malaria: A Review. Madonna University journal of Medicine and Health Sciences ISSN: 2814-3035, 2(3), 6-15.
  53. Nemeth, E., & Ganz, T. (2006). Regulation of iron metabolism by hepcidin. Rev. Nutr., 26, 323-342.
  54. Anyiam, A. F., Arinze-Anyiam, O. C., Omosigho, P. O., Ibrahim, M., Irondi, E. A., Obeagu, E. I., & Obi, E. (2022). Blood Group, Genotype, Malaria, Blood Pressure and Blood Glucose Screening Among Selected Adults of a Community in Kwara State: Implications to Public Health. Asian Hematology Research Journal, 6(3), 9-17.
  55. Okorie, H. M., Obeagu, E. I., Eze, E. N., & Jeremiah, Z. A. (2018). Assessment of some haematological parameters in malaria infected pregnant women in Imo state Nigeria. J. Curr. Res. Biol. Med, 3(9), 1-14.
  56. Offie, D. C., Ibekwe, A. M., Agu, C. C., Esimai, B. N., Okpala, P. U., Obeagu, E. I., … & Ogbonna, L. N. (2021). Fibrinogen and C-Reactive Protein Significance in Children Infected by Plasmodium falciparum Species in Enugu, Enugu State, Nigeria. Journal of Pharmaceutical Research International, 33(15), 1-8.
  57. Okorie, H. M., Obeagu, E. I., Eze, E. N., & Jeremiah, Z. A. (2018). Assessment of coagulation parameters in malaria infected pregnant women in Imo state, Nigeria. International Journal of Current Research in Medical Sciences, 4(9), 41-49.
  58. Ogbonna, L. N., Ezeoru, V. C., Ofodile, A. C., Ochiabuto, O. M. T. B., Obi-Ezeani, C. N., Okpala, P. U., … & Obeagu, E. I. (2021). Gender Based Variations of Haematological Parameters of Patients with Asymptomatic Malaria in Akure, Ondo State, Nigeria. Journal of Pharmaceutical Research International, 33(8), 75-80.
  59. Wideman, S. K. (2022). Cellular iron governs the host response to malaria infection and vaccination (Doctoral dissertation, University of Oxford).
  60. Obeagu, E. I., Ofodile, A. C., & Okwuanaso, C. B. A review on socio economic and behavioral aspects of malaria and its control among children under 5 years of age in Africa. J Pub Health Nutri. 2023; 6 (1): 136.
  61. Ifeanyi, O., Uzoma, O., Amaeze, A., Ijego, A., Felix, C., Ngozi, A., … & Chinenye, K. (2020). Maternal expressions (serum levels) of alpha tumour necrosis factor, interleukin 10, interleukin 6 and interleukin 4 in malaria infected pregnant women based on parity in a Tertiary Hospital in Southeast, Nigeria. Journal of Pharmaceutical Research International, 32(23), 35-41.
  62. Ogalue, U. M., Ekejindu, I. M., Ochiabuto, O. M., Obi, M. C., Obeagu, E., & Ekelozie, I. S. (2018). Intestinal parasites, Malaria and Anaemia among school children in some flood affected areas of Ogbaru Local Government Area of Anambra State, Nigeria. Archives of Clinical Microbiology, 9(2), 1-6.
  63. Leticia, O. I., Ifeanyi, O. E., Queen, E., & Chinedum, O. K. (2014). Some hematological parameters in malaria parasitaemia. IOSR Journal of Dental and Medical Sciences, 13(9).
  64. Obeagu, E. I., Uzoije, N. U., Afoma, I., Ogbodo, O. R., & Onyenweaku, F. C. (2013). Malaria, ABO blood group and haemoglobin genotypes in Michael Okpara University of Agriculture, Umudike, Abia State. PHARMANEST, 4(5), 1110-1113.
  65. Ifeanyi, E. O., & Uzoma, G. O. (2020). Malaria and The Sickle Cell Trait: Conferring Selective Protective Advantage to Malaria. J Clin Med Res, 2, 1-4.
  66. Obeagu, E. I., Ochei, K. C., & Mbah, P. C. (2019). Haemolysis associated with malaria infection: A threat to human existence. World Journal of Pharmaceutical and Medical Research, 5(6), 47-49.
  67. Nwosu, D. C., Nwanjo, H. U., Obeagu, E. I., Ibebuike, J. E., & Ezeama, M. C. (2015). Ihekireh. Changes in liver enzymes and lipid profile of pregnant women with malaria in Owerri, Nigeria. International Journal of Current Research and Academic Review, 3(5), 376-83.
  68. Ifeanyi, O. E. (2020). Iron Status of Malarial Infected Pregnant Women: A Review. International Journal of Research, 5(1), 08-18.
  69. Ifeanyi, O., Nonyelum, E., Stella, E., Ijego, A. E., Amaeze, A. A., Nchekwubedi, C., … & Kyrian, C. (2020). Maternal Serum Levels of Alpha Tumour Necrotic Factor, Interleukin 10, Interleukin 6 and Interleukin 4 in Malaria Infected Pregnant Women Based on Their Gestational Age in Southeast, Nigeria. Journal of Pharmaceutical Research International, 32(14), 64-70.
  70. Rishi, G., Wallace, D. F., & Subramaniam, V. N. (2015). Hepcidin: regulation of the master iron regulator. Bioscience reports, 35(3), e00192.
  71. Wideman, S. K., Frost, J. N., Richter, F. C., Naylor, C., Lopes, J. M., Viveiros, N., … & Drakesmith, H. (2023). Cellular iron governs the host response to malaria. Plos Pathogens, 19(10), e1011679.
  72. Martins, A. C., Almeida, J. I., Lima, I. S., Kapitao, A. S., & Gozzelino, R. (2017). Iron metabolism and the inflammatory response. IUBMB life, 69(6), 442-450.
  73. Müller, S. (2004). Redox and antioxidant systems of the malaria parasite Plasmodium falciparum. Molecular microbiology, 53(5), 1291-1305.
  74. Rauf, A., Shariati, M. A., Khalil, A. A., Bawazeer, S., Heydari, M., Plygun, S., … & Aljohani, A. S. (2020). Hepcidin, an overview of biochemical and clinical properties. Steroids, 160, 108661.
  75. Abosalif, K. O. A., Abdalla, A. E., Junaid, K., Eltayeb, L. B., & Ejaz, H. (2023). The interleukin-10 family: Major regulators of the immune response against Plasmodium falciparum infections. Saudi Journal of Biological Sciences, 103805.
  76. Iron chelation therapies, which involve the administration of iron-binding molecules, can help sequester iron within the host, making it less accessible to Plasmodium parasites
  77. Busbridge, M. (2013). The physiology and pathophysiology of hepcidin.
  78. Ugwu, O. P.C., Nwodo, O. F.C., Joshua, P. E., Odo, C. E., Bawa, A., Ossai, E. C. and Adonu C. C. (2013). Anti-malaria and Hematological Analyses of Ethanol Extract of Moringa oleifera Leaf on Malaria Infected Mice. International Journal of Pharmacy and Biological Sciences,3(1):360-371.
  79. Ugwu O.P.C.(2011).Anti-Malaria Effect of Ethanol Extract of Moringa Oleifera (Agbaji) Leaves on Malaria Induced Mice. University of Nigeria Nsukka. 39.
  80. Ugwu Okechukwu P.C., Nwodo, Okwesili F.C., Joshua, Parker E., Odo, Christian E. and Ossai Emmanuel C. (2013). Effect of Ethanol Leaf Extract of Moringa oleifera on Lipid profile of malaria infected mice. Research Journal of Pharmaceutical, Biological and Chemical Sciences,4(1): 1324-1332.
  81. Ugwu OPC, OFC Nwodo, PE Joshua, CE Odo, EC Ossai, B Aburbakar(2013). Ameliorative effects of ethanol leaf extract of Moringa oleifera on the liver and kidney markers of malaria infected mice. International Journal of Life Sciences Biotechnology and Pharma Research,2(2): 43-52.
  82. Enechi OC, CC Okpe, GN Ibe, KO Omeje and PC Ugwu Okechukwu (2016). Effect of Buchholzia coriacea methanol extract on haematological indices and liver function parameters in Plasmodium berghei-infected mice. Global Veterinaria, 16 (1): 57-66.   CITE AS: Emmanuel Ifeanyi Obeagu, Esther U. Alum and Okechukwu P.C. Ugwu (2023). Hepcidin: The Gatekeeper of Iron in Malaria Resistance NEWPORT INTERNATIONAL JOURNAL OF RESEARCH IN MEDICAL SCIENCES 4(2):1-8. https://doi.org/10.59298/NIJRMS/2023/10.1.1400
    DOWNLOAD PDF