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Navidifar T, Meftah E, Baghsheikhi H, Kazemzadeh K, Karimi H, Rezaei N. Dual role of hepcidin in response to pathogens. Microb Pathog 2025; 203:107496. [PMID: 40118299 DOI: 10.1016/j.micpath.2025.107496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 03/15/2025] [Accepted: 03/19/2025] [Indexed: 03/23/2025]
Abstract
Hepcidin is the primary regulator of vertebrate iron homeostasis. Its production is stimulated by systemic iron levels and inflammatory signals. Although the role of hepcidin in iron homeostasis is well characterized, its response to pathogenic agents is complex and diverse. In this review, we examine studies that investigate the role of hepcidin in response to infectious agents. Interleukin-6 (IL-6) is a key factor responsible for the induction of hepcidin expression. During infection, hepcidin-mediated depletion of extracellular iron serves as a protective mechanism against a variety of pathogens. However, accumulation of iron in macrophages through hepcidin-mediated pathways may increase susceptibility to intracellular pathogens such as Mycobacterium tuberculosis. Prolonged elevation of hepcidin production can lead to anemia due to reduced iron availability for erythropoiesis, a condition referred to as anemia of inflammation. In addition, we highlight the role of hepcidin upregulation in several infectious contexts, including HIV-associated anemia, iron deficiency anemia in Helicobacter pylori infection, and post-malarial anemia in pediatric patients. In addition, we show that certain infectious agents, such as hepatitis C virus (HCV), can suppress hepcidin production during both the acute and chronic phases of infection, while hepatitis B virus (HBV) exhibits similar suppression during the chronic phase.
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Affiliation(s)
- Tahereh Navidifar
- Department of Basic Sciences, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran; Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Elahe Meftah
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hediyeh Baghsheikhi
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; USERN Office, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimia Kazemzadeh
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hanie Karimi
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Science, Tehran, Iran.
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D’Elia JA, Weinrauch LA. Role of Divalent Cations in Infections in Host-Pathogen Interaction. Int J Mol Sci 2024; 25:9775. [PMID: 39337264 PMCID: PMC11432163 DOI: 10.3390/ijms25189775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/29/2024] [Accepted: 09/05/2024] [Indexed: 09/30/2024] Open
Abstract
With increasing numbers of patients worldwide diagnosed with diabetes mellitus, renal disease, and iatrogenic immune deficiencies, an increased understanding of the role of electrolyte interactions in mitigating pathogen virulence is necessary. The levels of divalent cations affect host susceptibility and pathogen survival in persons with relative immune insufficiency. For instance, when host cellular levels of calcium are high compared to magnesium, this relationship contributes to insulin resistance and triples the risk of clinical tuberculosis. The movement of divalent cations within intracellular spaces contributes to the host defense, causing apoptosis or autophagy of the pathogen. The control of divalent cation flow is dependent in part upon the mammalian natural resistance-associated macrophage protein (NRAMP) in the host. Survival of pathogens such as M tuberculosis within the bronchoalveolar macrophage is also dependent upon NRAMP. Pathogens evolve mutations to control the movement of calcium through external and internal channels. The host NRAMP as a metal transporter competes for divalent cations with the pathogen NRAMP in M tuberculosis (whether in latent, dormant, or active phase). This review paper summarizes mechanisms of pathogen offense and patient defense using inflow and efflux through divalent cation channels under the influence of parathyroid hormone vitamin D and calcitonin.
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Affiliation(s)
| | - Larry A. Weinrauch
- Kidney and Hypertension Section, E P Joslin Research Laboratory, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Davids R, Robinson G, Van Tonder C, Robinson J, Ahmed N, Domingo A. Jehovah's Witness Needing Critical Care: A Narrative Review on the Expanding Arsenal. Crit Care Res Pract 2024; 2024:1913237. [PMID: 38813134 PMCID: PMC11136542 DOI: 10.1155/2024/1913237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 03/08/2024] [Accepted: 04/13/2024] [Indexed: 05/31/2024] Open
Abstract
Present day Jehovah's Witness (JW) religion accounts for 8.5 million followers. A tenant feature of the JW faith is religious objection to transfusions of blood and blood products. Interpatient variability, as it pertains to blood and blood products may occur; hence, a confidential interview will determine which products individual may consent to (Marsh and Bevan, 2002). This belief and practice place great restrictions on treating medical professionals in scenarios of life-threatening anaemia and active haemorrhage. The review to follow explores the physiological and pathophysiological consequences of severe anaemia. Non-blood transfusion practices are explored, many of which are potentially lifesaving. Particular attention is drawn to the evolving science involving artificial oxygen carriers and their use in emergency situations. A greater safety profile ensures its future use amongst religious objectors to be greatly beneficial. Intravenous iron supplementation has enjoyed a lively debate within the critical care community. A review of recent systematic and meta-analysis supports its use in the ICU; however, more investigation is needed into the complementary use of hepcidin.
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Affiliation(s)
- Ryan Davids
- Department of Anaesthesiology and Critical Care, Stellenbosch University, Stellenbosch, Western Cape, South Africa
| | - Gareth Robinson
- Department of Anaesthesiology and Critical Care, Stellenbosch University, Stellenbosch, Western Cape, South Africa
| | - Charmé Van Tonder
- Department of Anaesthesiology and Critical Care, Stellenbosch University, Stellenbosch, Western Cape, South Africa
| | - Jordan Robinson
- Department of Anaesthesiology and Critical Care, Stellenbosch University, Stellenbosch, Western Cape, South Africa
| | - Nadiyah Ahmed
- Department of Critical Care, University of Free State, Bloemfontein, South Africa
| | - Abdurragmaan Domingo
- Department of Anaesthesiology and Perioperative Medicine, University of Cape Town, Cape Town, Western Cape, South Africa
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Peng C, Cheng Y, Ma M, Chen Q, Duan Y, Liu S, Cheng H, Yang H, Huang J, Bu W, Shi C, Wu X, Chen J, Zheng R, Liu Z, Ji Z, Wang J, Huang X, Wang P, Sha W, Ge B, Wang L. Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine. Nat Commun 2024; 15:4216. [PMID: 38760394 PMCID: PMC11101664 DOI: 10.1038/s41467-024-48588-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 05/07/2024] [Indexed: 05/19/2024] Open
Abstract
Antimicrobial peptides (AMPs), ancient scavengers of bacteria, are very poorly induced in macrophages infected by Mycobacterium tuberculosis (M. tuberculosis), but the underlying mechanism remains unknown. Here, we report that L-alanine interacts with PRSS1 and unfreezes the inhibitory effect of PRSS1 on the activation of NF-κB pathway to induce the expression of AMPs, but mycobacterial alanine dehydrogenase (Ald) Rv2780 hydrolyzes L-alanine and reduces the level of L-alanine in macrophages, thereby suppressing the expression of AMPs to facilitate survival of mycobacteria. Mechanistically, PRSS1 associates with TAK1 and disruptes the formation of TAK1/TAB1 complex to inhibit TAK1-mediated activation of NF-κB pathway, but interaction of L-alanine with PRSS1, disables PRSS1-mediated impairment on TAK1/TAB1 complex formation, thereby triggering the activation of NF-κB pathway to induce expression of AMPs. Moreover, deletion of antimicrobial peptide gene β-defensin 4 (Defb4) impairs the virulence by Rv2780 during infection in mice. Both L-alanine and the Rv2780 inhibitor, GWP-042, exhibits excellent inhibitory activity against M. tuberculosis infection in vivo. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses its own alanine dehydrogenase to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.
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Affiliation(s)
- Cheng Peng
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China
| | - Yuanna Cheng
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China
| | - Mingtong Ma
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China
| | - Qiu Chen
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China
| | - Yongjia Duan
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China
| | - Shanshan Liu
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China
| | - Hongyu Cheng
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China
| | - Hua Yang
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jingping Huang
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China
| | - Wenyi Bu
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China
| | - Chenyue Shi
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China
| | - Xiangyang Wu
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jianxia Chen
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ruijuan Zheng
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhonghua Liu
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhe Ji
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China
| | - Jie Wang
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaochen Huang
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Peng Wang
- Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wei Sha
- Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Baoxue Ge
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China.
- Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
- Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Lin Wang
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China.
- Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
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Hayakawa K, Zhou Y, Shinton SA. B-1 derived anti-Thy-1 B cells in old aged mice develop lymphoma/leukemia with high expression of CD11b and Hamp2 that different from TCL1 transgenic mice. Immun Ageing 2024; 21:22. [PMID: 38570827 PMCID: PMC10988983 DOI: 10.1186/s12979-024-00415-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 02/05/2024] [Indexed: 04/05/2024]
Abstract
Human old aged unmutated chronic lymphocytic leukemia U-CLL are the TCL1+ZAP70+CD5+ B cells. Since CD5 makes the BCR signaling tolerance, ZAP70 increased in U-CLL not only TCL1+ alone. In mice, TCL1 (TCL1A) is the negative from neonate to old aged, as TC-. VH8-12/Vk21-5 is the anti-thymocyte/Thy-1 autoreactive ATA B cell. When ATA μκTg generation in mice, ATA B cells are the neonate generated CD5+ B cells in B-1, and in the middle age, CD5+ can be down or continuously CD5+, then, old aged CLL/lymphoma generation with increased CD11b in TC-ZAP70-CD5- or TC-ZAP70+CD5+. In this old aged TC-ATA B microarray analysis showed most similar to human CLL and U-CLL, and TC-ZAP70+CD5+ showed certain higher present as U-CLL. Original neonate ATA B cells showed with several genes down or further increase in old aged tumor, and old aged T-bet+CD11c+, CTNNB1hi, HMGBhi, CXCR4hi, DPP4hi and decreased miR181b. These old aged increased genes and down miR181b are similar to human CLL. Also, in old age ATA B cell tumor, high CD38++CD44++, increased Ki67+ AID+, and decreased CD180- miR15Olow are similar to U-CLL. In this old aged ATA B, increased TLR7,9 and Wnt10b. TC+Tg generated with ATAμκTg mice occurred middle age tumor as TC+ZAP70-CD5+ or TC+ZAP70+CD5+, with high NF-kB1, TLR4,6 and Wnt5b,6 without increased CD11b. Since neonatal state to age with TC+Tg continuously, middle age CLL/lymphoma generation is not similar to old aged generated, however, some increased in TC+ZAP70+ are similar to the old age TC- ATA B tumor. Then, TC- ATA B old age tumor showed some difference to human CLL. ATA B cells showed CD11b+CD22++, CD24 down, and hepcidin Hamp2++ with iron down. This mouse V8-12 similar to human V2-5, and V2-5 showed several cancers with macrophages/neutrophils generated hepcidin+ ironlow or some showed hepcidin- iron+ with tumor, and mouse V8-12 with different Vk19-17 generate MZ B cells strongly increased macrophage++ in old aged and generated intestine/colon tumor. Conclusion, neonate generated TC-ATA B1 cells in old aged tumor generation are CD11b+ in the leukemia CLL together with lymphoma cancer with hepcidin-related Hamp2++ in B-1 cell generation to control iron.
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Affiliation(s)
- Kyoko Hayakawa
- Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA, 19111, USA.
| | - Yan Zhou
- Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA, 19111, USA
| | - Susan A Shinton
- Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA, 19111, USA
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Krepuska M, Mayer B, Vitale-Cross L, Myneni VD, Boyajian MK, Németh K, Szalayova I, Cho T, McClain-Caldwell I, Gingerich AD, Han H, Westerman M, Rada B, Mezey É. Bone marrow stromal cell-derived hepcidin has antimicrobial and immunomodulatory activities. Sci Rep 2024; 14:3986. [PMID: 38368463 PMCID: PMC10874407 DOI: 10.1038/s41598-024-54227-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 02/09/2024] [Indexed: 02/19/2024] Open
Abstract
Bone marrow stromal cells (BMSCs) have immunomodulatory activities in numerous species and have been used in clinical trials. BMSCs also make antibacterial agents. Since hepcidin is known to have antimicrobial effects in fish, we wondered if it might also be used as an antimicrobial agent by mammalian BMSCs. In the present study, we show hepcidin expression in both mouse (mBMSC) and human BMSCs (hBMSC). We observed a hBMSC hepcidin-dependent degradation of ferroportin in HEK-293 reporter cells in vitro. In human and mouse bone marrows (BM) we detected hepcidin-positive BMSCs in close proximity to hematopoietic progenitors. The conditioned culture medium of hBMSCs significantly reduced bacterial proliferation that was partially blocked by a hepcidin-neutralizing antibody. Similarly, medium in which hepcidin-deficient (Hamp-/-) mouse BMSCs had been grown was significantly less effective in reducing bacterial counts than the medium of wild-type cells. In a zymosan-induced peritonitis mouse model we found that mBMSC-derived hepcidin reduced the number of invading polymorphonuclear (PMN) cells in the peritoneal cavity. Our results show that BMSC-derived hepcidin has antimicrobial properties in vitro and also reduces inflammation in vivo. We conclude that hepcidin should be added to the expanding arsenal of agents available to BMSCs to fight infections and inflammation.
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Affiliation(s)
- Miklós Krepuska
- National Institutes of Health, NIDCR, ASCS, Bethesda, MD, USA
- Department of Neuroradiology, University Hospital Zürich, Zürich, Switzerland
| | - Balázs Mayer
- National Institutes of Health, NIDCR, ASCS, Bethesda, MD, USA
- Stem Cell Laboratory, Department of Dermatology, Venereology and Dermato-Oncology, Semmelweis University, Budapest, Hungary
| | | | - Vamsee D Myneni
- National Institutes of Health, NIDCR, ASCS, Bethesda, MD, USA
| | | | - Krisztián Németh
- National Institutes of Health, NIDCR, ASCS, Bethesda, MD, USA
- Stem Cell Laboratory, Department of Dermatology, Venereology and Dermato-Oncology, Semmelweis University, Budapest, Hungary
| | | | - Ted Cho
- National Institutes of Health, NIDCR, ASCS, Bethesda, MD, USA
| | | | - Aaron D Gingerich
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | | | | | - Balázs Rada
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, USA.
| | - Éva Mezey
- National Institutes of Health, NIDCR, ASCS, Bethesda, MD, USA
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Ahmadi Badi S, Bereimipour A, Rohani P, Khatami S, Siadat SD. Interplay between gut microbiota and the master iron regulator, hepcidin, in the pathogenesis of liver fibrosis. Pathog Dis 2024; 82:ftae005. [PMID: 38555503 PMCID: PMC10990161 DOI: 10.1093/femspd/ftae005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 02/12/2024] [Accepted: 03/28/2024] [Indexed: 04/02/2024] Open
Abstract
INTRODUCTION There is a proven role for hepcidin and the composition of gut microbiota and its derivatives in the pathophysiology of liver fibrosis. AREA COVERED This review focuses on the literature search regarding the effect of hepcidin and gut microbiota on regulating liver physiology. We presented the regulating mechanisms of hepcidin expression and discussed the possible interaction between gut microbiota and hepcidin regulation. Furthermore, we investigated the importance of the hepcidin gene in biological processes and bacterial interactions using bioinformatics analysis. EXPERT OPINION One of the main features of liver fibrosis is iron accumulation in hepatic cells, including hepatocytes. This accumulation can induce an oxidative stress response, inflammation, and activation of hepatic stellate cells. Hepcidin is a crucial regulator of iron by targeting ferroportin expressed on hepatocytes, macrophages, and enterocytes. Various stimuli, such as iron load and inflammatory signals, control hepcidin regulation. Furthermore, a bidirectional relationship exists between iron and the composition and metabolic activity of gut microbiota. We explored the potential of gut microbiota to influence hepcidin expression and potentially manage liver fibrosis, as the regulation of iron metabolism plays a crucial role in this context.
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Affiliation(s)
- Sara Ahmadi Badi
- Biochemistry Department, Pasteur Institute of Iran, Tehran, 1963737611, Iran
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, 1416753955, Iran
| | - Ahmad Bereimipour
- Department of Biological Sciences and BioDiscovery Institute, University of North Texas, Denton, TX 76203, USA
| | - Pejman Rohani
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, 1416753955, Iran
| | - Shohreh Khatami
- Biochemistry Department, Pasteur Institute of Iran, Tehran, 1963737611, Iran
| | - Seyed Davar Siadat
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, 1963737611, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran,1963737611, Iran
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Hong J, Mukherjee B, Sanjoba C, Yamagishi J, Goto Y. Upregulation of ATP6V0D2 benefits intracellular survival of Leishmania donovani in erythrocytes-engulfing macrophages. Front Cell Infect Microbiol 2024; 14:1332381. [PMID: 38357442 PMCID: PMC10864549 DOI: 10.3389/fcimb.2024.1332381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 01/12/2024] [Indexed: 02/16/2024] Open
Abstract
Visceral leishmaniasis (VL) is the most severe type of leishmaniasis which is caused by infection of Leishmania donovani complex. In the BALB/c mouse model of VL, multinucleated giant cells (MGCs) with heavy parasite infection consist of the largest population of hemophagocytes in the spleen of L. donovani-infected mice, indicating that MGCs provide the parasites a circumstance beneficial for their survival. Although ATP6V0D2 is a demonstrated factor inducing the formation of hemophagocytic MGCs during L. donovani infection, functions of this protein in shaping the infection outcome in macrophages remain unclear. Here we evaluated the influence of upregulated ATP6V0D2 on intracellular survival of the parasites. L. donovani infection-induced hemophagocytosis of normal erythrocytes by macrophages was suppressed by RNAi-based knockdown of Atp6v0d2. The knockdown of Atp6v0d2 did not improve the survival of amastigotes within macrophages when the cells were cultured in the absence of erythrocytes. On the other hand, reduced intracellular survival of amastigotes in macrophages by the knockdown was observed when macrophages were supplemented with antibody-opsonized erythrocytes before infection. There, increase in cytosolic labile iron pool was observed in the L. donovani-infected knocked-down macrophages. It suggests that ATP6V0D2 plays roles not only in upregulation of hemophagocytosis but also in iron trafficking within L. donovani-infected macrophages. Superior access to iron in macrophages may be how the upregulated expression of the molecule brings benefit to Leishmania for their intracellular survival in the presence of erythrocytes.
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Affiliation(s)
- Jing Hong
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Budhaditya Mukherjee
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Chizu Sanjoba
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Junya Yamagishi
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Yasuyuki Goto
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
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R PA, Anbarasu A. Antimicrobial Peptides as Immunomodulators and Antimycobacterial Agents to Combat Mycobacterium tuberculosis: a Critical Review. Probiotics Antimicrob Proteins 2023; 15:1539-1566. [PMID: 36576687 DOI: 10.1007/s12602-022-10018-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/22/2022] [Indexed: 12/29/2022]
Abstract
Tuberculosis (TB) is a devastating disease foisting a significantly high morbidity, prepotent in low- and middle-income developing countries. Evolution of drug resistance among Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, has made the TB treatment more complicated. The protracted nature of present TB treatment, persistent and tolerant Mtb populations, interaction with antiretroviral therapy and existing toxicity concerned with conventional anti-TB drugs are the four major challenges inflicted with emergence of drug-resistant mycobacterial strains, and the standard medications are unable to combat these strains. These factors emphasize an exigency to develop new drugs to overcome these barriers in current TB therapy. With this regard, antimycobacterial peptides derived from various sources such as human cells, bacterial sources, mycobacteriophages, fungal, plant and animal sources could be considered as antituberculosis leads as most of these peptides are associated with dual advantages of having both bactericidal activity towards Mtb as well as immuno-regulatory property. Some of the peptides possess the additional advantage of interacting synergistically with antituberculosis medications too, thereby increasing their efficiency, underscoring the vigour of antimicrobial peptides (AMPs) as best possible alternative therapeutic candidates or adjuvants in TB treatment. Albeit the beneficiary features of these peptides, few obstacles allied with them like cytotoxicity and proteolytic degradation are matter of concerns too. In this review, we have focused on structural hallmarks, targeting mechanisms and specific structural aspects contributing to antimycobacterial activity and discovered natural and synthetic antimycobacterial peptides along with their sources, anti-TB, immuno-regulatory properties, merits and demerits and possible delivery methods of AMPs.
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Affiliation(s)
- Preethi A R
- Medical & Biological Computing Laboratory, School of Bio-Sciences & Technology, Vellore Institute of Technology, Vellore-632014, India
- Department of Biotechnology, SBST, VIT, Vellore-632014, Tamil Nadu, India
| | - Anand Anbarasu
- Medical & Biological Computing Laboratory, School of Bio-Sciences & Technology, Vellore Institute of Technology, Vellore-632014, India.
- Department of Biotechnology, SBST, VIT, Vellore-632014, Tamil Nadu, India.
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Stefanache A, Lungu II, Butnariu IA, Calin G, Gutu C, Marcu C, Grierosu C, Bogdan Goroftei ER, Duceac LD, Dabija MG, Popa F, Damir D. Understanding How Minerals Contribute to Optimal Immune Function. J Immunol Res 2023; 2023:3355733. [PMID: 37946846 PMCID: PMC10632063 DOI: 10.1155/2023/3355733] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/16/2023] [Accepted: 09/09/2023] [Indexed: 11/12/2023] Open
Abstract
Sufficient mineral supply is vital not only for the innate immune system but also for the components of the adaptive immune defense, which encompass defense mechanisms against pathogens and the delicate balance of pro- and anti-inflammatory regulation in the long term. Generally, a well-balanced diet is capable of providing the necessary minerals to support the immune system. Nevertheless, specific vulnerable populations should be cautious about obtaining adequate amounts of minerals such as magnesium, zinc, copper, iron, and selenium. Inadequate levels of these minerals can temporarily impair immune competence and disrupt the long-term regulation of systemic inflammation. Therefore, comprehending the mechanisms and sources of these minerals is crucial. In exceptional circumstances, mineral deficiencies may necessitate supplementation; however, excessive intake of supplements can have adverse effects on the immune system and should be avoided. Consequently, any supplementation should be approved by medical professionals and administered in recommended doses. This review emphasizes the crucial significance of minerals in promoting optimal functioning of the immune system. It investigates the indispensable minerals required for immune system function and the regulation of inflammation. Moreover, it delves into the significance of maintaining an optimized intake of minerals from a nutritional standpoint.
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Affiliation(s)
- Alina Stefanache
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Ionut-Iulian Lungu
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | | | - Gabriela Calin
- Faculty of Dental Medicine, “Apollonia” University of Iasi, 11 Pacurari Street, Iasi 700511, Romania
| | - Cristian Gutu
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Constantin Marcu
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Carmen Grierosu
- Faculty of Dental Medicine, “Apollonia” University of Iasi, 11 Pacurari Street, Iasi 700511, Romania
| | | | - Letitia-Doina Duceac
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | | | - Florina Popa
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Daniela Damir
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
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11
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Jacobo-Delgado YM, Rodríguez-Carlos A, Serrano CJ, Rivas-Santiago B. Mycobacterium tuberculosis cell-wall and antimicrobial peptides: a mission impossible? Front Immunol 2023; 14:1194923. [PMID: 37266428 PMCID: PMC10230078 DOI: 10.3389/fimmu.2023.1194923] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 04/25/2023] [Indexed: 06/03/2023] Open
Abstract
Mycobacterium tuberculosis (Mtb) is one of the most important infectious agents worldwide and causes more than 1.5 million deaths annually. To make matters worse, the drug resistance among Mtb strains has risen substantially in the last few decades. Nowadays, it is not uncommon to find patients infected with Mtb strains that are virtually resistant to all antibiotics, which has led to the urgent search for new molecules and therapies. Over previous decades, several studies have demonstrated the efficiency of antimicrobial peptides to eliminate even multidrug-resistant bacteria, making them outstanding candidates to counterattack this growing health problem. Nevertheless, the complexity of the Mtb cell wall makes us wonder whether antimicrobial peptides can effectively kill this persistent Mycobacterium. In the present review, we explore the complexity of the Mtb cell wall and analyze the effectiveness of antimicrobial peptides to eliminate the bacilli.
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Aksoyalp ZŞ, Temel A, Erdogan BR. Iron in infectious diseases friend or foe?: The role of gut microbiota. J Trace Elem Med Biol 2023; 75:127093. [PMID: 36240616 DOI: 10.1016/j.jtemb.2022.127093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 09/13/2022] [Accepted: 10/05/2022] [Indexed: 12/07/2022]
Abstract
Iron is a trace element involved in metabolic functions for all organisms, from microorganisms to mammalians. Iron deficiency is a prevalent health problem that affects billions of people worldwide, and iron overload could have some hazardous effect. The complex microbial community in the human body, also called microbiota, influences the host immune defence against infections. An imbalance in gut microbiota, dysbiosis, changes the host's susceptibility to infections by regulating the immune system. In recent years, the number of studies on the relationship between infectious diseases and microbiota has increased. Gut microbiota is affected by different parameters, including mode of delivery, hygiene habits, diet, drugs, and plasma iron levels during the lifetime. Gut microbiota may influence iron levels in the body, and iron overload and deficiency can also affect gut microbiota composition. Novel researches on microbiota shed light on the fact that the bidirectional interactions between gut microbiota and iron play a role in the pathogenesis of many diseases, especially infections. A better understanding of these interactions may help us to comprehend the pathogenesis of many infectious and metabolic diseases affecting people worldwide and following the development of more effective preventive and/or therapeutic strategies. In this review, we aimed to present the iron-mediated host-gut microbiota interactions, susceptibility to bacterial infections, and iron-targeted therapy approaches for infections.
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Affiliation(s)
- Zinnet Şevval Aksoyalp
- Izmir Katip Celebi University, Faculty of Pharmacy, Department of Pharmacology, Izmir, Turkey.
| | - Aybala Temel
- Izmir Katip Celebi University, Faculty of Pharmacy, Department of Pharmaceutical Microbiology, Izmir, Turkey.
| | - Betul Rabia Erdogan
- Izmir Katip Celebi University, Faculty of Pharmacy, Department of Pharmacology, Izmir, Turkey.
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Amoah K, Yan X, Liu H, Pan S, Li T, Suo X, Tan B, Zhang S, Huang W, Xie M, Yang S, Zhang H, Yang Y, Dong X. Substituting fish meal with castor meal in diets of hybrid grouper (Epinephelus fuscoguttatus♀ × E. lanceolatus♂): Effects on growth performance, immune response, antioxidant and digestive enzyme activities, gut morphology, and inflammatory-related gene expression. FISH & SHELLFISH IMMUNOLOGY 2022; 131:181-195. [PMID: 36206996 DOI: 10.1016/j.fsi.2022.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 09/25/2022] [Accepted: 10/01/2022] [Indexed: 06/16/2023]
Abstract
The present study was conducted to investigate the effects of replacing fishmeal (FM) with castormeal (CM) on the growth performance, immune response, antioxidant and digestive enzyme activities, intestinal morphology, and expression of inflammatory-related genes in juvenile hybrid grouper (Epinephelus fuscoguttatus♀ ×E. lanceolatus♂). Six iso-nitrogenous (50% crude protein) and iso-lipidic (10% crude lipid) diets were formulated; namely, a reference diet (FM) containing 50% FM and five experimental diets (4% (CM4), 8% (CM8), 12% (CM12), 16% (CM16), and 20% (CM20)) in which FM protein was substituted with CM at varying levels to feed fish (initial weight: 9.12 ± 0.01 g) for 8 weeks. The results showed that the final weight, weight gain rate, and specific growth rate were highest in the FM, CM4, and CM8 groups, whereas the feed conversion ratio, hepatosomatic and viscerosomatic indexes were significantly enhanced in the CM4 group in comparison to the others. The CM4 and CM12 groups were observed to show the highest intestinal length index values compared to the other groups, with the CM20 revealing the worst growth performance. The serum total protein content first increased (P < 0.05) in the CM4 group and decreased (P < 0.05) afterward. Nonetheless, a decreasing significant (P < 0.05) cholesterol and triglyceride contents were witnessed with the increasing replacement of FM with CM. Compared to the control group, a significant increase (P < 0.05) in the activities of serum and liver immunoglobulin-M, superoxide dismutase, glutathione peroxidase, total antioxidant capacity, and complement-3 (except serum activity for CM12 group); liver lysozyme; intestinal amylase, and lipase, was witnessed in the CM groups. However, the serum lysozyme activity was highest (P < 0.05) in the CM4 group and lowest in the CM20 group. While the least serum malondialdehyde contents were observed in the CM4 group, that of the liver malondialdehyde was least witnessed in the FM, CM4, CM8, CM12, and CM16 groups as compared to the CM20. The intestinal histological examination revealed a significantly decreasing trend for villi height and villi width with increasing replacement levels. However, the muscle thickness, crypt depth, and type II mucus cells first increased upto 4% replacement level and later decreased. The increasing of dietary replacement levels significantly up-regulated pro-inflammatory (il-1β, tnf-α, myd88, ifn-γ, tlr-22, and il-12p40) and down-regulated anti-inflammatory (il-10, tgf-β, mhc-iiβ) and anti-bacterial peptide (epinecidin and hepcidin) mRNA levels in the intestine. The mRNA levels of il-6 was up-regulated firstly upto 4 and 8% replacement levels, and later down-regulated with increasing replacement. These results suggested that, although higher dietary CM replacement enhances the immune, antioxidant and digestive enzymes, it aggravates intestinal inflammation. Replacing 4 and 8% of FM with CM could enhance the growth performance of fish.
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Affiliation(s)
- Kwaku Amoah
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, PR China; Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, 524088, PR China
| | - Xiaobo Yan
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, PR China; Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, 524088, PR China
| | - Hao Liu
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, PR China; Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, 524088, PR China
| | - Simiao Pan
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, PR China; Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, 524088, PR China
| | - Tao Li
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, PR China; Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, 524088, PR China
| | - Xiangxiang Suo
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, PR China; Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, 524088, PR China
| | - Beiping Tan
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, PR China; Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, 524088, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, Guangdong, 524000, China
| | - Shuang Zhang
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, PR China; Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, 524088, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, Guangdong, 524000, China
| | - Weibin Huang
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, PR China; Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, 524088, PR China
| | - Mingsheng Xie
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, PR China; Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, 524088, PR China
| | - Shipei Yang
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, PR China; Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, 524088, PR China
| | - Haitao Zhang
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, Guangdong, 524000, China
| | - Yuanzhi Yang
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, PR China
| | - Xiaohui Dong
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, PR China; Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, 524088, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, Guangdong, 524000, China.
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Jadhav K, Singh R, Ray E, Singh AK, Verma RK. Taming the Devil: Antimicrobial Peptides for Safer TB Therapeutics. Curr Protein Pept Sci 2022; 23:643-656. [PMID: 35619262 DOI: 10.2174/1389203723666220526161109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 03/16/2022] [Accepted: 03/16/2022] [Indexed: 12/29/2022]
Abstract
Tuberculosis (TB) is a highly contagious infection with extensive mortality and morbidity. The rise of TB-superbugs (drug-resistant strains) with the increase of their resistance to conventional antibiotics has prompted a further search for new anti-mycobacterial agents. It is difficult to breach the barriers around TB bacteria, including mycolic cell wall, granuloma, biofilm and mucus, by conventional antibiotics in a short span of time. Hence, there is an essential need for molecules with an unconventional mode of action and structure that can efficiently break the barriers around mycobacterium. Antimicrobial peptides (AMP) are essential components of innate immunity having cationic and amphipathic characteristics. Lines of evidence show that AMPs have good myco-bactericidal and antibiofilm activity against normal as well as antibiotic-resistant TB bacteria. These peptides have shown direct killing of bacteria by membrane lysis and indirect killing by activation of innate immune response in host cells by interacting with the component of the bacterial membrane and intracellular targets through diverse mechanisms. Despite a good anti-mycobacterial activity, some undesirable characteristics are also associated with AMP, including hemolysis, cytotoxicity, susceptibility to proteolysis and poor pharmacokinetic profile, and hence only a few clinical studies have been conducted with these biomolecules. The design of new combinatorial therapies, including AMPs and particulate drug delivery systems, could be new potential alternatives to conventional antibiotics to fight MDR- and XDRTB. This review outlined the array of AMP roles in TB therapy, possible mechanisms of actions, activities, and current advances in pragmatic strategies to improve challenges accompanying the delivery of AMP for tuberculosis therapeutics.
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Affiliation(s)
- Krishna Jadhav
- Institute of Nano Science and Technology (INST), Habitat Centre, Phase-10, Sector-64, Mohali, Punjab-160062, India
| | - Raghuraj Singh
- Institute of Nano Science and Technology (INST), Habitat Centre, Phase-10, Sector-64, Mohali, Punjab-160062, India
| | - Eupa Ray
- Institute of Nano Science and Technology (INST), Habitat Centre, Phase-10, Sector-64, Mohali, Punjab-160062, India
| | - Amit Kumar Singh
- National JALMA Institute for Leprosy and Other Mycobacterial Diseases (ICMR), Tajganj, Agra-282001, India
| | - Rahul Kumar Verma
- Institute of Nano Science and Technology (INST), Habitat Centre, Phase-10, Sector-64, Mohali, Punjab-160062, India
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Mokgalaboni K, Phoswa W. Cross-link between type 2 diabetes mellitus and iron deficiency anemia. A mini-review. CLINICAL NUTRITION OPEN SCIENCE 2022. [DOI: 10.1016/j.nutos.2022.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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16
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Sherbiny HS, Mostafa HAEF, Sherief LM, Kamal NM, El-Shal AS, Abdel-el Halm MM, Khan HY, Ali ASA. Validity of serum and urinary hepcidin as biomarkers for late-onset sepsis in premature infants. Ther Adv Chronic Dis 2022; 13:20406223221122527. [PMID: 36093263 PMCID: PMC9459492 DOI: 10.1177/20406223221122527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 07/19/2022] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND Sepsis remains one of the leading causes of neonatal morbidity and mortality, particularly among premature infants. Blood culture is the 'gold standard' for the diagnosis of neonatal sepsis but is associated with several pitfalls. AIM OF THE WORK We aim to evaluate the validity of measuring serum (S.Hep) and urinary hepcidin (U.Hep) concentrations as diagnostic biomarkers for late-onset sepsis (LOS) in preterm infants. PATIENTS AND METHODS The current case-control study included 73 cases of clinically and laboratory confirmed late-onset sepsis as the 'case group' and 50 nonseptic premature infants of comparable age and sex as the 'control group'. S.Hep and U.Hep concentrations were evaluated at enrollment (acute sample) and after 1 week of treatment (convalescent sample). RESULTS Patients had a statistically significant higher concentration of both S.Hep and U.Hep as compared with nonseptic controls (p = 0.0001). Similarly, a significant reduction of both S.Hep and U.Hep was detected after 1 week of treatment (p = 0.001). A cut-off value of ⩾ 94.8 ng/ml of S.Hep and ⩾ 264 ng/mg of U.Hep/urinary creatinine showed high sensitivity, specificity, and positive predictive value in the diagnosis of neonatal LOS. CONCLUSIONS Both S.Hep and U.Hep can function as promising accurate and rapid surrogate tests for the diagnosis of LOS. U.Hep measurement has the advantage of being noninvasive, with no hazards of phlebotomy, and is less variable throughout the day.
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Affiliation(s)
- Hanan Sakr Sherbiny
- Pediatric Department, Zagazig University,
Zagazig, Egypt, Pediatric Department, College of Medicine, Bisha University,
Bisha, Saudi Arabia
| | | | | | - Naglaa M. Kamal
- Professor of Pediatrics and Pediatric
Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Amal Saeed El-Shal
- Zagazig University, Zagazig, Egypt, Armed
Forces College of Medicine (AFCM), Cairo, Egypt
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Abstract
The liver is the major target organ of continued alcohol consumption at risk and resulting alcoholic liver disease (ALD) is the most common liver disease worldwide. The underlying molecular mechanisms are still poorly understood despite decades of scientific effort limiting our abilities to identify those individuals who are at risk to develop the disease, to develop appropriate screening strategies and, in addition, to develop targeted therapeutic approaches. ALD is predestined for the newly evolving translational medicine, as conventional clinical and health care structures seem to be constrained to fully appreciate this disease. This concept paper aims at summarizing the 15 years translational experience at the Center of Alcohol Research in Heidelberg, namely based on the long-term prospective and detailed characterization of heavy drinkers with mortality data. In addition, novel experimental findings will be presented. A special focus will be the long-known hepatic iron accumulation, the somewhat overlooked role of the hematopoietic system and novel insights into iron sensing and the role of hepcidin. Our preliminary work indicates that enhanced red blood cell (RBC) turnover is critical for survival in ALD patients. RBC turnover is not primarily due to vitamin deficiency but rather to ethanol toxicity directly targeted to erythrocytes but also to the bone marrow stem cell compartment. These novel insights also help to explain long-known aspects of ALD such as mean corpuscular volume of erythrocytes (MCV) and elevated aspartate transaminase (GOT/AST) levels. This work also aims at identifying future projects, naming unresolved observations, and presenting novel hypothetical concepts still requiring future validation.
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18
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Iksanova AM, Arzumanian VG, Konanykhina SY, Samoylikov PV. Antimicrobial peptides and proteins in human biological fluids. MICROBIOLOGY INDEPENDENT RESEARCH JOURNAL 2022. [DOI: 10.18527/2500-2236-2022-9-1-37-55] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Antimicrobial peptides and proteins (AMPs) are endogenous compounds that have a direct antimicrobial effect on bacteria (e. g., by disrupting bacterial membranes), as well as on fungi and viruses. AMPs are the main component of the innate immunity of living organisms and are produced by both epithelial cells (skin cells, cells of respiratory tract, intestine, urinary and genital tracts) and cells of the immune system and are secreted into secretory fluids. AMPs can also act as chemoattractants for immunocompetent cells (neutrophils, monocytes, T lymphocytes, dendritic cells) in the inflammation site and affect the antigen presenting cells by modulating adaptive T cell immune responses. The representatives of the main 15 AMP classes, that we describe in this review, are the most studied group of the large pool of these compounds. We discuss their localization, expression, and concentration in various biofluids of humans under normal and pathological conditions.
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Iakobachvili N, Leon‐Icaza SA, Knoops K, Sachs N, Mazères S, Simeone R, Peixoto A, Bernard C, Murris‐Espin M, Mazières J, Cam K, Chalut C, Guilhot C, López‐Iglesias C, Ravelli RBG, Neyrolles O, Meunier E, Lugo‐Villarino G, Clevers H, Cougoule C, Peters P. Mycobacteria-host interactions in human bronchiolar airway organoids. Mol Microbiol 2022; 117:682-692. [PMID: 34605588 PMCID: PMC9298242 DOI: 10.1111/mmi.14824] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 09/27/2021] [Indexed: 02/04/2023]
Abstract
Respiratory infections remain a major global health concern. Tuberculosis is one of the top 10 causes of death worldwide, while infections with Non-Tuberculous Mycobacteria are rising globally. Recent advances in human tissue modeling offer a unique opportunity to grow different human "organs" in vitro, including the human airway, that faithfully recapitulates lung architecture and function. Here, we have explored the potential of human airway organoids (AOs) as a novel system in which to assess the very early steps of mycobacterial infection. We reveal that Mycobacterium tuberculosis (Mtb) and Mycobacterium abscessus (Mabs) mainly reside as extracellular bacteria and infect epithelial cells with very low efficiency. While the AO microenvironment was able to control, but not eliminate Mtb, Mabs thrives. We demonstrate that AOs responded to infection by modulating cytokine, antimicrobial peptide, and mucin gene expression. Given the importance of myeloid cells in mycobacterial infection, we co-cultured infected AOs with human monocyte-derived macrophages and found that these cells interact with the organoid epithelium. We conclude that adult stem cell (ASC)-derived AOs can be used to decipher very early events of mycobacteria infection in human settings thus offering new avenues for fundamental and therapeutic research.
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Affiliation(s)
- Nino Iakobachvili
- M4i Nanoscopy DivisionMaastricht UniversityMaastrichtThe Netherlands
| | - Stephen Adonai Leon‐Icaza
- Institut de Pharmacologie et Biologie Structurale (IPBS)Université de Toulouse, CNRS, UPSToulouseFrance
| | - Kèvin Knoops
- M4i Nanoscopy DivisionMaastricht UniversityMaastrichtThe Netherlands
| | - Norman Sachs
- Oncode Institute, Hubrecht InstituteRoyal Netherlands Academy of Arts and Sciences and University Medical CenterUtrechtThe Netherlands
| | - Serge Mazères
- Institut de Pharmacologie et Biologie Structurale (IPBS)Université de Toulouse, CNRS, UPSToulouseFrance
| | - Roxane Simeone
- Institut Pasteur, Unit for Integrated Mycobacterial PathogenomicsCNRS UMR3525ParisFrance
| | - Antonio Peixoto
- Institut de Pharmacologie et Biologie Structurale (IPBS)Université de Toulouse, CNRS, UPSToulouseFrance
| | - Célia Bernard
- Institut de Pharmacologie et Biologie Structurale (IPBS)Université de Toulouse, CNRS, UPSToulouseFrance
| | | | - Julien Mazières
- Service de PneumologieHôpital Larrey, CHU de ToulouseToulouseFrance
| | - Kaymeuang Cam
- Institut de Pharmacologie et Biologie Structurale (IPBS)Université de Toulouse, CNRS, UPSToulouseFrance
| | - Christian Chalut
- Institut de Pharmacologie et Biologie Structurale (IPBS)Université de Toulouse, CNRS, UPSToulouseFrance
| | - Christophe Guilhot
- Institut de Pharmacologie et Biologie Structurale (IPBS)Université de Toulouse, CNRS, UPSToulouseFrance
| | | | | | - Olivier Neyrolles
- Institut de Pharmacologie et Biologie Structurale (IPBS)Université de Toulouse, CNRS, UPSToulouseFrance
- International Associated Laboratory (LIA) CNRS “IM‐TB/HIV” (1167)ToulouseFrance
- International Associated Laboratory (LIA) CNRS “IM‐TB/HIV” (1167)Buenos AiresArgentina
| | - Etienne Meunier
- Institut de Pharmacologie et Biologie Structurale (IPBS)Université de Toulouse, CNRS, UPSToulouseFrance
| | - Geanncarlo Lugo‐Villarino
- Institut de Pharmacologie et Biologie Structurale (IPBS)Université de Toulouse, CNRS, UPSToulouseFrance
- International Associated Laboratory (LIA) CNRS “IM‐TB/HIV” (1167)ToulouseFrance
- International Associated Laboratory (LIA) CNRS “IM‐TB/HIV” (1167)Buenos AiresArgentina
| | - Hans Clevers
- Oncode Institute, Hubrecht InstituteRoyal Netherlands Academy of Arts and Sciences and University Medical CenterUtrechtThe Netherlands
| | - Céline Cougoule
- Institut de Pharmacologie et Biologie Structurale (IPBS)Université de Toulouse, CNRS, UPSToulouseFrance
- International Associated Laboratory (LIA) CNRS “IM‐TB/HIV” (1167)ToulouseFrance
- International Associated Laboratory (LIA) CNRS “IM‐TB/HIV” (1167)Buenos AiresArgentina
| | - Peter J. Peters
- M4i Nanoscopy DivisionMaastricht UniversityMaastrichtThe Netherlands
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Shaw TD, Krasnodembskaya AD, Schroeder GN, Zumla A, Maeurer M, O’Kane CM. Mesenchymal Stromal Cells: an Antimicrobial and Host-Directed Therapy for Complex Infectious Diseases. Clin Microbiol Rev 2021; 34:e0006421. [PMID: 34612662 PMCID: PMC8510528 DOI: 10.1128/cmr.00064-21] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
There is an urgent need for new antimicrobial strategies for treating complex infections and emerging pathogens. Human mesenchymal stromal cells (MSCs) are adult multipotent cells with antimicrobial properties, mediated through direct bactericidal activity and modulation of host innate and adaptive immune cells. More than 30 in vivo studies have reported on the use of human MSCs for the treatment of infectious diseases, with many more studies of animal MSCs in same-species models of infection. MSCs demonstrate potent antimicrobial effects against the major classes of human pathogens (bacteria, viruses, fungi, and parasites) across a wide range of infection models. Mechanistic studies have yielded important insight into their immunomodulatory and bactericidal activity, which can be enhanced through various forms of preconditioning. MSCs are being investigated in over 80 clinical trials for difficult-to-treat infectious diseases, including sepsis and pulmonary, intra-abdominal, cutaneous, and viral infections. Completed trials consistently report MSCs to be safe and well tolerated, with signals of efficacy against some infectious diseases. Although significant obstacles must be overcome to produce a standardized, affordable, clinical-grade cell therapy, these studies suggest that MSCs may have particular potential as an adjunct therapy in complex or resistant infections.
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Affiliation(s)
- Timothy D. Shaw
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Anna D. Krasnodembskaya
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Gunnar N. Schroeder
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Alimuddin Zumla
- Center for Clinical Microbiology, Division of Infection and Immunity, University College London, NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, United Kingdom
| | - Markus Maeurer
- Immunosurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Department of Oncology and Haematology, Krankenhaus Nordwest, Frankfurt, Germany
| | - Cecilia M. O’Kane
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
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21
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Wang S, Chen C, Yu L, Mueller J, Rausch V, Mueller S. Bone morphogenetic protein 6-mediated crosstalk between endothelial cells and hepatocytes recapitulates the iron-sensing pathway in vitro. J Biol Chem 2021; 297:101378. [PMID: 34740612 PMCID: PMC8637636 DOI: 10.1016/j.jbc.2021.101378] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 10/26/2021] [Accepted: 10/27/2021] [Indexed: 12/21/2022] Open
Abstract
Liver sinusoidal endothelial cell–derived bone morphogenetic protein 6 (BMP6) and the BMP6–small mothers against decapentaplegic homolog (SMAD) signaling pathway are essential for the expression of hepcidin, the secretion of which is considered the systemic master switch of iron homeostasis. However, there are continued controversies related to the strong and direct suppressive effect of iron on hepatocellular hepcidin in vitro in contrast to in vivo conditions. Here, we directly studied the crosstalk between endothelial cells (ECs) and hepatocytes using in vitro coculture models that mimic hepcidin signaling in vivo. Huh7 cells were directly cocultured with ECs, and EC conditioned media (CM) were also used to culture Huh7 cells and primary mouse hepatocytes. To explore the reactions of ECs to surrounding iron, they were grown in the presence of ferric ammonium citrate and heme, two iron-containing molecules. We found that both direct coculture with ECs and EC-CM significantly increased hepcidin expression in Huh7 cells. The upstream SMAD pathway, including phosphorylated SMAD1/5/8, SMAD1, and inhibitor of DNA binding 1, was induced by EC-CM, promoting hepcidin expression. Efficient blockage of this EC-mediated hepcidin upregulation by an inhibitor of the BMP6 receptor ALK receptor tyrosine kinase 2/3 or BMP6 siRNA identified BMP6 as a major hepcidin regulator in this coculture system, which highly fits the model of hepcidin regulation by iron in vivo. In addition, EC-derived BMP6 and hepcidin were highly sensitive to levels of not only ferric iron but also heme as low as 500 nM. We here establish a hepatocyte–endothelial coculture system to fully recapitulate iron regulation by hepcidin using EC-derived BMP6.
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Affiliation(s)
- Shijin Wang
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg, Germany
| | - Cheng Chen
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg, Germany
| | - Linna Yu
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg, Germany
| | - Johannes Mueller
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg, Germany
| | - Vanessa Rausch
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg, Germany
| | - Sebastian Mueller
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg, Germany.
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22
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Yu LN, Wang SJ, Chen C, Rausch V, Elshaarawy O, Mueller S. Direct modulation of hepatocyte hepcidin signaling by iron. World J Hepatol 2021; 13:1378-1393. [PMID: 34786173 PMCID: PMC8568584 DOI: 10.4254/wjh.v13.i10.1378] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/04/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver-secreted hepcidin is the systemic master switch of iron homeostasis and decreased levels of hepcidin are considered to cause iron overload not only in hereditary hemochromatosis but also in hemolytic anemia and chronic liver diseases. The regulation of hepcidin is complex and its response to iron is still not completely understood.
AIM To study the direct effect of iron on various established hepcidin signaling pathways in hepatoma cells or primary hepatocytes.
METHODS Hepcidin mRNA expression was studied by quantitative real-time (qRT)-PCR in the presence of various forms of iron including ferric ammonium citrate (FAC) in hepatoma cells (Huh7), murine primary hepatocytes and an established co-culture model of phorbol myristate acetate-differentiated THP-1 monocytes and Huh7 cells. To analyze hepcidin signaling, the response to bone morphogenetic protein 6 (BMP6), interleukin (IL)-6, IL-1β, hypoxia and lipopolysaccharide (LPS) were studied. Hepcidin and small mothers against decapentaplegic 6 (SMAD6) mRNA levels were assessed by qRT-PCR and the expression of phosphorylated signal transducer and activator of transcription 3 (phospho-STAT3), STAT3, phospho-SMAD1/5/8 and SMAD1 proteins were analyzed by western blot.
RESULTS All iron III forms including FAC efficiently blocked hepcidin mRNA expression at non-toxic dosages in Huh7 cells or primary hepatocytes in a time and dose-dependent manner (P < 0.001; P < 0.05). Hepcidin blockage could be efficiently blunted by iron chelators salicylaldehyde isonicotinoyl hydrazone (SIH) and Desferal (P < 0.001). FAC also inhibited BMP6, hypoxia, IL-1β and IL-6-mediated hepcidin induction (P < 0.001; P < 0.001; P < 0.05; P < 0.001), and FAC also inhibited LPS-mediated hepatic hepcidin induction in co-culture model (P < 0.001). Moreover, FAC reduced SMAD6 mRNA and p-SMAD1/5/8 protein expression at basal or upon stimulation by BMP6 (P < 0.05; P < 0.01), and FAC also reduced SMAD6 and p-SMAD1/5/8 expression under hypoxia (P < 0.01; P < 0.05). However, FAC has no significant effect on p-STAT3 protein expression at basal or upon stimulation by various stimuli. Notably, in the presence of the BMP/SMAD signaling pathway inhibitor LDN193189 Hydrochloride (LDN), FAC was unable to further decrease hepcidin, SMAD6 and p-SMAD1/5/8 expression compared with LDN alone.
CONCLUSION Iron directly blocks hepatocellular hepcidin signaling through the BMP/SMAD pathway but independent of STAT3. This mechanism may contribute to continued iron overload in many pathophysiological conditions ultimately causing a vicious cycle of continued hepcidin suppression.
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Affiliation(s)
- Lin-Na Yu
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg 69121, Germany
| | - Shi-Jin Wang
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg 69121, Germany
| | - Cheng Chen
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg 69121, Germany
| | - Vanessa Rausch
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg 69121, Germany
| | - Omar Elshaarawy
- Department of Hepatology, Gastroenterology and Liver Transplantation, National Liver Institute, Menoufia University, Shebine Elkom 35121, El Salvador
- Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool L7 8XP, United Kingdom
| | - Sebastian Mueller
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg 69121, Germany
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Tofacitinib Suppresses IL-10/IL-10R Signaling and Modulates Host Defense Responses in Human Macrophages. J Invest Dermatol 2021; 142:559-570.e6. [PMID: 34536483 DOI: 10.1016/j.jid.2021.07.180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/12/2021] [Accepted: 07/15/2021] [Indexed: 12/20/2022]
Abstract
Jak inhibitors are increasingly used in dermatology. Despite broad inhibitory effects on cytokine signaling cascades, they only modestly increase the risk for infectious diseases. To address the molecular mechanisms underlying this unexpected clinical observation, we investigated how tofacintib (tofa), a first-in-class Jak inhibitor, regulates host defense responses in toll-like receptor 4-activated human macrophages. Specifically, we asked whether tofa inhibits anti-inflammatory IL-10 signaling, thereby counteracting the downregulation of inflammatory, host-protective pathways. We found that tofa blocked macrophage responses to IL-10 at the level of signal transducer and activator of transcription 3 phosphorylation. Furthermore, toll-like receptor 4-induced, autocrine/paracrine IL-10/IL-10R activation promoted the expression of hepcidin, the master regulator of iron metabolism, resulting in intracellular iron sequestration. In contrast, autocrine/paracrine IL-10/IL-10R activation repressed the expression of cathelicidin antimicrobial peptide as well as antigen-presenting molecules, thus together, inducing a pathogen-favoring environment. Although tofa further repressed cathelicidin, it prevented the induction of intracellular HAMP and restored the expression of antigen-presentation molecules in toll-like receptor 4-activated macrophages. Our study supports the concept that induction of IL-10/IL-10R signaling drives a complex immune evasion strategy of intracellular microbes. Moreover, we conclude that tofa has diverging effects on macrophage host response pathways, and we identify the toll-like receptor 4-IL-10-signal transducer and activator of transcription 3-HAMP axis as a potential therapeutic target to counteract immune evasion.
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24
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The Role of Copper in the Regulation of Ferroportin Expression in Macrophages. Cells 2021; 10:cells10092259. [PMID: 34571908 PMCID: PMC8469096 DOI: 10.3390/cells10092259] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 11/17/2022] Open
Abstract
The critical function of ferroportin (Fpn) in maintaining iron homeostasis requires complex and multilevel control of its expression. Besides iron-dependent cellular and systemic control of Fpn expression, other metals also seem to be involved in regulating the Fpn gene. Here, we found that copper loading significantly enhanced Fpn transcription in an Nrf2-dependent manner in primary bone-marrow-derived macrophages (BMDMs). However, prolonged copper loading resulted in decreased Fpn protein abundance. Moreover, CuCl2 treatment induced Fpn expression in RAW 264.7 macrophages at both the mRNA and protein level. These data suggest that cell-type-specific regulations have an impact on Fpn protein stability after copper loading. Transcriptional suppression of Fpn after lipopolysaccharide (LPS) treatment contributes to increased iron storage inside macrophages and may result in anemia of inflammation. Here, we observed that in both primary BMDMs and RAW 264.7 macrophages, LPS treatment significantly decreased Fpn mRNA levels, but concomitant CuCl2 stimulation counteracted the transcriptional suppression of Fpn and restored its expression to the control level. Overall, we show that copper loading significantly enhances Fpn transcription in macrophages, while Fpn protein abundance in response to CuCl2 treatment, depending on macrophage type and factors specific to the macrophage population, can influence Fpn regulation in response to copper loading.
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25
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Parwani D, Bhattacharya S, Rathore A, Mallick C, Asati V, Agarwal S, Rajoriya V, Das R, Kashaw SK. Current Insights into the Chemistry and Antitubercular Potential of Benzimidazole and Imidazole Derivatives. Mini Rev Med Chem 2021; 21:643-657. [PMID: 33138762 DOI: 10.2174/1389557520666201102094401] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/27/2020] [Accepted: 09/09/2020] [Indexed: 11/22/2022]
Abstract
Tuberculosis is a disease caused by Mycobacterium tuberculosis (Mtb), affecting millions of people worldwide. The emergence of drug resistance is a major problem in the successful treatment of tuberculosis. Due to the commencement of MDR-TB (multi-drug resistance) and XDR-TB (extensively drug resistance), there is a crucial need for the development of novel anti-tubercular agents with improved characteristics such as low toxicity, enhanced inhibitory activity and short duration of treatment. In this direction, various heterocyclic compounds have been synthesized and screened against Mycobacterium tuberculosis. Among them, benzimidazole and imidazole containing derivatives have been found to have potential anti-tubercular activity. The present review focuses on various imidazole and benzimidazole derivatives (from 2015-2019) with their structure-activity relationships in the treatment of tuberculosis.
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Affiliation(s)
- Deepa Parwani
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Sushanta Bhattacharya
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Akash Rathore
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Chaitali Mallick
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Vivek Asati
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivangi Agarwal
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Vaibhav Rajoriya
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Ratnesh Das
- Department of Chemistry, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Sushil Kumar Kashaw
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
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26
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Oh TK, Song KH, Song IA. History of anemia and long-term mortality due to infection: a cohort study with 12 years follow-up in South Korea. BMC Infect Dis 2021; 21:674. [PMID: 34247585 PMCID: PMC8272955 DOI: 10.1186/s12879-021-06377-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 06/29/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Anemia, which is a condition with reduced healthy red blood cells, is reported to be closely related to the development of infectious diseases. We aimed to investigate the association between history of anemia and 12-year mortality rate due to infections, and compare it with that among non-anemic individuals. METHODS Data from the National Health Insurance Service Health Screening Cohort were used in this population-based cohort study. Adults who underwent standardized medical examination between and 2002-2003 were included, and the mortality rate due to infection between 2004 and 2015 was analyzed. Individuals were considered to have a history of anemia if the serum hemoglobin level in 2002-2003 was < 12 g/dL for women and < 13 g/dL for men. The severity of anemia at that time was categorized as mild (12 g/dL > hemoglobin ≥11 g/dL in women and 13 g/dL > hemoglobin ≥11 g/dL in men), moderate (hemoglobin 8-10.9 g/dL), or severe (hemoglobin < 8 g/dL). Propensity score (PS) matching and Cox regression analysis were used as statistical methods. RESULTS Overall, 512,905 individuals were included in this study. The mean age of the participants was 54.5 years old (range: 40-98), and 49,042 (9.6%) individuals were classified in the anemic group, which comprised of 36,383 (7.1%), 11,787 (2.3%), and 872 (0.2%) participants in the mild, moderate, and severe sub-groups, respectively. After PS matching, 49,039 individuals in each group were included in the analysis. The risk of mortality due to infection in the anemic group was 1.77-fold higher (hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.52-2.60; P < 0.001) than that in the non-anemic group. In the subgroup analysis, the mild and moderate anemia groups had 1.38-fold (HR: 1.38, 95% CI: 1.23 to 1.55; P < 0.001) and 2.02-fold (HR: 2.02, 95% CI: 1.62 to 2.50; P < 0.001) risk of mortality due to infection compared to that of the non-anemic group, respectively. The severe anemia group did not have a significantly different risk of mortality due to infection (P = 0.448). CONCLUSIONS History of anemia was associated with increased mortality rate due to infection at 12-year follow-up.
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Affiliation(s)
- Tak Kyu Oh
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Gumi-ro, 173, Beon-gil, Bundang-gu, Seongnam, 13620, South Korea
| | - Kyung-Ho Song
- Department of Internal Medicine, Seoul National University Bundang Hospital, Gumi-ro, 173, Beon-gil, Bundang-gu, Seongnam, 13620, South Korea
| | - In-Ae Song
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Gumi-ro, 173, Beon-gil, Bundang-gu, Seongnam, 13620, South Korea.
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27
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Turpin C, Catan A, Meilhac O, Bourdon E, Canonne-Hergaux F, Rondeau P. Erythrocytes: Central Actors in Multiple Scenes of Atherosclerosis. Int J Mol Sci 2021; 22:ijms22115843. [PMID: 34072544 PMCID: PMC8198892 DOI: 10.3390/ijms22115843] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 05/26/2021] [Accepted: 05/26/2021] [Indexed: 12/16/2022] Open
Abstract
The development and progression of atherosclerosis (ATH) involves lipid accumulation, oxidative stress and both vascular and blood cell dysfunction. Erythrocytes, the main circulating cells in the body, exert determinant roles in the gas transport between tissues. Erythrocytes have long been considered as simple bystanders in cardiovascular diseases, including ATH. This review highlights recent knowledge concerning the role of erythrocytes being more than just passive gas carriers, as potent contributors to atherosclerotic plaque progression. Erythrocyte physiology and ATH pathology is first described. Then, a specific chapter delineates the numerous links between erythrocytes and atherogenesis. In particular, we discuss the impact of extravasated erythrocytes in plaque iron homeostasis with potential pathological consequences. Hyperglycaemia is recognised as a significant aggravating contributor to the development of ATH. Then, a special focus is made on glycoxidative modifications of erythrocytes and their role in ATH. This chapter includes recent data proposing glycoxidised erythrocytes as putative contributors to enhanced atherothrombosis in diabetic patients.
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Affiliation(s)
- Chloé Turpin
- Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), INSERM, UMR 1188, Université de La Réunion, 97400 Saint Denis, France; (C.T.); (A.C.); (O.M.); (E.B.)
| | - Aurélie Catan
- Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), INSERM, UMR 1188, Université de La Réunion, 97400 Saint Denis, France; (C.T.); (A.C.); (O.M.); (E.B.)
| | - Olivier Meilhac
- Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), INSERM, UMR 1188, Université de La Réunion, 97400 Saint Denis, France; (C.T.); (A.C.); (O.M.); (E.B.)
- Centre Hospitalier Universitaire de La Réunion, 97400 Saint Denis, France
| | - Emmanuel Bourdon
- Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), INSERM, UMR 1188, Université de La Réunion, 97400 Saint Denis, France; (C.T.); (A.C.); (O.M.); (E.B.)
| | | | - Philippe Rondeau
- Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), INSERM, UMR 1188, Université de La Réunion, 97400 Saint Denis, France; (C.T.); (A.C.); (O.M.); (E.B.)
- Correspondence: ; Tel.: +262(0)-2-62-93-88-43; Fax: +262-(0)-2-62-93-88-01
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28
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Effect of hepcidin antagonists on anemia during inflammatory disorders. Pharmacol Ther 2021; 226:107877. [PMID: 33895185 DOI: 10.1016/j.pharmthera.2021.107877] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 04/20/2021] [Indexed: 12/11/2022]
Abstract
Iron is an essential element for the mammalian body however, its homeostasis must be regulated accurately for appropriate physiological functioning. Alterations in physiological iron levels can lead to moderate to severe iron disorders like chronic and acute iron deficiency (anemia) or iron overload. Hepcidin plays an important role in regulating homeostasis between circulating iron and stored iron in the cells as well as the absorption of dietary iron in the intestine. Inflammatory disorders restrict iron absorption from food due to increased circulating levels of hepcidin. Increased production of hepcidin causes ubiquitination of ferroportin (FPN) leading to its degradation, thereby retaining iron in the spleen, duodenal enterocytes, macrophages, and hepatocytes. Hepcidin inhibitors and antagonists play a consequential role to ameliorate inflammation-associated anemia. Many natural and synthesized compounds, able to reduce hepcidin expression during inflammation have been identified in recent years. Few of which are currently at various phases of clinical trial. This article comprises a comprehensive review of therapeutic approaches for the efficient treatment of anemia associated with inflammation. Many strategies have been developed targeting the hepcidin-FPN axis to rectify iron disorders. Hepcidin modulation with siRNAs, antibodies, chemical compounds, and plant extracts provides new insights for developing advanced therapeutics for iron-related disorders. Hepcidin antagonist's treatment has a high potential to improve iron status in patients with iron disorders, but their clinical success needs further recognition along with the identification and application of new therapeutic approaches.
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29
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Antimicrobial Peptides as Potential Anti-Tubercular Leads: A Concise Review. Pharmaceuticals (Basel) 2021; 14:ph14040323. [PMID: 33918182 PMCID: PMC8065624 DOI: 10.3390/ph14040323] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 03/30/2021] [Accepted: 03/31/2021] [Indexed: 12/11/2022] Open
Abstract
Despite being considered a public health emergency for the last 25 years, tuberculosis (TB) is still one of the deadliest infectious diseases, responsible for over a million deaths every year. The length and toxicity of available treatments and the increasing emergence of multidrug-resistant strains of Mycobacterium tuberculosis renders standard regimens increasingly inefficient and emphasizes the urgency to develop new approaches that are not only cost- and time-effective but also less toxic. Antimicrobial peptides (AMP) are small cationic and amphipathic molecules that play a vital role in the host immune system by acting as a first barrier against invading pathogens. The broad spectrum of properties that peptides possess make them one of the best possible alternatives for a new “post-antibiotic” era. In this context, research into AMP as potential anti-tubercular agents has been driven by the increasing danger revolving around the emergence of extremely-resistant strains, the innate resistance that mycobacteria possess and the low compliance of patients towards the toxic anti-TB treatments. In this review, we will focus on AMP from various sources, such as animal, non-animal and synthetic, with reported inhibitory activity towards Mycobacterium tuberculosis.
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30
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Liang W, Ferrara N. Iron Metabolism in the Tumor Microenvironment: Contributions of Innate Immune Cells. Front Immunol 2021; 11:626812. [PMID: 33679721 PMCID: PMC7928394 DOI: 10.3389/fimmu.2020.626812] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 12/30/2020] [Indexed: 12/21/2022] Open
Abstract
Cells of the innate immune system are a major component of the tumor microenvironment. They play complex and multifaceted roles in the regulation of cancer initiation, growth, metastasis and responses to therapeutics. Innate immune cells like neutrophils and macrophages are recruited to cancerous tissues by chemotactic molecules released by cancer cells and cancer-associated stromal cells. Once they reach the tumor, they can be instructed by a network of proteins, nucleic acids and metabolites to exert protumoral or antitumoral functions. Altered iron metabolism is a feature of cancer. Epidemiological studies suggest that increased presence of iron and/or iron binding proteins is associated with increased risks of cancer development. It has been shown that iron metabolism is involved in shaping the immune landscapes in inflammatory/infectious diseases and cancer-associated inflammation. In this article, we will dissect the contribution of macrophages and neutrophils to dysregulated iron metabolism in malignant cells and its impact on cancer growth and metastasis. The mechanisms involved in regulating the actions of macrophages and neutrophils will also be discussed. Moreover, we will examine the effects of iron metabolism on the phenotypes of innate immune cells. Both iron chelating and overloading agents are being explored in cancer treatment. This review highlights alternative strategies for management of iron content in cancer cells by targeting the iron donation and modulation properties of macrophages and neutrophils in the tumor microenvironment.
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Affiliation(s)
- Wei Liang
- Oncology, BioDuro LLC, San Diego, CA, United States
| | - Napoleone Ferrara
- Moores Cancer Center, University of California San Diego, La Jolla, CA, United States
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31
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Pidwill GR, Gibson JF, Cole J, Renshaw SA, Foster SJ. The Role of Macrophages in Staphylococcus aureus Infection. Front Immunol 2021; 11:620339. [PMID: 33542723 PMCID: PMC7850989 DOI: 10.3389/fimmu.2020.620339] [Citation(s) in RCA: 171] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 12/02/2020] [Indexed: 12/23/2022] Open
Abstract
Staphylococcus aureus is a member of the human commensal microflora that exists, apparently benignly, at multiple sites on the host. However, as an opportunist pathogen it can also cause a range of serious diseases. This requires an ability to circumvent the innate immune system to establish an infection. Professional phagocytes, primarily macrophages and neutrophils, are key innate immune cells which interact with S. aureus, acting as gatekeepers to contain and resolve infection. Recent studies have highlighted the important roles of macrophages during S. aureus infections, using a wide array of killing mechanisms. In defense, S. aureus has evolved multiple strategies to survive within, manipulate and escape from macrophages, allowing them to not only subvert but also exploit this key element of our immune system. Macrophage-S. aureus interactions are multifaceted and have direct roles in infection outcome. In depth understanding of these host-pathogen interactions may be useful for future therapeutic developments. This review examines macrophage interactions with S. aureus throughout all stages of infection, with special emphasis on mechanisms that determine infection outcome.
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Affiliation(s)
- Grace R. Pidwill
- Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom
- Florey Institute, University of Sheffield, Sheffield, United Kingdom
| | - Josie F. Gibson
- Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom
- Florey Institute, University of Sheffield, Sheffield, United Kingdom
- The Bateson Centre, University of Sheffield, Sheffield, United Kingdom
| | - Joby Cole
- Florey Institute, University of Sheffield, Sheffield, United Kingdom
- Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, United Kingdom
| | - Stephen A. Renshaw
- Florey Institute, University of Sheffield, Sheffield, United Kingdom
- The Bateson Centre, University of Sheffield, Sheffield, United Kingdom
- Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, United Kingdom
| | - Simon J. Foster
- Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom
- Florey Institute, University of Sheffield, Sheffield, United Kingdom
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32
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Noschka R, Gerbl F, Löffler F, Kubis J, Rodríguez AA, Mayer D, Grieshober M, Holch A, Raasholm M, Forssmann WG, Spellerberg B, Wiese S, Weidinger G, Ständker L, Stenger S. Unbiased Identification of Angiogenin as an Endogenous Antimicrobial Protein With Activity Against Virulent Mycobacterium tuberculosis. Front Microbiol 2021; 11:618278. [PMID: 33537017 PMCID: PMC7848861 DOI: 10.3389/fmicb.2020.618278] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 12/23/2020] [Indexed: 12/13/2022] Open
Abstract
Tuberculosis is a highly prevalent infectious disease with more than 1.5 million fatalities each year. Antibiotic treatment is available, but intolerable side effects and an increasing rate of drug-resistant strains of Mycobacterium tuberculosis (Mtb) may hamper successful outcomes. Antimicrobial peptides (AMPs) offer an alternative strategy for treatment of infectious diseases in which conventional antibiotic treatment fails. Human serum is a rich resource for endogenous AMPs. Therefore, we screened a library generated from hemofiltrate for activity against Mtb. Taking this unbiased approach, we identified Angiogenin as the single compound in an active fraction. The antimicrobial activity of endogenous Angiogenin against extracellular Mtb could be reproduced by synthetic Angiogenin. Using computational analysis, we identified the hypothetical active site and optimized the lytic activity by amino acid exchanges. The resulting peptide-Angie1-limited the growth of extra- and intracellular Mtb and the fast-growing pathogens Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Toward our long-term goal of evaluating Angie1 for therapeutic efficacy in vivo, we demonstrate that the peptide can be efficiently delivered into human macrophages via liposomes and is not toxic for zebrafish embryos. Taken together, we define Angiogenin as a novel endogenous AMP and derive the small, bioactive fragment Angie1, which is ready to be tested for therapeutic activity in animal models of tuberculosis and infections with fast-growing bacterial pathogens.
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Affiliation(s)
- Reiner Noschka
- Institute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany
| | - Fabian Gerbl
- Institute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany
| | - Florian Löffler
- Institute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany
| | - Jan Kubis
- Institute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany
| | - Armando A Rodríguez
- Core Unit Mass Spectrometry and Proteomics, Ulm University, Ulm, Germany.,Core Facility of Functional Peptidomics, Ulm University, Ulm, Germany
| | - Daniel Mayer
- Institute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany
| | - Mark Grieshober
- Institute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany
| | - Armin Holch
- Institute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany
| | - Martina Raasholm
- Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
| | | | - Barbara Spellerberg
- Institute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany
| | - Sebastian Wiese
- Core Unit Mass Spectrometry and Proteomics, Ulm University, Ulm, Germany
| | - Gilbert Weidinger
- Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
| | - Ludger Ständker
- Core Facility of Functional Peptidomics, Ulm University, Ulm, Germany
| | - Steffen Stenger
- Institute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany
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Hsu MY, Mina E, Roetto A, Porporato PE. Iron: An Essential Element of Cancer Metabolism. Cells 2020; 9:cells9122591. [PMID: 33287315 PMCID: PMC7761773 DOI: 10.3390/cells9122591] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 11/24/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer cells undergo considerable metabolic changes to foster uncontrolled proliferation in a hostile environment characterized by nutrient deprivation, poor vascularization and immune infiltration. While metabolic reprogramming has been recognized as a hallmark of cancer, the role of micronutrients in shaping these adaptations remains scarcely investigated. In particular, the broad electron-transferring abilities of iron make it a versatile cofactor that is involved in a myriad of biochemical reactions vital to cellular homeostasis, including cell respiration and DNA replication. In cancer patients, systemic iron metabolism is commonly altered. Moreover, cancer cells deploy diverse mechanisms to increase iron bioavailability to fuel tumor growth. Although iron itself can readily participate in redox reactions enabling vital processes, its reactivity also gives rise to reactive oxygen species (ROS). Hence, cancer cells further rely on antioxidant mechanisms to withstand such stress. The present review provides an overview of the common alterations of iron metabolism occurring in cancer and the mechanisms through which iron promotes tumor growth.
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Affiliation(s)
- Myriam Y. Hsu
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Turin, Italy; (M.Y.H.); (E.M.)
| | - Erica Mina
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Turin, Italy; (M.Y.H.); (E.M.)
| | - Antonella Roetto
- Department of Clinical and Biological Science, University of Turin, AOU San Luigi Gonzaga, 10043 Orbassano, Italy
- Correspondence: (A.R.); (P.E.P.)
| | - Paolo E. Porporato
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Turin, Italy; (M.Y.H.); (E.M.)
- Correspondence: (A.R.); (P.E.P.)
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Banerjee S, Datta R. Leishmania infection triggers hepcidin-mediated proteasomal degradation of Nramp1 to increase phagolysosomal iron availability. Cell Microbiol 2020; 22:e13253. [PMID: 32827218 DOI: 10.1111/cmi.13253] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 07/31/2020] [Accepted: 08/17/2020] [Indexed: 12/22/2022]
Abstract
Natural resistance-associated macrophage protein 1 (Nramp1) was originally discovered as a genetic determinant of resistance against multiple intracellular pathogens, including Leishmania. It encodes a transmembrane protein of the phago-endosomal compartments, where it functions as an iron transporter. But the mechanism by which Nramp1 controls host-pathogen dynamics and determines final outcome of an infection is yet to be fully deciphered. Whether the expression of Nramp1 is altered in response to a pathogen attack is also unknown. To address these, Nramp1 status was examined in Leishmania major-infected murine macrophages. We observed that at 12 hrs post infection, there was drastic lowering of Nramp1 level accompanied by increased phagolysosomal iron content and enhanced intracellular parasite growth. Leishmania infection-induced Nramp1 downregulation was caused by ubiquitin-proteasome degradation pathway, which in turn was found to be mediated by the iron-regulatory peptide hormone hepcidin. Blocking of Nramp1 degradation with proteasome inhibitor or transcriptional agonist of hepcidin resulted in depletion of phagolysosomal iron pool that led to significant reduction of intracellular parasite burden. Interestingly, Nramp1 level was restored to normalcy after 30 hrs of infection with a concomitant drop in phagolysosomal iron, which is suggestive of a host counteractive response to deprive the pathogen of this essential micronutrient. Taken together, our study implicates Nramp1 as a central player in the host-pathogen battle for phagolysosomal iron. We also report Nramp1 as a novel target for hepcidin, and this 'hepcidin-Nramp1' axis may have a broader role in regulating macrophage iron homeostasis.
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Affiliation(s)
- Sourav Banerjee
- Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur, India
| | - Rupak Datta
- Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur, India
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Phan-Aram P, Mahasri G, Kayansamruaj P, Amparyup P, Srisapoome P. Immune Regulation, but Not Antibacterial Activity, Is a Crucial Function of Hepcidins in Resistance against Pathogenic Bacteria in Nile Tilapia ( Oreochromis niloticus Linn.). Biomolecules 2020; 10:biom10081132. [PMID: 32751990 PMCID: PMC7464455 DOI: 10.3390/biom10081132] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/20/2020] [Accepted: 07/28/2020] [Indexed: 12/12/2022] Open
Abstract
In this study, the functions of a recombinant propeptide (rProOn-Hep1) and the synthetic FITC-labelled mature peptides sMatOn-Hep1 and sMatOn-Hep2 were analyzed. Moreover, sMatOn-Hep1 and sMatOn-Hep2 were mildly detected in the lymphocytes of peripheral blood mononuclear cells (PBMCs) and strongly detected in head kidney macrophages. The in vitro binding and antibacterial activities of these peptides were slightly effective against several pathogenic bacteria. Immune regulation by sMatOn-Hep1 was also analyzed, and only sMatOn-Hep1 significantly enhanced the phagocytic index in vitro (p < 0.05). Interestingly, intraperitoneal injection of sMatOn-Hep1 (10 or 100 µg) significantly elevated the phagocytic activity, phagocytic index, and lysozyme activity and clearly decreased the iron ion levels in the livers of the treated fish (p < 0.05). Additionally, sMatOn-Hep1 enhanced the expression levels of CC and CXC chemokines, transferrin and both On-Hep genes in the liver, spleen and head kidney, for 1–96 h after injection, but did not properly protect the experimental fish from S. agalactiae infection after 7 days of treatment. However, the injection of S. agalactiae and On-Heps indicated that 100 μg of sMatOn-Hep1 was very effective, while 100 μg of rProOn-Hep1 and sMatOn-Hep2 demonstrated moderate protection. Therefore, On-Hep is a crucial iron-regulating molecule and a key immune regulator of disease resistance in Nile tilapia.
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Affiliation(s)
- Pagaporn Phan-Aram
- Laboratory of Aquatic Animal Health Management, Department of Aquaculture, Faculty of Fisheries, Kasetsart University, 50 Paholayothin Rd, Ladyao, Chatuchak, Bangkok 10900, Thailand; (P.P.-A.); (P.K.)
| | - Gunanti Mahasri
- Department of Fish Health Management and Aquaculture, Faculty of Fisheries and Marine, Universitas Airlangga, Campus C Mulyorejo, Surabaya 60115, Indonesia;
| | - Pattanapon Kayansamruaj
- Laboratory of Aquatic Animal Health Management, Department of Aquaculture, Faculty of Fisheries, Kasetsart University, 50 Paholayothin Rd, Ladyao, Chatuchak, Bangkok 10900, Thailand; (P.P.-A.); (P.K.)
| | - Piti Amparyup
- Marine Biotechnology Research Team, Integrative Aquaculture Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand;
| | - Prapansak Srisapoome
- Laboratory of Aquatic Animal Health Management, Department of Aquaculture, Faculty of Fisheries, Kasetsart University, 50 Paholayothin Rd, Ladyao, Chatuchak, Bangkok 10900, Thailand; (P.P.-A.); (P.K.)
- Correspondence:
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Mehta KJ, Busbridge M, Patel VB, Farnaud SJ. Hepcidin secretion was not directly proportional to intracellular iron-loading in recombinant-TfR1 HepG2 cells: short communication. Mol Cell Biochem 2020; 468:121-128. [PMID: 32185675 PMCID: PMC7145775 DOI: 10.1007/s11010-020-03716-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 03/06/2020] [Indexed: 02/08/2023]
Abstract
Hepcidin is the master regulator of systemic iron homeostasis and its dysregulation is observed in several chronic liver diseases. Unlike the extracellular iron-sensing mechanisms, the intracellular iron-sensing mechanisms in the hepatocytes that lead to hepcidin induction and secretion are incompletely understood. Here, we aimed to understand the direct role of intracellular iron-loading on hepcidin mRNA and peptide secretion using our previously characterised recombinant HepG2 cells that over-express the cell-surface iron-importer protein transferrin receptor-1. Gene expression of hepcidin (HAMP) was determined by real-time PCR. Intracellular iron levels and secreted hepcidin peptide levels were measured by ferrozine assay and immunoassay, respectively. These measurements were compared in the recombinant and wild-type HepG2 cells under basal conditions at 30 min, 2 h, 4 h and 24 h. Data showed that in the recombinant cells, intracellular iron content was higher than wild-type cells at 30 min (3.1-fold, p < 0.01), 2 h (4.6-fold, p < 0.01), 4 h (4.6-fold, p < 0.01) and 24 h (1.9-fold, p < 0.01). Hepcidin (HAMP) mRNA expression was higher than wild-type cells at 30 min (5.9-fold; p = 0.05) and 24 h (6.1-fold; p < 0.03), but at 4 h, the expression was lower than that in wild-type cells (p < 0.05). However, hepcidin secretion levels in the recombinant cells were similar to those in wild-type cells at all time-points, except at 4 h, when the level was lower than wild-type cells (p < 0.01). High intracellular iron in recombinant HepG2 cells did not proportionally increase hepcidin peptide secretion. This suggests a limited role of elevated intracellular iron in hepcidin secretion.
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Affiliation(s)
- Kosha J Mehta
- Centre for Education, Faculty of Life Sciences and Medicine, King's College London, London, UK.
- School of Life Sciences, University of Westminster, London, UK.
| | - Mark Busbridge
- Department of Clinical Biochemistry, Northwest London Pathology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Vinood B Patel
- School of Life Sciences, University of Westminster, London, UK
| | - Sebastien Je Farnaud
- Centre for Sport, Exercise and Life Sciences, Faculty of Health & Life Sciences, Coventry University, Coventry, UK
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Hawula ZJ, Wallace DF, Subramaniam VN, Rishi G. Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis. Pharmaceuticals (Basel) 2019; 12:ph12040170. [PMID: 31775259 PMCID: PMC6958404 DOI: 10.3390/ph12040170] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/15/2019] [Accepted: 11/19/2019] [Indexed: 12/15/2022] Open
Abstract
The interaction between hepcidin and ferroportin is the key mechanism involved in regulation of systemic iron homeostasis. This axis can be affected by multiple stimuli including plasma iron levels, inflammation and erythropoietic demand. Genetic defects or prolonged inflammatory stimuli results in dysregulation of this axis, which can lead to several disorders including hereditary hemochromatosis and anaemia of chronic disease. An imbalance in iron homeostasis is increasingly being associated with worse disease outcomes in many clinical conditions including multiple cancers and neurological disorders. Currently, there are limited treatment options for regulating iron levels in patients and thus significant efforts are being made to uncover approaches to regulate hepcidin and ferroportin expression. These approaches either target these molecules directly or regulatory steps which mediate hepcidin or ferroportin expression. This review examines the current status of hepcidin and ferroportin agonists and antagonists, as well as inducers and inhibitors of these proteins and their regulatory pathways.
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Affiliation(s)
- Zachary J. Hawula
- Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia; (Z.J.H.); (D.F.W.)
- School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia
| | - Daniel F. Wallace
- Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia; (Z.J.H.); (D.F.W.)
- School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia
| | - V. Nathan Subramaniam
- Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia; (Z.J.H.); (D.F.W.)
- School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia
- Correspondence: (V.N.S.); (G.R.)
| | - Gautam Rishi
- Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia; (Z.J.H.); (D.F.W.)
- School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia
- Correspondence: (V.N.S.); (G.R.)
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Hashemi SH, Esna-Ashari F, Nemat Gorgani F, Tayebinia H, Mamani M. Increased serum levels of hepcidin and C-reactive protein in patients with brucellosis. Trans R Soc Trop Med Hyg 2019; 112:509-512. [PMID: 30137576 DOI: 10.1093/trstmh/try092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Accepted: 08/11/2018] [Indexed: 12/17/2022] Open
Abstract
Background Increased serum level of C-reactive protein (CRP) as a classic acute phase protein has commonly been reported in acute brucellosis. Hepcidin is also an acute phase protein and has a critical role in host defense. The aim of this study was to compare the level of hepcidin and CRP in patients with brucellosis. Methods All patients with brucellosis referred to Sina Hospital during a 10-month period were included. Serum samples were checked for hepcidin levels in patients and also in the control group. Information on demographic and clinical characteristics was determined through completion of a questionnaire. Results A total of 42 patients with brucellosis and 42 healthy controls were enrolled. The most common symptoms of brucellosis were fever (76%) and arthralgia (69%). The mean serum level of hepcidin in patients (42.6±11.7 pg/mL) was significantly higher than in the controls (17.3±4.2 pg/mL) (p<0.001). The mean serum levels of CRP in patients and controls were 12.6±12.2 and 3.1±2.4 mg/L, respectively (p=0.001). Conclusions Increased serum levels of hepcidin in brucellosis can be considered a diagnostic biomarker of inflammation and active disease. Further studies are needed to identify the role of hepcidin as a host defense mechanism in brucellosis.
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Affiliation(s)
- Seyyed Hamid Hashemi
- Brucellosis Research Center, Department of Infectious Diseases, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Farzaneh Esna-Ashari
- Department of Community Medicine, Hamadan University of Medical Sciences, Fahmideh Street, Hamadan, Iran
| | - Farnaz Nemat Gorgani
- Brucellosis Research Center, Department of Infectious Diseases, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Heydar Tayebinia
- Brucellosis Research Center, Department of Clinical Biochemistry, Hamadan University of Medical Sciences, Hamedan, Iran
| | - Mojgan Mamani
- Brucellosis Research Center, Department of Infectious Diseases, Hamadan University of Medical Sciences, Hamadan, Iran
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Yathursan S, Wiles S, Read H, Sarojini V. A review on anti-tuberculosis peptides: Impact of peptide structure on anti-tuberculosis activity. J Pept Sci 2019; 25:e3213. [PMID: 31515916 DOI: 10.1002/psc.3213] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 08/03/2019] [Accepted: 08/07/2019] [Indexed: 12/18/2022]
Abstract
Antibiotic resistance is a major public health problem globally. Particularly concerning amongst drug-resistant human pathogens is Mycobacterium tuberculosis that causes the deadly infectious tuberculosis (TB) disease. Significant issues associated with current treatment options for drug-resistant TB and the high rate of mortality from the disease makes the development of novel treatment options against this pathogen an urgent need. Antimicrobial peptides are part of innate immunity in all forms of life and could provide a potential solution against drug-resistant TB. This review is a critical analysis of antimicrobial peptides that are reported to be active against the M tuberculosis complex exclusively. However, activity on non-TB strains such as Mycobacterium avium and Mycobacterium intracellulare, whenever available, have been included at appropriate sections for these anti-TB peptides. Natural and synthetic antimicrobial peptides of diverse sequences, along with their chemical structures, are presented, discussed, and correlated to their observed antimycobacterial activities. Critical analyses of the structure allied to the anti-mycobacterial activity have allowed us to draw important conclusions and ideas for research and development on these promising molecules to realise their full potential. Even though the review is focussed on peptides, we have briefly summarised the structures and potency of the various small molecule drugs that are available and under development, for TB treatment.
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Affiliation(s)
- Sutharsana Yathursan
- School of Chemical Sciences, University of Auckland, Private Bag, 92019, Auckland, New Zealand
| | - Siouxsie Wiles
- Bioluminescent Superbugs Lab, Department of Molecular Medicine and Pathology, University of Auckland, Private Bag, 92019, Auckland, New Zealand
| | - Hannah Read
- Bioluminescent Superbugs Lab, Department of Molecular Medicine and Pathology, University of Auckland, Private Bag, 92019, Auckland, New Zealand
| | - Vijayalekshmi Sarojini
- School of Chemical Sciences, University of Auckland, Private Bag, 92019, Auckland, New Zealand.,The MacDiarmid Institute for Advanced Materials and Nanotechnology, Wellington, 6140, New Zealand
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Ismail NA, Habib SA, Talaat AA, Mostafa NO, Elghoroury EA. The Relation between Serum Hepcidin, Ferritin, Hepcidin: Ferritin Ratio, Hydroxyurea and Splenectomy in Children with β-Thalassemia. Open Access Maced J Med Sci 2019; 7:2434-2439. [PMID: 31666842 PMCID: PMC6814476 DOI: 10.3889/oamjms.2019.636] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 08/09/2019] [Accepted: 08/10/2019] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND: Hepcidin, a small peptide hormone, is established as the main regulator of iron homeostasis. AIM: To estimate serum hepcidin, ferritin, and hepcidin: ferritin ratio in β-thalassemia patients and to determine the effect of splenectomy and hydroxyurea on serum hepcidin. METHODS: A study was conducted on 30 thalassemia major (βTM), 29 thalassemia intermedia (βTI) and 29 healthy children’s controls. Data were collected by patient interviewing where detailed history-taking and thorough clinical examinations were carried out. Serum ferritin and hepcidin were measured by ELISA assay (Bioneovan Co. Ltd Beijing, China). RESULTS: Βeta-thalassemia patients had higher serum ferritin, serum hepcidin and lower Hb and hepcidin: ferritin ratio compared to the controls (p < 0.001, 0.010, 0.001, 0.001) respectively. Β-TM patients had higher mean serum hepcidin and serum ferritin compared to β-TI, with statistically significant difference (P = 0.042, P < 0.001, respectively). Twenty-one patients out of 29 βTI was on hydroxyurea therapy; these patients had significantly lower levels of serum ferritin (P < 0.004) and significantly higher levels of Hb (P < 0.004). Serum ferritin was statistically significantly higher in splenectomized patients P < 0.009. Serum hepcidin level was insignificantly higher in splenectomized patients than non-splenectomized patients (21.6 ± 14.75, 17.76 ± 10.01 ng/mL). Hepcidin showed a significantly positive correlation with hepcidin: ferritin ratio in all studied groups. CONCLUSION: Serum hepcidin was elevated in β-thalassemia children with more evident elevation in βTM patients. Splenectomy played no major role in hepcidin regulation. Knowing that hepcidin in serum has a dynamic and multi-factorial regulation, individual evaluation of serum hepcidin and follow up, e.g. every 6 months could be valuable, and future therapeutic hepcidin agonists could be helpful in management of iron burden in such patient.
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Affiliation(s)
| | | | - Ahmed A Talaat
- Pediatric Department, National Research Center, Cairo, Egypt
| | | | - Eman A Elghoroury
- Clinical Pathology Department, National Research Center, Cairo, Egypt
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Golpour A, Bereswill S, Heimesaat MM. Antimicrobial and Immune-Modulatory Effects of Vitamin D Provide Promising Antibiotics-Independent Approaches to Tackle Bacterial Infections - Lessons Learnt from a Literature Survey. Eur J Microbiol Immunol (Bp) 2019; 9:80-87. [PMID: 31662886 PMCID: PMC6798578 DOI: 10.1556/1886.2019.00014] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 07/24/2019] [Indexed: 12/19/2022] Open
Abstract
Antimicrobial multidrug-resistance (MDR) constitutes an emerging threat to global health and makes the effective prevention and treatment of many, particularly severe infections challenging, if not impossible. Many antibiotic classes have lost antimicrobial efficacy against a plethora of infectious agents including bacterial species due to microbial acquisition of distinct resistance genes. Hence, the development of novel anti-infectious intervention strategies including antibiotic-independent approaches is urgently needed. Vitamins such as vitamin D and vitamin D derivates might be such promising molecular candidates to combat infections caused by bacteria including MDR strains. Using the Pubmed database, we therefore performed an in-depth literature survey, searching for publications on the antimicrobial effect of vitamin D directed against bacteria including MDR strains. In vitro and clinical studies between 2009 and 2019 revealed that vitamin D does, in fact, possess antimicrobial properties against both Gram-positive and Gram-negative bacterial species, whereas conflicting results could be obtained from in vivo studies. Taken together, the potential anti-infectious effects for the antibiotic-independent application of vitamin D and/or an adjunct therapy in combination with antibiotic compounds directed against infectious diseases such as tuberculosis, H. pylori infections, or skin diseases, for instance, should be considered and further investigated in more detail.
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Affiliation(s)
- Ainoosh Golpour
- Institute of Microbiology, Infectious Diseases and Immunology Charité - University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Stefan Bereswill
- Institute of Microbiology, Infectious Diseases and Immunology Charité - University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Markus M Heimesaat
- Institute of Microbiology, Infectious Diseases and Immunology Charité - University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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Daher R, Lefebvre T, Puy H, Karim Z. Extrahepatic hepcidin production: The intriguing outcomes of recent years. World J Clin Cases 2019; 7:1926-1936. [PMID: 31423425 PMCID: PMC6695539 DOI: 10.12998/wjcc.v7.i15.1926] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 06/18/2019] [Accepted: 06/27/2019] [Indexed: 02/05/2023] Open
Abstract
Hepcidin is the hyposideremic hormone regulating iron metabolism. It is a defensin-like disulfide-bonded peptide with antimicrobial activity. The main site of hepcidin production is the liver where its synthesis is modulated by iron, inflammation and erythropoietic signaling. However, hepcidin locally produced in several peripheral organs seems to be an important actor for the maintenance of iron homeostasis in these organs. This review highlights the presence of peripheral hepcidin and its potential functions. Understanding the role of extrahepatic hepcidin could be of great physiological and therapeutic importance for several specific pathologies.
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Affiliation(s)
- Raêd Daher
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
| | - Thibaud Lefebvre
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
| | - Hervé Puy
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
| | - Zoubida Karim
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
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Increased hepcidin in hemorrhagic plaques correlates with iron-stimulated IL-6/STAT3 pathway activation in macrophages. Biochem Biophys Res Commun 2019; 515:394-400. [DOI: 10.1016/j.bbrc.2019.05.123] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 05/19/2019] [Indexed: 01/24/2023]
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Tashiro K, Yamamoto M, Ushio R, Kobayashi N, Sato T, Kudo M, Kaneko T. Hepcidin exerts a negative immunological effect in pulmonary tuberculosis without HIV co-infection, prolonging the time to culture-negative. Int J Infect Dis 2019; 86:47-54. [PMID: 31252187 DOI: 10.1016/j.ijid.2019.06.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 06/19/2019] [Accepted: 06/20/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES A major regulatory peptide in iron metabolism, hepcidin, has been shown to predict mortality in HIV-infected tuberculosis patients. The aim of this study was to evaluate whether plasma hepcidin levels on admission can be used to predict the treatment outcome of patients with smear-positive pulmonary tuberculosis (PTB) without HIV co-infection. METHODS In this prospective observational study, a total of 35 PTB patients with Mycobacterium tuberculosis-positive sputum smears were enrolled. The relationship between plasma hepcidin levels on admission and the time period to sputum culture-negative was explored. RESULTS Plasma hepcidin levels of PTB patients were significantly higher than those of healthy subjects (p<0.001). A positive correlation between hepcidin level on admission and the period until culture-negative was also observed (r=0.46, p=0.006). Furthermore, the hepcidin level showed a negative correlation with spot numbers in the positive control wells of the T-SPOT.TB assay; thus the effect of the peptide on interferon-gamma production in T cells was explored. Hepcidin reduced interferon-gamma gene transcription and interferon-gamma production in a dose-dependent manner in Jurkat cells stimulated with phytohaemagglutinin, an antigen non-specific stimulation. CONCLUSIONS These findings indicate that hepcidin alters immunological reactions against M. tuberculosis infection and has an influence on the outcomes of PTB patients without HIV co-infection.
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Affiliation(s)
- Ken Tashiro
- Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masaki Yamamoto
- Respiratory Disease Centre, Yokohama City University Medical Centre, Yokohama, Japan.
| | - Ryota Ushio
- Respiratory Disease Centre, Yokohama City University Medical Centre, Yokohama, Japan
| | - Nobuaki Kobayashi
- Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takashi Sato
- Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Makoto Kudo
- Respiratory Disease Centre, Yokohama City University Medical Centre, Yokohama, Japan
| | - Takeshi Kaneko
- Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Iron Supplementation Therapy, A Friend and Foe of Mycobacterial Infections? Pharmaceuticals (Basel) 2019; 12:ph12020075. [PMID: 31108902 PMCID: PMC6630247 DOI: 10.3390/ph12020075] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 05/14/2019] [Accepted: 05/15/2019] [Indexed: 12/21/2022] Open
Abstract
Iron is an essential element that is required for oxygen transfer, redox, and metabolic activities in mammals and bacteria. Mycobacteria, some of the most prevalent infectious agents in the world, require iron as growth factor. Mycobacterial-infected hosts set up a series of defense mechanisms, including systemic iron restriction and cellular iron distribution, whereas mycobacteria have developed sophisticated strategies to acquire iron from their hosts and to protect themselves from iron’s harmful effects. Therefore, it is assumed that host iron and iron-binding proteins, and natural or synthetic chelators would be keys targets to inhibit mycobacterial proliferation and may have a therapeutic potential. Beyond this hypothesis, recent evidence indicates a host protective effect of iron against mycobacterial infections likely through promoting remodeled immune response. In this review, we discuss experimental procedures and clinical observations that highlight the role of the immune response against mycobacteria under various iron availability conditions. In addition, we discuss the clinical relevance of our knowledge regarding host susceptibility to mycobacteria in the context of iron availability and suggest future directions for research on the relationship between host iron and the immune response and the use of iron as a therapeutic agent.
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IL-1 beta-mediated macrophage-hepatocyte crosstalk upregulates hepcidin under physiological low oxygen levels. Redox Biol 2019; 24:101209. [PMID: 31108461 PMCID: PMC6526398 DOI: 10.1016/j.redox.2019.101209] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 04/25/2019] [Accepted: 04/27/2019] [Indexed: 12/19/2022] Open
Abstract
In mammals, the iron masterswitch hepcidin efficiently controls iron recycling by the macrophage-liver axis but the exact interplay between macrophages and hepatocytes remains poorly understood. We here study hepcidin response during macrophage differentiation as well as the macrophage-hepatocyte crosstalk and its subsequent effects on hepatocyte hepcidin using an in vitro co-culture model that mimics the physiological liver microenvironment. We show that macrophage differentiation strongly induces hepcidin by 60-fold both in THP1 macrophages and primary isolated monocyte-derived macrophages. Removal of H2O2 by catalase or inhibition of NOX2 efficiently blocked hepcidin induction. After differentiation, macrophage hepcidin accounted for 10% of total hepatocyte hepcidin and did not respond to low oxygen levels. In contrast, co-culture of differentiated macrophages with Huh7 cells significantly induced hepatocyte hepcidin, which was further potentiated under low oxygen levels. Hepatocyte hepcidin was also upregulated when Huh7 cells were solely exposed to macrophage-conditioned hypoxic medium. A cytokine screen identified macrophage secreted IL-1β as major inducer of hepcidin in hepatocytes. In confirmation, treatment of Huh7 cells with the IL-1 receptor antagonist (anakinra) completely blunted macrophage-mediated hepcidin transcription in hepatocytes. Finally, detailed analysis of potentially involved signaling pathways points toward STAT3 and CEBPδ-mediated hepcidin induction independent of IL-6. In conclusion, our study demonstrates a strong NOX2-mediated hepcidin induction during macrophage differentiation. These differentiated macrophages are able to efficiently induce hepatocyte hepcidin mainly through secretion of IL-1β. Our data highlight a hitherto unrecognized role of macrophage-hepatocyte crosstalk for a joint and oxygen-dependent hepcidin production through STAT3 and CEBPδ.
Hepcidin is strongly induced during NOX2-mediated macrophage differentiation in a H2O2-dependent manner. In contrast to hepatocyte hepcidin, macrophage hepcidin transcription is not modulated by low O2 level. Macrophage released IL1-β strongly induces hepatocyte hepcidin via STAT3 signaling. IL1-β mediated hepatocyte hepcidin induction is independent of IL-6. Despite the mandatory requirement of STAT3, CEBPδ also involved in IL1-β induced hepatocyte hepcidin transcription.
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Saprina TV, Zima AP, Musina NN, Prokhorenko TS, Latypova AV, Shakhmanova NS, Budeeva SV. Pathogenetic aspects of hepcidin metabolism and ferrocinetics dysregulation in carbohydrate metabolism disorders. DIABETES MELLITUS 2019. [DOI: 10.14341/dm9378] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Hepcidin, a hormone regulating iron metabolism, has received attention for its role in the pathogenesis of dysregulations in carbohydrate metabolism. Hepcidin disorders in patients with diabetes mellitus are bi-directional: manifesting as iron overload syndrome in cases of decreased hepcidin production and as anaemia of chronic disease in cases of hepcidin hypersecretion. However, till date, detailed analyses of mechanisms underlying hepcidin dysregulation have not been conducted nor have the interactions of ferrocinetic and carbohydrate-metabolic disorders been examined. An association between diabetes mellitus and neurodegenerative diseases as well as the role of iron metabolism in Alzheimer or Parkinson diseases is a subject of ongoing research. This review provides a summary of the current understanding of hepcidin regulation and its disorders in various diseases, including diabetes mellitus and neurodegenerative diseases. In addition, we provide an overview of the available therapies that address ferrocinetic disorders resulting from the dysregulation of hepcidin.
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Singh B, Singh SS, Sundar S. Hepcidin mediated iron homoeostasis as immune regulator in visceral leishmaniasis patients. Parasite Immunol 2018; 41:e12601. [PMID: 30402883 DOI: 10.1111/pim.12601] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 10/29/2018] [Accepted: 10/31/2018] [Indexed: 12/12/2022]
Abstract
AIM Iron is key ingredient for immunosurveillance and host-pathogen interaction. Intracellular pathogen steals the iron from the host, but how parasite orchestrates iron acquisition and affects immune responses remains controversial. We aimed to study the iron homoeostasis in visceral leishmaniasis (VL) and its influence on immune machinery. METHODS AND RESULTS This study was performed on purified monocytes and T cells, peripheral blood mononuclear cells and splenic aspirates for transcriptional analyses of iron homoeostasis (hepcidin, DMT1, transferrin receptor, ferroportin) and immune modulations (IFN-γ, HLA-DR, IL-10, iNOS, IL-6). Serum/plasma was used for determination of iron, total/transferrin iron-binding capacity and anti-leishmania antibody titres in cases. We report that VL-induced perturbation in iron homoeostasis may cause immune dysfunctions. VL cases had decreased iron uptake by transferrin-dependent and transferrin-independent routes while elevated hepcidin, degraded sole iron exporter ferroportin. Therefore, it appears that perturbation in iron homoeostasis has essential role in HLA-DR mediated antigen presentation and innate armoury by downregulating iNOS as well as altering IFN-γ, IL-6 and IL-10 profiles. CONCLUSION The iron homoeostasis by hepcidin can serve as one of the crucial determinants for regulating immune cell signalling; therefore, targeting iron metabolism, specifically hepcidin alone or in combination with agonists, can serve to clear infection.
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Affiliation(s)
- Bhawana Singh
- Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Siddharth Sankar Singh
- Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Shyam Sundar
- Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
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Yin B, Liu H, Tan B, Dong X, Chi S, Yang Q, Zhang S, Chen L. Cottonseed protein concentrate (CPC) suppresses immune function in different intestinal segments of hybrid grouper ♀Epinephelus fuscoguttatus×♂Epinephelus lanceolatu via TLR-2/MyD88 signaling pathways. FISH & SHELLFISH IMMUNOLOGY 2018; 81:318-328. [PMID: 30030116 DOI: 10.1016/j.fsi.2018.07.038] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 06/11/2018] [Accepted: 07/17/2018] [Indexed: 06/08/2023]
Abstract
Cottonseed protein concentrate (CPC) has similar amino acid composition compared with fish meal, and has the characteristics of low gossypol and low toxicity. The present study was conducted to investigate the growth performance, antioxidant capacity and different intestinal segments immune responses of hybrid grouper to replacement dietary fish meal ofCPC. Six iso-nitrogenous (50% crude protein) and iso-lipidic (10% crude lipid) diets were formulated: a reference diet (FM) containing 60% fishmeal and five experimental diets (12%, 24%, 36%, 48 and 60%) in which fishmeal protein was substituted at different levels by CPC to feed fish (initial body weight: 11 ± 0.23 g) for 8 weeks. Thena challenge test with injection of Vibrio parahaemolyticus was conducted for 7 days until the fish stabilized. The results showed that specific growth rate (SGR) was the highest with 24% replacement level and feed conversion ratio (FCR)was significantly increased when the replacement level reached 48% (P < 0.05). The content of malonaldehyde (MDA) in the serum was significantly increased when the replacement level reached 36% (P < 0.05). The plica height in the proximal, mid and distal intestine were significantly decreased with the replacement level up to 48% (P < 0.05). Hepatic fat deposition wasaggravatedwhen the replacement level reached 36% (P < 0.05). The expression of IL-6, TNF-α, and IL-1β mRNAs were significantly up-regulated (P < 0.05). The hepcidin mRNA expression was significantly down-regulated (P < 0.05). In proximal intestine (PI) and mid intestine (MI), IFN-γ mRNA expression was significantly up-regulated (P < 0.05). These results suggested that the CPC decreased hybrid grouper growth performance and inflammation function, and different inflammation function responses in PI,MI, and distal intestine (DI) were mediated partly by the TLR-2/MyD88 signaling pathway. According to the analysis of specific growth rate, the dietary optimum replacement level and maximum replacement level were estimated to be 17% and 34%, respectively.
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Affiliation(s)
- Bin Yin
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, PR China
| | - Hongyu Liu
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, PR China
| | - Beiping Tan
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, PR China.
| | - Xiaohui Dong
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, PR China
| | - Shuyan Chi
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, PR China
| | - Qihui Yang
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, PR China
| | - Shuang Zhang
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, PR China
| | - Liqiao Chen
- College of Life Sciences, East China Normal University, Shanghai, 200062, PR China
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