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Ren Q, Xu X, Dong Z, Qiu J, Shan Q, Chen R, Liu Y, Ma J, Liu S. Iron Deficiency Impairs Dendritic Cell Development and Function, Compromising Host Anti-Infection Capacity. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2408348. [PMID: 40305750 DOI: 10.1002/advs.202408348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 03/23/2025] [Indexed: 05/02/2025]
Abstract
The prevalence of acute lower respiratory infections in individuals with iron deficiency (ID) has significantly increased, and is correlated with reduced numbers of immune cells and impaired immune function. Dendritic cells (DCs) play a crucial role in combating the influenza A virus (IAV) by initiating adaptive immune responses. However, the impact of ID on DCs and their response to IAV infection remain unclear. This study showed that ID impairs the antigen-presenting ability of DCs, thereby hindering their capacity to mediate T-cell proliferation and clear viruses. The restrictive effects of ID on DCs begin in the bone marrow and specifically affect the monocyte DC progenitor (MDP) stage. A reduction in the number of MDPs and compromised immune potential lead to a decrease in the population and functionality of DCs in the subsequent common DC precursor (CDP) stage in the blood, spleen, and lungs. This study highlights the previously unrecognized impact of ID on DCs and provides valuable insights into immune cell responses and the application of iron supplementation in the fight against viral infections.
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Affiliation(s)
- Quanzhong Ren
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, P. R. China
- JST sarcopenia Research Centre, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, P. R. China
| | - Xiaotong Xu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, P. R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Zheng Dong
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, P. R. China
| | - Jiahuang Qiu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, P. R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Qing'e Shan
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, P. R. China
| | - Rui Chen
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, P. R. China
| | - Yajun Liu
- JST sarcopenia Research Centre, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, P. R. China
| | - Juan Ma
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, P. R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Sijin Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, P. R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, P. R. China
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Foulon N, Haeger SM, Okamura K, He Z, Park BD, Budnick IM, Madison D, Kennis M, Blaine R, Miyazaki M, Jalal DI, Griffin BR, Aftab M, Colbert JF, Faubel S. Procalcitonin levels in septic and nonseptic subjects with AKI and ESKD prior to and during continuous kidney replacement therapy (CKRT). Crit Care 2025; 29:171. [PMID: 40307866 PMCID: PMC12044748 DOI: 10.1186/s13054-025-05414-7] [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: 02/03/2025] [Accepted: 04/11/2025] [Indexed: 05/02/2025] Open
Abstract
BACKGROUND Procalcitonin is a 14.5 kDa protein used clinically as a marker of sepsis and therapeutic response to antibiotic therapy. However, its utility in critically ill patients with either acute kidney injury (AKI) or end-stage kidney disease (ESKD) who require continuous kidney replacement therapy (CKRT) is unknown. The aim of this study was to determine if plasma levels of procalcitonin could reliably distinguish septic from nonseptic status in patients with AKI or ESKD prior to or during CKRT. METHODS Procalcitonin concentrations were measured in plasma of 41 critically ill septic or non-septic subjects with AKI or ESKD prior to CKRT (pre-CKRT) and on days 1, 2, and 3 of CKRT in this retrospective cohort study (n = 111 total plasma measurements). Continuous venovenous hemodialysis was the modality of CKRT in these patients. Sepsis status was stringently defined based on culture results. Effluent procalcitonin levels were ascertained on days 1, 2, and 3 of CKRT to assess the clearance of procalcitonin and effects on plasma levels. RESULTS 92% (66/72) of the plasma procalcitonin measurements among nonseptic patients with either AKI or ESKD were ≥ 0.5 ng/mL (the diagnostic threshold beyond which bacterial infection is very likely). Prior to CKRT initiation, procalcitonin levels were (median (IQR), ng/mL) 5.6 (1.5-18.9) in nonseptic AKI and 58.1 (6.9-195.5) in septic AKI (P = 0.03) and were 3.3 (1.2-8.3) in nonseptic ESKD and 3.7 (1.4-209.8) in septic ESKD (P = 0.79). However, despite being significantly elevated in septic patients with AKI, substantial overlap among procalcitonin levels was present and ROC curve analysis found no cut point that could reliably separate septic from nonseptic patients. Effluent procalcitonin levels were consistently ~ 20% of plasma levels throughout the course of CKRT (i.e., sieving coefficient was 0.2) suggesting that clearance occurs during therapy. However, plasma procalcitonin levels did not significantly decline during CKRT in either AKI or ESKD. CONCLUSION Procalcitonin levels are markedly elevated in nonseptic critically ill patients with either AKI or ESKD and do not effectively distinguish sepsis from nonseptic status prior to or during CKRT. We conclude that procalcitonin testing should be avoided in critically ill patients with kidney failure since results are nonspecific in this population.
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Affiliation(s)
- North Foulon
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, 12700 East 19th Ave, Box C281, Aurora, CO, 80045, USA
| | - Sarah M Haeger
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, 12700 East 19th Ave, Box C281, Aurora, CO, 80045, USA
| | - Kayo Okamura
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, 12700 East 19th Ave, Box C281, Aurora, CO, 80045, USA
| | - Zhibin He
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, 12700 East 19th Ave, Box C281, Aurora, CO, 80045, USA
| | - Bryan D Park
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Isadore M Budnick
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - David Madison
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, 12700 East 19th Ave, Box C281, Aurora, CO, 80045, USA
| | - Matthew Kennis
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, 12700 East 19th Ave, Box C281, Aurora, CO, 80045, USA
| | - Rachel Blaine
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, 12700 East 19th Ave, Box C281, Aurora, CO, 80045, USA
| | - Makoto Miyazaki
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, 12700 East 19th Ave, Box C281, Aurora, CO, 80045, USA
| | - Diana I Jalal
- Department of Medicine, Division of Nephrology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Benjamin R Griffin
- Department of Medicine, Division of Nephrology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Muhammad Aftab
- Department of Surgery, Division of Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - James F Colbert
- Department of Medicine, Division of Infectious Diseases, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Sarah Faubel
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, 12700 East 19th Ave, Box C281, Aurora, CO, 80045, USA.
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Kim JH, Yeo IJ, Son DJ, Han SB, Yoon DY, Lee DH, Hong JT. Chitinase 3-like protein 1 deficiency ameliorates drug-induced acute liver injury by inhibition of neutrophil recruitment through lipocalin-2. Front Pharmacol 2025; 16:1548832. [PMID: 40196357 PMCID: PMC11973357 DOI: 10.3389/fphar.2025.1548832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/06/2025] [Indexed: 04/09/2025] Open
Abstract
Chitinase-3-like protein 1 (Chi3l1) is a member of the mammalian Chitinase-like protein family, and several studies reported that Chi3l1 is associated with various inflammatory diseases as well as liver diseases. Acetaminophen (APAP) is usually used for antipyretic drug, but its overdose induces acute liver injury (ALI). Several studies reported that subsequent inflammatory responses of the immune system play a critical role in the severity and outcome of APAP-induced ALI. In the present study, we investigated the role of Chi3l1 and its mechanism during APAP-induced ALI using Chi3l1 knock-out (KO) mice. We explored the function of Chi3l1 using APAP-injected KO mice and sought proteins associated with Chi3l1 through biological research data program for investigating mechanism. Liver histological analysis revealed that APAP-induced ALI was attenuated in KO mice compared to wild-type (WT) mice. We observed that APAP-induced neutrophil infiltration was decreased in the liver of KO mice compared to WT mice. To investigate this mechanism, we sought proteins potentially associated with Chi3l1 by mRNA sequencing and protein correlation analysis data. We found lipocalin-2 (Lcn2) and examined Chi3l1, Lcn2, and their relationship in the APAP-induced ALI model using recombinant proteins and antibodies. Our results suggest that Chi3l1 deficiency ameliorates APAP-induced liver injury through abrogating Lcn2-mediated neutrophil infiltration in the liver.
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Affiliation(s)
- Ji Hye Kim
- Department of Biological Sciences, Research Center of Ecomimetics, Chonnam National University, Gwangju, Republic of Korea
| | - In Jun Yeo
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
- College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Dong Ju Son
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Sang Bae Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Do Young Yoon
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea
| | - Dong Hun Lee
- Department of Biological Sciences, Research Center of Ecomimetics, Chonnam National University, Gwangju, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
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Tang S, Wu S, Zhang W, Ma L, Zuo L, Wang H. Immunology and treatments of fatty liver disease. Arch Toxicol 2025; 99:127-152. [PMID: 39692857 DOI: 10.1007/s00204-024-03920-1] [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: 09/05/2024] [Accepted: 11/26/2024] [Indexed: 12/19/2024]
Abstract
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are two major chronic liver diseases worldwide. The triggers for fatty liver can be derived from external sources such as adipose tissue, the gut, personal diet, and genetics, or internal sources, including immune cell responses, lipotoxicity, hepatocyte death, mitochondrial dysfunction, and extracellular vesicles. However, their pathogenesis varies to some extent. This review summarizes various immune mechanisms and therapeutic targets associated with these two types of fatty liver disease. It describes the gut-liver axis and adipose tissue-liver crosstalk, as well as the roles of different immune cells (both innate and adaptive immune cells) in fatty liver disease. Additionally, mitochondrial dysfunction, extracellular vesicles, microRNAs (miRNAs), and gastrointestinal hormones are also related to the pathogenesis of fatty liver. Understanding the pathogenesis of fatty liver and corresponding therapeutic strategies provides a new perspective for developing novel treatments for fatty liver disease.
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Affiliation(s)
- Sainan Tang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Shanshan Wu
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Wenzhe Zhang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Lili Ma
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Li Zuo
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China.
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, 230022, Anhui, China.
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China.
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Zhang ZX, Peng J, Ding WW. Lipocalin-2 and intestinal diseases. World J Gastroenterol 2024; 30:4864-4879. [PMID: 39679305 PMCID: PMC11612708 DOI: 10.3748/wjg.v30.i46.4864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 09/25/2024] [Accepted: 11/04/2024] [Indexed: 11/21/2024] Open
Abstract
Dysfunction of the intestinal barrier is a prevalent phenomenon observed across a spectrum of diseases, encompassing conditions such as mesenteric artery dissection, inflammatory bowel disease, cirrhosis, and sepsis. In these pathological states, the integrity of the intestinal barrier, which normally serves to regulate the selective passage of substances between the gut lumen and the bloodstream, becomes compromised. This compromised barrier function can lead to a range of adverse consequences, including increased permeability to harmful substances, the translocation of bacteria and their products into systemic circulation, and heightened inflammatory responses within the gut and beyond. Understanding the mechanisms underlying intestinal barrier dysfunction in these diverse disease contexts is crucial for the development of targeted therapeutic interventions aimed at restoring barrier integrity and ameliorating disease progression. Lipocalin-2 (LCN2) expression is significantly upregulated during episodes of intestinal inflammation, making it a pivotal indicator for gauging the extent of such inflammatory processes. Notably, however, LCN2 derived from distinct cellular sources, whether intestinal epithelial cells or immune cells, exhibits notably divergent functional characteristics. Furthermore, the multifaceted nature of LCN2 is underscored by its varying roles across different diseases, sometimes even demonstrating contradictory effects.
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Affiliation(s)
- Zhong-Xu Zhang
- Department of Trauma and Acute Care Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Jian Peng
- Department of Trauma and Acute Care Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Wei-Wei Ding
- Department of Trauma and Acute Care Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, Jiangsu Province, China
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Mestekemper AN, Pirschel W, Krieg N, Paulmann MK, Daniel C, Amann K, Coldewey SM. Reduction in Renal Heme Oxygenase-1 Is Associated with an Aggravation of Kidney Injury in Shiga Toxin-Induced Murine Hemolytic-Uremic Syndrome. Toxins (Basel) 2024; 16:543. [PMID: 39728801 PMCID: PMC11679022 DOI: 10.3390/toxins16120543] [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: 10/11/2024] [Revised: 12/07/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024] Open
Abstract
Hemolytic-uremic syndrome (HUS) is a systemic complication of an infection with Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli, primarily leading to acute kidney injury (AKI) and microangiopathic hemolytic anemia. Although free heme has been found to aggravate renal damage in hemolytic diseases, the relevance of the heme-degrading enzyme heme oxygenase-1 (HO-1, encoded by Hmox1) in HUS has not yet been investigated. We hypothesized that HO-1, also important in acute phase responses in damage and inflammation, contributes to renal pathogenesis in HUS. The effect of tamoxifen-induced Hmox1 gene deletion on renal HO-1 expression, disease progression and AKI was investigated in mice 7 days after HUS induction. Renal HO-1 levels were increased in Stx-challenged mice with tamoxifen-induced Hmox1 gene deletion (Hmox1R26Δ/Δ) and control mice (Hmox1lox/lox). This HO-1 induction was significantly lower (-43%) in Hmox1R26Δ/Δ mice compared to Hmox1lox/lox mice with HUS. Notably, the reduced renal HO-1 expression was associated with an exacerbation of kidney injury in mice with HUS as indicated by a 1.7-fold increase (p = 0.02) in plasma neutrophil gelatinase-associated lipocalin (NGAL) and a 1.3-fold increase (p = 0.06) in plasma urea, while other surrogate parameters for AKI (e.g., periodic acid Schiff staining, kidney injury molecule-1, fibrin deposition) and general disease progression (HUS score, weight loss) remained unchanged. These results indicate a potentially protective role of HO-1 in the pathogenesis of Stx-mediated AKI in HUS.
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Affiliation(s)
- Antonio N. Mestekemper
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; (A.N.M.); (N.K.); (M.K.P.)
- Septomics Research Center, Jena University Hospital, 07745 Jena, Germany
| | - Wiebke Pirschel
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; (A.N.M.); (N.K.); (M.K.P.)
- Septomics Research Center, Jena University Hospital, 07745 Jena, Germany
| | - Nadine Krieg
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; (A.N.M.); (N.K.); (M.K.P.)
- Septomics Research Center, Jena University Hospital, 07745 Jena, Germany
| | - Maria K. Paulmann
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; (A.N.M.); (N.K.); (M.K.P.)
- Septomics Research Center, Jena University Hospital, 07745 Jena, Germany
| | - Christoph Daniel
- Department of Nephropathology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany; (C.D.); (K.A.)
| | - Kerstin Amann
- Department of Nephropathology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany; (C.D.); (K.A.)
| | - Sina M. Coldewey
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; (A.N.M.); (N.K.); (M.K.P.)
- Septomics Research Center, Jena University Hospital, 07745 Jena, Germany
- Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07747 Jena, Germany
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Li Y, Li L, Zhang Y, Yun Q, Du R, Ye H, Li Z, Gao Q. Lipocalin-2 silencing alleviates sepsis-induced liver injury through inhibition of ferroptosis. Ann Hepatol 2024; 30:101756. [PMID: 39662594 DOI: 10.1016/j.aohep.2024.101756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 09/23/2024] [Accepted: 10/23/2024] [Indexed: 12/13/2024]
Abstract
INTRODUCTION AND OBJECTIVES Liver plays a key role in sepsis, a systemic inflammatory response syndrome caused by infection. Ferroptosis is involved in sepsis-induced liver injury. We aimed to assess the changes in ferroptosis in cecal ligation and puncture (CLP)-induced septic mice, and determine the role of lipocalin-2 (LCN2) in liver ferroptosis. MATERIALS AND METHODS CLP was used to induce sepsis in mice. The morphological changes in liver tissues and mitochondrial structure were observed using hematoxylin and eosin staining and transmission electron microscopy. The levels of serum alanine transaminase, aspartate aminotransferase, superoxide dismutase, and malondialdehyde were detected using the corresponding kits. The changes of reactive oxygen species level in liver tissues were detected using dihydroethidium as a fluorescence probe. LCN2, cysteine-glutamate reverse transport system, and dihydroorotate dehydrogenase protein levels in the liver were detected by western blotting. The ferroptosis inhibitor ferrostatin-1 (Fer-1), iron chelator dexrazoxane (DXZ), iron-dextran, and LCN2 knockdown studies were performed to determine role of ferroptosis and LCN2 in liver injury during sepsis. RESULTS Ferroptosis levels increased in the liver tissues of CLP-induced septic mice. Both Fer-1 and DXZ suppressed ferroptosis and attenuated liver injury following sepsis challenge, whereas iron-dextran increased ferroptosis and liver injury in mice with sepsis. LCN2 knockdown suppressed ferroptosis and reduced oxidative stress in the liver. CONCLUSIONS Ferroptosis inhibition attenuates septic liver injury. LCN2 knockdown alleviates sepsis-induced liver injury by inhibiting ferroptosis and reducing oxidative stress.
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Affiliation(s)
- Yuping Li
- School of Life Sciences, Bengbu Medical University, Bengbu, Anhui 233000, PR China; Anhui Nerve Regeneration Technology and Medical new Materials Engineering Research Center, Bengbu, Anhui 233000, PR China.
| | - Lu Li
- Department of Physiology, Bengbu Medical University, Bengbu, Anhui 233000, PR China; Key Laboratory of Cardiovascular and cerebrovascular Diseases, Bengbu Medical University, Bengbu, Anhui 233000, PR China.
| | - Yuming Zhang
- Department of Physiology, Bengbu Medical University, Bengbu, Anhui 233000, PR China; Key Laboratory of Cardiovascular and cerebrovascular Diseases, Bengbu Medical University, Bengbu, Anhui 233000, PR China.
| | - Qi Yun
- School of Life Sciences, Bengbu Medical University, Bengbu, Anhui 233000, PR China; Key Laboratory of Cardiovascular and cerebrovascular Diseases, Bengbu Medical University, Bengbu, Anhui 233000, PR China.
| | - Ruoli Du
- Department of Physiology, Bengbu Medical University, Bengbu, Anhui 233000, PR China; Key Laboratory of Cardiovascular and cerebrovascular Diseases, Bengbu Medical University, Bengbu, Anhui 233000, PR China.
| | - Hongwei Ye
- Department of Physiology, Bengbu Medical University, Bengbu, Anhui 233000, PR China; Key Laboratory of Cardiovascular and cerebrovascular Diseases, Bengbu Medical University, Bengbu, Anhui 233000, PR China.
| | - Zhenghong Li
- School of Life Sciences, Bengbu Medical University, Bengbu, Anhui 233000, PR China; Department of Physiology, Bengbu Medical University, Bengbu, Anhui 233000, PR China; Anhui Nerve Regeneration Technology and Medical new Materials Engineering Research Center, Bengbu, Anhui 233000, PR China.
| | - Qin Gao
- Department of Physiology, Bengbu Medical University, Bengbu, Anhui 233000, PR China; Key Laboratory of Cardiovascular and cerebrovascular Diseases, Bengbu Medical University, Bengbu, Anhui 233000, PR China.
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Zywno H, Figiel W, Grat M, Nazarewski S, Galazka Z, Malyszko J. Can Novel Biomarkers Effectively Predict Acute Kidney Injury in Liver or Kidney Transplant Recipients? Int J Mol Sci 2024; 25:12072. [PMID: 39596140 PMCID: PMC11593440 DOI: 10.3390/ijms252212072] [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: 10/22/2024] [Revised: 11/05/2024] [Accepted: 11/09/2024] [Indexed: 11/28/2024] Open
Abstract
Acute kidney injury (AKI) constitutes a common complication associated with liver or kidney transplantation, which may significantly impact the graft condition and perioperative mortality. Current AKI diagnostic criteria based on serum creatinine (sCr) and urine output alterations are widely utilized in routine clinical practice. However, the diagnostic value of sCr may be limited by various confounding factors, including age, sex, reduced or increased muscle mass, and pre-existing chronic kidney disease (CKD). Furthermore, sCr is rather a late indicator of AKI, as its concentration tends to increase only when the severity of the injury is enough to decrease the estimated glomerular filtration rate (eGFR). Recent expertise highlights the need for novel biomarkers in post-transplantation AKI diagnosis, prediction of event-associated mortality, or evaluation of indications for renal replacement treatment (RRT). Over the last decade, the diagnostic performance of various AKI biomarkers has been assessed, among which some showed the potential to outperform sCr in AKI diagnosis. Identifying susceptible individuals, early diagnosis, and prompt intervention are crucial for successful transplantation, undisturbed graft function in long-term follow-up, and decreased mortality. However, the research on AKI biomarkers in transplantation still needs to be explored. The field lacks consistent results, rigorous study designs, and external validation. Considering the rapidly growing prevalence of CKD and cirrhosis that are associated with the transplantation at their end-stage, as well as the existing knowledge gap, the aim of this article was to provide the most up-to-date review of the studies on novel biomarkers in the diagnosis of post-transplantation AKI.
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Affiliation(s)
- Hubert Zywno
- Department of Nephrology, Dialysis, and Internal Diseases, University Clinical Centre, Medical University of Warsaw, 02-097 Warsaw, Poland;
- Doctoral School of Medical University of Warsaw, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Wojciech Figiel
- Department of General, Transplant, and Liver Surgery, University Clinical Centre, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Michal Grat
- Department of General, Transplant, and Liver Surgery, University Clinical Centre, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Slawomir Nazarewski
- Department of General, Endocrinological, and Vascular Surgery, University Clinical Centre, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Zbigniew Galazka
- Department of General, Endocrinological, and Vascular Surgery, University Clinical Centre, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Jolanta Malyszko
- Department of Nephrology, Dialysis, and Internal Diseases, University Clinical Centre, Medical University of Warsaw, 02-097 Warsaw, Poland;
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Wang Y, Jia J, Wang F, Fang Y, Yang Y, Zhou Q, Yuan W, Gu X, Hu J, Yang S. Pre-metastatic niche: formation, characteristics and therapeutic implication. Signal Transduct Target Ther 2024; 9:236. [PMID: 39317708 PMCID: PMC11422510 DOI: 10.1038/s41392-024-01937-7] [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: 02/28/2024] [Revised: 06/29/2024] [Accepted: 07/23/2024] [Indexed: 09/26/2024] Open
Abstract
Distant metastasis is a primary cause of mortality and contributes to poor surgical outcomes in cancer patients. Before the development of organ-specific metastasis, the formation of a pre-metastatic niche is pivotal in promoting the spread of cancer cells. This review delves into the intricate landscape of the pre-metastatic niche, focusing on the roles of tumor-derived secreted factors, extracellular vesicles, and circulating tumor cells in shaping the metastatic niche. The discussion encompasses cellular elements such as macrophages, neutrophils, bone marrow-derived suppressive cells, and T/B cells, in addition to molecular factors like secreted substances from tumors and extracellular vesicles, within the framework of pre-metastatic niche formation. Insights into the temporal mechanisms of pre-metastatic niche formation such as epithelial-mesenchymal transition, immunosuppression, extracellular matrix remodeling, metabolic reprogramming, vascular permeability and angiogenesis are provided. Furthermore, the landscape of pre-metastatic niche in different metastatic organs like lymph nodes, lungs, liver, brain, and bones is elucidated. Therapeutic approaches targeting the cellular and molecular components of pre-metastatic niche, as well as interventions targeting signaling pathways such as the TGF-β, VEGF, and MET pathways, are highlighted. This review aims to enhance our understanding of pre-metastatic niche dynamics and provide insights for developing effective therapeutic strategies to combat tumor metastasis.
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Affiliation(s)
- Yuhang Wang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Jiachi Jia
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Fuqi Wang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Yingshuai Fang
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Yabing Yang
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Quanbo Zhou
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Weitang Yuan
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Xiaoming Gu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
| | - Junhong Hu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
| | - Shuaixi Yang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
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10
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Platt E, Robertson F, Al-Rashed A, Klootwijk R, Hall A, Quaglia A, Salama A, Heptinstall L, Davidson B. NGAL in the Development of Acute Kidney Injury in a Murine Model of Remote Ischaemic Preconditioning and Liver Ischaemia Reperfusion. Int J Mol Sci 2024; 25:5061. [PMID: 38791106 PMCID: PMC11121231 DOI: 10.3390/ijms25105061] [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: 02/22/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 05/26/2024] Open
Abstract
Acute kidney injury (AKI) is common following liver transplantation and is associated with liver ischeamia reperfusion (IR) injury. The purpose of this study was to use a mouse model of liver IR injury and AKI to study the role of Neutrophil Gelatinase Associated Lipocalin (NGAL), a biomarker of AKI, in liver IR injury and AKI. We demonstrate an adapted, reproducible model of liver IR injury and AKI in which remote ischemic preconditioning (RIPC) by repeated episodes of hindleg ischemia prior to liver IR reduced the severity of the IR injury. In this model, serum NGAL at 2 h post reperfusion correlated with AKI development early following IR injury. This early rise in serum NGAL was associated with hepatic but not renal upregulation of NGAL mRNA, suggesting NGAL production in the liver but not the kidney in the early phase post liver IR injury.
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Affiliation(s)
- Esther Platt
- Division of Surgery and Interventional Science, University College London, London NW3 2PF, UK; (E.P.); (F.R.)
| | - Francis Robertson
- Division of Surgery and Interventional Science, University College London, London NW3 2PF, UK; (E.P.); (F.R.)
| | - Ali Al-Rashed
- Department of Renal Medicine, University College London, London NW3 2PF, UK; (A.A.-R.); (A.S.)
| | - Riko Klootwijk
- Department of Renal Medicine, University College London, London NW3 2PF, UK; (A.A.-R.); (A.S.)
| | - Andrew Hall
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
| | - Alberto Quaglia
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
| | - Alan Salama
- Department of Renal Medicine, University College London, London NW3 2PF, UK; (A.A.-R.); (A.S.)
| | - Lauren Heptinstall
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
| | - Brian Davidson
- Division of Surgery and Interventional Science, University College London, London NW3 2PF, UK; (E.P.); (F.R.)
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11
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Lu H. Inflammatory liver diseases and susceptibility to sepsis. Clin Sci (Lond) 2024; 138:435-487. [PMID: 38571396 DOI: 10.1042/cs20230522] [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: 09/03/2023] [Revised: 01/09/2024] [Accepted: 03/12/2024] [Indexed: 04/05/2024]
Abstract
Patients with inflammatory liver diseases, particularly alcohol-associated liver disease and metabolic dysfunction-associated fatty liver disease (MAFLD), have higher incidence of infections and mortality rate due to sepsis. The current focus in the development of drugs for MAFLD is the resolution of non-alcoholic steatohepatitis and prevention of progression to cirrhosis. In patients with cirrhosis or alcoholic hepatitis, sepsis is a major cause of death. As the metabolic center and a key immune tissue, liver is the guardian, modifier, and target of sepsis. Septic patients with liver dysfunction have the highest mortality rate compared with other organ dysfunctions. In addition to maintaining metabolic homeostasis, the liver produces and secretes hepatokines and acute phase proteins (APPs) essential in tissue protection, immunomodulation, and coagulation. Inflammatory liver diseases cause profound metabolic disorder and impairment of energy metabolism, liver regeneration, and production/secretion of APPs and hepatokines. Herein, the author reviews the roles of (1) disorders in the metabolism of glucose, fatty acids, ketone bodies, and amino acids as well as the clearance of ammonia and lactate in the pathogenesis of inflammatory liver diseases and sepsis; (2) cytokines/chemokines in inflammatory liver diseases and sepsis; (3) APPs and hepatokines in the protection against tissue injury and infections; and (4) major nuclear receptors/signaling pathways underlying the metabolic disorders and tissue injuries as well as the major drug targets for inflammatory liver diseases and sepsis. Approaches that focus on the liver dysfunction and regeneration will not only treat inflammatory liver diseases but also prevent the development of severe infections and sepsis.
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Affiliation(s)
- Hong Lu
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, U.S.A
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12
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Yan L, Yang F, Wang Y, Shi L, Wang M, Yang D, Wang W, Jia Y, So KF, Zhang L. Stress increases hepatic release of lipocalin 2 which contributes to anxiety-like behavior in mice. Nat Commun 2024; 15:3034. [PMID: 38589429 PMCID: PMC11001612 DOI: 10.1038/s41467-024-47266-9] [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: 01/31/2024] [Accepted: 03/26/2024] [Indexed: 04/10/2024] Open
Abstract
Chronic stress induces anxiety disorders via both neural pathways and circulating factors. Although many studies have elucidated the neural circuits involved in stress-coping behaviors, the origin and regulatory mechanism of peripheral cytokines in behavioural regulation under stress conditions are not fully understood. Here, we identified a serum cytokine, lipocalin 2 (LCN2), that was upregulated in participants with anxiety disorders. Using a mouse model of chronic restraint stress (CRS), circulating LCN2 was found to be related to stress-induced anxiety-like behaviour via modulation of neural activity in the medial prefrontal cortex (mPFC). These results suggest that stress increases hepatic LCN2 via a neural pathway, leading to disrupted cortical functions and behaviour.
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Affiliation(s)
- Lan Yan
- Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Fengzhen Yang
- Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Yajie Wang
- Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Lingling Shi
- Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Mei Wang
- Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Diran Yang
- Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Wenjing Wang
- Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Yanbin Jia
- The First Affiliated Hospital, Jinan University, Guangzhou, China
- Institute of Clinical Research for Mental Health, Jinan University, Guangzhou, China
| | - Kwok-Fai So
- Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
- Institute of Clinical Research for Mental Health, Jinan University, Guangzhou, China
- State Key Laboratory of Brain and Cognitive Science, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou, China
- Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao, China
- Center for Exercise and Brain Science, School of Psychology, Shanghai University of Sport, Shanghai, China
| | - Li Zhang
- Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.
- Institute of Clinical Research for Mental Health, Jinan University, Guangzhou, China.
- Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou, China.
- Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao, China.
- Center for Exercise and Brain Science, School of Psychology, Shanghai University of Sport, Shanghai, China.
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13
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Zhou Y, McClain C, Feng W. Porphyromonas gingivalis Strain W83 Infection Induces Liver Injury in Experimental Alcohol-Associated Liver Disease (ALD) in Mice. Appl Microbiol 2024; 4:620-634. [DOI: 10.3390/applmicrobiol4020043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The liver plays a vital role in the defense against infections. Porphyromonas gingivalis (P. gingivalis), a dominant etiologic oral bacterium implicated in periodontal disease (PD), has been associated with various systemic diseases. This study aimed to investigate the influence of P. gingivalis on alcohol-associated liver diseases (ALD). Mice were fed a Lieber–DeCarli liquid diet containing 5% ethanol for 10 days after an initial adaptation period on a diet with lower ethanol content for 7 days. Two days before tissue sample collection, the mice were administered P. gingivalis strain W83 (Pg) through intraperitoneal injection (IP). Pair-fed mice with Pg infection (PF+Pg) exhibited an activated immune response to combat infections. However, alcohol-fed mice with Pg infection (AF+Pg) showed liver injury with noticeable abscess lesions and elevated serum alanine aminotransferase (ALT) levels. Additionally, these mice displayed liver infiltration of inflammatory monocytes and significant downregulation of proinflammatory cytokine gene expression levels; and AF+Pg mice also demonstrated increased intrahepatic neutrophil infiltration, as confirmed by chloroacetate esterase (CAE) staining, along with elevated gene expression levels of neutrophil cytosol factor 1 (Ncf1), neutrophilic inflammation driver lipocalin 2 (Lcn2), and complement component C5a receptor 1 (C5ar1), which are associated with neutrophilic inflammation. Interestingly, compared to PF+Pg mice, the livers of AF+Pg mice exhibited downregulation of gene expression levels of NADPH oxidase 2 (Cybb), the leukocyte adhesion molecule Cd18, and the Toll-like receptor adaptor Myd88. Consequently, impaired clearance of P. gingivalis and other bacteria in the liver, increased susceptibility to infections, and inflammation-associated hepatic necrotic cell death were observed in AF+Pg mice, which is likely to have facilitated immune cell infiltration and contributed to liver injury. Furthermore, in addition to the Srebf1/Fasn pathway induced by alcohol feeding, Pg infection also activated carbohydrate response element-binding protein (ChREBP) in AF+Pg mice. In summary, this study demonstrates that P. gingivalis infection, acting as a “second hit”, induces dysfunction of immune response and impairs the clearance of bacteria and infections in alcohol-sensitized livers. This process drives the development of liver injury.
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Affiliation(s)
- Yun Zhou
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Craig McClain
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
- Hepatobiology and Toxicology Center, University of Louisville, Louisville, KY 40202, USA
- Robley Rex VA Medical Center, Louisville, KY 40202, USA
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
| | - Wenke Feng
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
- Hepatobiology and Toxicology Center, University of Louisville, Louisville, KY 40202, USA
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
- Department of Structural and Cellular Biology, Tulane University, New Orleans, LA 70112, USA
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14
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Chen F, Wu SS, Chen C, Zhou C. Dynamic changes and clinical value of lipocalin 2 in liver diseases caused by microbial infections. World J Hepatol 2024; 16:177-185. [PMID: 38495277 PMCID: PMC10941746 DOI: 10.4254/wjh.v16.i2.177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 12/04/2023] [Accepted: 01/09/2024] [Indexed: 02/27/2024] Open
Abstract
Lipocalin 2 (LCN2) plays a pivotal role in iron metabolism, particularly in the context of microbial infection resistance (e.g., viruses, bacteria, parasites, etc.). LCN2 combats microbial infection by directly assisting the body in competing with microorganisms for iron, inducing immune cells to secrete various cytokines to enhance systemic immune responses, or recruiting neutrophils to infectious sites. The liver serves as the primary organ for LCN2 secretion during microbial infections. This review encapsulates recent advances in dynamic changes, clinical values, and the effects of LCN2 in infectious liver diseases caused by various microbial microorganisms.
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Affiliation(s)
- Feng Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Shan-Shan Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Chao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Cheng Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China.
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15
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Qiu B, Zhong Z, Dou L, Xu Y, Zou Y, Weldon K, Wang J, Zhang L, Liu M, Williams KE, Spence JP, Bell RL, Lai Z, Yong W, Liang T. Knocking out Fkbp51 decreases CCl 4-induced liver injury through enhancement of mitochondrial function and Parkin activity. Cell Biosci 2024; 14:1. [PMID: 38167156 PMCID: PMC10763032 DOI: 10.1186/s13578-023-01184-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 12/12/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND AND AIMS Previously, we found that FK506 binding protein 51 (Fkbp51) knockout (KO) mice resist high fat diet-induced fatty liver and alcohol-induced liver injury. The aim of this research is to identify the mechanism of Fkbp51 in liver injury. METHODS Carbon tetrachloride (CCl4)-induced liver injury was compared between Fkbp51 KO and wild type (WT) mice. Step-wise and in-depth analyses were applied, including liver histology, biochemistry, RNA-Seq, mitochondrial respiration, electron microscopy, and molecular assessments. The selective FKBP51 inhibitor (SAFit2) was tested as a potential treatment to ameliorate liver injury. RESULTS Fkbp51 knockout mice exhibited protection against liver injury, as evidenced by liver histology, reduced fibrosis-associated markers and lower serum liver enzyme levels. RNA-seq identified differentially expressed genes and involved pathways, such as fibrogenesis, inflammation, mitochondria, and oxidative metabolism pathways and predicted the interaction of FKBP51, Parkin, and HSP90. Cellular studies supported co-localization of Parkin and FKBP51 in the mitochondrial network, and Parkin was shown to be expressed higher in the liver of KO mice at baseline and after liver injury relative to WT. Further functional analysis identified that KO mice exhibited increased ATP production and enhanced mitochondrial respiration. KO mice have increased mitochondrial size, increased autophagy/mitophagy and mitochondrial-derived vesicles (MDV), and reduced reactive oxygen species (ROS) production, which supports enhancement of mitochondrial quality control (MQC). Application of SAFit2, an FKBP51 inhibitor, reduced the effects of CCl4-induced liver injury and was associated with increased Parkin, pAKT, and ATP production. CONCLUSIONS Downregulation of FKBP51 represents a promising therapeutic target for liver disease treatment.
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Affiliation(s)
- Bin Qiu
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
- Department of Pharmacology, Yale University School of Medicine, New Haven, CI, 06520, USA
| | - Zhaohui Zhong
- General Surgery Department, Peking University People's Hospital, Beijing, 100032, China
| | - Longyu Dou
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Yuxue Xu
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Yi Zou
- Greehey Children's Cancer Research Institute, UT Health, San Antonio, TX, 78229, USA
| | - Korri Weldon
- Greehey Children's Cancer Research Institute, UT Health, San Antonio, TX, 78229, USA
| | - Jun Wang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Lingling Zhang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Ming Liu
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Kent E Williams
- Department of Medicine, Indiana University, School of Medicine, Indianapolis, 46202, USA
| | - John Paul Spence
- Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, 46202, USA
| | - Richard L Bell
- Department of Psychiatry, Indiana University, School of Medicine, Indianapolis, 46202, USA
| | - Zhao Lai
- Greehey Children's Cancer Research Institute, UT Health, San Antonio, TX, 78229, USA
| | - Weidong Yong
- Department of Surgery, Indiana University, School of Medicine, Indianapolis, 46202, USA.
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China.
| | - Tiebing Liang
- Department of Medicine, Indiana University, School of Medicine, Indianapolis, 46202, USA.
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16
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Khor AHP, Koguchi T, Liu H, Kakuta M, Matsubara D, Wen R, Sagiya Y, Imoto S, Nakagawa H, Matsuda K, Tanikawa C. Regulation of the innate immune response and gut microbiome by p53. Cancer Sci 2024; 115:184-196. [PMID: 38050344 PMCID: PMC10823282 DOI: 10.1111/cas.15991] [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: 01/16/2023] [Revised: 08/25/2023] [Accepted: 09/28/2023] [Indexed: 12/06/2023] Open
Abstract
p53 is a key tumor suppressor mutated in half of human cancers. In recent years, p53 was shown to regulate a wide variety of functions. From the transcriptome analysis of 24 tissues of irradiated mice, we identified 553 genes markedly induced by p53. Gene Ontology (GO) enrichment analysis found that the most associated biological process was innate immunity. 16S rRNA-seq analysis revealed that Akkermansia, which has anti-inflammatory properties and is involved in the regulation of intestinal barrier integrity, was decreased in p53-knockout (p53-/- ) mice after radiation. p53-/- mice were susceptible to radiation-induced GI toxicity and had a significantly shorter survival time than p53-wild-type (p53+/+ ) mice following radiation. However, administration of antibiotics resulted in a significant improvement in survival and protection against GI toxicity. Mbl2 and Lcn2, which have antimicrobial activity, were identified to be directly transactivated by p53 and secreted by liver into the circulatory system. We also found the expression of MBL2 and LCN2 was decreased in liver cancer tissues with p53 mutations compared with those without p53 mutations. These results indicate that p53 is involved in shaping the gut microbiome through its downstream targets related to the innate immune system, thus protecting the intestinal barrier.
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Affiliation(s)
- Amy Hui Ping Khor
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoMinato City, TokyoJapan
| | - Tomoyuki Koguchi
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
| | - Hao Liu
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoMinato City, TokyoJapan
| | - Masanori Kakuta
- Department of Integrated Analytics, M&D Data Science CenterTokyo Medical and Dental UniversityTokyoJapan
| | - Daisuke Matsubara
- Department of Pathology, Faculty of MedicineUniversity of TsukubaIbarakiJapan
| | - Ruimeng Wen
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoMinato City, TokyoJapan
| | - Yoji Sagiya
- Laboratory of Genome Technology, Human Genome Center, The Institute of Medical ScienceThe University of TokyoMinato City, TokyoJapan
| | - Seiya Imoto
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical ScienceThe University of TokyoMinato City, TokyoJapan
| | - Hidewaki Nakagawa
- Laboratory for Cancer GenomicsRIKEN Center for Integrative Medical SciencesYokohamaJapan
| | - Koichi Matsuda
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoMinato City, TokyoJapan
- Laboratory of Genome Technology, Human Genome Center, The Institute of Medical ScienceThe University of TokyoMinato City, TokyoJapan
| | - Chizu Tanikawa
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoMinato City, TokyoJapan
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17
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Kubota N, Hori S, Ishizuka S. Differences in iron balance observed with dietary cholic acid supplementation and marginal iron deficiency in rats. Biosci Biotechnol Biochem 2023; 88:79-85. [PMID: 37813822 DOI: 10.1093/bbb/zbad140] [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: 06/14/2023] [Accepted: 09/27/2023] [Indexed: 10/11/2023]
Abstract
We investigated whether a cholic acid (CA)-supplemented diet and marginal iron deficiency (MID) diet influence hepatic lipid accumulation and iron balance in rats for 2 weeks. The CA diet enhanced hepatic lipid accumulation and modulated iron metabolism such as enhancement of fecal iron excretion, reduction in iron absorption, and no alteration in plasma iron levels. The MID diet did not alter hepatic lipid concentrations with reduced iron concentration in the liver and plasma. In combination, influence of the CA supplementation on the hepatic iron concentration was opposite between iron-sufficient and MID conditions. In the liver, the CA diet enhanced lipocalin 2 expression, whereas the MID diet enhanced transferrin receptor 1 expression and reduced hepcidin expression. This study revealed an involvement of 12-hydroxylated bile acids in regulation of hepatic iron concentration under MID condition.
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Affiliation(s)
- Natsuki Kubota
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Shota Hori
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Satoshi Ishizuka
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
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18
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Tzouanas CN, Sherman MS, Shay JE, Rubin AJ, Mead BE, Dao TT, Butzlaff T, Mana MD, Kolb KE, Walesky C, Pepe-Mooney BJ, Smith CJ, Prakadan SM, Ramseier ML, Tong EY, Joung J, Chi F, McMahon-Skates T, Winston CL, Jeong WJ, Aney KJ, Chen E, Nissim S, Zhang F, Deshpande V, Lauer GM, Yilmaz ÖH, Goessling W, Shalek AK. Chronic metabolic stress drives developmental programs and loss of tissue functions in non-transformed liver that mirror tumor states and stratify survival. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.30.569407. [PMID: 38077056 PMCID: PMC10705501 DOI: 10.1101/2023.11.30.569407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Under chronic stress, cells must balance competing demands between cellular survival and tissue function. In metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH), hepatocytes cooperate with structural and immune cells to perform crucial metabolic, synthetic, and detoxification functions despite nutrient imbalances. While prior work has emphasized stress-induced drivers of cell death, the dynamic adaptations of surviving cells and their functional repercussions remain unclear. Namely, we do not know which pathways and programs define cellular responses, what regulatory factors mediate (mal)adaptations, and how this aberrant activity connects to tissue-scale dysfunction and long-term disease outcomes. Here, by applying longitudinal single-cell multi -omics to a mouse model of chronic metabolic stress and extending to human cohorts, we show that stress drives survival-linked tradeoffs and metabolic rewiring, manifesting as shifts towards development-associated states in non-transformed hepatocytes with accompanying decreases in their professional functionality. Diet-induced adaptations occur significantly prior to tumorigenesis but parallel tumorigenesis-induced phenotypes and predict worsened human cancer survival. Through the development of a multi -omic computational gene regulatory inference framework and human in vitro and mouse in vivo genetic perturbations, we validate transcriptional (RELB, SOX4) and metabolic (HMGCS2) mediators that co-regulate and couple the balance between developmental state and hepatocyte functional identity programming. Our work defines cellular features of liver adaptation to chronic stress as well as their links to long-term disease outcomes and cancer hallmarks, unifying diverse axes of cellular dysfunction around core causal mechanisms.
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Affiliation(s)
- Constantine N. Tzouanas
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA
- Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
- These authors contributed equally
| | - Marc S. Sherman
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- These authors contributed equally
| | - Jessica E.S. Shay
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
- Alcohol Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- These authors contributed equally
| | - Adam J. Rubin
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Benjamin E. Mead
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Tyler T. Dao
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Titus Butzlaff
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Miyeko D. Mana
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- School of Life Sciences, Arizona State University, Tempe, AZ, USA
| | - Kellie E. Kolb
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Chad Walesky
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Brian J. Pepe-Mooney
- Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Colton J. Smith
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Sanjay M. Prakadan
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Michelle L. Ramseier
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA
- Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Evelyn Y. Tong
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA
- Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Julia Joung
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Brain and Cognitive Science, MA, Cambridge, MA, USA
- McGovern Institute for Brain Research at MIT, Cambridge, MA, USA
- Howard Hughes Medical Institute, MIT, Cambridge, MA, USA
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
| | - Fangtao Chi
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
| | - Thomas McMahon-Skates
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Carolyn L. Winston
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Woo-Jeong Jeong
- Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | - Katherine J. Aney
- Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ethan Chen
- Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sahar Nissim
- Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
- Gastroenterology Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Feng Zhang
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Brain and Cognitive Science, MA, Cambridge, MA, USA
- McGovern Institute for Brain Research at MIT, Cambridge, MA, USA
- Howard Hughes Medical Institute, MIT, Cambridge, MA, USA
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Georg M. Lauer
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ömer H. Yilmaz
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA
- These senior authors contributed equally
| | - Wolfram Goessling
- Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Stem Cell Institute, Cambridge, MA, USA
- Developmental and Regenerative Biology Program, Harvard Medical School, Boston, MA, USA
- These senior authors contributed equally
| | - Alex K. Shalek
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA
- Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
- These senior authors contributed equally
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19
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Tornai D, Mitchell M, McClain CJ, Dasarathy S, McCullough A, Radaeva S, Kroll-Desrosiers A, Lee J, Barton B, Szabo G. A novel score of IL-13 and age predicts 90-day mortality in severe alcohol-associated hepatitis: A multicenter plasma biomarker analysis. Hepatol Commun 2023; 7:e0296. [PMID: 37994498 PMCID: PMC10666984 DOI: 10.1097/hc9.0000000000000296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 08/15/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Severe alcoholic hepatitis (AH) has a high short-term mortality rate. The MELD assesses disease severity and mortality; however, it is not specific for AH. We screened plasma samples from patients with severe AH for biomarkers of multiple pathological processes and identified predictors of short-term mortality. METHODS Plasma was collected at baseline from 85 patients with severe AH (MELD≥20, Maddrey's discriminant function≥32) enrolled in the Defeat Alcoholic Steatohepatitis clinical trial (investigating IL-1 receptor antagonist+pentoxifylline+zinc vs. methylprednisolone+placebo). Samples were analyzed for 43 biomarkers and the markers' association with 28- and 90-day mortalities was assessed. RESULTS Thirty-one (36.5%) patients died during the 90-day follow-up with similar ratios in the treatment groups. Eight biomarkers showed an association with mortality. IL-6, IL-22, interferon-α2, soluble TNF receptor 1, lipocalin-2, and α-fetoprotein levels were associated with 28-day mortality, while IL-6, IL-13, and endotoxin levels with 90-day mortality. In multivariable Cox regression, encephalopathy, lipocalin-2, and α-fetoprotein levels were independent predictors of 28-day mortality, and IL-6, IL-13, international normalized ratio levels, and age were independent predictors of 90-day mortality. The combination of IL-13 and age had superior performance in predicting 90-day mortality compared with MELD in the total cohort and the individual treatment groups. CONCLUSIONS We identified predictors of short-term mortality in a cohort exclusively involving patients with severe AH. We created a composite score of IL-13 and age that predicts 90-day mortality regardless of the treatment type with a performance superior to MELD in severe AH.
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Affiliation(s)
- David Tornai
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Mack Mitchell
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Craig J. McClain
- Department of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Srinivasan Dasarathy
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
- Department of Inflammation and Immunity, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
| | - Arthur McCullough
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
- Department of Inflammation and Immunity, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
| | - Svetlana Radaeva
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, Marylansd, USA
| | - Aimee Kroll-Desrosiers
- Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- VA Central Western Massachusetts Healthcare System, Leeds, Massachusetts, USA
| | - JungAe Lee
- Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Bruce Barton
- Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
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20
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Gong YQ, Zhao Y, Jia YH, Li M, Jiang Y. Diagnostic value of combined detection of urine NGAL, KIM-1, and TFF3 in acute tubular necrosis associated with cirrhosis. Shijie Huaren Xiaohua Zazhi 2023; 31:808-815. [DOI: 10.11569/wcjd.v31.i19.808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/04/2023] [Accepted: 09/18/2023] [Indexed: 10/08/2023] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is a common complication of decompensated cirrhosis with high clinical mortality and poor prognosis, of which acute tubular necrosis (ATN) has the worst prognosis. Timely and accurate identification of ATN is a difficult problem to solve clinically. Previous studies have shown that urinary neutrophil gelatinase-associated lipocalin (NGAL), trefoil factor 3 (TFF3), and kidney injury molecule-1 (KIM-1) have potential value in the differential diagnosis of ATN and other types of AKI in patients with liver cirrhosis, but they still cannot be applied in clinical practice due to the low diagnostic efficacy. It is necessary to further explore whether the combined detection of the indicators can improve their diagnostic efficacy for ATN associated with cirrhosis.
AIM To analyze the value of urinary NGAL, KIM-1, and TFF3, either alone or in combination, in the differential diagnosis of ATN in patients with cirrhosis complicated with AKI, and explore the cut-off values of urinary NGAL and other indicators in the differential diagnosis of ATN.
METHODS A total of 190 patients with decompensated cirrhosis were selected, including 108 patients with AKI. They were divided into different subgroups according to the cause of AKI, including 33 cases of prerenal azotemia, 27 cases of acute renal injury with hepatorenal syndrome, and 48 cases of ATN. The value of urinary NGAL, TFF3, and KIM-1, either alone or in combination, in the differential diagnosis of ATN in patients with cirrhosis complicated with AKI was then assessed.
RESULTS Urinary NGAL was of great value in the differential diagnosis of ATN in patients with cirrhosis complicated with AKI. The area under the curve (AUC) was 0.902; when the diagnostic threshold was 271.8 μg/g Cr, the sensitivity was 81.3% and the specificity was 85.0%. The combination of two biomarkers could improve the efficacy of differential diagnosis, with the diagnostic perfomance of urinary NGAL combined with urinary TFF3 being the best (AUC = 0.933, sensitivity 85.4%, specificity 88.3%).
CONCLUSION Urinary NGAL, KIM-1, and TFF3 are of great value in differentiating ATN from other types of AKI in patients with cirrhosis. The combined detection of any two of these biomarkers can further improve the diagnostic efficiency, which is worthy of further study and clinical promotion.
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Affiliation(s)
- Yan-Qing Gong
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Ying Zhao
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Yan-Hui Jia
- Laboratory Department, Tianjin Third Central Hospital, Tianjin 300100, China
| | - Man Li
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Yong Jiang
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
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21
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Bazid HAS, Sakr HG, Abdallah RA, Arafat ES, Ragheb A, Seleit I. Serum and Tissue Lipocalin-2 Expression in Chronic Kidney Disease Pruritic Patients. Appl Immunohistochem Mol Morphol 2023; 31:635-643. [PMID: 37698956 DOI: 10.1097/pai.0000000000001151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 07/19/2023] [Indexed: 09/14/2023]
Abstract
BACKGROUND Uremic pruritus is an irritating symptom for patients with end-stage kidney disease. Lipocalin-2 (LCN2) has relevant importance in several biological cellular processes and immunity. It is also a major player in the progression of many disorders, such as renal injury. AIM To evaluate LCN2 expression in chronic kidney disease (CKD) pruritic patients in serum together with immunohistochemical expression in skin samples and further correlation of their results with the studied clinicopathologic parameters. MATERIALS AND METHODS Serum level of LCN2 (assessed by enzyme-linked immunosorbent assay) and skin immunohistochemical expression were investigated in 25 CKD patients and 25 healthy controls. Ten patients were subjected to narrowband ultraviolet B phototherapy for 12 weeks then re-evaluated for serum and tissue LCN2 after therapy. RESULTS LCN2 expression was increased significantly in both the epidermis and dermal adnexa in CKD patients over controls. Also, serum LCN2 level was higher in patients than in healthy subjects and was significantly associated with itching severity, grades of CKD, urea, and creatinine serum level. Tissue and serum levels of LCN2 were significantly diminished in CKD patients following narrowband therapy along with improvement of the severity of pruritus. CONCLUSIONS The increased serum and tissue LCN2 expression in CKD pruritic patients and its pronounced decrease, in addition to the improvement of pruritus after treatment, suggest a major pathogenic role of LCN2 in uremic pruritus.
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Affiliation(s)
- Heba A S Bazid
- Department of Dermatology, Andrology and STDS, Faculty of Medicine, Menoufia University
| | - Hanaa G Sakr
- Department of Dermatology, Andrology and STDS, Faculty of Medicine, Menoufia University
| | | | | | - Ahmed Ragheb
- Internal Medicine, Faculty of Medicine, Menoufia University, Cairo, Egypt
| | - Iman Seleit
- Department of Dermatology, Andrology and STDS, Faculty of Medicine, Menoufia University
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22
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Qiu X, Zhou J, Xu H, Li Y, Ma S, Qiao H, Zeng K, Wang Q, Ouyang J, Liu Y, Ding J, Liu Y, Zhang J, Shi M, Liao Y, Liao W, Lin L. Alcohol reshapes a liver premetastatic niche for cancer by extra- and intrahepatic crosstalk-mediated immune evasion. Mol Ther 2023; 31:2662-2680. [PMID: 37469143 PMCID: PMC10492032 DOI: 10.1016/j.ymthe.2023.07.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 06/22/2023] [Accepted: 07/17/2023] [Indexed: 07/21/2023] Open
Abstract
Cancer metastatic organotropism is still a mystery. The liver is known to be susceptible to cancer metastasis and alcoholic injury. However, it is unclear whether and how alcohol facilitates liver metastasis and how to intervene. Here, we show that alcohol preferentially promotes liver metastasis in colon-cancer-bearing mice and post-surgery pancreatic cancer patients. The mechanism is that alcohol triggers an extra- and intrahepatic crosstalk to reshape an immunosuppressive liver microenvironment. In detail, alcohol upregulates extrahepatic IL-6 and hepatocellular IL-6 receptor expression, resulting in hepatocyte STAT3 signaling activation and downstream lipocalin-2 (Lcn2) upregulation. Furthermore, LCN2 promotes T cell-exhaustion neutrophil recruitment and cancer cell epithelial plasticity. In contrast, knocking out hepatocellular Stat3 or systemic Il6 in alcohol-treated mice preserves the liver microenvironment and suppresses liver metastasis. This mechanism is reflected in hepatocellular carcinoma patients, in that alcohol-associated signaling elevation in noncancerous liver tissue indicates adverse prognosis. Accordingly, we discover a novel application for BBI608, a small molecular STAT3 inhibitor that can prevent liver metastasis. BBI608 pretreatment protects the liver and suppresses alcohol-triggered premetastatic niche formation. In conclusion, under extra- and intrahepatic crosstalk, the alcoholic injured liver forms a favorable niche for cancer cell metastasis, while BBI608 is a promising anti-metastatic agent targeting such microenvironments.
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Affiliation(s)
- Xiaofang Qiu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jiaqi Zhou
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hong Xu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yongyin Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Shudong Ma
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hang Qiao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Kangxin Zeng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Qiongqiong Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jiahe Ouyang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yuanhan Liu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jian Ding
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yantan Liu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Junhao Zhang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Min Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yulin Liao
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Li Lin
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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23
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Gong YQ, Zhao Y, Jia YH, Li M, Jiang Y. Role of urine/serum NGAL ratio in differential diagnosis of acute kidney injury in patients with cirrhosis. Shijie Huaren Xiaohua Zazhi 2023; 31:630-637. [DOI: 10.11569/wcjd.v31.i15.630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 07/21/2023] [Accepted: 08/03/2023] [Indexed: 08/08/2023] Open
Abstract
BACKGROUND Neutrophil gelatinase-associated lipocalin (NGAL) can be used for the differential diagnosis of acute kidney necrosis (ATN) and other types of acute kidney injury (AKI) in patients with liver cirrhosis complicated with AKI. However, serum NGAL is directly related to urine NGAL, and there are few existing studies on the role of urine /serum NGAL ratio in the differential diagnosis of ATN.
AIM To assess the significance of serum and urine NGAL as well as urine/serum NGAL ratio in differentiating ATN from other types of AKI in cirrhosis.
METHODS A total of 180 patients with decompensated cirrhosis were included in the study, of whom 98 were complicated with AKI. According to the etiology of AKI, there were 33 patients with prerenal azotemia, 25 with hepatorenal syndrome-AKI, and 40 with ATN. The patients were divided into different subgroups to assess the value of NGAL in differentiating the types of AKI.
RESULTS Urine NGAL and urine/serum NGAL ratio showed signi-ficant value in the differential diagnosis of ATN in patients with liver cirrhosis. At an optimal cut-off of 271.35 ng/mL, urine NGAL distinguished ATN from other types of AKI (area under the cuve [AUC] = 0.964; sensitivity, 87.5%; specificity, 96.6%). As well, at an optimal cut-off of 2.96, urine/serum NGAL ratio could also distinguish ATN from other types of AKI (AUC = 0.953, sensitivity 92.5% and specificity 91.4%).
CONCLUSION Urine NGAL and urine/serum NGAL ratio have significant value in the differential diagnosis of ATN and other types of AKI in patients with liver cirrhosis, which is worthy of further study and clinical promotion.
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Affiliation(s)
- Yan-Qing Gong
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Ying Zhao
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Yan-Hui Jia
- Laboratory Department, Tianjin Third Central Hospital, Tianjin 300100, China
| | - Man Li
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Yong Jiang
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
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24
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Gravina G, Ardalan M, Chumak T, Nilsson AK, Ek JC, Danielsson H, Svedin P, Pekny M, Pekna M, Sävman K, Hellström A, Mallard C. Proteomics identifies lipocalin-2 in neonatal inflammation associated with cerebrovascular alteration in mice and preterm infants. iScience 2023; 26:107217. [PMID: 37496672 PMCID: PMC10366453 DOI: 10.1016/j.isci.2023.107217] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 05/07/2023] [Accepted: 06/22/2023] [Indexed: 07/28/2023] Open
Abstract
Staphylococcus (S.) epidermidis is the most common nosocomial coagulase-negative staphylococci infection in preterm infants. Clinical signs of infection are often unspecific and novel markers to complement diagnosis are needed. We investigated proteomic alterations in mouse brain after S. epidermidis infection and in preterm infant blood. We identified lipocalin-2 (LCN2) as a crucial protein associated with cerebrovascular changes and astrocyte reactivity in mice. We further proved that LCN2 protein expression was associated with endothelial cells but not astrocyte reactivity. By combining network analysis and differential expression approaches, we identified LCN2 linked to blood C-reactive protein levels in preterm infants born <28 weeks of gestation. Blood LCN2 levels were associated with similar alterations of cytokines and chemokines in both infected mice and human preterm infants with increased levels of C-reactive protein. This experimental and clinical study suggests that LCN2 may be a marker of preterm infection/inflammation associated with cerebrovascular changes and neuroinflammation.
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Affiliation(s)
- Giacomo Gravina
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maryam Ardalan
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Translational Neuropsychiatric Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Tetyana Chumak
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anders K. Nilsson
- Section for Ophthalmology, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Joakim C. Ek
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Hanna Danielsson
- Centre for Translational Microbiome Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Sach’s Children’s and Youth Hospital, Södersjukhuset, Stockholm, Sweden
| | - Pernilla Svedin
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Milos Pekny
- Laboratory of Astrocyte Biology and CNS Regeneration, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- University of Newcastle, Newcastle, NSW, Australia
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
| | - Marcela Pekna
- University of Newcastle, Newcastle, NSW, Australia
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
- Laboratory of Regenerative Neurobiology, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Karin Sävman
- Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden
- Region Västra Götaland, Department of Neonatology, The Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Ann Hellström
- Section for Ophthalmology, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Carina Mallard
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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25
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Romejko K, Markowska M, Niemczyk S. The Review of Current Knowledge on Neutrophil Gelatinase-Associated Lipocalin (NGAL). Int J Mol Sci 2023; 24:10470. [PMID: 37445650 DOI: 10.3390/ijms241310470] [Citation(s) in RCA: 75] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein that is secreted mostly by immune cells such as neutrophils, macrophages, and dendritic cells. Its production is stimulated in response to inflammation. The concentrations of NGAL can be measured in plasma, urine, and biological fluids such as peritoneal effluent. NGAL is known mainly as a biomarker of acute kidney injury and is released after tubular damage and during renal regeneration processes. NGAL is also elevated in chronic kidney disease and dialysis patients. It may play a role as a predictor of the progression of renal function decreases with complications and mortality due to kidney failure. NGAL is also useful in the diagnostic processes of cardiovascular diseases. It is highly expressed in injured heart tissue and atherosclerostic plaque; its serum concentrations correlate with the severity of heart failure and coronary artery disease. NGAL increases inflammatory states and its levels rise in arterial hypertension, obesity, diabetes, and metabolic complications such as insulin resistance, and is also involved in carcinogenesis. In this review, we present the current knowledge on NGAL and its involvement in different pathologies, especially its role in renal and cardiovascular diseases.
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Affiliation(s)
- Katarzyna Romejko
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine-National Research Institute, 128 Szaserów Street, 04-141 Warsaw, Poland
| | - Magdalena Markowska
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine-National Research Institute, 128 Szaserów Street, 04-141 Warsaw, Poland
| | - Stanisław Niemczyk
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine-National Research Institute, 128 Szaserów Street, 04-141 Warsaw, Poland
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Song XJ, Yang CL, Chen D, Yang Y, Mao Y, Cao P, Jiang A, Wang W, Zhang Z, Tao W. Up-regulation of LCN2 in the anterior cingulate cortex contributes to neural injury-induced chronic pain. Front Cell Neurosci 2023; 17:1140769. [PMID: 37362002 PMCID: PMC10285483 DOI: 10.3389/fncel.2023.1140769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 05/02/2023] [Indexed: 06/28/2023] Open
Abstract
Chronic pain caused by disease or injury affects more than 30% of the general population. The molecular and cellular mechanisms underpinning the development of chronic pain remain unclear, resulting in scant effective treatments. Here, we combined electrophysiological recording, in vivo two-photon (2P) calcium imaging, fiber photometry, Western blotting, and chemogenetic methods to define a role for the secreted pro-inflammatory factor, Lipocalin-2 (LCN2), in chronic pain development in mice with spared nerve injury (SNI). We found that LCN2 expression was upregulated in the anterior cingulate cortex (ACC) at 14 days after SNI, resulting in hyperactivity of ACC glutamatergic neurons (ACCGlu) and pain sensitization. By contrast, suppressing LCN2 protein levels in the ACC with viral constructs or exogenous application of neutralizing antibodies leads to significant attenuation of chronic pain by preventing ACCGlu neuronal hyperactivity in SNI 2W mice. In addition, administering purified recombinant LCN2 protein in the ACC could induce pain sensitization by inducing ACCGlu neuronal hyperactivity in naïve mice. This study provides a mechanism by which LCN2-mediated hyperactivity of ACCGlu neurons contributes to pain sensitization, and reveals a new potential target for treating chronic pain.
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Affiliation(s)
- Xiang-Jie Song
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Chen-Ling Yang
- Key Laboratory of Oral Diseases Research of Anhui Province, College and Hospital of Stomatology, Anhui Medical University, Hefei, China
- Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Danyang Chen
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yumeng Yang
- Key Laboratory of Oral Diseases Research of Anhui Province, College and Hospital of Stomatology, Anhui Medical University, Hefei, China
- Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Yu Mao
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Peng Cao
- Department of Neurology, Stroke Center, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Aijun Jiang
- Department of Endocrinology and Laboratory for Diabetes, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wei Wang
- Department of Endocrinology and Laboratory for Diabetes, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Zhi Zhang
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wenjuan Tao
- Key Laboratory of Oral Diseases Research of Anhui Province, College and Hospital of Stomatology, Anhui Medical University, Hefei, China
- Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
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Jo D, Jung YS, Song J. Lipocalin-2 Secreted by the Liver Regulates Neuronal Cell Function Through AKT-Dependent Signaling in Hepatic Encephalopathy Mouse Model. Clin Nutr Res 2023; 12:154-167. [PMID: 37214781 PMCID: PMC10193436 DOI: 10.7762/cnr.2023.12.2.154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/17/2023] [Accepted: 03/23/2023] [Indexed: 05/24/2023] Open
Abstract
Hepatic encephalopathy (HE) associated with liver failure is accompanied by hyperammonemia, severe inflammation, depression, anxiety, and memory deficits as well as liver injury. Recent studies have focused on the liver-brain-inflammation axis to identify a therapeutic solution for patients with HE. Lipocalin-2 is an inflammation-related glycoprotein that is secreted by various organs and is involved in cellular mechanisms including iron homeostasis, glucose metabolism, cell death, neurite outgrowth, and neurogenesis. In this study, we investigated that the roles of lipocalin-2 both in the brain cortex of mice with HE and in Neuro-2a (N2A) cells. We detected elevated levels of lipocalin-2 both in the plasma and liver in a bile duct ligation mouse model of HE. We confirmed changes in cytokine expression, such as interleukin-1β, cyclooxygenase 2 expression, and iron metabolism related to gene expression through AKT-mediated signaling both in the brain cortex of mice with HE and N2A cells. Our data showed negative effects of hepatic lipocalin-2 on cell survival, iron homeostasis, and neurite outgrowth in N2A cells. Thus, we suggest that regulation of lipocalin-2 in the brain in HE may be a critical therapeutic approach to alleviate neuropathological problems focused on the liver-brain axis.
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Affiliation(s)
- Danbi Jo
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea
- Biomedical Science Graduate Program (BMSGP), Chonnam National University, Hwasun 58128, Korea
| | - Yoon Seok Jung
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea
- Biomedical Science Graduate Program (BMSGP), Chonnam National University, Hwasun 58128, Korea
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Deng M, Aberle MR, van Bijnen AAJHM, van der Kroft G, Lenaerts K, Neumann UP, Wiltberger G, Schaap FG, Olde Damink SWM, Rensen SS. Lipocalin-2 and neutrophil activation in pancreatic cancer cachexia. Front Immunol 2023; 14:1159411. [PMID: 37006254 PMCID: PMC10057111 DOI: 10.3389/fimmu.2023.1159411] [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: 02/05/2023] [Accepted: 03/03/2023] [Indexed: 03/17/2023] Open
Abstract
BackgroundCancer cachexia is a multifactorial syndrome characterized by body weight loss and systemic inflammation. The characterization of the inflammatory response in patients with cachexia is still limited. Lipocalin-2, a protein abundant in neutrophils, has recently been implicated in appetite suppression in preclinical models of pancreatic cancer cachexia. We hypothesized that lipocalin-2 levels could be associated with neutrophil activation and nutritional status of pancreatic ductal adenocarcinoma (PDAC) patients.MethodsPlasma levels of neutrophil activation markers calprotectin, myeloperoxidase, elastase, and bactericidal/permeability-increasing protein (BPI) were compared between non-cachectic PDAC patients (n=13) and cachectic PDAC patients with high (≥26.9 ng/mL, n=34) or low (<26.9 ng/mL, n=34) circulating lipocalin-2 levels. Patients’ nutritional status was assessed by the patient-generated subjective global assessment (PG-SGA) and through body composition analysis using CT-scan slices at the L3 level.ResultsCirculating lipocalin-2 levels did not differ between cachectic and non-cachectic PDAC patients (median 26.7 (IQR 19.7-34.8) vs. 24.8 (16.6-29.4) ng/mL, p=0.141). Cachectic patients with high systemic lipocalin-2 levels had higher concentrations of calprotectin, myeloperoxidase, and elastase than non-cachectic patients or cachectic patients with low lipocalin-2 levels (calprotectin: 542.3 (355.8-724.9) vs. 457.5 (213.3-606.9), p=0.448 vs. 366.5 (294.5-478.5) ng/mL, p=0.009; myeloperoxidase: 30.3 (22.1-37.9) vs. 16.3 (12.0-27.5), p=0.021 vs. 20.2 (15.0-29.2) ng/mL, p=0.011; elastase: 137.1 (90.8-253.2) vs. 97.2 (28.8-215.7), p=0.410 vs. 95.0 (72.2-113.6) ng/mL, p=0.006; respectively). The CRP/albumin ratio was also higher in cachectic patients with high lipocalin-2 levels (2.3 (1.3-6.0) as compared to non-cachectic patients (1.0 (0.7-4.2), p=0.041). Lipocalin-2 concentrations correlated with those of calprotectin (rs=0.36, p<0.001), myeloperoxidase (rs=0.48, p<0.001), elastase (rs=0.50, p<0.001), and BPI (rs=0.22, p=0.048). Whereas no significant correlations with weight loss, BMI, or L3 skeletal muscle index were observed, lipocalin-2 concentrations were associated with subcutaneous adipose tissue index (rs=-0.25, p=0.034). Moreover, lipocalin-2 tended to be elevated in severely malnourished patients compared with well-nourished patients (27.2 (20.3-37.2) vs. 19.9 (13.4-26.4) ng/mL, p=0.058).ConclusionsThese data suggest that lipocalin-2 levels are associated with neutrophil activation in patients with pancreatic cancer cachexia and that it may contribute to their poor nutritional status.
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Affiliation(s)
- Min Deng
- Department of Surgery and School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
| | - Merel R. Aberle
- Department of Surgery and School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
| | - Annemarie A. J. H. M. van Bijnen
- Department of Surgery and School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
| | - Gregory van der Kroft
- Department of Surgery and School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
- Department of General, Visceral- and Transplantation Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Kaatje Lenaerts
- Department of Surgery and School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
| | - Ulf P. Neumann
- Department of Surgery and School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
- Department of General, Visceral- and Transplantation Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Georg Wiltberger
- Department of General, Visceral- and Transplantation Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Frank G. Schaap
- Department of Surgery and School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
- Department of General, Visceral- and Transplantation Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Steven W. M. Olde Damink
- Department of Surgery and School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
- Department of General, Visceral- and Transplantation Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Sander S. Rensen
- Department of Surgery and School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
- *Correspondence: Sander S. Rensen,
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Kim KE, Lee J, Shin HJ, Jeong EA, Jang HM, Ahn YJ, An HS, Lee JY, Shin MC, Kim SK, Yoo WG, Kim WH, Roh GS. Lipocalin-2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high-fat diet-fed Ob/Ob mice. Hepatology 2023; 77:888-901. [PMID: 35560370 PMCID: PMC9936980 DOI: 10.1002/hep.32569] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 04/19/2022] [Accepted: 05/08/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS In obesity and type 2 diabetes mellitus, leptin promotes insulin resistance and contributes to the progression of NASH via activation of hepatic stellate cells (HSCs). However, the pathogenic mechanisms that trigger HSC activation in leptin-deficient obesity are still unknown. This study aimed to determine how HSC-targeting lipocalin-2 (LCN2) mediates the transition from simple steatosis to NASH. APPROACH AND RESULTS Male wild-type (WT) and ob/ob mice were fed a high-fat diet (HFD) for 20 weeks to establish an animal model of NASH with fibrosis. Ob/ob mice were subject to caloric restriction or recombinant leptin treatment. Double knockout (DKO) mice lacking both leptin and lcn2 were also fed an HFD for 20 weeks. In addition, HFD-fed ob/ob mice were treated with gadolinium trichloride to deplete Kupffer cells. The LX-2 human HSCs and primary HSCs from ob/ob mice were used to investigate the effects of LCN2 on HSC activation. Serum and hepatic LCN2 expression levels were prominently increased in HFD-fed ob/ob mice compared with normal diet-fed ob/ob mice or HFD-fed WT mice, and these changes were closely linked to liver fibrosis and increased hepatic α-SMA/matrix metalloproteinase 9 (MMP9)/signal transducer and activator of transcription 3 (STAT3) protein levels. HFD-fed DKO mice showed a marked reduction of α-SMA protein compared with HFD-fed ob/ob mice. In particular, the colocalization of LCN2 and α-SMA was increased in HSCs from HFD-fed ob/ob mice. In primary HSCs from ob/ob mice, exogenous LCN2 treatment induced HSC activation and MMP9 secretion. By contrast, LCN2 receptor 24p3R deficiency or a STAT3 inhibitor reduced the activation and migration of primary HSCs. CONCLUSIONS LCN2 acts as a key mediator of HSC activation in leptin-deficient obesity via α-SMA/MMP9/STAT3 signaling, thereby exacerbating NASH.
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Affiliation(s)
- Kyung Eun Kim
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Jaewoong Lee
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Hyun Joo Shin
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Eun Ae Jeong
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Hye Min Jang
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Yu Jeong Ahn
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Hyeong Seok An
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Jong Youl Lee
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Meong Cheol Shin
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Soo Kyoung Kim
- Department of Internal Medicine, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Won Gi Yoo
- Department of Parasitology and Tropical Medicine, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Won Ho Kim
- Division of Cardiovascular Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Cheongju, Republic of Korea
| | - Gu Seob Roh
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
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Zhai H, Zhang J, Shang D, Zhu C, Xiang X. The progress to establish optimal animal models for the study of acute-on-chronic liver failure. Front Med (Lausanne) 2023; 10:1087274. [PMID: 36844207 PMCID: PMC9947362 DOI: 10.3389/fmed.2023.1087274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 01/23/2023] [Indexed: 02/11/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) defines a complicated and multifaceted syndrome characterized by acute liver dysfunction following an acute insult on the basis of chronic liver diseases. It is usually concurrent with bacterial infection and multi-organ failure resulting in high short-term mortality. Based on the cohort studies in ACLF worldwide, the clinical course of ACLF was demonstrated to comprise three major stages including chronic liver injury, acute hepatic/extrahepatic insult, and systemic inflammatory response caused by over-reactive immune system especially bacterial infection. However, due to the lack of optimal experimental animal models for ACLF, the progress of basic study on ACLF is limping. Though several experimental ACLF models were established, none of them can recapitulate and simulate the whole pathological process of ACLF patients. Recently, we have developed a novel mouse model for ACLF combining chronic liver injury [injection of carbon tetrachloride (CCl4) for 8 weeks], acute hepatic insult (injection of a double dose CCl4), and bacterial infection (intraperitoneal injection of Klebsiella pneumoniae), which could recapitulate the major clinical features of patients with ACLF worsened by bacterial infection.
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Affiliation(s)
- Hengben Zhai
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinming Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dabao Shang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Fifth People’s Hospital of Suzhou, Suzhou, China,Chuanwu Zhu,
| | - Xiaogang Xiang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,*Correspondence: Xiaogang Xiang,
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Yewale RV, Ramakrishna BS. Novel biomarkers of acute kidney injury in chronic liver disease: Where do we stand after a decade of research? Hepatol Res 2023; 53:3-17. [PMID: 36262036 DOI: 10.1111/hepr.13847] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/06/2022] [Accepted: 10/14/2022] [Indexed: 01/03/2023]
Abstract
Acute kidney injury (AKI) is a frequently encountered complication in decompensated chronic liver disease (CLD) with an estimated prevalence of 20%-50% among hospitalized patients. AKI often heralds the onset of a downhill course in the natural history of CLD. Serum creatinine has several limitations as a stand-alone marker of AKI in patients with decompensated CLD. The concept of hepatorenal syndrome, the prototype of AKI in decompensated CLD, has evolved tremendously over recent years. There is emerging evidence of an additional "structural" component in the pathophysiology of hepatorenal syndrome-AKI, which was previously identified as a purely "functional" form of renal impairment. Lacunae in the existent biochemical arsenal for diagnosis and prognosis of AKI have fueled enthusiastic research in the field of novel biomarkers of kidney injury in patients with cirrhosis. The advent of these biomarkers provides a crucial window of opportunity to improve the diagnosis and clinical outcomes of this vulnerable cohort of patients. This review summarizes the dynamic concept of renal dysfunction in CLD and the available literature on the role of novel biomarkers of AKI in assessing renal function, identifying AKI subtypes, and predicting prognosis. There is special emphasis on the renal tubular injury marker, neutrophil gelatinase-associated lipocalin, the most exhaustively studied biomarker of AKI in the CLD population.
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Affiliation(s)
- Rohan Vijay Yewale
- Institute of Gastroenterology, Hepatobiliary Sciences and Transplantation, SRM Institutes for Medical Science, Chennai, India
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Adzuki Bean MY59 Extract Reduces Insulin Resistance and Hepatic Steatosis in High-Fat-Fed Mice via the Downregulation of Lipocalin-2. Nutrients 2022; 14:nu14235049. [PMID: 36501079 PMCID: PMC9739659 DOI: 10.3390/nu14235049] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 11/25/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022] Open
Abstract
Adzuki bean is well known as a potential functional food that improves metabolic complications from obesity and diabetes. Lipocalin-2 (LCN2) has been implicated to have an important role in obesity and diabetes. However, the protective roles of adzuki bean MY59 extract (ABE) on insulin resistance and hepatic steatosis are not fully understood. In the present study, we investigated the effects of ABE on LCN2 expression in high-fat diet (HFD)-fed mice. ABE reduced HFD-induced fat mass and improved insulin resistance. In addition to hepatic steatosis, HFD-fed mice showed many apoptotic cells and neutrophils in the epididymal fat pads. However, these findings were significantly reduced by ABE supplementation. In particular, we found that increased LCN2 proteins from serum, epididymal fat pads, and liver in HFD-fed mice are significantly reduced by ABE. Furthermore, ABE reduced increased heme oxygenase-1 and superoxide dismutase-1 expressions in adipose tissue and liver in HFD-fed mice. We found that hepatic nuclear factor-kappa B (NF-κB) p65 expression in HFD-fed mice was also reduced by ABE. Thus, these findings indicate that ABE feeding could improve insulin resistance and hepatic steatosis by decreasing LCN2-mediated inflammation and oxidative stress in HFD-fed mice.
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Osna NA, Rasineni K, Ganesan M, Donohue TM, Kharbanda KK. Pathogenesis of Alcohol-Associated Liver Disease. J Clin Exp Hepatol 2022; 12:1492-1513. [PMID: 36340300 PMCID: PMC9630031 DOI: 10.1016/j.jceh.2022.05.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. While chronic, heavy alcohol consumption causes structural damage and/or disrupts normal organ function in virtually every tissue of the body, the liver sustains the greatest damage. This is primarily because the liver is the first to see alcohol absorbed from the gastrointestinal tract via the portal circulation and second, because the liver is the principal site of ethanol metabolism. Alcohol-induced damage remains one of the most prevalent disorders of the liver and a leading cause of death or transplantation from liver disease. Despite extensive research on the pathophysiology of this disease, there are still no targeted therapies available. Given the multifactorial mechanisms for alcohol-associated liver disease pathogenesis, it is conceivable that a multitherapeutic regimen is needed to treat different stages in the spectrum of this disease.
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Key Words
- AA, Arachidonic acid
- ADH, Alcohol dehydrogenase
- AH, Alcoholic hepatitis
- ALD, Alcohol-associated liver disease
- ALDH, Aldehyde dehydrogenase
- ALT, Alanine transaminase
- ASH, Alcohol-associated steatohepatitis
- AST, Aspartate transaminase
- AUD, Alcohol use disorder
- BHMT, Betaine-homocysteine-methyltransferase
- CD, Cluster of differentiation
- COX, Cycloxygenase
- CTLs, Cytotoxic T-lymphocytes
- CYP, Cytochrome P450
- CYP2E1, Cytochrome P450 2E1
- Cu/Zn SOD, Copper/zinc superoxide dismutase
- DAMPs, Damage-associated molecular patterns
- DC, Dendritic cells
- EDN1, Endothelin 1
- ER, Endoplasmic reticulum
- ETOH, Ethanol
- EVs, Extracellular vesicles
- FABP4, Fatty acid-binding protein 4
- FAF2, Fas-associated factor family member 2
- FMT, Fecal microbiota transplant
- Fn14, Fibroblast growth factor-inducible 14
- GHS-R1a, Growth hormone secretagogue receptor type 1a
- GI, GOsteopontinastrointestinal tract
- GSH Px, Glutathione peroxidase
- GSSG Rdx, Glutathione reductase
- GST, Glutathione-S-transferase
- GWAS, Genome-wide association studies
- H2O2, Hydrogen peroxide
- HA, Hyaluronan
- HCC, Hepatocellular carcinoma
- HNE, 4-hydroxynonenal
- HPMA, 3-hydroxypropylmercapturic acid
- HSC, Hepatic stellate cells
- HSD17B13, 17 beta hydroxy steroid dehydrogenase 13
- HSP 90, Heat shock protein 90
- IFN, Interferon
- IL, Interleukin
- IRF3, Interferon regulatory factor 3
- JAK, Janus kinase
- KC, Kupffer cells
- LCN2, Lipocalin 2
- M-D, Mallory–Denk
- MAA, Malondialdehyde-acetaldehyde protein adducts
- MAT, Methionine adenosyltransferase
- MCP, Macrophage chemotactic protein
- MDA, Malondialdehyde
- MIF, Macrophage migration inhibitory factor
- Mn SOD, Manganese superoxide dismutase
- Mt, Mitochondrial
- NK, Natural killer
- NKT, Natural killer T-lymphocytes
- OPN, Osteopontin
- PAMP, Pathogen-associated molecular patterns
- PNPLA3, Patatin-like phospholipase domain containing 3
- PUFA, Polyunsaturated fatty acid
- RIG1, Retinoic acid inducible gene 1
- SAH, S-adenosylhomocysteine
- SAM, S-adenosylmethionine
- SCD, Stearoyl-CoA desaturase
- STAT, Signal transduction and activator of transcription
- TIMP1, Tissue inhibitor matrix metalloproteinase 1
- TLR, Toll-like receptor
- TNF, Tumor necrosis factor-α
- alcohol
- alcohol-associated liver disease
- ethanol metabolism
- liver
- miRNA, MicroRNA
- p90RSK, 90 kDa ribosomal S6 kinase
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Affiliation(s)
- Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Karuna Rasineni
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
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Gasterich N, Bohn A, Sesterhenn A, Nebelo F, Fein L, Kaddatz H, Nyamoya S, Kant S, Kipp M, Weiskirchen R, Zendedel A, Beyer C, Clarner T. Lipocalin 2 attenuates oligodendrocyte loss and immune cell infiltration in mouse models for multiple sclerosis. Glia 2022; 70:2188-2206. [PMID: 35856297 DOI: 10.1002/glia.24245] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 06/28/2022] [Accepted: 07/01/2022] [Indexed: 11/06/2022]
Abstract
Multiple sclerosis (MS) is a central nervous system disease characterized by both degenerative and inflammatory processes. Various mediators are involved in the interplay of degeneration and innate immunity on one hand and peripheral adaptive immunity on the other hand. The secreted protein lipocalin 2 (LCN2) is an inflammatory modulator in a variety of pathologies. Although elevated intrathecal levels of LCN2 have been reported in MS patients, it's functional role is widely unknown. Here, we identified a subpopulation of astrocytes as a source of LCN2 in MS lesions and respective animal models. We investigated the functional role of LCN2 for both autoimmune and degenerative aspects in three MS mouse models including both wild type (WT) and Lcn2-/- mouse strains. While the experimental autoimmune encephalomyelitis (EAE) model reflects primary autoimmunity, the cuprizone model reflects selective oligodendrocyte loss and demyelination. In addition, we included a combinatory Cup/EAE model in which primary cytodegeneration is followed by inflammatory lesions within the forebrain. While in the EAE model, the disease outcome was comparable in between the two mouse strains, cuprizone intoxicated Lcn2-/- animals showed an increased loss of oligodendrocytes. In the Cup/EAE model, Lcn2-/- animals showed increased inflammation when compared to WT mice. Together, our results highlight LCN2 as a potentially protective molecule in MS lesion formation, which might be able to limit loss of oligodendrocytes immune-cell invasion. Despite these findings, it is not yet clear which glial cell phenotype (and to which extent) contributes to the observed neuroprotective effects, that is, microglia and/or astroglia or even endothelial cells in the brain.
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Affiliation(s)
- Natalie Gasterich
- RWTH University Hospital Aachen, Institute of Neuroanatomy, Aachen, Germany
| | - Amelie Bohn
- RWTH University Hospital Aachen, Institute of Neuroanatomy, Aachen, Germany
| | - Anika Sesterhenn
- RWTH University Hospital Aachen, Institute of Neuroanatomy, Aachen, Germany
| | - Frederik Nebelo
- RWTH University Hospital Aachen, Institute of Neuroanatomy, Aachen, Germany
| | - Lena Fein
- RWTH University Hospital Aachen, Institute of Neuroanatomy, Aachen, Germany
| | - Hannes Kaddatz
- Rostock University Medical Center, Institute of Anatomy, Rostock, Germany
| | - Stella Nyamoya
- RWTH University Hospital Aachen, Institute of Neuroanatomy, Aachen, Germany
| | - Sebastian Kant
- RWTH University Hospital Aachen, Institute of Molecular and Cellular Anatomy, Aachen, Germany
| | - Markus Kipp
- Rostock University Medical Center, Institute of Anatomy, Rostock, Germany
| | - Ralf Weiskirchen
- RWTH University Hospital Aachen, Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), Aachen, Germany
| | - Adib Zendedel
- RWTH University Hospital Aachen, Institute of Neuroanatomy, Aachen, Germany
| | - Cordian Beyer
- RWTH University Hospital Aachen, Institute of Neuroanatomy, Aachen, Germany
| | - Tim Clarner
- RWTH University Hospital Aachen, Institute of Neuroanatomy, Aachen, Germany
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Li F, Liao X, Jiang L, Zhao J, Wu S, Ming J. Orientin Attenuated d-GalN/LPS-Induced Liver Injury through the Inhibition of Oxidative Stress via Nrf2/Keap1 Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:7953-7967. [PMID: 35729734 DOI: 10.1021/acs.jafc.2c02015] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Oxidative stress is involved in the pathogenesis of liver diseases, including liver injury, a serious health problem worldwide. Natural polyphenols have attracted increasing attention as potential agents for the prevention and treatment of liver diseases. Orientin, a flavonoid component with antioxidant capacity, has been regarded as a promising nutraceutical for patients with liver damage. This study aimed to investigate the amelioration effect of orientin on d-galactosamine and lipopolysaccharides (d-GalN/LPS) induced liver injury in mice, with a focus on its underlying mechanisms by using the H2O2-induced oxidative damage model of HepG2 cells. Results indicated that orientin alleviated d-GalN/LPS-induced liver damage by improving the hepatic histological changes and reducing the levels of hepatic and serum alanine aminotransferase and aspartic acid aminotransferase. Additionally, supplementation of orientin improved the antioxidant ability in mice by decreasing the levels of hepatic malondialdehyde, protein carbonyl, myeloperoxidase, nitric oxide, glutathione, glutathione peroxidase, gluathione reductase, and superoxide dismutase. Orientin treatment significantly elevated both the protein and mRNA expressions of nuclear factor erythroid 2-related factor 2, Kelch-like ECH-associated protein-1, heme oxygenase-1, and nicotinamide quinone oxidoreductase 1 in liver and HepG2 cells. The management of orientin also elevated the protein expression of glutathione S-transferase and Maf in HepG2 cells. Taken together, it suggested that orientin played an amelioration effect on liver injury by suppressing oxidative stress, which might be strongly related to the activation of Nrf2/ARE through PI3K/Akt and P38/MAPK signal pathways.
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Affiliation(s)
- Fuhua Li
- College of Food Science, Southwest University, Chongqing, 400715, People's Republic of China
- Chongqing Key Laboratory of Speciality Food Co-Built by Sichuan and Chongqing, Chongqing 400715, People's Republic of China
| | - Xia Liao
- College of Food Science, Southwest University, Chongqing, 400715, People's Republic of China
| | - Ling Jiang
- College of Food Science, Southwest University, Chongqing, 400715, People's Republic of China
| | - Jichun Zhao
- College of Food Science, Southwest University, Chongqing, 400715, People's Republic of China
- Chongqing Key Laboratory of Speciality Food Co-Built by Sichuan and Chongqing, Chongqing 400715, People's Republic of China
| | - Surui Wu
- Kunming Edible Fungi Institute, All China Federation of Supply and Marketing Cooperatives, Kunming, 650223, People's Republic of China
| | - Jian Ming
- College of Food Science, Southwest University, Chongqing, 400715, People's Republic of China
- Chongqing Key Laboratory of Speciality Food Co-Built by Sichuan and Chongqing, Chongqing 400715, People's Republic of China
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Abstract
PURPOSE OF REVIEW Fibroblast growth factor 23 (FGF23) excess is associated with left ventricular hypertrophy (LVH) and early mortality in patients with chronic kidney disease (CKD) and in animal models. Elevated Lipocalin-2 (LCN2), produced by the injured kidneys, contributes to CKD progression and might aggravate cardiovascular outcomes. The current review aims to highlight the role of LCN2 in CKD, particularly its interactions with FGF23. RECENT FINDINGS Inflammation, disordered iron homeostasis and altered metabolic activity are common complications of CKD, and are associated with elevated levels of kidney-produced LCN2 and bone-secreted FGF23. A recent study shows that elevated LCN2 increases FGF23 production, and contributes to cardiac injury in patients and animals with CKD, whereas LCN2 reduction in mice with CKD reduces FGF23, improves cardiovascular outcomes and prolongs lifespan. SUMMARY In this manuscript, we discuss the potential pathophysiological functions of LCN2 as a major kidney-bone crosstalk molecule, linking the progressive decline in kidney function to excessive bone FGF23 production. We also review associations of LCN2 with kidney, cardiovascular and bone and mineral alterations. We conclude that the presented data support the design of novel therapeutic approaches to improve outcomes in CKD.
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Affiliation(s)
- Guillaume Courbon
- Division of Nephrology and Hypertension, Center for Translational Metabolism and Health, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Valentin David
- Division of Nephrology and Hypertension, Center for Translational Metabolism and Health, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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Grander M, Hoffmann A, Seifert M, Demetz E, Grubwieser P, Pfeifhofer-Obermair C, Haschka D, Weiss G. DMT1 Protects Macrophages from Salmonella Infection by Controlling Cellular Iron Turnover and Lipocalin 2 Expression. Int J Mol Sci 2022; 23:ijms23126789. [PMID: 35743233 PMCID: PMC9223531 DOI: 10.3390/ijms23126789] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/10/2022] [Accepted: 06/15/2022] [Indexed: 02/04/2023] Open
Abstract
Macrophages are at the center of innate pathogen control and iron recycling. Divalent metal transporter 1 (DMT1) is essential for the uptake of non-transferrin-bound iron (NTBI) into macrophages and for the transfer of transferrin-bound iron from the endosome to the cytoplasm. As the control of cellular iron trafficking is central for the control of infection with siderophilic pathogens such as Salmonella Typhimurium, a Gram-negative bacterium residing within the phagosome of macrophages, we examined the potential role of DMT1 for infection control. Bone marrow derived macrophages lacking DMT1 (DMT1fl/flLysMCre(+)) present with reduced NTBI uptake and reduced levels of the iron storage protein ferritin, the iron exporter ferroportin and, surprisingly, of the iron uptake protein transferrin receptor. Further, DMT1-deficient macrophages have an impaired control of Salmonella Typhimurium infection, paralleled by reduced levels of the peptide lipocalin-2 (LCN2). LCN2 exerts anti-bacterial activity upon binding of microbial siderophores but also facilitates systemic and cellular hypoferremia. Remarkably, nifedipine, a pharmacological DMT1 activator, stimulates LCN2 expression in RAW264.7 macrophages, confirming its DMT1-dependent regulation. In addition, the absence of DMT1 increases the availability of iron for Salmonella upon infection and leads to increased bacterial proliferation and persistence within macrophages. Accordingly, mice harboring a macrophage-selective DMT1 disruption demonstrate reduced survival following Salmonella infection. This study highlights the importance of DMT1 in nutritional immunity and the significance of iron delivery for the control of infection with siderophilic bacteria.
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Affiliation(s)
- Manuel Grander
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (M.G.); (A.H.); (M.S.); (E.D.); (P.G.); (C.P.-O.)
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Alexander Hoffmann
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (M.G.); (A.H.); (M.S.); (E.D.); (P.G.); (C.P.-O.)
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Markus Seifert
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (M.G.); (A.H.); (M.S.); (E.D.); (P.G.); (C.P.-O.)
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Egon Demetz
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (M.G.); (A.H.); (M.S.); (E.D.); (P.G.); (C.P.-O.)
| | - Philipp Grubwieser
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (M.G.); (A.H.); (M.S.); (E.D.); (P.G.); (C.P.-O.)
| | - Christa Pfeifhofer-Obermair
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (M.G.); (A.H.); (M.S.); (E.D.); (P.G.); (C.P.-O.)
| | - David Haschka
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (M.G.); (A.H.); (M.S.); (E.D.); (P.G.); (C.P.-O.)
- Correspondence: (D.H.); (G.W.)
| | - Günter Weiss
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (M.G.); (A.H.); (M.S.); (E.D.); (P.G.); (C.P.-O.)
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Correspondence: (D.H.); (G.W.)
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Lipocalin2 as a useful biomarker for risk stratification in patients with acute cholangitis: A single-center prospective and observational study. Clin Chim Acta 2022; 533:22-30. [DOI: 10.1016/j.cca.2022.05.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/18/2022] [Accepted: 05/25/2022] [Indexed: 12/07/2022]
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Lipocalin2 as a potential antibacterial drug against Acinetobacter baumannii infection. J Microbiol 2022; 60:444-449. [DOI: 10.1007/s12275-022-2007-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/10/2022] [Accepted: 02/22/2022] [Indexed: 10/18/2022]
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Yang C, Wu Y, Wang L, Li S, Zhou J, Tan Y, Song J, Xing H, Yi K, Zhan Q, Zhao J, Wang Q, Yuan X, Kang C. Glioma-derived exosomes hijack the blood-brain barrier to facilitate nanocapsule delivery via LCN2. J Control Release 2022; 345:537-548. [PMID: 35341902 DOI: 10.1016/j.jconrel.2022.03.038] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 03/18/2022] [Accepted: 03/20/2022] [Indexed: 12/15/2022]
Abstract
Exosomes are small extracellular vehicles which could transport genetic materials and proteins between cells. Although there are reports about exosomes crossing the blood-brain barrier (BBB), the underlying mechanisms still need further study. We found that exosomes from primary brain tumors could upregulate the expression of Lipocalin-2 (LCN2) in bEnd.3 brain microvascular endothelial cells (BMVECs). Furthermore, exosomes increased the membrane fluidity of bEnd.3 cells in an LCN2 dependent manner. Both intraperitoneal injection and caudal vein injection of LCN2 increased the number of nanocapsules crossing the BBB. Evans Blue staining revealed that LCN2 does not interrupt the integrity of the BBB, as observed in the traumatic brain injury model. Tandem mass tags quantitative proteomics and bioinformatics analysis revealed that LCN2 is upregulated by exosomes via the JAK-STAT3 pathway, but not delivered from exosomes. Knocking down LCN2 in bEnd.3 cells significantly abrogated the effect of exosomes on BMVEC membrane fluidity. Previously, we have reported that 2-methacryloyloxyethyl phosphorylcholine (MPC) and a peptide crosslinker could encapsulate mAbs to achieve nanocapsules. The nanocapsules containing choline analogs could effectively penetrate the BBB to deliver therapeutic monoclonal antibodies (tAbs) to the glioma. However, the delivered tAbs could be significantly reduced by blocking the release of exosomes from the gliomas. Application of tAb nanocapsules prior to treatment with MK2206, an AKT pathway inhibitor that has been shown to inhibit the production of exosomes, resulted in a better combination. Insights from this study provide a mechanistic framework with regard to how glioblastomas hijack BMVECs using exosomes. In addition, we provide a strategy for maximizing the effect of the choline-containing nanocapsules and MK2206 combination. These results also demonstrate the therapeutic role of tAbs in glioblastoma and brain tumor metastasis, by shedding new light on strategies that can be used for BBB-penetrating therapies.
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Affiliation(s)
- Chao Yang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Department of Neurosurgery, Tianjin Medical University General Hospital and Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin 300052, China
| | - Ye Wu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Department of Neurosurgery, Tianjin Medical University General Hospital and Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin 300052, China
| | - Lin Wang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Department of Neurosurgery, Tianjin Medical University General Hospital and Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin 300052, China
| | - Sidi Li
- Tianjin Key Laboratory of Composite and Functional Materials, School of Material Science and Engineering, Tianjin University, Tianjin 300072, China
| | - Junhu Zhou
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Department of Neurosurgery, Tianjin Medical University General Hospital and Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin 300052, China
| | - Yanli Tan
- Department of Pathology, Medical College of Hebei University, Baoding, Hebei 071000, China; Key Laboratory of Precise Diagnosis and Treatment of Glioma in Hebei Province, Baoding 071000, China
| | - Jia Song
- Medical College of Hebei University, Baoding, Hebei 071000, China; Key Laboratory of Precise Diagnosis and Treatment of Glioma in Hebei Province, Baoding 071000, China
| | - Huike Xing
- Tianjin Key Laboratory of Composite and Functional Materials, School of Material Science and Engineering, Tianjin University, Tianjin 300072, China
| | - Kaikai Yi
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Department of Neurosurgery, Tianjin Medical University General Hospital and Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin 300052, China
| | - Qi Zhan
- Tianjin Key Laboratory of Composite and Functional Materials, School of Material Science and Engineering, Tianjin University, Tianjin 300072, China
| | - Jin Zhao
- Tianjin Key Laboratory of Composite and Functional Materials, School of Material Science and Engineering, Tianjin University, Tianjin 300072, China
| | - Qixue Wang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Department of Neurosurgery, Tianjin Medical University General Hospital and Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin 300052, China.
| | - Xubo Yuan
- Tianjin Key Laboratory of Composite and Functional Materials, School of Material Science and Engineering, Tianjin University, Tianjin 300072, China.
| | - Chunsheng Kang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Department of Neurosurgery, Tianjin Medical University General Hospital and Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin 300052, China.
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Zhou K, Yin F, Li Y, Ma C, Liu P, Xin Z, Ren R, Wei S, Khan M, Wang H, Zhang H. MicroRNA-29b ameliorates hepatic inflammation via suppression of STAT3 in alcohol-associated liver disease. Alcohol 2022; 99:9-22. [PMID: 34688828 DOI: 10.1016/j.alcohol.2021.10.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 09/11/2021] [Accepted: 10/18/2021] [Indexed: 02/08/2023]
Abstract
Alcohol-associated liver disease (ALD) is induced by chronic excessive alcohol consumption resulting in the clinical manifestations of steatosis, inflammation, and cirrhosis. MicroRNA-29b (miR-29b) is mainly expressed in hepatic nonparenchymal cells, and its expression level varies in different diseases. In this study, we aimed to determine the role of miR-29b in a mouse model of alcohol-associated liver disease. Wild-type (WT) and miR-29b knockout (miR-29b-/-) mice were fed a Lieber-DeCarli liquid diet containing 5% alcohol for 10 days, followed by gavage of a single dose of ethanol (5 g/kg body weight). Histology, immunoblotting, and biochemical analyses were then conducted for comparison. miR-29b expression was decreased in the livers of chronic-plus-binge ethanol-fed mice. Further analysis revealed that alcohol exposure exacerbated hepatic injury by significantly increasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, with decreased survival rates for miR-29b-/- mice. Results from the luciferase assay indicated that miR-29b negatively regulated the signal transducer and activator of transcription 3 (STAT3). Depletion of miR-29b led to an increase in STAT3 and more noticeable inflammation in the liver, whereas overexpression of miR-29b downregulated STAT3 and proinflammatory cytokine expression in primary mouse peritoneal macrophages. Taken together, these results demonstrate a novel association between miR-29b and ALD. miR-29b plays a hepatoprotective role in alcohol-induced inflammation and liver injury by targeting STAT3.
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The effect of lipocalin-2 (LCN2) on apoptosis: a proteomics analysis study in an LCN2 deficient mouse model. BMC Genomics 2021; 22:892. [PMID: 34903175 PMCID: PMC8670060 DOI: 10.1186/s12864-021-08211-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 11/23/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Recent studies have shown that lipocalin-2 (LCN2) has multiple functions involved in various biological and pathological processes including energy homeostasis, cancer, inflammation, and apoptosis. We aimed to investigate the effect of LCN2 on apoptosis that influences the pathogenetic process of metabolic diseases and cancer. METHODS We performed a proteomics analysis of livers taken from LCN2-knockout mice and wild type mice by using label-free LC-MS/MS quantitative proteomics. RESULTS Proteomic analysis revealed that there were 132 significantly differentially expressed proteins (49 upregulated and 83 downregulated) among 2140 proteins in the liver of LCN2-knockout mice compared with wild type mice. Of these, seven apoptosis-associated proteins were significantly upregulated and seven apoptosis-associated proteins downregulated. CONCLUSION Proteomics demonstrated that there were seven upregulated and seven downregulated apoptosis-associated proteins in liver of LCN2-knockout mice. It is important to clarify the effect of LCN2 on apoptosis that might contribute to the pathogenesis of insulin resistance, cancer, and various nervous system diseases.
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Klüber P, Meurer SK, Lambertz J, Schwarz R, Zechel-Gran S, Braunschweig T, Hurka S, Domann E, Weiskirchen R. Depletion of Lipocalin 2 (LCN2) in Mice Leads to Dysbiosis and Persistent Colonization with Segmented Filamentous Bacteria. Int J Mol Sci 2021; 22:ijms222313156. [PMID: 34884961 PMCID: PMC8658549 DOI: 10.3390/ijms222313156] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/26/2021] [Accepted: 12/01/2021] [Indexed: 12/15/2022] Open
Abstract
Lipocalin 2 (LCN2) mediates key roles in innate immune responses. It has affinity for many lipophilic ligands and binds various siderophores, thereby limiting bacterial growth by iron sequestration. Furthermore, LCN2 protects against obesity and metabolic syndrome by interfering with the composition of gut microbiota. Consequently, complete or hepatocyte-specific ablation of the Lcn2 gene is associated with higher susceptibility to bacterial infections. In the present study, we comparatively profiled microbiota in fecal samples of wild type and Lcn2 null mice and show, in contrast to previous reports, that the quantity of DNA in feces of Lcn2 null mice is significantly lower than that in wild type mice (p < 0.001). By using the hypervariable V4 region of the 16S rDNA gene and Next-Generation Sequencing methods, we found a statistically significant change in 16 taxonomic units in Lcn2-/- mice, including eight gender-specific deviations. In particular, members of Clostridium, Escherichia, Helicobacter, Lactococcus, Prevotellaceae_UCG-001 and Staphylococcus appeared to expand in the intestinal tract of knockout mice. Interestingly, the proportion of Escherichia (200-fold) and Staphylococcus (10-fold) as well as the abundance of intestinal bacteria encoding the LCN2-sensitive siderphore enterobactin (entA) was significantly increased in male Lcn2 null mice (743-fold, p < 0.001). This was accompanied by significant higher immune cell infiltration in the ileum as demonstrated by increased immunoreactivity against the pan-leukocyte protein CD45, the lymphocyte transcription factor MUM-1/IRF4, and the macrophage antigen CD68/Macrosialin. In addition, we found a higher expression of mucosal mast cell proteases indicating a higher number of those innate immune cells. Finally, the ileum of Lcn2 null mice displayed a high abundance of segmented filamentous bacteria, which are intimately associated with the mucosal cell layer, provoking epithelial antimicrobial responses and affecting T-helper cell polarization.
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Affiliation(s)
- Patrick Klüber
- German Centre for Infection Research, Institute of Medical Microbiology, Justus-Liebig-University, D-35392 Giessen, Germany; (P.K.); (S.Z.-G.)
| | - Steffen K. Meurer
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, D-52074 Aachen, Germany; (S.K.M.); (J.L.)
| | - Jessica Lambertz
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, D-52074 Aachen, Germany; (S.K.M.); (J.L.)
| | - Roman Schwarz
- Labor Mönchengladbach, Medical Care Centre, D-41169 Mönchengladbach, Germany;
| | - Silke Zechel-Gran
- German Centre for Infection Research, Institute of Medical Microbiology, Justus-Liebig-University, D-35392 Giessen, Germany; (P.K.); (S.Z.-G.)
| | - Till Braunschweig
- Institute of Pathology, RWTH Aachen University Hospital, D-52074 Aachen, Germany;
| | - Sabine Hurka
- Institute for Insect Biotechnology, Justus-Liebig-University, D-35392 Giessen, Germany;
| | - Eugen Domann
- German Centre for Infection Research, Institute of Hygiene and Environmental Medicine, Justus-Liebig-University, D-35392 Giessen, Germany
- Correspondence: (E.D.); (R.W.); Tel.: +49-(0)641-99-41280 (E.D.); +49-(0)241-80-88683 (R.W.)
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, D-52074 Aachen, Germany; (S.K.M.); (J.L.)
- Correspondence: (E.D.); (R.W.); Tel.: +49-(0)641-99-41280 (E.D.); +49-(0)241-80-88683 (R.W.)
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Borkham-Kamphorst E, Haas U, Pinoé-Schmidt M, Abdallah AT, Weiskirchen R. Chronic mineral oil administration increases hepatic inflammation in wild type mice compared to lipocalin 2 null mice. J Transl Med 2021; 101:1528-1539. [PMID: 34518636 PMCID: PMC8590977 DOI: 10.1038/s41374-021-00672-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 08/22/2021] [Accepted: 08/23/2021] [Indexed: 11/09/2022] Open
Abstract
Lipocalin 2 (LCN2), an acute-phase protein produced during acute liver injury, plays an important role in the innate immune response against bacterial infection via iron scavenging. LCN2 further influences neutrophil development and physiology leading to increased inflammatory responses. We investigated the roles of LCN2 in chronic inflammation and fibrosis, using repeated carbon tetrachloride (CCl4) in mineral-oil injection. Surprisingly, mice treated with the mineral oil vehicle alone showed liver inflammation, evidenced by neutrophil and monocyte-macrophage infiltration. Fluorescence-activated cell sorting (FACS) of isolated liver leukocytes showed significantly high CD45+ leukocyte concentrations in CCl4 mice, but no difference of Ly6G+ neutrophils between mineral oil and CCl4 application. Liver CD11b+ F4/80+ cells counted higher in CCl4 mice, but the proportions of Gr1high, an indicator of inflammation, were significantly higher in mineral oil groups. Liver myeloperoxidase (MPO), expressed in neutrophils and monocytes, showed higher levels in wild type mice compared to Lcn2-/- in both mineral-oil and CCl4 treated groups. Hepatic and serum LCN2 levels were remarkably higher in the mineral oil-injected wild type group compared to the CCl4. Wild type animals receiving mineral oil showed significantly higher inflammatory cytokine- and chemokine mRNA levels compared to Lcn2-/- mice, with no differences in the CCl4 treated groups. RNA sequencing (RNA-Seq) confirmed significant downregulation of gene sets involved in myeloid cell activation and immune responses in Lcn2 null mice receiving chronic mineral oil versus wild-type. We observed significant upregulation of gene sets and proteins involved in cell cycle DNA replication, with downregulation of collagen-containing extracellular matrix genes in Lcn2-/- mice receiving CCl4, compared to the wild type. Consequently, the wild type mice developed slightly more liver fibrosis compared to Lcn2-/- mice, evidenced by higher levels of collagen type I in the CCl4 groups and no liver fibrosis in mineral oil-treated mice. Our findings indicate that serum and hepatic LCN2 levels correlate with hepatic inflammation rather than fibrosis.
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Affiliation(s)
- Erawan Borkham-Kamphorst
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, Aachen, Germany.
| | - Ute Haas
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, Aachen, Germany
| | - Manuela Pinoé-Schmidt
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, Aachen, Germany
| | - Ali T Abdallah
- Interdisciplinary Center for Clinical Research, University Hospital RWTH, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, Aachen, Germany.
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George J, Zhang Y, Sloan J, Sims JM, Imig JD, Zhao X. Tim-1 Deficiency Aggravates High-Fat Diet-Induced Steatohepatitis in Mice. Front Immunol 2021; 12:747794. [PMID: 34675931 PMCID: PMC8523998 DOI: 10.3389/fimmu.2021.747794] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/16/2021] [Indexed: 11/08/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is commonly associated with obesity and characterized by excessive lipid accumulation and liver inflammation. The T cell immunoglobulin and mucin domain 1 (Tim-1), also known as hepatitis A virus cellular receptor 1 (Havcr-1) and kidney injury molecule 1 (Kim-1), has been shown to affect innate immunity-driven proinflammatory cascade in liver ischemia-reperfusion injury. However, its contribution to obesity-related NAFLD/NASH remains unknown. Thus, this study was designed to evaluate the role of Tim-1 in obesity-related liver inflammation and injury in wild-type (WT) and Tim-1-deficient (Tim-1-/-) C57BL/6J mice fed a high-fat diet (HFD) for 5-6 months. HFD feeding induced steatosis and upregulated Tim-1 gene expression in the liver of WT mice. Surprisingly, Tim-1-/- mice on HFD diet exhibited an exacerbation of hepatic steatosis, accompanied with an elevation of protein levels of fatty acid translocase CD36 and sterol regulatory element binding protein 1 (SREBP1). Tim-1 deficiency also enhanced HFD-induced liver inflammation and injury, as evidenced by augmented increase in hepatic expression of pro-inflammatory factor lipocalin 2 and elevated serum alanine transaminase (ALT). In addition, gene expression of type I, III and IV collagens and liver fibrosis were greatly enhanced in HFD Tim-1-/- mice compared with HFD WT mice. HFD-induced hepatic expression of YM-1, a specific mouse M2 macrophage marker, was further upregulated by deletion of Tim-1. Together, these results show that Tim-1 deficiency aggravates the effects of HFD diet on lipid accumulation and liver fibrosis, most likely through enhanced infiltration and activation of inflammatory cells.
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Affiliation(s)
- Jasmine George
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Yuanyuan Zhang
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Jacob Sloan
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Joya M Sims
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - John D Imig
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Xueying Zhao
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
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Zhang Y, Long X, Ruan X, Wei Q, Zhang L, Wo L, Huang D, Lin L, Wang D, Xia L, Zhao Q, Liu J, Zhao Q, He M. SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver injury. Cell Discov 2021; 7:93. [PMID: 34642310 PMCID: PMC8511299 DOI: 10.1038/s41421-021-00326-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023] Open
Abstract
Protein acetylation has emerged to play pivotal roles in alcoholic liver disease (ALD). Sirutin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase involved in the regulation of aging, metabolism, and stress. However, the role of SIRT2 in ALD remains unclear. Here, we report that the SIRT2-mediated deacetylation-deubiquitination switch of CCAAT/enhancer-binding protein beta (C/EBPβ) prevents ALD. Our results showed that hepatic SIRT2 protein expression was negatively correlated with the severity of alcoholic liver injury in ALD patients. Liver-specific SIRT2 deficiency sensitized mice to ALD, whereas transgenic SIRT2 overexpression in hepatocytes significantly prevented ethanol-induced liver injury via normalization of hepatic steatosis, lipid peroxidation, and hepatocyte apoptosis. Mechanistically, we identified C/EBPβ as a critical substrate of SIRT2 implicated in ALD. SIRT2-mediated deacetylation at lysines 102 and 211 decreased C/EBPβ ubiquitination, resulting in enhanced protein stability and subsequently increased transcription of C/EBPβ-target gene LCN2. Importantly, hepatic deacetylated C/EBPβ and LCN2 compensation reversed SIRT2 deletion-induced ALD aggravation in mice. Furthermore, C/EBPβ protein expression was positively correlated with SIRT2 and LCN2 expression in the livers of ALD patients and was inversely correlated with ALD development. Therefore, activating SIRT2-C/EBPβ-LCN2 signaling pathway is a potential therapy for ALD.
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Affiliation(s)
- Yingting Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xidai Long
- Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Xin Ruan
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Wei
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Zhang
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lulu Wo
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dongdong Huang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Longshuai Lin
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Difei Wang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Xia
- Department of Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qinghua Zhao
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Junling Liu
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Zhao
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Ming He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Lipocalin-2: Structure, function, distribution and role in metabolic disorders. Biomed Pharmacother 2021; 142:112002. [PMID: 34463264 DOI: 10.1016/j.biopha.2021.112002] [Citation(s) in RCA: 193] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/26/2021] [Accepted: 08/01/2021] [Indexed: 12/27/2022] Open
Abstract
Lipocalin-2 (LCN-2) is a novel, 198 amino acid adipocytokine also referred to as neutrophil gelatinase-associated lipocalin (NGAL). LCN-2 is a circulatory protein responsible for the transportation of small and hydrophobic molecules (steroid, free fatty acids, prostaglandins and hormones) to target organs after binding to megalin/glycoprotein and GP330 SLC22A17 or 24p3R LCN-2 receptors. LCN-2 has been used as a biomarker for acute and chronic renal injury. It is present in a large variety of cells including neutrophil, hepatocytes, lung, bone marrow, adipose tissue, macrophages, thymus, non-neoplastic breast duct, prostate, and renal cells. Different functions have been associated with LCN-2. These functions include antibacterial, anti-inflammatory, and protection against cell and tissue stress. Moreover, LCN-2 can increase the pool of matrix metalloproteinase 9 in human neutrophil granulocytes. Other reported functions of LCN-2 include its ability to destroy the extracellular matrix, which could enable cancer progression and spread of metastasis. Recent reports show that the tissue level of LCN-2 is increased in metabolic disorders such as obesity and type 2 diabetes, suggesting an association between LCN-2 and insulin sensitivity and glucose homeostasis. The precise role of LCN-2 in the modulation of insulin sensitivity, glucose and lipid metabolism is still unclear. This review explores the structure of LCN-2, tissue distribution, and its interaction with important metabolic pathways.
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Dekens DW, Eisel ULM, Gouweleeuw L, Schoemaker RG, De Deyn PP, Naudé PJW. Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases. Ageing Res Rev 2021; 70:101414. [PMID: 34325073 DOI: 10.1016/j.arr.2021.101414] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 12/12/2022]
Abstract
Chronic (neuro)inflammation plays an important role in many age-related central nervous system (CNS) diseases, including Alzheimer's disease, Parkinson's disease and vascular dementia. Inflammation also characterizes many conditions that form a risk factor for these CNS disorders, such as physical inactivity, obesity and cardiovascular disease. Lipocalin 2 (Lcn2) is an inflammatory protein shown to be involved in different age-related CNS diseases, as well as risk factor conditions thereof. Lcn2 expression is increased in the periphery and the brain in different age-related CNS diseases and also their risk factor conditions. Experimental studies indicate that Lcn2 contributes to various neuropathophysiological processes of age-related CNS diseases, including exacerbated neuroinflammation, cell death and iron dysregulation, which may negatively impact cognitive function. We hypothesize that increased Lcn2 levels as a result of age-related risk factor conditions may sensitize the brain and increase the risk to develop age-related CNS diseases. In this review we first provide a comprehensive overview of the known functions of Lcn2, and its effects in the CNS. Subsequently, this review explores Lcn2 as a potential (neuro)inflammatory link between different risk factor conditions and the development of age-related CNS disorders. Altogether, evidence convincingly indicates Lcn2 as a key constituent in ageing and age-related brain diseases.
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Affiliation(s)
- Doortje W Dekens
- Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands
| | - Ulrich L M Eisel
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands
| | - Leonie Gouweleeuw
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands
| | - Regien G Schoemaker
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands
| | - Peter P De Deyn
- Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Laboratory of Neurochemistry and Behaviour, Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
| | - Petrus J W Naudé
- Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands; Department of Psychiatry and Mental Health and Neuroscience Institute, Brain Behaviour Unit, University of Cape Town, Cape Town, South Africa.
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Lipocalin 2 stimulates bone fibroblast growth factor 23 production in chronic kidney disease. Bone Res 2021; 9:35. [PMID: 34334787 PMCID: PMC8326281 DOI: 10.1038/s41413-021-00154-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 03/23/2021] [Accepted: 04/20/2021] [Indexed: 12/15/2022] Open
Abstract
Bone-produced fibroblast growth factor 23 (FGF23) increases in response to inflammation and iron deficiency and contributes to cardiovascular mortality in chronic kidney disease (CKD). Neutrophil gelatinase-associated lipocalin (NGAL or lipocalin 2; LCN2 the murine homolog) is a pro-inflammatory and iron-shuttling molecule that is secreted in response to kidney injury and may promote CKD progression. We investigated bone FGF23 regulation by circulating LCN2. At 23 weeks, Col4a3KO mice showed impaired kidney function, increased levels of kidney and serum LCN2, increased bone and serum FGF23, anemia, and left ventricular hypertrophy (LVH). Deletion of Lcn2 in CKD mice did not improve kidney function or anemia but prevented the development of LVH and improved survival in association with marked reductions in serum FGF23. Lcn2 deletion specifically prevented FGF23 elevations in response to inflammation, but not iron deficiency or phosphate, and administration of LCN2 increased serum FGF23 in healthy and CKD mice by stimulating Fgf23 transcription via activation of cAMP-mediated signaling in bone cells. These results show that kidney-produced LCN2 is an important mediator of increased FGF23 production by bone in response to inflammation and in CKD. LCN2 inhibition might represent a potential therapeutic approach to lower FGF23 and improve outcomes in CKD.
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50
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Chen XR, Wang DX. Serum MCP-1 and NGAL Play an Important Role in the Acute Inflammatory Event of Chronic Obstructive Pulmonary Disease. COPD 2021; 18:425-431. [PMID: 34325599 DOI: 10.1080/15412555.2021.1954151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
NGAL is mainly secreted by neutrophils which play the core role in AECOPD. MCP-1 is secreted specifically by monocytes and macrophages. Both biomarkers are involved in the core process of acute inflammatory reaction in COPD. So We analyzed serum NGAL and MCP-1levels to explore their potential clinical values in the chronic obstructive pulmonary disease (COPD) .This study enrolled 97 COPD patients and 50 healthy controls. All participants received blood collection and lung function test and arterial blood gas measurements. The expression levels of serum NGAL and MCP-1 were measured by ELISA. The serum NGAL and MCP-1 levels of COPD with community-acquired pneumonia (COPD-CAP) patients were significantly higher than those of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients and healthy adults. The NGAL levels of the GOLD III and IV groups were significantly higher than those of the GOLD II group. Spearman correlation analysis showed a negative correlation between NGAL and FEV1%pred, FVC% pred. ROC curves indicated that NGAL has a high diagnostic value for both AECOPD and COPD-CAP. NGAL has the value of distinguishing GOLD I and II from GOLD III and IV. MCP-1 have moderate diagnostic value for COPD-CAP and can differentiate COPD-CAP from AECOPD. This study shows NGAL has certain diagnostic value for AECOPD and COPD-CAP, but can not distinguish the two. NGAL is closely related to airway remodeling and can be used as a potential indicator to distinguish the higher GOLD degree. MCP-1 can be used as potential indicator for the diagnosis of COPD-CAP.
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Affiliation(s)
- Xing-Ru Chen
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dao-Xin Wang
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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