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Mincheva G, Moreno-Manzano V, Felipo V, Llansola M. Extracellular vesicles from mesenchymal stem cells improve liver injury in rats with mild liver damage. Underlying mechanisms and role of TGFβ. Life Sci 2025; 364:123429. [PMID: 39884339 DOI: 10.1016/j.lfs.2025.123429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/21/2025] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
Preventing the progression of liver damage to fibrosis would be beneficial for patients with steatotic liver disease (SLD). Mesenchymal stem cells (MSC) are a promising therapy for SLD and derived extracellular vesicles (EVs) could even improve the treatment's efficacy and safety. However, the mechanisms of MSC-EVs beneficial effects are not well known. It has been suggested that modifying the EVs cargo could improve their beneficial effects. The aims of this study were to assess if MSC-EVs reduce liver damage in a rat model of mild liver damage; to analyze the underlying mechanisms and to assess if silencing TGFβ enhances the beneficial effects of MSC-EVs. CCl4 was injected three times per week during four weeks to induce mild liver damage. EVs from human adipocyte MSC and from TGFβ-depleted MSC (siTGFβ-MSC-EVs) were injected in the tail vein. Steatosis, fibrosis, liver inflammation, macrophage infiltration and liver content of fibrotic markers, DAMPs, cytokines and bile acids were analyzed. Normal MSC-EVs reduce the CCL2 increase in liver, macrophage infiltration and the increases in the fibrosis markers collagen I and α-SMA. Treatment with siTGFβ-MSC-EVs, in addition, reduces liver steatosis, the increase of bile acids (mainly TCA), and DAMP HMGB1 levels, inducing a larger reduction of collagen I in liver of CCl4 rats. Treatment with MSCs-EVs effectively reduces early liver damage. Silencing of TGFβ in MSCs enhances the beneficial effects by additional mechanisms. Early treatment with MSC-EVs, especially after silencing TGFβ, could improve liver damage in SLD patients.
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Affiliation(s)
- Gergana Mincheva
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Victoria Moreno-Manzano
- Laboratory of Neuronal and Tissue Regeneration, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
| | - Marta Llansola
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
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Al-Mohannadi A, Yahia RM, Bibawi H, Lachica CA, Ahmed W, Pavlovski I, Gentilcore G, Elgaali EE, Ejaz A, Ahmed A, Elanbari M, Awada Z, Al-Kubaisi MJ, Elnaggar M, Saleh A, Cugno C, Deola S. Flow Cytometry Evaluation of Blood-Cell-Bound Surface FVIII in Hemophilia A and Thrombosis. Cells 2025; 14:73. [PMID: 39851501 PMCID: PMC11764290 DOI: 10.3390/cells14020073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/24/2024] [Accepted: 12/29/2024] [Indexed: 01/26/2025] Open
Abstract
Hemophilia A (HA) is associated with FVIII coagulation insufficiency or inactivity leading to excessive bleeding. Elevated FVIII, on the contrary, is associated with thrombophilia, thrombosis, myocardial infarctions, and stroke. Active FVIII (aFVIII) uses its C2 domain to bind to blood cells' membranes, consequently carrying out its coagulative function. We developed a reliable flow cytometry (FC) method for FVIII detection that can be utilized for assessing surface-bound FVIII on leukocytes in different coagulation/clinical states; we analyzed 49 pediatric subjects, encompassing patients with HA, other coagulopathies, venous thrombosis, and normal coagulation. Interestingly, the total leukocyte surface FVIII showed a declining trend across thrombosis, normal, and hypo-coagulation states. As expected, the leukocytes of HA patients displayed significantly lower levels of cellular-surface FVIII in comparison to patients with thrombosis. However, no significant correlation was observed between circulating levels of FVIII in plasma and the levels of FVIII bound to leukocytes, indicating that the differences in FVIII surface binding are not directly proportional to the availability of FVIII in the circulation and suggesting a specific binding mechanism governing the interaction between FVIII and leukocytes. Intriguingly, when analyzing the distinct blood subpopulations, we observed that surface FVIII levels were significantly elevated in classical monocytes of thrombosis patients compared to HA patients, healthy controls, and patients with other coagulopathies. Our study highlights the reliability of our FC platform in assessing FVIII abundance on leukocytes' membranes across coagulation states. Monocytes, particularly in cases of thrombosis, exhibit active binding of FVIII on their surface, suggesting a potential role in the pathophysiology of thrombosis that requires further investigation.
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Affiliation(s)
- Anjud Al-Mohannadi
- Research Department, Sidra Medicine, Doha P.O. Box 26999, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar
| | | | - Hani Bibawi
- Pathology Department, Sidra Medicine, Doha P.O. Box 26999, Qatar
| | - Che-Ann Lachica
- Research Department, Sidra Medicine, Doha P.O. Box 26999, Qatar
| | - Watfa Ahmed
- Research Department, Sidra Medicine, Doha P.O. Box 26999, Qatar
| | - Igor Pavlovski
- Research Department, Sidra Medicine, Doha P.O. Box 26999, Qatar
| | | | | | - Anila Ejaz
- Hematology-Oncology Clinic, Sidra Medicine, Doha P.O. Box 26999, Qatar
| | - Areeg Ahmed
- Hematology-Oncology Clinic, Sidra Medicine, Doha P.O. Box 26999, Qatar
| | | | - Zainab Awada
- Research Department, Sidra Medicine, Doha P.O. Box 26999, Qatar
| | | | | | - Ayman Saleh
- Hematology-Oncology Clinic, Sidra Medicine, Doha P.O. Box 26999, Qatar
| | - Chiara Cugno
- Research Department, Sidra Medicine, Doha P.O. Box 26999, Qatar
- Pathology Department, Sidra Medicine, Doha P.O. Box 26999, Qatar
| | - Sara Deola
- Research Department, Sidra Medicine, Doha P.O. Box 26999, Qatar
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Huang LZ, Ni ZB, Yao QR, Huang WF, Li J, Wang YQ, Zhang JY. Association of pan-immune-inflammatory value with metabolic dysfunction-associated steatotic liver disease: findings from NHANES 2017-2020. BMC Gastroenterol 2025; 25:4. [PMID: 39754093 PMCID: PMC11697488 DOI: 10.1186/s12876-024-03584-2] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 12/27/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide. The pan-immune-inflammation value (PIV) has been proposed as a biomarker for assessing immune status and inflammation. There is currently no evidence regarding the effect of PIV on the risk of MASLD. This study aimed to investigate the association between PIV and MASLD. METHODS The cross-sectional study included 6462 adults aged ≥ 20 years from the National Health and Nutrition Examination Survey 2017-2020. PIV was calculated based on blood count data. Weighted multivariable logistic regression was employed to calculate the odds ratio (OR) and 95% confidence interval (CI) to investigate the association of PIV and MASLD. Restricted cubic spline (RCS) analysis was conducted to explore the dose-response relationship between PIV and MASLD. Stratified and sensitivity analyses were performed to confirm the robustness of our findings. RESULTS Among 6462 participants, 2458 were diagnosed with MASLD. Positive associations between LnPIV and MASLD were observed in all three models (Model 1: OR = 1.46, 95% CI: 1.28-1.66, P < 0.001; Model 2: OR = 1.41, 95% CI: 1.24-1.60, P < 0.001; Model 3: OR = 1.39, 95% CI: 1.16-1.65, P = 0.004). When PIV was classified into quartiles, both Q3 and Q4 exhibited significantly increased risks of MASLD compared with the reference Q1 in full adjusted Model 3 (Q3: OR = 1.63, 95% CI: 1.20-2.22, P = 0.012; Q4: OR = 1.76, 95% CI: 1.28-2.41, P = 0.008; P for trend = 0.002). RCS analysis did not show a nonlinear relationship between LnPIV and MASLD (P = 0.093 for nonlinearity). Stratified analysis showed a consistent positive association between LnPIV and MASLD in all subgroups, and sensitivity analyses supported the reliability of these results. CONCLUSIONS Higher PIV levels are significantly associated with an increased prevalence of MASLD, indicating that PIV is a potentially effective inflammatory marker for assessing MASLD in participants.
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Affiliation(s)
- Lian-Zhen Huang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, No. 55 Zhenhai Road, Xiamen, 361003, China
| | - Ze-Bin Ni
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, No. 55 Zhenhai Road, Xiamen, 361003, China
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
| | - Qi-Rong Yao
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, No. 55 Zhenhai Road, Xiamen, 361003, China
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
| | - Wei-Feng Huang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, No. 55 Zhenhai Road, Xiamen, 361003, China
| | - Ji Li
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, No. 55 Zhenhai Road, Xiamen, 361003, China
| | - Yan-Qing Wang
- Department of Ultrasound, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, No. 55 Zhenhai Road, Xiamen, 361003, China.
| | - Jin-Yan Zhang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, No. 55 Zhenhai Road, Xiamen, 361003, China.
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China.
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Dyba M, Berezenko V, Zabara D, Bezpala A, Donskoi B. Monocyte subpopulations in children with autoimmune liver disease. Pathol Res Pract 2024; 263:155622. [PMID: 39357182 DOI: 10.1016/j.prp.2024.155622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 09/16/2024] [Accepted: 09/25/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND Patients with autoimmune liver diseases require individualized long-term immunosuppressive therapy, whose discontinuation is possible after complete histological remission and that requires repeated liver biopsy. In view of this, the search for non-invasive markers is essential for patients with autoimmune liver disease. PURPOSE The purpose of this research is to assess the possibility of predicting the recurrence of autoimmune liver disease in children. METHOD The biological material used in the study was blood serum from 80 children diagnosed with autoimmune hepatitis and autoimmune sclerosing cholangitis. Patients were divided into four groups according to disease activity and therapeutic approach. RESULTS The percentage of monocyte subpopulations was determined by flow cytometry, and disease activity, inflammation, and fibrosis markers were analyzed to study the relationship and diagnostic value of the parameters studied in detail. The results of the study indicate a significant relationship between disease activity and changes in the distribution of the percentage of monocyte subpopulations in the blood. The percentage of intermediate CD14++/CD16+ monocytes was found to correlate with disease activity, and non-classical CD14lowCD16+ monocytes were found to be of high diagnostic value in the diagnosis of disease relapse. CONCLUSIONS These findings not only expand the understanding of the pathogenesis of autoimmune liver disease but also point to the prospects of using monocyte subpopulations as potential biomarkers for predicting relapse, contributing to the development of more effective clinical management strategies.
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Affiliation(s)
- Maryna Dyba
- Department of Hepatology and Comorbidities in Children, Institute of Pediatrics, Obstetrics and Gynecology of the National Academy of Medical Sciences of Ukraine, Kyiv 04050, Ukraine.
| | - Valentyna Berezenko
- Department of Hepatology and Comorbidities in Children, Institute of Pediatrics, Obstetrics and Gynecology of the National Academy of Medical Sciences of Ukraine, Kyiv 04050, Ukraine
| | - Dariia Zabara
- Laboratory of Immunology, Institute of Pediatrics, Obstetrics and Gynecology of the National Academy of Medical Sciences of Ukraine, Kyiv 04050, Ukraine
| | - Anna Bezpala
- Department of Hepatology and Comorbidities in Children, Institute of Pediatrics, Obstetrics and Gynecology of the National Academy of Medical Sciences of Ukraine, Kyiv 04050, Ukraine
| | - Boris Donskoi
- Laboratory of Immunology, Institute of Pediatrics, Obstetrics and Gynecology of the National Academy of Medical Sciences of Ukraine, Kyiv 04050, Ukraine
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Grisolia JC, Santos LA, Dias NA, Malaquias LCC, Burger E. Low-level LASER therapy accelerates fungal lesions cicatrization by increasing the production of Th1 and Th2 cytokines. Photochem Photobiol Sci 2024; 23:1295-1307. [PMID: 38806861 DOI: 10.1007/s43630-024-00595-6] [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: 03/04/2024] [Accepted: 05/11/2024] [Indexed: 05/30/2024]
Abstract
Paracoccidioidomycosis (PCM) is a systemic mycosis with serious clinical consequences in which the use of antifungal drugs requires long-term treatment. Therefore, we studied the effect of low-level LASER therapy (LLLT) to evaluate its prospects as a complementary treatment for PCM and improve the clinical response to the disease. OBJECTIVES Our study focused on the resolution of lesions caused by fungal infection using a subcutaneous air pouch model of infection. METHODS We evaluated cell profile and cytokines, fungi viability, and the presence of fibroblasts and fibrocytes at the site of infection. Inoculation of P. brasiliensis (Pb) was performed using a subcutaneous air pouch model and the LLLT irradiation was performed on alternate days on the rear paws of mice for 10 days, after which the cells from the air pouch were collected and analyzed. RESULTS In animals irradiated with LLLT, the influx of cells to the air pouch was reduced, but they were more activated and produced pro-inflammatory (IL-12, IL-17 and TNF-α) and neutrophil (PMN) activating cytokines (IL-8, GM-CSF and γ-IFN). A better resolution of the infection, evidenced by the reduction in the number of viable fungi with preserved morphology in the air pouch, and an increase in the number of fibrocytes, indicating a healing profile were also observed. CONCLUSION LLLT decreased the influx of PMN, but those presents were highly activated, with increased fungicidal activity. LLLT irradiation also resulted in earlier cicatrization at the site of infection, leading to a better outcome of the infection. These data are favorable to the use of LLLT as a complementary therapy in PCM.
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Affiliation(s)
- Julianne Caravita Grisolia
- Department of Microbiology and Immunology, Institute of Biomedical Sciences, Federal University of Alfenas UNIFAL-MG, Rua Gabriel Monteiro da Silva, 700, Centro, Alfenas, MG, 37130-001, Brazil.
| | - Lauana Aparecida Santos
- Department of Microbiology and Immunology, Institute of Biomedical Sciences, Federal University of Alfenas UNIFAL-MG, Rua Gabriel Monteiro da Silva, 700, Centro, Alfenas, MG, 37130-001, Brazil
| | - Nayara Andrade Dias
- Department of Microbiology and Immunology, Institute of Biomedical Sciences, Federal University of Alfenas UNIFAL-MG, Rua Gabriel Monteiro da Silva, 700, Centro, Alfenas, MG, 37130-001, Brazil
| | - Luiz Cosme Cotta Malaquias
- Department of Microbiology and Immunology, Institute of Biomedical Sciences, Federal University of Alfenas UNIFAL-MG, Rua Gabriel Monteiro da Silva, 700, Centro, Alfenas, MG, 37130-001, Brazil
| | - Eva Burger
- Department of Microbiology and Immunology, Institute of Biomedical Sciences, Federal University of Alfenas UNIFAL-MG, Rua Gabriel Monteiro da Silva, 700, Centro, Alfenas, MG, 37130-001, Brazil
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Yang XY, Chen Z, Tan J, Xue YK, Zheng H. KLF4 Inhibits the Activation of Human Hepatic Stellate Cell In Vitro. Curr Med Sci 2024; 44:512-518. [PMID: 38789819 DOI: 10.1007/s11596-024-2860-8] [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: 01/08/2024] [Accepted: 03/08/2024] [Indexed: 05/26/2024]
Abstract
OBJECTIVE Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis. Early-stage liver fibrosis is reversible and intimately associated with the state of HSCs. Kruppel-like factor 4 (KLF4) plays a pivotal role in a wide array of physiological and pathological processes. This study aimed to investigate the effect of KLF4 on the proliferation, apoptosis and phenotype of quiescent HSCs METHODS: We designed a KLF4 lentiviral vector and a KLF4 siRNA lentiviral vector, to upregulate and silence KLF4 expression in human HSC LX-2 cells via transfection. Cell proliferation was assessed using the CCK-8 assay. Flow cytometry was used to detect the cell cycle distribution and apoptosis rate. Western blotting was used to determine the levels of some quiescence and activation markers of HSCs RESULTS: Overexpression of KLF4 significantly increased the levels of E-cadherin and ZO-1, which are quiescent HSC markers, while significantly decreased the levels of N-cadherin and a-SMA, known activated HSC markers. In contrast, cell proliferation and apoptosis rates were elevated in LX-2 cells in which KLF4 expression was silenced CONCLUSION: KLF4 inhibits the proliferation and activation of human LX-2 HSCs. It might be a key regulatory protein in the maintenance of HSC quiescence and may serve as a target for the inhibition of hepatic fibrosis.
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Affiliation(s)
- Xing-Yu Yang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhe Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jun Tan
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yin-Kai Xue
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Hai Zheng
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Zhang B, Lai RC, Sim WK, Tan TT, Lim SK. An Assessment of Administration Route on MSC-sEV Therapeutic Efficacy. Biomolecules 2024; 14:622. [PMID: 38927026 PMCID: PMC11202284 DOI: 10.3390/biom14060622] [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: 04/09/2024] [Revised: 05/15/2024] [Accepted: 05/22/2024] [Indexed: 06/28/2024] Open
Abstract
Mesenchymal stem/stromal cell-derived small extracellular vesicles (MSC-sEVs) are promising therapeutic agents. In this study, we investigated how the administration route of MSC-sEVs affects their therapeutic efficacy in a mouse model of bleomycin (BLM)-induced skin scleroderma (SSc). We evaluated the impact of topical (TOP), subcutaneous (SC), and intraperitoneal (IP) administration of MSC-sEVs on dermal fibrosis, collagen density, and thickness. All three routes of administration significantly reduced BLM-induced fibrosis in the skin, as determined by Masson's Trichrome staining. However, only TOP administration reduced BLM-induced dermal collagen density, with no effect on dermal thickness observed for all administration routes. Moreover, SC, but not TOP or IP administration, increased anti-inflammatory profibrotic CD163+ M2 macrophages. These findings indicate that the administration route influences the therapeutic efficacy of MSC-sEVs in alleviating dermal fibrosis, with TOP administration being the most effective, and this efficacy is not mediated by M2 macrophages. Since both TOP and SC administration target the skin, the difference in their efficacy likely stems from variations in MSC-sEV delivery in the skin. Fluorescence-labelled TOP, but not SC MSC-sEVs when applied to skin explant cultures, localized in the stratum corneum. Hence, the superior efficacy of TOP over SC MSC-sEVs could be attributed to this localization. A comparison of the proteomes of stratum corneum and MSC-sEVs revealed the presence of >100 common proteins. Most of these proteins, such as filaggrin, were known to be crucial for maintaining skin barrier function against irritants and toxins, thereby mitigating inflammation-induced fibrosis. Therefore, the superior efficacy of TOP MSC-sEVs over SC and IP MSC-sEVs against SSc is mediated by the delivery of proteins to the stratum corneum to reinforce the skin barrier.
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Affiliation(s)
- Bin Zhang
- Paracrine Therapeutics Pte. Ltd., 1 Tai Seng Ave, #02-04 Tai Seng Exchange, Singapore 536464, Singapore; (B.Z.); (R.C.L.); (W.K.S.); (T.T.T.)
| | - Ruenn Chai Lai
- Paracrine Therapeutics Pte. Ltd., 1 Tai Seng Ave, #02-04 Tai Seng Exchange, Singapore 536464, Singapore; (B.Z.); (R.C.L.); (W.K.S.); (T.T.T.)
| | - Wei Kian Sim
- Paracrine Therapeutics Pte. Ltd., 1 Tai Seng Ave, #02-04 Tai Seng Exchange, Singapore 536464, Singapore; (B.Z.); (R.C.L.); (W.K.S.); (T.T.T.)
| | - Thong Teck Tan
- Paracrine Therapeutics Pte. Ltd., 1 Tai Seng Ave, #02-04 Tai Seng Exchange, Singapore 536464, Singapore; (B.Z.); (R.C.L.); (W.K.S.); (T.T.T.)
| | - Sai Kiang Lim
- Paracrine Therapeutics Pte. Ltd., 1 Tai Seng Ave, #02-04 Tai Seng Exchange, Singapore 536464, Singapore; (B.Z.); (R.C.L.); (W.K.S.); (T.T.T.)
- Department of Surgery, YLL School of Medicine, National University Singapore (NUS), 5 Lower Kent Ridge Road, Singapore 119074, Singapore
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Chelko SP, Penna VR, Engel M, Shiel EA, Centner AM, Farra W, Cannon EN, Landim-Vieira M, Schaible N, Lavine K, Saffitz JE. NFĸB signaling drives myocardial injury via CCR2+ macrophages in a preclinical model of arrhythmogenic cardiomyopathy. J Clin Invest 2024; 134:e172014. [PMID: 38564300 PMCID: PMC11093597 DOI: 10.1172/jci172014] [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: 05/03/2023] [Accepted: 03/20/2024] [Indexed: 04/04/2024] Open
Abstract
Nuclear factor κ-B (NFκB) is activated in iPSC-cardiac myocytes from patients with arrhythmogenic cardiomyopathy (ACM) under basal conditions, and inhibition of NFκB signaling prevents disease in Dsg2mut/mut mice, a robust mouse model of ACM. Here, we used genetic approaches and single-cell RNA-Seq to define the contributions of immune signaling in cardiac myocytes and macrophages in the natural progression of ACM using Dsg2mut/mut mice. We found that NFκB signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2mut/mut mice. NFκB signaling in cardiac myocytes mobilizes macrophages expressing C-C motif chemokine receptor-2 (CCR2+ cells) to affected areas within the heart, where they mediate myocardial injury and arrhythmias. Contractile dysfunction in Dsg2mut/mut mice is caused both by loss of heart muscle and negative inotropic effects of inflammation in viable muscle. Single nucleus RNA-Seq and cellular indexing of transcriptomes and epitomes (CITE-Seq) studies revealed marked proinflammatory changes in gene expression and the cellular landscape in hearts of Dsg2mut/mut mice involving cardiac myocytes, fibroblasts, and CCR2+ macrophages. Changes in gene expression in cardiac myocytes and fibroblasts in Dsg2mut/mut mice were dependent on CCR2+ macrophage recruitment to the heart. These results highlight complex mechanisms of immune injury and regulatory crosstalk between cardiac myocytes, inflammatory cells, and fibroblasts in the pathogenesis of ACM.
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Affiliation(s)
- Stephen P. Chelko
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Vinay R. Penna
- Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Morgan Engel
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Emily A. Shiel
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Ann M. Centner
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Waleed Farra
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Elisa N. Cannon
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Maicon Landim-Vieira
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Niccole Schaible
- Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Kory Lavine
- Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Jeffrey E. Saffitz
- Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
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Miron RJ, Bohner M, Zhang Y, Bosshardt DD. Osteoinduction and osteoimmunology: Emerging concepts. Periodontol 2000 2024; 94:9-26. [PMID: 37658591 DOI: 10.1111/prd.12519] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/23/2023] [Accepted: 07/20/2023] [Indexed: 09/03/2023]
Abstract
The recognition and importance of immune cells during bone regeneration, including around bone biomaterials, has led to the development of an entire field termed "osteoimmunology," which focuses on the connection and interplay between the skeletal system and immune cells. Most studies have focused on the "osteogenic" capacity of various types of bone biomaterials, and much less focus has been placed on immune cells despite being the first cell type in contact with implantable devices. Thus, the amount of literature generated to date on this topic makes it challenging to extract needed information. This review article serves as a guide highlighting advancements made in the field of osteoimmunology emphasizing the role of the osteoimmunomodulatory properties of biomaterials and their impact on osteoinduction. First, the various immune cell types involved in bone biomaterial integration are discussed, including the prominent role of osteal macrophages (OsteoMacs) during bone regeneration. Thereafter, key biomaterial properties, including topography, wettability, surface charge, and adsorption of cytokines, growth factors, ions, and other bioactive molecules, are discussed in terms of their impact on immune responses. These findings highlight and recognize the importance of the immune system and osteoimmunology, leading to a shift in the traditional models used to understand and evaluate biomaterials for bone regeneration.
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Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | | | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
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10
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Chen H, Jin C, Xie L, Wu J. Succinate as a signaling molecule in the mediation of liver diseases. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166935. [PMID: 37976628 DOI: 10.1016/j.bbadis.2023.166935] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 10/25/2023] [Accepted: 10/27/2023] [Indexed: 11/19/2023]
Abstract
Succinate, one of the intermediates of the tricarboxylic acid (TCA) cycle, plays an essential role in the metabolism of mitochondria and the production of energy, and is considered as a signaling molecule in metabolism as well as in initiation and progression of hepatic diseases. Of note, succinate activates a downstream signaling pathway through GPR91, and elicits a variety of intracellular responses, such as succinylation, production of reactive oxygen species (ROS), stabilization of hypoxia-inducible factor-1α (HIF-1α), and significant impact in cellular metabolism because of the pivotal role in the TCA cycle. Therefore, it is intriguing to deeply elucidate signaling mechanisms of succinate in hepatic fibrosis, metabolic reprogramming in inflammatory or immune responses, as well as carcinogenesis. This manuscript intends to review current understanding of succinate in mediating metabolism, inflammatory and immunologic reactions in liver diseases in order to establish molecular basis for the development of therapeutic strategies.
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Affiliation(s)
- Hui Chen
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Cheng Jin
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China; College of Clinical College, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Li Xie
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Jian Wu
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China; Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China.
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Jiang Y, Hou L, Dou J, Xuan M, Cui Z, Lian L, Nan J, Wu Y. Sesamol as a potential candidate for the treatment of hepatic fibrosis, based on its regulation of FXR/LXR axis-mediated inhibition of autophagy through crosstalk between hepatic cells and macrophage. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 123:155145. [PMID: 37976698 DOI: 10.1016/j.phymed.2023.155145] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 10/01/2023] [Accepted: 10/12/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND Sesamol (SEM), a natural lignan compound isolated from sesame, has strong anti-oxidant property, regulating lipid metabolism, decreasing cholesterol and hepatoprotection. However, its anti-hepatic fibrosis effect and mechanisms have not been comprehensively elucidated. HYPOTHESIS/PURPOSE This study aims to investigate the anti-hepatic fibrosis of SEM and its underlying mechanisms. METHOD C57BL/6 mice with hepatic fibrosis were induced by TAA, then administrated with SEM or curcumin, respectively. HSCs were stimulated by TGF-β or conditioned medium, and then cultured with SEM, GW4064, GW3965, Rapamycin (RA) or 3-methyladenine (3-MA), respectively. Mice with hepatic fibrosis also were administrated with SEM, RA or 3-MA to estimate the effect of SEM on autophagy. RESULTS In vitro, SEM significantly inhibited extracellular matrix deposition, P2 × 7r-NLRP3, and inflammatory cytokines. SEM increased FXR and LXRα/β expressions and decreased MAPLC3α/β and P62 expressions, functioning as 3-MA (autophagy inhibitor). In vivo, SEM reduced serum transaminase, histopathology changes, fibrogenesis, autophagy markers and inflammatory cytokines caused by TAA. LX-2 were activated with conditioned medium from LPS-primed THP-1, which resulted in significant enhance of autophagy markers and inflammatory cytokines and decrease of FXR and LXRα/β expressions. SEM could reverse above these changes and function as 3-MA, GW4064, or GW3965. Deficiency of FXR or LXR attenuated the regulation of SEM on α-SMA, MAPLC3α/β, P62 and IL-1β in activated LX-2. In activated THP-1, deficiency of FXR could decrease the expression of LXR, and vice versa. Deficiency of FXR or LXR in activated MΦ decreased the expressions of FXR and LXR in activated LX-2. Deficiency FXR or LXR in activated MΦ also attenuated the regulation of SEM on α-SMA, MAPLC3α/β, P62, caspase-1 and IL-1β. In vivo, SEM significantly reversed hepatic fibrosis via FXR/LXR and autophagy. CONCLUSION SEM could regulate hepatic fibrosis by inhibiting fibrogenesis, autophagy and inflammation. FXR/LXR axis-mediated inhibition of autophagy contributed to the regulation of SEM against hepatic fibrosis, especially based on involving in the crosstalk of HSCs-macrophage. SEM might be a prospective therapeutic candidate, and its mechanism would be a new direction or strategy for hepatic fibrosis treatment.
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Affiliation(s)
- YuChen Jiang
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - LiShuang Hou
- Air Force Medical University, Xi'an 710032, China
| | - JiaYi Dou
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - MeiYan Xuan
- School of Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan
| | - ZhenYu Cui
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - LiHua Lian
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - JiXing Nan
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
| | - YanLing Wu
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
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12
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Liang W, Huang X, Shi J. Macrophages Serve as Bidirectional Regulators and Potential Therapeutic Targets for Liver Fibrosis. Cell Biochem Biophys 2023; 81:659-671. [PMID: 37695501 DOI: 10.1007/s12013-023-01173-w] [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: 12/23/2022] [Accepted: 09/02/2023] [Indexed: 09/12/2023]
Abstract
Liver fibrosis is a dynamic pathological process in which the structure and function of the liver abnormally change due to long-term complex inflammatory reactions and chronic liver injury caused by multiple internal and external factors. Previous studies believed that the activation of hepatic stellate cells is a critical part of the occurrence and development of liver fibrosis. However, an increasing number of studies have indicated that the macrophage plays an important role as a central regulator in liver fibrosis, and it directly affects the development and recovery of liver fibrosis. Studies of macrophages and liver fibrosis in the recent 10 years will be reviewed in this paper. This review will not only clarify the molecular mechanism of liver fibrosis regulated by macrophages but also provide new strategies and methods for ameliorating and treating liver fibrosis.
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Affiliation(s)
- Wei Liang
- Clinical Medical Research Center, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, Guangxi, China.
| | - Xianing Huang
- Guangxi International Travel Healthcare Centre (Port Clinic of Nanning Customs District), Nanning, 530021, Guangxi, China
| | - Jingjing Shi
- Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Colorectal Cancer, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
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13
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Kholodenko IV, Yarygin KN. Hepatic Macrophages as Targets for the MSC-Based Cell Therapy in Non-Alcoholic Steatohepatitis. Biomedicines 2023; 11:3056. [PMID: 38002056 PMCID: PMC10669188 DOI: 10.3390/biomedicines11113056] [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: 10/15/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 11/26/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a serious public health issue associated with the obesity pandemic. Obesity is the main risk factor for the non-alcoholic fatty liver disease (NAFLD), which progresses to NASH and then to end-stage liver disease. Currently, there are no specific pharmacotherapies of NAFLD/NASH approved by the FDA or other national regulatory bodies and the treatment includes lifestyle adjustment and medicines for improving lipid metabolism, enhancing sensitivity to insulin, balancing oxidation, and counteracting fibrosis. Accordingly, further basic research and development of new therapeutic approaches are greatly needed. Mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles prevent induced hepatocyte death in vitro and attenuate NASH symptoms in animal models of the disease. They interact with hepatocytes directly, but also target other liver cells, including Kupffer cells and macrophages recruited from the blood flow. This review provides an update on the pathogenesis of NAFLD/NASH and the key role of macrophages in the development of the disease. We examine in detail the mechanisms of the cross-talk between the MSCs and the macrophages, which are likely to be among the key targets of MSCs and their derivatives in the course of NAFLD/NASH cell therapy.
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Affiliation(s)
- Irina V. Kholodenko
- Laboratory of Cell Biology, Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia;
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14
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Chelko SP, Penna V, Engel M, Landim-Vieira M, Cannon EN, Lavine K, Saffitz JE. Mechanisms of Innate Immune Injury in Arrhythmogenic Cardiomyopathy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.12.548682. [PMID: 37503283 PMCID: PMC10370013 DOI: 10.1101/2023.07.12.548682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Inhibition of nuclear factor kappa-B (NFκB) signaling prevents disease in Dsg2 mut/mut mice, a model of arrhythmogenic cardiomyopathy (ACM). Moreover, NFκB is activated in ACM patient-derived iPSC-cardiac myocytes under basal conditions in vitro . Here, we used genetic approaches and sequencing studies to define the relative pathogenic roles of immune signaling in cardiac myocytes vs. inflammatory cells in Dsg2 mut/mut mice. We found that NFκB signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2 mut/mut mice. It does this by mobilizing cells expressing C-C motif chemokine receptor-2 (CCR2+ cells) to the heart, where they mediate myocardial injury and arrhythmias. Contractile dysfunction in Dsg2 mut/mut mice is caused both by loss of heart muscle and negative inotropic effects of inflammation in viable muscle. Single nucleus RNA sequencing and cellular indexing of transcriptomes and epitomes (CITE-seq) studies revealed marked pro-inflammatory changes in gene expression and the cellular landscape in hearts of Dsg2 mut/mut mice involving cardiac myocytes, fibroblasts and CCR2+ cells. Changes in gene expression in cardiac myocytes and fibroblasts in Dsg2 mut/mut mice were modulated by actions of CCR2+ cells. These results highlight complex mechanisms of immune injury and regulatory crosstalk between cardiac myocytes, inflammatory cells, and fibroblasts in the pathogenesis of ACM. BRIEF SUMMARY We have uncovered a therapeutically targetable innate immune mechanism regulating myocardial injury and cardiac function in a clinically relevant mouse model of Arrhythmogenic Cardiomyopathy (ACM).
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15
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Vanderborght B, De Muynck K, Gijbels E, Lefere S, Scott CL, Guilliams M, Beschin A, Vinken M, Verhelst X, Geerts A, Van Vlierberghe H, Devisscher L. Transient Kupffer cell depletion and subsequent replacement by infiltrating monocyte-derived cells does not alter the induction or progression of hepatocellular carcinoma. Int J Cancer 2023; 152:2615-2628. [PMID: 36912275 DOI: 10.1002/ijc.34505] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 01/17/2023] [Accepted: 02/09/2023] [Indexed: 03/14/2023]
Abstract
Due to a combination of rapid disease progression and the lack of curative treatment options, hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. Infiltrated, monocyte-derived, tumor-associated macrophages are known to play a role in HCC pathogenesis, but the involvement of Kupffer cells (KCs) remains elusive. Here, we used the Clec4F-diphteria toxin receptor transgenic mouse model to specifically investigate the effect of KC depletion on HCC initiation, progression and neoplastic growth following liver resection. For this purpose, several HCC mouse models with varying underlying etiologies were used and partial hepatectomy was performed. Our results show that in HCC, developed on a fibrotic or non-alcoholic steatohepatitis background, depletion of embryonic KCs at the onset of HCC induction and the subsequent replacement by monocyte-derived KCs does not affect the tumor burden, tumor microenvironment or the phenotype of isolated KCs at end-stage disease. In non-chronic liver disease-associated diethylnitrosamine-induced HCC, ablation of Clec4F+ KCs did not alter tumor progression or neoplastic growth following liver resection. Our results show that temporal ablation of resident KCs does not impact HCC pathogenesis, neither in the induction phase nor in advanced disease, and indicate that bone marrow-derived KCs are able to swiftly repopulate the available KC niche and adopt their phenotype.
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Affiliation(s)
- Bart Vanderborght
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Ghent, 9000, Belgium
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Ghent, 9000, Belgium
| | - Kevin De Muynck
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Ghent, 9000, Belgium
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Ghent, 9000, Belgium
| | - Eva Gijbels
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Ghent, 9000, Belgium
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, 1090, Belgium
| | - Sander Lefere
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Ghent, 9000, Belgium
| | - Charlotte L Scott
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, 9000, Belgium
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, 9000, Belgium
| | - Martin Guilliams
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, 9000, Belgium
- Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Ghent, 9000, Belgium
| | - Alain Beschin
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, 1090, Belgium
- Myeloid Cell Immunology Laboratory, Vrije Universiteit Brussel, Brussels, 1090, Belgium
| | - Mathieu Vinken
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, 1090, Belgium
| | - Xavier Verhelst
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Ghent, 9000, Belgium
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, 9000, Belgium
| | - Anja Geerts
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Ghent, 9000, Belgium
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, 9000, Belgium
| | - Hans Van Vlierberghe
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Ghent, 9000, Belgium
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, 9000, Belgium
| | - Lindsey Devisscher
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Ghent, 9000, Belgium
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Zhang B, Zhang B, Lai RC, Sim WK, Lam KP, Lim SK. MSC-sEV Treatment Polarizes Pro-Fibrotic M2 Macrophages without Exacerbating Liver Fibrosis in NASH. Int J Mol Sci 2023; 24:ijms24098092. [PMID: 37175803 PMCID: PMC10179074 DOI: 10.3390/ijms24098092] [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: 03/03/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Mesenchymal stem/stromal cell small extracellular vesicles (MSC-sEVs) have shown promise in treating a wide range of animal models of various human diseases, which has led to their consideration for clinical translation. However, the possibility of contraindication for MSC-sEV use is an important consideration. One concern is that MSC-sEVs have been shown to induce M2 macrophage polarization, which is known to be pro-fibrotic, potentially indicating contraindication in fibrotic diseases such as liver fibrosis. Despite this concern, previous studies have shown that MSC-sEVs alleviate high-fat diet (HFD)-induced non-alcoholic steatohepatitis (NASH). To assess whether the pro-fibrotic M2 macrophage polarization induced by MSC-sEVs could worsen liver fibrosis, we first verified that our MSC-sEV preparations could promote M2 polarization in vitro prior to their administration in a mouse model of NASH. Our results showed that treatment with MSC-sEVs reduced or had comparable NAFLD Activity Scores and liver fibrosis compared to vehicle- and Telmisartan-treated animals, respectively. Although CD163+ M2 macrophages were increased in the liver, and serum IL-6 levels were reduced in MSC-sEV treated animals, our data suggests that MSC-sEV treatment was efficacious in reducing liver fibrosis in a mouse model of NASH despite an increase in pro-fibrotic M2 macrophage polarization.
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Affiliation(s)
- Bin Zhang
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Biyan Zhang
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore
| | - Ruenn Chai Lai
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Wei Kian Sim
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Kong Peng Lam
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore
- School of Biological Sciences, College of Science, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
- Department of Surgery, YLL School of Medicine, NUS, 5 Lower Kent Ridge Road, Singapore 119074, Singapore
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Ahmad AA, Maurice MN, Monib MESM, Soliman M, Al-Thagfan SS, Huseein EAM. Eugenol Essential Oil and Nanoemulsion as Antihydatic Agents with Antifibrotic and Immunomodulatory Effects in Cystic Echinococcosis. Trop Med Infect Dis 2023; 8:tropicalmed8050253. [PMID: 37235301 DOI: 10.3390/tropicalmed8050253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/23/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
Conventional scolicidal agents are still unsatisfactory in combating hydatid disease due to their low efficacy and increased drug side effects. Therefore, novel scolicides are required. This study aimed to evaluate the antihydatic and immunomodulatory effects of eugenol essential oil (Eug) and its nanoemulsion (Eug-NE) in cystic echinococcosis (CE). Eug and Eug-NE were administered orally to CE-infected rats and compared to albendazole (ABZ). Hydatid cyst development was assessed based on organ weight and hypertrophy indicators of the infected organs, along with a histopathological and histochemical evaluation of collagen content. The immunomodulatory effects of treatment on CE were evaluated by serum cytokine levels measurement of interferon-γ (IFN-γ) and interleukin (IL)-4 and immunohistochemical (IHC) analysis of signal transducer and activator of transcription 4 (STAT4) and GATA-binding protein 3 (GATA3) markers. Eug-NE was the most effective in reducing the cyst weights, organ weights, and hypertrophy indicators and improving histopathological lesions with reduced collagen content. Eug and Eug-NE significantly increased the IFN-γ levels and decreased the IL-4 levels, while IHC analysis demonstrated a significant reduction in STAT4 and GATA3 expression in all treated groups. Eug and Eug-NE demonstrated antihydatic and preventative effects, with a substantial decrease in liver fibrosis compared to that of ABZ. Besides their promising immunomodulatory effects, their good treatment response suggests their use as alternatives or complementary scolicidal agents in hydatid cyst treatment.
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Affiliation(s)
| | - Maria Naged Maurice
- Department of Medical Parasitology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | | | - Mahmoud Soliman
- Department of Pathology and Clinical Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut 71515, Egypt
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA
| | - Sultan S Al-Thagfan
- Department of Clinical and Hospital Pharmacy, College of Pharmacy, Taibah University, Al Madinah Al Munawarah 30001, Saudi Arabia
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Research progress of metformin in the treatment of liver fibrosis. Int Immunopharmacol 2023; 116:109738. [PMID: 36696857 DOI: 10.1016/j.intimp.2023.109738] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 01/12/2023] [Accepted: 01/12/2023] [Indexed: 01/24/2023]
Abstract
Liver fibrosis is a disease with significant morbidity and mortality. It is a chronic pathological process characterized by an imbalance of extracellular matrix production and degradation in liver tissue. Metformin is a type of hypoglycemic biguanide drug, which can be used in the treatment of liver fibrosis, but its anti-fibrotic effect and mechanism of action are unclear. The purpose of this article is to review the research progress of metformin in the treatment of liver fibrosis and to provide a theoretical basis for its application in the treatment of liver fibrosis.
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Zhang S, Wan D, Zhu M, Wang G, Zhang X, Huang N, Zhang J, Zhang C, Shang Q, Zhang C, Liu X, Liang F, Zhang C, Kong G, Geng J, Yao L, Lu S, Chen Y, Li Z. CD11b + CD43 hi Ly6C lo splenocyte-derived macrophages exacerbate liver fibrosis via spleen-liver axis. Hepatology 2022; 77:1612-1629. [PMID: 36098707 PMCID: PMC10113005 DOI: 10.1002/hep.32782] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 09/03/2022] [Accepted: 09/09/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS Monocyte-derived macrophages (MoMFs), a dominant population of hepatic macrophages under inflammation, play a crucial role in liver fibrosis progression. The spleen serves as an extra monocyte reservoir in inflammatory conditions; however, the precise mechanisms of involvement of the spleen in the pathogenesis of liver fibrosis remain unclear. APPROACH AND RESULTS By splenectomy and splenocyte transfusion, it was observed that splenic CD11b+ cells accumulated intrahepatically as Ly6Clo MoMFs to exacerbate CCl4 -induced liver fibrosis. The splenocyte migration into the fibrotic liver was further directly visualized by spleen-specific photoconversion with KikGR mice and confirmed by CD45.1+ /CD45.2+ spleen transplantation. Spleen-derived CD11b+ cells purified from fibrotic livers were then annotated by single-cell RNA sequencing, and a subtype of CD11b+ CD43hi Ly6Clo splenic monocytes (sM-1s) was identified, which was markedly expanded in both spleens and livers of mice with liver fibrosis. sM-1s exhibited mature feature with high expressions of F4/80, produced much ROS, and manifested preferential migration into livers. Once recruited, sM-1s underwent sequential transformation to sM-2s (highly expressed Mif, Msr1, Clec4d, and Cstb) and then to spleen-derived macrophages (sMφs) with macrophage features of higher expressions of CX3 CR1, F4/80, MHC class II, and CD64 in the fibrotic hepatic milieu. Furthermore, sM-2s and sMφs were demonstrated capable of activating hepatic stellate cells and thus exacerbating liver fibrosis. CONCLUSIONS CD11b+ CD43hi Ly6Clo splenic monocytes migrate into the liver and shift to macrophages, which account for the exacerbation of liver fibrosis. These findings reveal precise mechanisms of spleen-liver axis in hepatic pathogenesis and shed light on the potential of sM-1 as candidate target for controlling liver diseases.
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Affiliation(s)
- Shaoying Zhang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi International Cooperation Base for Inflammation and Immunity, Xi'an, China
| | - Dan Wan
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi International Cooperation Base for Inflammation and Immunity, Xi'an, China
| | - Mengchen Zhu
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi International Cooperation Base for Inflammation and Immunity, Xi'an, China
| | - Guihu Wang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi International Cooperation Base for Inflammation and Immunity, Xi'an, China
| | - Xurui Zhang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi International Cooperation Base for Inflammation and Immunity, Xi'an, China
| | - Na Huang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Jian Zhang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Chongyu Zhang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi International Cooperation Base for Inflammation and Immunity, Xi'an, China
| | - Qi Shang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi International Cooperation Base for Inflammation and Immunity, Xi'an, China
| | - Chen Zhang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi International Cooperation Base for Inflammation and Immunity, Xi'an, China
| | - Xi Liu
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi International Cooperation Base for Inflammation and Immunity, Xi'an, China
| | - Fanfan Liang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi International Cooperation Base for Inflammation and Immunity, Xi'an, China
| | - Chunyan Zhang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Guangyao Kong
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Jing Geng
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi International Cooperation Base for Inflammation and Immunity, Xi'an, China
| | - Libo Yao
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Shemin Lu
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi International Cooperation Base for Inflammation and Immunity, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China
| | - Yongyan Chen
- Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Zongfang Li
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.,Shaanxi International Cooperation Base for Inflammation and Immunity, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China
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20
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Ma J, Kumar V, Mahato RI. Nanoparticle Delivery of Novel PDE4B Inhibitor for the Treatment of Alcoholic Liver Disease. Pharmaceutics 2022; 14:pharmaceutics14091894. [PMID: 36145643 PMCID: PMC9501368 DOI: 10.3390/pharmaceutics14091894] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 08/24/2022] [Accepted: 09/04/2022] [Indexed: 11/30/2022] Open
Abstract
The incidence of alcoholic liver disease (ALD) is increasing worldwide while no effective treatment has been approved. The progression of ALD has proven to be related to the upregulation of phosphodiesterase 4 (PDE4) expression, and PDE4 inhibitors showed potential to improve ALD. However, the application of PDE4 inhibitors is limited by the gastrointestinal side effects due to PDE4D inhibition. Therefore, we used a novel PDE4B inhibitor KVA-D88 as the therapeutic for ALD treatment. KVA-D88 inhibited inflammatory response, promoted β-oxidation, increased the level of antioxidants in the hepatocytes, and suppressed hepatic stellate cell (HSC) activation in vitro. To improve the solubility and availability in vivo, KVA-D88 was encapsulated into mPEG-b-P(CB-co-LA) nanoparticles (NPs) by solvent evaporation, with a mean particle size of 135 nm and drug loading of 4.2%. We fed the male C57BL/6 mice with a Lieber–DeCarli liquid diet containing 5% (v/v) ethanol for 6 weeks to induce ALD. Systemic administration of KVA-D88 free drug and KVA-D88-loaded NPs at 5 mg/kg significantly improved the ALD in mice. KVA-D88 significantly ameliorated alcohol-induced hepatic injury and inflammation. KVA-D88 also markedly reduced steatosis by promoting fatty acid β-oxidation. Liver fibrosis and reactive oxygen species (ROS)-caused cellular damage was observed to be alleviated by KVA-D88. KVA-D88-loaded NPs proved better efficacy than free drug in the animal study. In conclusion, the novel PDE4B inhibitor KVA-D88-loaded NPs have the potential to treat ALD in mice
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Affiliation(s)
| | - Virender Kumar
- Correspondence: (V.K.); (R.I.M.); Tel.: +1-(402)-559-6422 (R.I.M.); Fax: +1-(402)-559-9543 (R.I.M.)
| | - Ram I. Mahato
- Correspondence: (V.K.); (R.I.M.); Tel.: +1-(402)-559-6422 (R.I.M.); Fax: +1-(402)-559-9543 (R.I.M.)
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21
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Labsi M, Soufli I, Amir ZC, Touil-Boukoffa C. Hepatic inflammation and liver fibrogenesis: A potential target for the treatment of cystic echinococcosis-associated hepatic injury. Acta Trop 2022; 226:106265. [PMID: 34896103 DOI: 10.1016/j.actatropica.2021.106265] [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: 01/31/2021] [Revised: 11/09/2021] [Accepted: 12/05/2021] [Indexed: 02/08/2023]
Abstract
To investigate the effect of cystic echinococcosis (CE) on liver damage, we developed a secondary experimental echinococcosis in Swiss mice by intraperitoneal inoculation of viable protoscoleces. Mice were randomly allocated into three groups: Ctrl group, PBS group, and CE group. Mice were euthanized and associated indications were investigated to evaluate inflammatory and fibrotic responses in liver. Hepatic damage and fibrotic reaction were histologically analyzed. The hepatic expression of iNOS, TNF-α, NF-κβ, vimentin, Bcl-2 and CD68 was evaluated by Immunohistochemical examinations. Interestingly, a significant iNOS, TNF-α, NF-κβ, vimentin, Bcl-2 and CD68 increase levels was observed in liver tissue and pericystic layer of hepatic hydatid cyst and correlate with the abundance of collagen and reticulin fibers. These observations could promote a potential target for the treatment of CE-associated hepatic injury.
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22
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Zhu H, Zhao H, Xu S, Zhang Y, Ding Y, Li J, Huang C, Ma T. Sennoside A alleviates inflammatory responses by inhibiting the hypermethylation of SOCS1 in CCl 4-induced liver fibrosis. Pharmacol Res 2021; 174:105926. [PMID: 34619344 DOI: 10.1016/j.phrs.2021.105926] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 02/07/2023]
Abstract
Liver fibrosis is the consequence of chronic liver injury and is a major challenge to global health. However, successful therapy for liver fibrosis is still lacking. Sennoside A (SA), a commonly used clinical stimulant laxative, is reported to improve hepatic disease, but the underlying mechanisms remain largely elusive. Here, we show for the first time that SA enhanced suppressor of cytokine signaling 1 (SOCS1) expression in a DNA methyltransferase 1 (DNMT1)-dependent manner and thereby attenuated liver fibrosis. Consistently, SA inhibited the expression of the liver fibrogenesis markers α-smooth muscle actin (α-SMA) and type I collagen alpha-1 (Col1α1) and suppressed inflammatory responses in vivo and in vitro. Coculture experiments with macrophages/hepatic stellate cells (HSCs) revealed that SA suppressed HSC proliferation by downregulating proinflammatory cytokines in macrophages. Mechanically, SA promoted the aberrant expression of SOCS1 in liver fibrosis. However, blocking SOCS1 expression weakened the inhibitory effect of SA on HSC proliferation, indicating that SOCS1 may play an important role in mediating the antifibrotic effect of SA. Furthermore, SA inhibited DNMT1-mediated SOCS1 and reduced HSC proliferation by inhibiting inflammatory responses in carbon tetrachloride (CCl4) -induced liver fibrosis.
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Affiliation(s)
- Hong Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Huizi Zhao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Songbing Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Yuan Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Yuhao Ding
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Taotao Ma
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
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23
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De Muynck K, Vanderborght B, Van Vlierberghe H, Devisscher L. The Gut-Liver Axis in Chronic Liver Disease: A Macrophage Perspective. Cells 2021; 10:2959. [PMID: 34831182 PMCID: PMC8616442 DOI: 10.3390/cells10112959] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/25/2021] [Accepted: 10/26/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic liver disease (CLD) is a growing health concern which accounts for two million deaths per year. Obesity, alcohol overconsumption, and progressive cholestasis are commonly characterized by persistent low-grade inflammation and advancing fibrosis, which form the basis for development of end-stage liver disease complications, including hepatocellular carcinoma. CLD pathophysiology extends to the intestinal tract and is characterized by intestinal dysbiosis, bile acid dysregulation, and gut barrier disruption. In addition, macrophages are key players in CLD progression and intestinal barrier breakdown. Emerging studies are unveiling macrophage heterogeneity and driving factors of their plasticity in health and disease. To date, in-depth investigation of how gut-liver axis disruption impacts the hepatic and intestinal macrophage pool in CLD pathogenesis is scarce. In this review, we give an overview of the role of intestinal and hepatic macrophages in homeostasis and gut-liver axis disruption in progressive stages of CLD.
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Affiliation(s)
- Kevin De Muynck
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Bart Vanderborght
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Hans Van Vlierberghe
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Lindsey Devisscher
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
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24
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Chen L, Huang Y, Duan Z, Huang P, Yao H, Zhou Y, Ji Q, Liu X. Exosomal miR-500 Derived From Lipopolysaccharide-Treated Macrophage Accelerates Liver Fibrosis by Suppressing MFN2. Front Cell Dev Biol 2021; 9:716209. [PMID: 34676206 PMCID: PMC8525629 DOI: 10.3389/fcell.2021.716209] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 09/10/2021] [Indexed: 01/03/2023] Open
Abstract
Liver fibrosis is an outcome of chronic hepatic injury, which can eventually result in cirrhosis, liver failure, and even liver cancer. The activation of hepatic stellate cell (HSC) is a prominent driver of liver fibrosis. Recently, it has been found that the crosstalk between HSCs and immune cells, including hepatic macrophages, plays an important role in the initiation and development of liver fibrosis. As a vital vehicle of intercellular communication, exosomes transfer specific cargos into HSCs from macrophages. Here, we show that exosomes derived from lipopolysaccharide (LPS)-treated macrophages has higher expression level of miR-500. And overexpression or inhibition of miR-500 in macrophage exosomes could promote or suppress HSC proliferation and activation. Treatment of exosomes with miR-500 overexpression can accelerate liver fibrosis in CCl4-induced liver fibrosis mouse model. miR-500 promotes HSC activation and liver fibrosis via suppressing MFN2. Moreover, miR-500 in serum exosomes could be a biomarker for liver fibrosis. Taken together, exosomal miR-500 derived from LPS-activated macrophages promotes HSC proliferation and activation by targeting MFN2 in liver fibrosis.
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Affiliation(s)
- Lisha Chen
- Central Laboratory, Department of Neurosurgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yan Huang
- Affiliated Changsha Hospital of Hunan Normal University, The Fourth Hospital of Changsha, Institute of Emergency and Critical Care Medicine of Changsha, Changsha, China
| | - Zhixi Duan
- Department of Emergency Medicine, Trauma Center, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Peiqi Huang
- Affiliated Changsha Hospital of Hunan Normal University, The Fourth Hospital of Changsha, Institute of Emergency and Critical Care Medicine of Changsha, Changsha, China
| | - Hongbing Yao
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Guilin Medical University, Guilin, China
| | - Yu Zhou
- Department of Emergency Medicine, Trauma Center, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qin Ji
- Department of Emergency Medicine, Trauma Center, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiangfeng Liu
- Department of Emergency Medicine, Trauma Center, The Second Xiangya Hospital, Central South University, Changsha, China
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25
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Vacani-Martins N, Meuser-Batista M, dos Santos CDLP, Hasslocher-Moreno AM, Henriques-Pons A. The Liver and the Hepatic Immune Response in Trypanosoma cruzi Infection, a Historical and Updated View. Pathogens 2021; 10:pathogens10091074. [PMID: 34578107 PMCID: PMC8465576 DOI: 10.3390/pathogens10091074] [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: 07/08/2021] [Revised: 08/05/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022] Open
Abstract
Chagas disease was described more than a century ago and, despite great efforts to understand the underlying mechanisms that lead to cardiac and digestive manifestations in chronic patients, much remains to be clarified. The disease is found beyond Latin America, including Japan, the USA, France, Spain, and Australia, and is caused by the protozoan Trypanosoma cruzi. Dr. Carlos Chagas described Chagas disease in 1909 in Brazil, and hepatomegaly was among the clinical signs observed. Currently, hepatomegaly is cited in most papers published which either study acutely infected patients or experimental models, and we know that the parasite can infect multiple cell types in the liver, especially Kupffer cells and dendritic cells. Moreover, liver damage is more pronounced in cases of oral infection, which is mainly found in the Amazon region. However, the importance of liver involvement, including the hepatic immune response, in disease progression does not receive much attention. In this review, we present the very first paper published approaching the liver's participation in the infection, as well as subsequent papers published in the last century, up to and including our recently published results. We propose that, after infection, activated peripheral T lymphocytes reach the liver and induce a shift to a pro-inflammatory ambient environment. Thus, there is an immunological integration and cooperation between peripheral and hepatic immunity, contributing to disease control.
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Affiliation(s)
- Natalia Vacani-Martins
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
| | - Marcelo Meuser-Batista
- Depto de Anatomia Patológica e Citopatologia, Instituto Fernandes Figueira, Fundação Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil;
| | - Carina de Lima Pereira dos Santos
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
| | | | - Andrea Henriques-Pons
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
- Correspondence:
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26
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Glucocorticoid-induced leucine zipper regulates liver fibrosis by suppressing CCL2-mediated leukocyte recruitment. Cell Death Dis 2021; 12:421. [PMID: 33927191 PMCID: PMC8085011 DOI: 10.1038/s41419-021-03704-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 04/08/2021] [Accepted: 04/12/2021] [Indexed: 12/16/2022]
Abstract
Liver fibrosis (LF) is a dangerous clinical condition with no available treatment. Inflammation plays a critical role in LF progression. Glucocorticoid-induced leucine zipper (GILZ, encoded in mice by the Tsc22d3 gene) mimics many of the anti-inflammatory effects of glucocorticoids, but its role in LF has not been directly addressed. Here, we found that GILZ deficiency in mice was associated with elevated CCL2 production and pro-inflammatory leukocyte infiltration at the early LF stage, resulting in enhanced LF development. RNA interference-mediated in vivo silencing of the CCL2 receptor CCR2 abolished the increased leukocyte recruitment and the associated hepatic stellate cell activation in the livers of GILZ knockout mice. To highlight the clinical relevance of these findings, we found that TSC22D3 mRNA expression was significantly downregulated and was inversely correlated with that of CCL2 in the liver samples of patients with LF. Altogether, these data demonstrate a protective role of GILZ in LF and uncover the mechanism, which can be targeted therapeutically. Therefore, modulating GILZ expression and its downstream targets represents a novel avenue for pharmacological intervention for treating LF and possibly other liver inflammatory disorders.
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27
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Wang HH, Huang JH, Sue MH, Ho WC, Hsu YH, Chang KC, Chang MS. Interleukin-24 protects against liver injury in mouse models. EBioMedicine 2021; 64:103213. [PMID: 33508745 PMCID: PMC7841303 DOI: 10.1016/j.ebiom.2021.103213] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 12/11/2020] [Accepted: 01/05/2021] [Indexed: 02/07/2023] Open
Abstract
Background Interleukin-24 (IL-24) binds to two kinds of receptor complexes, namely IL-20R1/IL-20R2 and IL-20R2/IL-22R1, which are also bound by IL-20. IL-20 plays a detrimental role in liver fibrosis. Due to the sharing of receptor complexes, we aimed to determine whether IL-24 also participates in liver fibrosis. Methods Clinical biopsy specimens from various stages of liver fibrosis were used to analyze IL-24 expression. IL-24 protein was administered to mice with thioacetamide (TAA)-induced liver injury. The direct effects of IL-24 on mouse primary hepatocytes or hepatic stellate cells (HSCs) were analyzed. Wild-type, IL-20R1-, and IL20R2-deficient mice were used to establish a model of acute TAA-induced liver injury. Findings Among patients with more severe liver fibrosis, there was a reduced IL-24/IL-20 ratio. Administration of IL-24 protein protected mice from TAA-induced liver injury and reduction of liver inflammation by antioxidant effects. IL-24 protected hepatocytes from TAA-induced apoptosis and prevented liver fibrosis through the inhibition of the HSCs activation. The protective role of IL-24 acted on liver cells were mainly IL-20R1-independent. IL-20R2-deficient mice exhibited more severe liver injury upon TAA treatment, thus confirming the protective role of IL-24. Interpretation IL-24 plays a key protective role in the progression of liver injury and has therapeutic potential for treating liver injuries. Funding This work was supported by the Ministry of Science and Technology of Taiwan (MOST 106–2320-B-006–024) and Taiwan Liver Disease Prevention & Treatment Research Foundation.
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Affiliation(s)
- Hsiao-Hsuan Wang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jian-Hao Huang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Min-Hao Sue
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Chih Ho
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Hsiang Hsu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Research Center of Clinical Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Kung-Chao Chang
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ming-Shi Chang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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28
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Xue J, Xiao T, Wei S, Sun J, Zou Z, Shi M, Sun Q, Dai X, Wu L, Li J, Xia H, Tang H, Zhang A, Liu Q. miR-21-regulated M2 polarization of macrophage is involved in arsenicosis-induced hepatic fibrosis through the activation of hepatic stellate cells. J Cell Physiol 2021; 236:6025-6041. [PMID: 33481270 DOI: 10.1002/jcp.30288] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 01/02/2021] [Accepted: 01/05/2021] [Indexed: 12/15/2022]
Abstract
Arsenicosis induced by chronic exposure to arsenic is recognized as one of the main damaging effects on public health. Exposure to arsenic can cause hepatic fibrosis, but the molecular mechanisms by which this occurs are complex and elusive. It is not known if miRNAs are involved in arsenic-induced liver fibrosis. We found that in the livers of mice exposed to arsenite, there were elevated levels of microRNA-21 (miR-21), phosphorylated mammalian target of rapamycin (p-mTOR), and arginase 1 (Arg1); low levels of phosphatase and tensin homolog (PTEN); and more extensive liver fibrosis. For cultured cells, arsenite-induced miR-21, p-mTOR, and Arg1; decreased PTEN; and promoted M2 polarization of macrophages derived from THP-1 monocytes (THP-M), which caused secretion of fibrogenic cytokines, including transforming growth factor-β1. Coculture of arsenite-treated, THP-M with LX-2 cells induced α-SMA and collagen I in the LX-2 cells and resulted in the activation of these cells. Downregulation of miR-21 in THP-M inhibited arsenite-induced M2 polarization and activation of LX-2 cells, but cotransfection with PTEN siRNA or a miR-21 inhibitor reversed this inhibition. Moreover, knockout of miR-21 in mice attenuated liver fibrosis and M2 polarization compared with WT mice exposed to arsenite. Additionally, LN, PCIII, and HA levels were higher in patients with higher hair arsenic levels, and levels of miR-21 were higher than controls and positively correlated with PCIII, LN, and HA levels. Thus, arsenite induces the M2 polarization of macrophages via miR-21 regulation of PTEN, which is involved in the activation of hepatic stellate cells and hepatic fibrosis. The results establish a previously unknown mechanism for arsenicosis-induced fibrosis.
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Affiliation(s)
- Junchao Xue
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tian Xiao
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shaofeng Wei
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, Guizhou, China
| | - Jing Sun
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhonglan Zou
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, Guizhou, China
| | - Ming Shi
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong, China
| | - Qian Sun
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiangyu Dai
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lu Wu
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Junjie Li
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haibo Xia
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Huanwen Tang
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong, China
| | - Aihua Zhang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, Guizhou, China
| | - Qizhan Liu
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
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29
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Yan M, Gu S, Pan C, Chen Y, Han X. MC-LR-induced interaction between M2 macrophage and biliary epithelial cell promotes biliary epithelial cell proliferation and migration through regulating STAT3. Cell Biol Toxicol 2021; 37:935-949. [PMID: 33474710 DOI: 10.1007/s10565-020-09575-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/01/2020] [Indexed: 01/14/2023]
Abstract
Microcystin-leucine-arginine (MC-LR) was produced by toxic cyanobacteria, which has been shown to have potent hepatotoxicity. Our previous study has proved that MC-LR were able to promote intrahepatic biliary epithelial cell excessive proliferation. However, the underlying mechanism is not yet entirely clarified. Herein, mice were fed with different concentrations (1, 7.5, 15, or 30 μg/L) of MC-LR by drinking water for 6 months. As the concentration of MC-LR increased, a growing number of macrophages were evaluated in the portal area of the mouse liver. Next, we built a co-culture system to explore the interaction between macrophages (THP-1 cells) and human intrahepatic biliary epithelial cells (HiBECs) in the presence of MC-LR. Under the exposure of MC-LR, HiBECs secreted a large amount of inflammatory factors (IL-6, IL-8, IL-1β, COX-2, XCL-1) and chemokine (MCP-1), which produced a huge chemotactic effect on THP-1 cells and induced elevation of the surface M2-subtype biomarkers (IL-10, CD163, CCL22, and Arg-1). In turn, high content of IL-6 in the medium activated JAK2/STAT3, MEK/ERK, and PI3K/AKT pathways in HiBECs, inducing HiBEC abnormal proliferation and migration. Together, these results suggested that MC-LR-mediated interaction between HiBECs and macrophages induced the M2-type polarization of macrophages, and activated IL-6/JAK2/STAT3, MEK/ERK, and PI3K/AKT pathways in HiBECs, further enhanced cell proliferation, improved cell migration, and hindered cell apoptosis by activating p-STAT3. MC-LR stimulates HiBECs to produce various inflammatory factors, recruiting a large number of macrophages and promoting the differentiation of macrophages into M2-type. In turn, the M2 macrophages could also produce amounts of IL-6 and activate STAT3 through JAK2/STAT3, MEK/ERK, and PI3K/AKT pathways in HiBECs, resulting in the promotion of cell proliferation, inhibition of apoptosis, and enhancement of migration.
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Affiliation(s)
- Minghao Yan
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, Jiangsu, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China
| | - Shen Gu
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, Jiangsu, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China.,Department of Hepatopancreatobiliary Surgery, Drum Tower Hospital, Medical School of Nanjing University, Zhongshan Road 321, Nanjing, 210008, Jiangsu, China
| | - Chun Pan
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, Jiangsu, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China
| | - Yabing Chen
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, Jiangsu, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China
| | - Xiaodong Han
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, Jiangsu, China. .,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China.
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30
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Relative contribution of fat diet and physical inactivity to the development of metabolic syndrome and non-alcoholic fat liver disease in Wistar rats. Physiol Behav 2020; 225:113040. [PMID: 32603747 DOI: 10.1016/j.physbeh.2020.113040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/24/2020] [Accepted: 06/26/2020] [Indexed: 01/22/2023]
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31
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Lurje I, Hammerich L, Tacke F. Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer. Int J Mol Sci 2020; 21:ijms21197378. [PMID: 33036244 PMCID: PMC7583774 DOI: 10.3390/ijms21197378] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/01/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a chronic, highly prevalent disease that may progress to cirrhosis and substantially increases the risk for development of hepatocellular carcinoma (HCC). Fibrotic livers are characterized by an inflammatory microenvironment that is composed of various immunologically active cells, including liver-resident populations (e.g., Kupffer cells, hepatic stellate cells and sinusoidal endothelium) and infiltrating leukocytes (e.g., monocytes, monocyte-derived macrophages, neutrophils and lymphocytes). While inflammatory injury drives both fibrogenesis and carcinogenesis, the tolerogenic microenvironment of the liver conveys immunosuppressive effects that encourage tumor growth. An insufficient crosstalk between dendritic cells (DCs), the professional antigen presenting cells, and T cells, the efficient anti-tumor effector cells, is one of the main mechanisms of HCC tumor tolerance. The meticulous analysis of patient samples and mouse models of fibrosis-HCC provided in-depth insights into molecular mechanisms of immune interactions in liver cancer. The therapeutic modulation of this multifaceted immunological response, e.g., by inhibiting immune checkpoint molecules, in situ vaccination, oncolytic viruses or combinations thereof, is a rapidly evolving field that holds the potential to improve the outcome of patients with HCC. This review aims to highlight the current understanding of DC–T cell interactions in fibrogenesis and hepatocarcinogenesis and to illustrate the potentials and pitfalls of therapeutic clinical translation.
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32
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Wasityastuti W, Habib NA, Sari DCR, Arfian N. Effects of low and moderate treadmill exercise on liver of d-galactose-exposed aging rat model. Physiol Rep 2020; 7:e14279. [PMID: 31724278 PMCID: PMC6854106 DOI: 10.14814/phy2.14279] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 10/08/2019] [Accepted: 10/10/2019] [Indexed: 12/15/2022] Open
Abstract
Aging increases liver susceptibility to diseases and it causes inflammation in liver tissue which can lead to fibrosis. Studies suggest that aging is caused by the accumulation of free radicals. Lack of physical activity can lower hormone levels and increase free radicals that can accelerate the aging process. Hence, physical activity is very important to maintain functions of organs. This research was aimed to study the effects of low and moderate treadmill exercise on d‐Galactose‐exposed aging rat model by evaluating the degree of hepatic fibrosis, number of M1 and M2, and M1/M2 ratio. Twenty‐four 3‐month‐old male Wistar aging model rats were randomly divided into four groups, that is, three treatment groups with daily 300 mg kgBW−1d‐Galactose injection administrated intraperitoneally for 4 weeks and 1 control group with normal saline injection. Two of the d‐Galactose treated groups were given low and moderate treadmill exercise for 4 weeks. It was concluded that low intensity treadmill exercise significantly lowered the degree of d‐Galactose‐exposed hepatic fibrosis, and moderate treadmill exercise was able to restore the injured liver tissue back to the non‐aging state. Administration of d‐Galactose causes inflammation marked by the elevated number of M1 and M2 macrophages. Moderate treadmill exercise drove M1/M2 ratio back to the control condition.
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Affiliation(s)
- Widya Wasityastuti
- Department of Physiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Nurfatma A Habib
- Master in Biomedical Sciences, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Dwi C R Sari
- Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Nur Arfian
- Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
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33
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Tang R, Wang YC, Mei X, Shi N, Sun C, Ran R, Zhang G, Li W, Staveley-O'Carroll KF, Li G, Chen SY. LncRNA GAS5 attenuates fibroblast activation through inhibiting Smad3 signaling. Am J Physiol Cell Physiol 2020; 319:C105-C115. [PMID: 32374674 DOI: 10.1152/ajpcell.00059.2020] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Transforming growth factor-β (TGF-β)-induced fibroblast activation is a key pathological event during tissue fibrosis. Long noncoding RNA (lncRNA) is a class of versatile gene regulators participating in various cellular and molecular processes. However, the function of lncRNA in fibroblast activation is still poorly understood. In this study, we identified growth arrest-specific transcript 5 (GAS5) as a novel regulator for TGF-β-induced fibroblast activation. GAS5 expression was downregulated in cultured fibroblasts by TGF-β and in resident fibroblasts from bleomycin-treated skin tissues. Overexpression of GAS5 suppressed TGF-β-induced fibroblast to myofibroblast differentiation. Mechanistically, GAS5 directly bound mothers against decapentaplegic homolog 3 (Smad3) and promoted Smad3 binding to Protein phosphatase 1A (PPM1A), a Smad3 dephosphatase, and thus accelerated Smad3 dephosphorylation in TGF-β-treated fibroblasts. In addition, GAS5 inhibited fibroblast proliferation. Importantly, local delivery of GAS5 via adenoviral vector suppressed bleomycin-induced skin fibrosis in mice. Collectively, our data revealed that GAS5 suppresses fibroblast activation and fibrogenesis through inhibiting TGF-β/Smad3 signaling, which provides a rationale for an lncRNA-based therapy to treat fibrotic diseases.
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Affiliation(s)
- Rui Tang
- Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia
| | - Yung-Chun Wang
- Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri
| | - Xiaohan Mei
- Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri.,Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia
| | - Ning Shi
- Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri
| | - Chenming Sun
- Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia
| | - Ran Ran
- Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia
| | - Gui Zhang
- Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia
| | - Wenjing Li
- Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia
| | - Kevin F Staveley-O'Carroll
- Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri.,The Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri
| | - Guangfu Li
- Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri
| | - Shi-You Chen
- Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri.,Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia.,Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri
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Tarragô AM, da Silva Neto PV, Ramasawmy R, Pereira GL, Toro DM, de Amorim Xabregas L, Costa AG, Victória MB, da Silva Victória F, Malheiro A. Combination of genetic polymorphisms in TLR influence cytokine profile in HCV patients treated with DAAs in the State of Amazonas. Cytokine 2020; 130:155052. [PMID: 32179425 DOI: 10.1016/j.cyto.2020.155052] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 11/26/2019] [Accepted: 02/24/2020] [Indexed: 02/08/2023]
Abstract
Hepatitis C is a public health problem and affects approximately 3% of the world's population. HCV infections have a wide spectrum of clinical manifestations, and several single nucleotide polymorphisms (SNPs) in the genes of the toll-like receptors are cited to influence the clinical outcomes. A cross-sectional study was conducted in the Amazonas State, Brazil in which SNPs in TLR4 and TLR9 genes were genotyped by PCR-RFLP in 151 HCV chronic liver disease patients and 206 healthy donors. The circulating cytokines IL-6, TNF, IL-10, IL-2, IFN-γ, IL-4 and IL-17A were measured by cytometric bead array (CBA) which revealed that the combined genotypes of TLR9 -1237T/T and -1486C/T seem to influence the cytokine profile under lipopolysaccharide (LPS) stimulation of the Th17 profile, especially among patients with advanced chronic liver disease when treated with DAAs.
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Affiliation(s)
- Andréa Monteiro Tarragô
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil; Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil.
| | - Pedro Vieira da Silva Neto
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil
| | - Rajendranath Ramasawmy
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil
| | - Grenda Leite Pereira
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil
| | - Diana Mota Toro
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil
| | - Lilyane de Amorim Xabregas
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil; Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil
| | - Allyson Guimaraes Costa
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil; Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil; Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil
| | - Marilú Barbieri Victória
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil; Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, Amazonas, Brazil
| | - Flamir da Silva Victória
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil; Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, Amazonas, Brazil
| | - Adriana Malheiro
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brazil; Laboratório de Genômica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Amazonas, Brazil; Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, Amazonas, Brazil.
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35
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The role of microRNAs in the pathogenesis, grading and treatment of hepatic fibrosis in schistosomiasis. Parasit Vectors 2019; 12:611. [PMID: 31888743 PMCID: PMC6937654 DOI: 10.1186/s13071-019-3866-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 12/19/2019] [Indexed: 12/16/2022] Open
Abstract
Schistosomiasis is a prevalent parasitic disease worldwide. The main pathological changes of hepatosplenic schistosomiasis are hepatic granuloma and fibrosis due to worm eggs. Portal hypertension and ascites induced by hepatic fibrosis are usually the main causes of death in patients with chronic hepatosplenic schistosomiasis. Currently, no effective vaccine exists for preventing schistosome infections. For quite a long time, praziquantel (PZQ) was widely used for the treatment of schistosomiasis and has shown benefit in treating liver fibrosis. However, drug resistance and chemical toxicity from PZQ are being increasingly reported in recent years; therefore, new and effective strategies for treating schistosomiasis-induced hepatic fibrosis are urgently needed. MicroRNA (miRNA), a non-coding RNA, has been proved to be associated with the development of many human diseases, including schistosomiasis. In this review, we present a balanced and comprehensive view of the role of miRNAs in the pathogenesis, grading, and treatment of schistosomiasis-associated hepatic fibrosis. The multiple regulatory roles of miRNAs, such as promoting or inhibiting the development of liver pathology in murine schistosomiasis are also discussed in depth. Additionally, miRNAs may serve as candidate biomarkers for diagnosing liver pathology of schistosomiasis and as novel therapeutic targets for treating schistosomiasis-associated hepatic fibrosis.![]()
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He W, Kapate N, Shields CW, Mitragotri S. Drug delivery to macrophages: A review of targeting drugs and drug carriers to macrophages for inflammatory diseases. Adv Drug Deliv Rev 2019; 165-166:15-40. [PMID: 31816357 DOI: 10.1016/j.addr.2019.12.001] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 11/28/2019] [Accepted: 12/04/2019] [Indexed: 12/16/2022]
Abstract
Macrophages play a key role in defending against foreign pathogens, healing wounds, and regulating tissue homeostasis. Driving this versatility is their phenotypic plasticity, which enables macrophages to respond to subtle cues in tightly coordinated ways. However, when this coordination is disrupted, macrophages can aid the progression of numerous diseases, including cancer, cardiovascular disease, and autoimmune disease. The central link between these disorders is aberrant macrophage polarization, which misguides their functional programs, secretory products, and regulation of the surrounding tissue microenvironment. As a result of their important and deterministic roles in both health and disease, macrophages have gained considerable attention as targets for drug delivery. Here, we discuss the role of macrophages in the initiation and progression of various inflammatory diseases, summarize the leading drugs used to regulate macrophages, and review drug delivery systems designed to target macrophages. We emphasize strategies that are approved for clinical use or are poised for clinical investigation. Finally, we provide a prospectus of the future of macrophage-targeted drug delivery systems.
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Affiliation(s)
- Wei He
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Neha Kapate
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - C Wyatt Shields
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
| | - Samir Mitragotri
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
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37
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Dewidar B, Meyer C, Dooley S, Meindl-Beinker N. TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019. Cells 2019; 8:cells8111419. [PMID: 31718044 PMCID: PMC6912224 DOI: 10.3390/cells8111419] [Citation(s) in RCA: 520] [Impact Index Per Article: 86.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/08/2019] [Accepted: 11/09/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.
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Affiliation(s)
- Bedair Dewidar
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (B.D.); (C.M.); (S.D.)
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, 31527 Tanta, Egypt
| | - Christoph Meyer
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (B.D.); (C.M.); (S.D.)
| | - Steven Dooley
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (B.D.); (C.M.); (S.D.)
| | - Nadja Meindl-Beinker
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (B.D.); (C.M.); (S.D.)
- Correspondence: ; Tel.: +49-621-383-4983; Fax: +49-621-383-1467
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Wu BM, Liu JD, Li YH, Li J. Margatoxin mitigates CCl4‑induced hepatic fibrosis in mice via macrophage polarization, cytokine secretion and STAT signaling. Int J Mol Med 2019; 45:103-114. [PMID: 31746414 PMCID: PMC6889929 DOI: 10.3892/ijmm.2019.4395] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 10/14/2019] [Indexed: 12/31/2022] Open
Abstract
A number of macrophage phenotypes have been previously identified as crucial regulators in the progression of hepatic fibrosis (HF). Cytokines from macrophages or Kupffer cells (KCs) have also been identified to be important regulators in HF. Blocking Kv1.3 in models of HF, regulating macrophage polarization and cytokine secretion have not yet been assessed as potential treatments options for this condition. In the current study, a model of carbon tetrachloride (CCl4)-induced HF was established and examined the effects of margatoxin (MgTX; an inhibitor of Kv1.3) on HF. Hematoxylin and eosin, Masson's trichrome and immunohistochemistry staining were performed to determine whether MgTX can alleviate liver fibrosis. To elucidate the mechanisms through which MgTX attenuates liver injury, reverse transcription-quantitative PCR and western blot analysis were used to detect polarized macrophage markers in RAW264.7 cells and cytokines were examined using ELISA. Furthermore, macrophage polarization signal transducer and activator of transcription (STAT) signaling, which is associated with macrophage polarization, was identified in RAW264.7 cells. The results revealed that MgTX protected the mice from CCl4-induced liver fibrosis. Furthermore, MgTX decreased the expression of M1 phenotype biomarkers, and increased the expression of M2 phenotype biomarkers in CCl4-induced HF. Additionally, the production of pro-inflammatory cytokines was decreased and interleukin-10 production was increased in the serum of mice with HF injected with MgTX. Furthermore, MgTX was found to regulate the expression of M1 markers by suppressing p-STAT1 activity and increasing the expression of M2 markers by promoting p-STAT6 activity. On the whole, the findings of this study demonstrate that MgTX is able to alleviate CCl4-induced HF in mice, possibly via macrophage polarization, cytokine secretion and STAT signaling.
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Affiliation(s)
- Bao-Ming Wu
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Anhui 230032, P.R. China
| | - Jun-Da Liu
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Anhui 230032, P.R. China
| | - Yuan-Hai Li
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Anhui 230032, P.R. China
| | - Jun Li
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Anhui 230032, P.R. China
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Gaydos J, McNally A, Burnham EL. The impact of alcohol use disorders on pulmonary immune cell inflammatory responses to Streptococcus pneumoniae. Alcohol 2019; 80:119-130. [PMID: 30195043 DOI: 10.1016/j.alcohol.2018.08.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 08/29/2018] [Accepted: 08/31/2018] [Indexed: 12/11/2022]
Abstract
Community-acquired pneumonia due to Streptococcus pneumoniae occurs commonly in alcohol use disorders (AUDs). Pneumonia in the AUD patient is associated with poorer outcomes, and specific therapies to mitigate disease severity in these patients do not exist. Numerous investigations have attributed increased severity of pneumonia in AUDs to aberrant function of the alveolar macrophage (AM), a lung immune cell critical in host defense initiation. No studies have examined the response of human AMs to S. pneumoniae in AUDs. We hypothesized that the inflammatory mediators released by AMs after S. pneumoniae stimulation would differ quantitatively in individuals with AUDs compared to non-AUD participants. We further postulated that AM inflammatory mediators would be diminished after exposure to the antioxidant, N-acetylcysteine (NAC). For comparison, responses of peripheral blood mononuclear cells (PBMCs) to pneumococcal protein were also examined. Otherwise healthy participants with AUDs and smoking-matched controls underwent bronchoalveolar lavage and peripheral blood sampling to obtain AMs and PBMCs, respectively. Freshly collected cells were cultured with increasing doses of heat-killed S. pneumoniae protein, with and without exposure to N-acetylcysteine. Cell culture supernatants were collected, and inflammatory mediators were measured, including interferon (IFN)-γ, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. IFN-γ and IL-6 were significantly higher in unstimulated AM cell culture supernatants from subjects with AUDs. After stimulation with pneumococcal protein, a dose-response and time-dependent increase in pro-inflammatory cytokine production by both AMs and PBMCs was also observed; differences were not observed between AUD and non-AUD subjects. Addition of NAC to pneumococcal-stimulated AMs and PBMCs was generally associated with diminished cytokine production, with the exception of IL-1β that was elevated in AM culture supernatants from subjects with AUDs. Our observations suggest that AUDs contribute to basal alterations in AM pro-inflammatory cytokine elaboration, but did not support consistent differences in pneumococcal-stimulated AM or PBMC inflammatory mediator secretion that were referable to AUDs.
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Deng D, Pei H, Lan T, Zhu J, Tang M, Xue L, Yang Z, Zheng S, Ye H, Chen L. Synthesis and discovery of new compounds bearing coumarin scaffold for the treatment of pulmonary fibrosis. Eur J Med Chem 2019; 185:111790. [PMID: 31699535 DOI: 10.1016/j.ejmech.2019.111790] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 10/07/2019] [Accepted: 10/14/2019] [Indexed: 02/05/2023]
Abstract
Idiopathic pulmonary fibrosis, characterized by excess accumulation of extracellular matrix, involved in many chronic diseases or injuries, threatens human health greatly. We have reported a series of compounds bearing coumarin scaffold which potently inhibited TGF-β-induced total collagen accumulation in NRK-49F cell line and migration of macrophages. Compound 9d also suppressed the TGF-β-induced protein expression of COL1A1, α-SMA, and p-Smad3 in vitro. Meanwhile, 9d at a dose of 100 mg/kg/day through oral administrations for 4 weeks effectively alleviated infiltration of inflammatory cells in lung tissue and fibrotic degree in bleomycin-induced pulmonary fibrosis model, which may related to its inhibition of TGF-β/Smad3 pathway and anti-inflammation efficacy. In addition, 9d demonstrated decent bioavailability (F = 39.88%) and suitable eliminated half-life time (T1/2 = 13.09 h), suggesting that 9d could be a potential drug candidate for the treatment of fibrotic diseases.
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Affiliation(s)
- Dexin Deng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Heying Pei
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Tingxuan Lan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Jiali Zhu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Minghai Tang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Linlin Xue
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Zhuang Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Shoujun Zheng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Haoyu Ye
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Lijuan Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China.
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A preventive effect of the combination of albendazole and pomegranate peel aqueous extract treatment in cystic echinococcosis mice model: An alternative approach. Acta Trop 2019; 197:105050. [PMID: 31170379 DOI: 10.1016/j.actatropica.2019.105050] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 05/31/2019] [Accepted: 05/31/2019] [Indexed: 12/23/2022]
Abstract
To investigate the preventive effect of the combination of albendazole (ABZ) and pomegranate peel aqueous extract (PGE) treatment in cystic echinococcosis, we assess in vivo the antihydatic and the anti-inflammatory effects of the combination of ABZ/ PGE in cystic echinococcosis mice model. To evaluate the in vivo efficacy, mice were inoculated intraperitoneally with viable protoscolices and then treated with ABZ and/or PGE during cystic echinococcosis development. Mice were randomly allocated into eight groups: ABZ/CE group, PGE/CE group, (ABZ+PGE)/CE group, CE group, and control groups (Ctrl, PBS, ABZ, and PGE groups). Drugs in diverse treated groups were orally administered daily during CE development for two months. Mice were then euthanized and associated indications were investigated to evaluate the therapeutic efficacy. Cyst development and hepatic damage were macroscopically and histologically analyzed. The hepatic expression of iNOS, TNF-α, NF-κβ, vimentin, and CD68 was examined. Interestingly, the association of ABZ and PGE enhanced a significant reduction of the rate of hydatid cyst growth inhibition in comparison to the infected or ABZ-treated groups. This effect was strongly related to the histological structure of liver improvement. A significant iNOS, TNF-α, NF-κβ, vimentin, and CD68 decrease expression was observed in liver tissue of (ABZ+PGE)-treated group compared with infested and ABZ-treated groups. PGE treatment indicates a significant beneficial additive antihydatic effect with a reduction of the liver side effects. The combination of albendazole and PGE treatment is more efficient and suggests its potential preventive value against Echinococcus granulosus infection.
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Kinjo T, Inoue H, Kusuda T, Fujiyoshi J, Ochiai M, Takahata Y, Honjo S, Koga Y, Hara T, Ohga S. Chemokine levels predict progressive liver disease in Down syndrome patients with transient abnormal myelopoiesis. Pediatr Neonatol 2019; 60:382-388. [PMID: 30314728 DOI: 10.1016/j.pedneo.2018.09.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 08/09/2018] [Accepted: 09/19/2018] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Transient abnormal myelopoiesis (TAM) is a neonatal preleukemic syndrome that occurs exclusively in neonates with Down syndrome (DS). Most affected infants spontaneously resolve, although some patients culminate in hepatic failure despite the hematological remission. It is impossible to determine the patients who are at high risk of progressive liver disease and leukemic transformation. The objective is to search for biomarkers predicting the development of hepatic failure in DS infants with TAM. METHODS Among 60 newborn infants with DS consecutively admitted to our institutions from 2003 to 2016, 41 infants with or without TAM were enrolled for the study. Twenty-two TAM-patients were classified into "progression group" (n = 7) that required any therapy and "spontaneous resolution group" (n = 15). Serum concentrations of chemokines (CXCL8, CXCL9, CXCL10, CCL2 and CCL5) and transforming growth factor (TGF)-β1 were measured at diagnosis of TAM for assessing the outcome of progressive disease. RESULTS Three patients developed leukemia during the study period (median, 1147 days; range, 33-3753). Three died of hepatic failure. All patients in the progression group were preterm birth <37 weeks of gestational age and were earlier than those in the spontaneous resolution group (median, 34.7 vs. 37.0 weeks, p < 0.01). The leukocyte counts and CXCL8 and CCL2 levels at diagnosis in the progression group were higher than those in the spontaneous resolution group (leukocyte: median, 81.60 vs. 27.30 × 109/L, p = 0.01; CXCL8: 173.8 vs. 34.3 pg/ml, p < 0.01; CCL2: 790.3 vs. 209.8 pg/mL, p < 0.01). Multivariate analyses indicated that an increased CCL2 value was independently associated with the progression and CXCL8 with the death of liver failure, respectively (CCL2: standardized coefficient [sc], 0.43, p < 0.01; CXCL8: sc = -0.46, p = 0.02). CONCLUSION High levels of circulating CXCL8 and CCL2 at diagnosis of TAM may predict progressive hepatic failure in DS infants.
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Affiliation(s)
- Tadamune Kinjo
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Comprehensive Maternity and Perinatal Care Center, Kyushu University Hospital, Fukuoka, Japan; Fukuoka Children's Hospital, Fukuoka, Japan.
| | - Hirosuke Inoue
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Comprehensive Maternity and Perinatal Care Center, Kyushu University Hospital, Fukuoka, Japan
| | - Takeshi Kusuda
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Fukuoka Children's Hospital, Fukuoka, Japan
| | - Junko Fujiyoshi
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Comprehensive Maternity and Perinatal Care Center, Kyushu University Hospital, Fukuoka, Japan
| | - Masayuki Ochiai
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Comprehensive Maternity and Perinatal Care Center, Kyushu University Hospital, Fukuoka, Japan
| | | | - Satoshi Honjo
- Department of Pediatrics, Fukuoka National Hospital, Fukuoka, Japan
| | - Yuhki Koga
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshiro Hara
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Fukuoka Children's Hospital, Fukuoka, Japan
| | - Shouichi Ohga
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Comprehensive Maternity and Perinatal Care Center, Kyushu University Hospital, Fukuoka, Japan
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Protein tyrosine phosphatase 1b deficiency protects against hepatic fibrosis by modulating nadph oxidases. Redox Biol 2019; 26:101263. [PMID: 31299613 PMCID: PMC6624458 DOI: 10.1016/j.redox.2019.101263] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 05/30/2019] [Accepted: 06/26/2019] [Indexed: 02/08/2023] Open
Abstract
Inflammation is typically associated with the development of fibrosis, cirrhosis and hepatocellular carcinoma. The key role of protein tyrosine phosphatase 1B (PTP1B) in inflammatory responses has focused this study in understanding its implication in liver fibrosis. Here we show that hepatic PTP1B mRNA expression increased after bile duct ligation (BDL), while BDL-induced liver fibrosis was markedly reduced in mice lacking Ptpn1 (PTP1B−/−) as assessed by decreased collagen deposition and α-smooth muscle actin (α-SMA) expression. PTP1B−/− mice also showed a significant increase in mRNA levels of key markers of monocytes recruitment (Cd68, Adgre1 and Ccl2) compared to their wild-type (PTP1B+/+) littermates at early stages of injury after BDL. Interestingly, the lack of PTP1B strongly increased the NADPH oxidase (NOX) subunits Nox1/Nox4 ratio and downregulated Cybb expression after BDL, revealing a pro-survival pattern of NADPH oxidase induction in response to liver injury. Chimeric mice generated by transplantation of PTP1B−/− bone marrow (BM) into irradiated PTP1B+/+ mice revealed similar hepatic expression profile of NOX subunits than PTP1B−/− mice while these animals did not show differences in infiltration of myeloid cells at 7 days post-BDL, suggesting that PTP1B deletion in other liver cells is necessary for boosting the early inflammatory response to the BDL. PTP1B−/− BM transplantation into PTP1B+/+ mice also led to a blockade of TGF-β and α-SMA induction after BDL. In vitro experiments demonstrated that deficiency of PTP1B in hepatocytes protects against bile acid-induced apoptosis and abrogates hepatic stellate cells (HSC) activation, an effect ameliorated by NOX1 inhibition. In conclusion, our results have revealed that the lack of PTP1B switches NOX expression pattern in response to liver injury after BDL and reduces HSC activation and liver fibrosis.
PTP1B deficiency in mice ameliorates liver damage induced by cholestasis. The increased NOX1/NOX4 ratio in livers from PTP1B-/- mice was associated with protection against BDL-induced fibrosis. The lack of PTP1B exacerbates macrophage recruitment upon BDL which is dispensable for ameliorating cholestatic liver damage. Resistance of PTP1B-/- hepatocytes against bile acid-induced apoptosis protects from HSC activation in a NOX1-dependent manner.
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Wang G, Zhao H, Zheng B, Li D, Yuan Y, Han Q, Tian Z, Zhang J. TLR2 Promotes Monocyte/Macrophage Recruitment Into the Liver and Microabscess Formation to Limit the Spread of Listeria Monocytogenes. Front Immunol 2019; 10:1388. [PMID: 31297109 PMCID: PMC6607897 DOI: 10.3389/fimmu.2019.01388] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 06/03/2019] [Indexed: 12/24/2022] Open
Abstract
TLR2 signaling plays a critical protective role against acute Listeria monocytogenes (Lm) infection by up-regulating inflammatory cytokines and promoting macrophage antimicrobial capabilities. However, the underlying mechanism by which TLR2 regulates hepatic macrophage-mediated anti-Lm immune responses remains poorly understood. In this study, we found that both the absolute number and proportion of monocyte/macrophage (Mo/MΦ) in the liver and spleen of Tlr2 -/- mice were significantly lower compared to wild type mice. Changes in TLR2 signaling in both hepatocytes and Mo/MΦs were associated with the infiltration of Mo/MΦs in response to Lm-infection. Analyses by proteome profiler array and ELISA revealed that hepatocytes recruited Mo/MΦs via TLR2-dependent secretion of CCL2 and CXCL1, which was confirmed by receptor blocking and exogenous chemokine administration. Importantly, we found that TLR2 contributed to macrophage mobility in the liver through a TLR2/NO/F-actin pathway, facilitating the formation of macrophage-associated hepatic microabscesses. Moreover, TLR2 activation induced the expression of several PRRs on hepatic macrophages associated with the recognition of Lm and augmented macrophage bacterial clearance activity. Our findings provide insight into the intrinsic mechanisms of TLR2-induced Mo/MΦ migration and mobility, as well as the interaction between macrophages and hepatocytes in resistance to Lm infection.
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Affiliation(s)
- Guan Wang
- School of Pharmaceutical Sciences, Institute of Immunopharmaceutical Sciences, Shandong University, Jinan, China
| | - Huajun Zhao
- School of Pharmaceutical Sciences, Institute of Immunopharmaceutical Sciences, Shandong University, Jinan, China
| | - Bingqing Zheng
- School of Pharmaceutical Sciences, Institute of Immunopharmaceutical Sciences, Shandong University, Jinan, China
| | - Dongxuan Li
- School of Pharmaceutical Sciences, Institute of Immunopharmaceutical Sciences, Shandong University, Jinan, China
| | - Yi Yuan
- School of Pharmaceutical Sciences, Institute of Immunopharmaceutical Sciences, Shandong University, Jinan, China
| | - Qiuju Han
- School of Pharmaceutical Sciences, Institute of Immunopharmaceutical Sciences, Shandong University, Jinan, China
| | - Zhigang Tian
- School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Jian Zhang
- School of Pharmaceutical Sciences, Institute of Immunopharmaceutical Sciences, Shandong University, Jinan, China
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Expression of LAIR-1 (CD305) on Human Blood Monocytes as a Marker of Hepatic Cirrhosis Progression. J Immunol Res 2019; 2019:2974753. [PMID: 31019980 PMCID: PMC6451821 DOI: 10.1155/2019/2974753] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 01/08/2019] [Accepted: 02/02/2019] [Indexed: 01/15/2023] Open
Abstract
Background and Aim The presumed role of the inhibitory receptor LAIR-1 (CD305) in the inflammatory response suggests that it might contribute to the pathophysiology of chronic inflammatory diseases such as liver cirrhosis. We studied the LAIR-1 expression on liver macrophages and blood monocytes related to the progression of liver cirrhosis. Methods The expression of LAIR-1 was analyzed by immunohistochemistry, flow cytometry, and Western blot. Results We found a decreased number of macrophages expressing LAIR-1 in cirrhotic liver that could be due to a high presence of collagen, ligand of LAIR-1, in the fibrotic tissue which could downregulate its expression or interfere with the immunostaining. The expression of LAIR-1 decreased after cell differentiation, and the total content, but not the cell surface expression, increased after activation in the HL-60 human macrophage in vitro model. Blood monocytes exhibited higher LAIR-1 expression levels in cirrhotic patients, which were evident even in early clinical stages in all monocyte subsets, and greater in the "intermediate" inflammatory monocyte subpopulation. The in vitro activation of human blood monocytes did not increase its expression on the cell surface suggesting that the in vivo increase of LAIR-1 must be the result of a specific combination of stimuli present in cirrhotic patients. This represents an exclusive feature of liver cirrhosis, since blood monocytes from other chronic inflammatory pathologies showed similar or lower LAIR-1 levels compared with those of healthy controls. Conclusions These results may indicate that monocyte LAIR-1 expression is a new biomarker to early detect liver damage caused by chronic inflammation in liver cirrhosis.
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Immunomodulatory Functions of Mesenchymal Stem Cells in Tissue Engineering. Stem Cells Int 2019; 2019:9671206. [PMID: 30766609 PMCID: PMC6350611 DOI: 10.1155/2019/9671206] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 10/26/2018] [Accepted: 11/29/2018] [Indexed: 02/06/2023] Open
Abstract
The inflammatory response to chronic injury affects tissue regeneration and has become an important factor influencing the prognosis of patients. In previous stem cell treatments, it was revealed that stem cells not only have the ability for direct differentiation or regeneration in chronic tissue damage but also have a regulatory effect on the immune microenvironment. Stem cells can regulate the immune microenvironment during tissue repair and provide a good "soil" for tissue regeneration. In the current study, the regulation of immune cells by mesenchymal stem cells (MSCs) in the local tissue microenvironment and the tissue damage repair mechanisms are revealed. The application of the concepts of "seed" and "soil" has opened up new research avenues for regenerative medicine. Tissue engineering (TE) technology has been used in multiple tissues and organs using its biomimetic and cellular cell abilities, and scaffolds are now seen as an important part of building seed cell microenvironments. The effect of tissue engineering techniques on stem cell immune regulation is related to the shape and structure of the scaffold, the preinflammatory microenvironment constructed by the implanted scaffold, and the material selection of the scaffold. In the application of scaffold, stem cell technology has important applications in cartilage, bone, heart, and liver and other research fields. In this review, we separately explore the mechanism of MSCs in different tissue and organs through immunoregulation for tissue regeneration and MSC combined with 3D scaffolds to promote MSC immunoregulation to repair damaged tissues.
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Fabregat I, Caballero-Díaz D. Transforming Growth Factor-β-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis. Front Oncol 2018; 8:357. [PMID: 30250825 PMCID: PMC6139328 DOI: 10.3389/fonc.2018.00357] [Citation(s) in RCA: 241] [Impact Index Per Article: 34.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 08/13/2018] [Indexed: 12/11/2022] Open
Abstract
The Transforming Growth Factor-beta (TGF-β) family plays relevant roles in the regulation of different cellular processes that are essential for tissue and organ homeostasis. In the case of the liver, TGF-β signaling participates in different stages of disease progression, from initial liver injury toward fibrosis, cirrhosis and cancer. When a chronic injury takes place, mobilization of lymphocytes and other inflammatory cells occur, thus setting the stage for persistence of an inflammatory response. Macrophages produce profibrotic mediators, among them, TGF-β, which is responsible for activation -transdifferentiation- of quiescent hepatic stellate cells (HSC) to a myofibroblast (MFB) phenotype. MFBs are the principal source of extracellular matrix protein (ECM) accumulation and prominent mediators of fibrogenesis. TGF-β also mediates an epithelial-mesenchymal transition (EMT) process in hepatocytes that may contribute, directly or indirectly, to increase the MFB population. In hepatocarcinogenesis, TGF-β plays a dual role, behaving as a suppressor factor at early stages, but contributing to later tumor progression, once cells escape from its cytostatic effects. As part of its potential pro-tumorigenic actions, TGF-β induces EMT in liver tumor cells, which increases its pro-migratory and invasive potential. In parallel, TGF-β also induces changes in tumor cell plasticity, conferring properties of a migratory tumor initiating cell (TIC). The main aim of this review is to shed light about the pleiotropic actions of TGF-β that explain its effects on the different liver cell populations. The cross-talk with other signaling pathways that contribute to TGF-β effects, in particular the Epidermal Growth Factor Receptor (EGFR), will be presented. Finally, we will discuss the rationale for targeting the TGF-β pathway in liver pathologies.
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Affiliation(s)
- Isabel Fabregat
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute, Barcelona, Spain.,Department of Physiological Sciences, School of Medicine, University of Barcelona, Barcelona, Spain.,Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Barcelona, Spain
| | - Daniel Caballero-Díaz
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute, Barcelona, Spain.,Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Barcelona, Spain
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Petrescu AD, Grant S, Frampton G, McMillin M, Kain J, Kodali M, Shetty AK, DeMorrow S. Gulf war illness-related chemicals increase CD11b/c + monocyte infiltration into the liver and aggravate hepatic cholestasis in a rodent model. Sci Rep 2018; 8:13147. [PMID: 30177688 PMCID: PMC6120951 DOI: 10.1038/s41598-018-31599-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 08/16/2018] [Indexed: 12/25/2022] Open
Abstract
Gulf War Illness (GWI) is a chronic multisymptom disorder affecting veterans of the 1990-91 Gulf war. GWI was linked with exposure to chemicals including the nerve gas prophylactic drug pyridostigmine-bromide (PB) and pesticides (DEET, permethrin). Veterans with GWI exhibit prolonged, low-level systemic inflammation, though whether this impacts the liver is unknown. While no evidence exists that GWI-related chemicals are hepatotoxic, the prolonged inflammation may alter the liver's response to insults such as cholestatic injury. We assessed the effects of GWI-related chemicals on macrophage infiltration and its subsequent influence on hepatic cholestasis. Sprague Dawley rats were treated daily with PB, DEET and permethrin followed by 15 minutes of restraint stress for 28 days. Ten weeks afterward, GWI rats or naïve age-matched controls underwent bile duct ligation (BDL) or sham surgeries. Exposure to GWI-related chemicals alone increased IL-6, and CD11b+F4/80- macrophages in the liver, with no effect on biliary mass or hepatic fibrosis. However, pre-exposure to GWI-related chemicals enhanced biliary hyperplasia and fibrogenesis caused by BDL, compared to naïve rats undergoing the same surgery. These data suggest that GWI patients could be predisposed to developing worse liver pathology due to sustained low-level inflammation of the liver when compared to patients without GWI.
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Affiliation(s)
- Anca D Petrescu
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, 76504, USA
- Central Texas Veterans Healthcare System, Temple, 76504, USA
| | - Stephanie Grant
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, 76504, USA
- Central Texas Veterans Healthcare System, Temple, 76504, USA
| | - Gabriel Frampton
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, 76504, USA
- Central Texas Veterans Healthcare System, Temple, 76504, USA
| | | | - Jessica Kain
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, 76504, USA
| | - Maheedhar Kodali
- Central Texas Veterans Healthcare System, Temple, 76504, USA
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, College Station, 77843, USA
| | - Ashok K Shetty
- Central Texas Veterans Healthcare System, Temple, 76504, USA
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, College Station, 77843, USA
| | - Sharon DeMorrow
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, 76504, USA.
- Central Texas Veterans Healthcare System, Temple, 76504, USA.
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Lian M, Selmi C, Gershwin ME, Ma X. Myeloid Cells and Chronic Liver Disease: a Comprehensive Review. Clin Rev Allergy Immunol 2018; 54:307-317. [PMID: 29313221 DOI: 10.1007/s12016-017-8664-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Myeloid cells play a major role in the sensitization to liver injury, particularly in chronic inflammatory liver diseases with a biliary or hepatocellular origin, and the interplay between myeloid cells and the liver may explain the increased incidence of hepatic osteodystrophy. The myeloid cell-liver axis involves several mature myeloid cells as well as immature or progenitor cells with the complexity of the liver immune microenvironment aggravating the mist of cell differentiation. The unique positioning of the liver at the junction of the peripheral and portal circulation systems underlines the interaction of myeloid cells and hepatic cells and leads to immune tolerance breakdown. We herein discuss the scenarios of different chronic liver diseases closely modulated by myeloid cells and illustrate the numerous potential targets, the understanding of which will ultimately steer the development of solid immunotherapeutic regimens. Ultimately, we are convinced that an adequate modulation of the liver microenvironment to modify the functional and quantitative characteristics of myeloid cells will be a successful approach to treating chronic liver diseases of different etiologies.
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Affiliation(s)
- Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Carlo Selmi
- Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.,BIOMETRA Department, University of Milan, Milan, Italy
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
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Labsi M, Soufli I, Khelifi L, Amir ZC, Touil-Boukoffa C. In vivo treatment with IL-17A attenuates hydatid cyst growth and liver fibrogenesis in an experimental model of echinococcosis. Acta Trop 2018; 181:6-10. [PMID: 29407850 DOI: 10.1016/j.actatropica.2018.01.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Revised: 01/18/2018] [Accepted: 01/23/2018] [Indexed: 12/13/2022]
Abstract
We aimed to assess the effect of exogenous Interleukin (IL)-17A in experimental model of echinococcosis. Swiss mice were inoculated intra-peritoneally with viable protoscoleces (PSCs). Then, IL-17A was administered at 100, 125 or 150 pg/mL two weeks after cystic echinococcosis (CE) induction. Cyst development and hepatic damage were macroscopically and histologically analyzed. We observed that in vivo IL-17A treatment at 100, 125, and 150 pg/mL, reduced metacestode growth by 72.3%, 93.8%, and 96.9%, respectively. Interestingly an amelioration of liver architecture was noted at 125 pg/mL without toxic effect. In this context, we showed less fibrosis reaction and reduced expression of iNOS, TNF-α, NF-κb and CD68 in hepatic parenchyma of treated mice by 125 pg/mL of IL-17A. Collectively, our results indicate an antihydatic effect and immunoprotective properties of IL-17A and suggest its potential therapeutic value against Echinococcus granulosus infection.
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Affiliation(s)
- Moussa Labsi
- Laboratory of Cellular and Molecular Biology, Department of Biology, University of Sciences and Technology Houari Boumediene. Algiers-Algeria.
| | - Imene Soufli
- Laboratory of Cellular and Molecular Biology, Department of Biology, University of Sciences and Technology Houari Boumediene. Algiers-Algeria.
| | - Lila Khelifi
- Laboratory of Cellular and Molecular Biology, Department of Biology, University of Sciences and Technology Houari Boumediene. Algiers-Algeria.
| | - Zine-Charaf Amir
- Department of Anatomy and Pathological Cytology, University Hospital Center Mustapha Pacha, Algiers-Algeria.
| | - Chafia Touil-Boukoffa
- Laboratory of Cellular and Molecular Biology, Department of Biology, University of Sciences and Technology Houari Boumediene. Algiers-Algeria.
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