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Liu H, Yang Z, Li J, Zhang J, Sun C. Expanding the horizons of bicyclol in multiple diseases: Mechanisms, therapeutic implications and challenges. Eur J Pharmacol 2025; 993:177381. [PMID: 39954842 DOI: 10.1016/j.ejphar.2025.177381] [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: 11/01/2024] [Revised: 01/25/2025] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
Bicyclol, a drug stemmed from the traditional Chinese medicine Schisandra chinensis, has been widely utilized in clinical practice due to its efficacy and safety to manage hepatopathy. Its diverse biological properties-including antiviral, anti-inflammatory, antifibrotic, immunomodulatory, antioxidative, antisteatotic, and antitumor effects-underscore its significant medicinal effects in versatile hepatic disorders, incorporating viral hepatitis, non-alcoholic fatty liver disease, hepatocellular carcinoma, acute hepatic failure, hepatic fibrosis as well as drug-induced liver injury. Furthermore, ongoing researches into the molecular mechanisms, biological activities and mode of actions concerning bicyclol have uncovered its potential therapeutic implications in other multiple diseases/conditions. Studies have indicated promising efficacy pertaining to bicyclol to treat idiopathic pulmonary fibrosis, acute lung injury, cerebral ischemia/reperfusion injury, renal dysfunction, renal cell carcinoma, and cardiovascular diseases. Accordingly, this narrative review article summarizes the current understanding of diverse biological activities and underpinning mechanisms of bicyclol across a range of diseases, as well as its pharmacokinetics, toxicity profile and shed light on future perspectives.
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Affiliation(s)
- Heng Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, China; Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin, 300308, China
| | - Ziyi Yang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, China
| | - Jia Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, China
| | - Jie Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, China.
| | - Chao Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, China; Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin, 300308, China.
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Ohshima K, Torii S, Shimizu S. Presence of Gut Microbiota Worsens D-Galactosamine and Lipopolysaccharide-Induced Hepatic Injury in Mice. Genes Cells 2025; 30:e13183. [PMID: 39624985 DOI: 10.1111/gtc.13183] [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: 05/08/2024] [Revised: 10/19/2024] [Accepted: 11/04/2024] [Indexed: 12/20/2024]
Abstract
Acute liver failure is a serious, life-threatening disease. Although the gut microbiota has been considered to play a role in liver failure, the extent to which it is involved in the pathogenesis of this disease has not been fully elucidated to date. Therefore, we here analyzed the importance of the presence of intestinal microbiota in the pathogenesis of acute liver injury, using D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-treated mice, which is a widely used experimental model of acute liver injury. First, administration of the antibiotic polymyxin B markedly alleviated liver injury. Liver injury was also reduced in germ-free mice, leading to the conclusion that the presence of intestinal microbiota aggravates D-GalN/LPS-induced liver injury. The amount of bacteria and LPS transferred from the gut to the blood was not increased by D-GalN/LPS, suggesting that the worsening of liver injury was not simply owing to the entry of bacteria into the circulation. In conclusion, acute liver injury in polymyxin B-pretreated or germ-free mice was ameliorated by modulation of the gut microbiota. Modification of the gut microbiota using polymyxin B may hence have the potential to alleviate acute liver injury in human patients.
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Affiliation(s)
- Kazuma Ohshima
- Department of Pathological Cell Biology, Advanced Research Initiative, Institute of Science Tokyo, Tokyo, Japan
| | - Satoru Torii
- Department of Pathological Cell Biology, Advanced Research Initiative, Institute of Science Tokyo, Tokyo, Japan
| | - Shigeomi Shimizu
- Department of Pathological Cell Biology, Advanced Research Initiative, Institute of Science Tokyo, Tokyo, Japan
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Xu FF, Li ZC, Zhang WJ, Li Q, Li DJ, Meng HB, Shen FM, Fu H. Activation of α7 Nicotinic Acetylcholine Receptors Inhibits Hepatic Necroptosis and Ameliorates Acute Liver Injury in Mice. Anesthesiology 2024; 141:1119-1138. [PMID: 39186677 DOI: 10.1097/aln.0000000000005206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/28/2024]
Abstract
BACKGROUND Acute liver injury is a disease characterized by severe liver dysfunction, caused by significant infiltration of immune cells and extensive cell death with a high mortality. Previous studies demonstrated that the α7 nicotinic acetylcholine receptor (α7nAChR) played a crucial role in various liver diseases. The hypothesis of this study was that activating α7nAChR could alleviate acute liver injury and investigate its possible mechanisms. METHODS Acute liver injury was induced by intraperitoneal injection of lipopolysaccharide (LPS)/D-galactosamine (D-Gal) in wild type, α7nAChR knockout (α7nAChR-/-) and stimulator of interferon gene (STING) mutation (Stinggt/gt) mice in the presence or absence of a pharmacologic selective α7nAChR agonist (PNU-282987). The effects of α7nAChR on hepatic injury, inflammatory response, mitochondrial damage, necroptosis, and infiltration of immune cells during acute liver injury were assessed. RESULTS The expression of α7nAChR in liver tissue was increased in LPS/D-Gal-induced acute liver injury mice. Compared to the age-matched wild-type mice, α7nAChR deficiency decreased the survival rate, exacerbated the hepatic injury accompanied with enhanced inflammatory response and oxidative stress, and aggravated hepatic mitochondrial damage and necroptosis. Conversely, pharmacologic activation of α7nAChR by PNU-282987 displayed the opposite trends. Furthermore, PNU-282987 significantly reduced the proportion of infiltrating monocyte-derived macrophages (CD45+CD11bhiF4/80int), M1 macrophages (CD45+CD11b+F4/80+CD86hiCD163low), and Ly6Chi monocytes (CD45+CD11b+MHC [major histocompatibility complex] ⅡlowLy6Chi), but increased the resident Kupffer cells (CD45+CD11bintF4/80hiTIM4hi) in the damaged hepatic tissues caused by LPS/D-Gal. Interestingly, α7nAChR deficiency promoted the STING signaling pathway under LPS/D-Gal stimulation, while PNU-282987 treatment significantly prevented its activation. Finally, it was found that Sting mutation abolished the protective effects against hepatic injury by activating α7nAChR. CONCLUSIONS The authors' study revealed that activating α7nAChR could protect against LPS/D-Gal-induced acute liver injury by inhibiting hepatic inflammation and necroptosis possibly via regulating immune cells infiltration and inhibiting STING signaling pathway. EDITOR’S PERSPECTIVE
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Affiliation(s)
- Fang-Fang Xu
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zi-Chen Li
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wen-Jing Zhang
- Department of Pharmacy, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China
| | - Qiao Li
- School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Dong-Jie Li
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hong-Bo Meng
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Fu-Ming Shen
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hui Fu
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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Zheng J, Xiao J, Fan Y, Zheng H, Liu H, Xiang J, Hai L, Wang Y, Zhang X. CD24 regulates liver immune response and ameliorates acute hepatic injury through controlling hepatic macrophages. Eur J Immunol 2024; 54:e2451178. [PMID: 39444061 DOI: 10.1002/eji.202451178] [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: 04/07/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/25/2024]
Abstract
Liver injury releases danger-associated molecular patterns, which trigger the immune response. CD24 negatively regulates the immune response by binding with danger-associated molecular patterns, but the specific role of CD24 in modulating macrophage-related inflammation during liver injury remains largely unexplored. Here, we aimed to investigate the mechanisms of macrophage CD24 in the development of liver injury. Our results show that CD24 expression is upregulated primarily in hepatic macrophages (HMs) during acute liver injury. CD24-deficient mice exhibited more severe liver injury and showed a significantly higher frequency and number of HMs, particularly Ly6Chi monocyte-derived macrophages. Mechanistically, the CD24-Siglec-G interaction plays a vital role in mitigating acute liver injury. CD24-mediated inhibitory signaling in HMs primarily limits downstream NF-κB and p38 MAPK activation through the recruitment of SHP1. Our work unveils the critical role of macrophage CD24 in negatively regulating innate immune responses and protecting against acute liver injury, thus providing potential therapeutic targets for liver-associated diseases.
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Affiliation(s)
- Jian Zheng
- Key Laboratory of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, P. R. China
| | - Jun Xiao
- Key Laboratory of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, P. R. China
| | - Yatong Fan
- Department of Blood Transfusion, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, P. R. China
| | - Honggang Zheng
- Department of Pathology, Tianjin Jinyu Medical Laboratory Co LTD, Tianjin, P. R. China
| | - Hongyu Liu
- Key Laboratory of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, P. R. China
| | - Jie Xiang
- Key Laboratory of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, P. R. China
| | - Lei Hai
- Key Laboratory of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, P. R. China
| | - Yan Wang
- Key Laboratory of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, P. R. China
| | - Xuejun Zhang
- Key Laboratory of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, P. R. China
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Lim HJ, Kwak HJ. Selective PPARδ Agonist GW501516 Protects Against LPS-Induced Macrophage Inflammation and Acute Liver Failure in Mice via Suppressing Inflammatory Mediators. Molecules 2024; 29:5189. [PMID: 39519830 PMCID: PMC11547330 DOI: 10.3390/molecules29215189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Inflammation is critical in the development of acute liver failure (ALF). Peroxisome proliferator-activated receptor delta (PPARδ) regulates anti-inflammatory responses and is protective in several diseases such as obesity and cancer. However, the beneficial effects and underlying mechanisms of PPARδ agonist GW501516 in ALF remain unclear. This study investigated the molecular mechanisms underlying the anti-inflammatory effects of GW501516 in macrophages and assessed its protective potential against lipopolysaccharide (LPS)/galactosamine (GalN)-induced ALF. In vivo administration of GW501516 significantly reduced LPS/GalN-induced hepatotoxicity, as evidenced by lower mortality, decreased liver damage, and attenuated secretion of IL-1β, IL-6, and TNF-α. GW501516 treatment also decreased LPS-induced nitric oxide synthase 2 (NOS2) expression and nitric oxide (NO) production in RAW264.7 cells, an effect reversed by PPARδ siRNA. Additionally, GW501516 inhibited LPS-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), suggesting that inactivation of these MAPKs contributes to its effects. The secretion of IL-6, TNF-α, and NF-κB DNA-binding activity were also suppressed by GW501516, while the nuclear translocation of the NF-κB p65 subunit was unaffected. In conclusion, our findings suggest that GW501516 exerts protective effects in ALF by inhibiting the production of inflammatory mediators. Therefore, GW501516 may act as a potential agent for developing anti-inflammatory therapies for ALF.
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Affiliation(s)
- Hyun-Joung Lim
- Division of Cardiovascular Diseases Research, Department of Chronic Diseases Convergence, National Institute of Health, Cheongju 28159, Republic of Korea;
| | - Hyun Jeong Kwak
- Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 02707, Republic of Korea
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Wang ZY, Gao ST, Gou XJ, Qiu FR, Feng Q. IL-1 receptor-associated kinase family proteins: An overview of their role in liver disease. Eur J Pharmacol 2024; 978:176773. [PMID: 38936453 DOI: 10.1016/j.ejphar.2024.176773] [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: 03/19/2024] [Revised: 06/16/2024] [Accepted: 06/23/2024] [Indexed: 06/29/2024]
Abstract
The interleukin-1 receptor-associated kinase (IRAK) family is a group of serine-threonine kinases that regulates various cellular processes via toll-like receptor (TLR)/interleukin-1 receptor (IL1R)-mediated signaling. The IRAK family comprises four members, including IRAK1, IRAK2, IRAK3, and IRAK4, which play an important role in the expression of various inflammatory genes, thereby contributing to the inflammatory response. IRAKs are key proteins in chronic and acute liver diseases, and recent evidence has implicated IRAK family proteins (IRAK1, IRAK3, and IRAK4) in the progression of liver-related disorders, including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis virus infection, acute liver failure, liver ischemia-reperfusion injury, and hepatocellular carcinoma. In this article, we provide a comprehensive review of the role of IRAK family proteins and their associated inflammatory signaling pathways in the pathogenesis of liver diseases. The purpose of this study is to explore whether IRAK family proteins can serve as the main target for the treatment of liver related diseases.
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Affiliation(s)
- Zhuo-Yuan Wang
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Si-Ting Gao
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiao-Jun Gou
- Central Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai University of Traditional Chinese Medicine, Shanghai, 201999, China
| | - Fu-Rong Qiu
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Qin Feng
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, 201203, China; Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, 201203, China.
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Lei R, Yang C, Sun Y, Li D, Hao L, Li Y, Wu S, Li H, Lan C, Fang X. Turning cationic antimicrobial peptide KR-12 into self-assembled nanobiotics with potent bacterial killing and LPS neutralizing activities. NANOSCALE 2024; 16:887-902. [PMID: 38105768 DOI: 10.1039/d3nr05174a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Gram-negative sepsis has become a substantial and escalating global healthcare challenge due to the growing antibiotic resistance crisis and the sluggish development of new antibiotics. LL-37, a unique Cathelicidin species found in humans, exhibits a wide range of bioactive properties, including direct bactericidal effects, inflammation regulation, and LPS neutralization. KR-12, the smallest yet potent peptide fragment of LL-37, has been modified to create more effective antimicrobials. In this study, we designed two myristoylated derivatives of KR-12, referred to as Myr-KR-12N and Myr-KR-12C. These derivatives displayed remarkable ability to spontaneously assemble into nanoparticles when mixed with deionized water. Myristoylated KR-12 derivatives exhibited broad-spectrum and intensified bactericidal activity by disrupting bacterial cell membranes. In particular, Myr-KR-12N showed superior capability to rescue mice from lethal E. coli-induced sepsis in comparison with the conventional antibiotic meropenem. We also confirmed that the myristoylated KR-12 nanobiotic possesses significant LPS binding capacity and effectively reduces inflammation in vitro. In an in vivo context, Myr-KR-12N outperformed polymyxin B in rescuing mice from LPS-induced sepsis. Crucially, toxicological assessments revealed that neither Myr-KR-12N nor Myr-KR-12C nanobiotics induced meaningful hemolysis or caused damage to the liver and kidneys. Collectively, our study has yielded an innovative nanobiotic with dual capabilities of bactericidal action and LPS-neutralization, offering substantial promise for advancing the clinical translation of antimicrobial peptides and the development of novel antibiotics. This addresses the critical need for effective solutions to combat Gram-negative sepsis, a pressing global medical challenge.
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Affiliation(s)
- Ruyi Lei
- Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Chujun Yang
- Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Yaqi Sun
- China National Clinical Research Center for Child Health, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Dejian Li
- Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Liman Hao
- Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
| | - Yang Li
- Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
| | - Shuijing Wu
- Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
| | - Hui Li
- Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
| | - Chao Lan
- Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Xiangming Fang
- Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
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Zhao X, Yin F, Fu L, Ma Y, Ye L, Huang Y, Fan W, Gao W, Cai Y, Mou X. Garlic-derived exosome-like nanovesicles as a hepatoprotective agent alleviating acute liver failure by inhibiting CCR2/CCR5 signaling and inflammation. BIOMATERIALS ADVANCES 2023; 154:213592. [PMID: 37717364 DOI: 10.1016/j.bioadv.2023.213592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 07/27/2023] [Accepted: 08/15/2023] [Indexed: 09/19/2023]
Abstract
Acute liver failure (ALF) is a life-threatening clinical syndrome mostly induced by viral infections or drug abuse. As a novel therapeutic adjuvant or delivery vehicle, plant-derived exosome-like nanovesicles (PELNVs) have been extensively studied in recent years. This study aimed to develop garlic-derived exosome-like nanovesicles (GaELNVs) in order to ameliorate liver injury induced by LPS/D-GalN in mice, inhibit inflammatory eruption and reduce inflammatory cells infiltration. The results showed that treatment with GaELNVs improved liver pathology and reduced the levels of soluble inflammatory mediators IL-6, IL-1β and TNF-α in the serum of ALF mice. GaELNVs reversed the upregulation of Cleaved Caspase-9, Cleaved Caspase-3, p53 and Bax expression and decreased Bcl2 activation caused by D-GalN/LPS, and inhibited NF-κB p65 expression and translocation to the nucleus. Meanwhile, treatment with GaELNVs resulted significant reduction in NLRP3 activation and Caspase-1 maturation, as well as decrease in the release of the inflammatory mediator IL-18. Additionally, an upregulation of the expression of proteins related to energy metabolism and autophagy occurrence including Foxo3a, Sirt1, and LC3-II was detected in the liver. Oral administration of GaELNVs also led to significant alteration in the expression of F4/80 and CD11b in the liver. Furthermore, the detection of chemokines in mouse liver tissue revealed that GaELNVs exhibited minimal reduction in the expression of CCL2, CCL3, CCL5 and CCL8. The decreased expression of CCR2 and CCR5 in the liver suggests that GaELNVs have the ability to decrease the recruitment of monocytes from the circulation to the liver. A reduction in the infiltration of F4/80loCD11bhi monocyte-derived macrophages into the liver was also observed. This study provides novel evidence that GaELNVs can ameliorate inflammatory eruptions and hinder the migration of circulating monocytes to the liver, as well as decrease macrophage infiltration by inhibiting CCR2/CCR5 signaling. Consequently, GaELNVs hold promise as a novel therapeutic agent for clinical management of liver disease.
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Affiliation(s)
- Xin Zhao
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China; College of Pharmacy, Hangzhou Medical College, Hangzhou 310059, China; Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China
| | - Fang Yin
- Shanghai Engineering Research Center of Human Intestinal Microflora Function Development, Shanghai Tenth People's Hospital, Shanghai 200072, China
| | - Luoqin Fu
- Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China
| | - Yingyu Ma
- Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China
| | - Luyi Ye
- College of Pharmacy, Hangzhou Medical College, Hangzhou 310059, China
| | - Yilin Huang
- College of Pharmacy, Hangzhou Medical College, Hangzhou 310059, China
| | - Weijiao Fan
- Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China
| | - Wenxue Gao
- Clinical Research Unit, Shanghai Tenth People's Hospital, Shanghai 200072, China.
| | - Yu Cai
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China; College of Pharmacy, Hangzhou Medical College, Hangzhou 310059, China; Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China.
| | - Xiaozhou Mou
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China; College of Pharmacy, Hangzhou Medical College, Hangzhou 310059, China; Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China.
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Zhang X, Lin L, Li L, Hu K, Shao R, Zhang L, Tang L, Zhu M, Ma Y, Yang Y. Janus kinase inhibitor Tofacitinib alleviated acute hepatitis induced by lipopolysaccharide/D-galactosamine in mice. Mol Biol Rep 2023; 50:1477-1485. [PMID: 36507969 DOI: 10.1007/s11033-022-08086-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 11/03/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND The Janus kinase (JAK) is a crucial intracellular signaling hub for numerous cytokines, which is extensively involved in the activation of inflammatory cascade and the induction of inflammatory injury. JAK inhibition provides protective effects in several inflammation-based disorders, but the potential effects of JAK inhibitor in inflammation-based acute hepatitis remain to be investigated. METHODS AND RESULTS Acute hepatitis is induced by Lipopolysaccharide/D-galactosamine (LPS/D-Gal) in mice with or without the JAK inhibitor Tofacitinib administration. The degree of liver injury, the production of pro-inflammatory cytokines and induction of hepatocytes apoptosis were determined. The results indicated that treatment with Tofacitinib decreased the levels of aminotransferases, attenuated the histological abnormalities in liver and decreased the plasma levels of TNF-α and IL-6 in LPS/D-Gal-insulted mice. In addition, Tofacitinib suppressed the activation of the caspase cascade, decreased the level of cleaved caspase-3, and reduced the count of TUNEL-positive cells. CONCLUSION Treatment with Tofacitinib alleviated LPS/D-Gal-induced acute hepatitis. JAK maybe become a promising target for the control of inflammation-based liver disorders.
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Affiliation(s)
- Xinyue Zhang
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing, PR China
| | - Ling Lin
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing, PR China
| | - Longjiang Li
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing, PR China
| | - Kai Hu
- Department of Histology and Embryology, Basic Medical College, Chongqing Medical University, Chongqing, PR China
| | - Ruyue Shao
- Clinical Medical School, Chongqing Medical and Pharmaceutical College, Chongqing, PR China
- Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing, PR China
| | - Li Zhang
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing, PR China
| | - Li Tang
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing, PR China
| | - Min Zhu
- Department of Pathology, Karamay Central Hosptial of XinJiang Karamay, Karamay, Xinjiang, PR China
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Yuhua Ma
- Department of Pathology, Karamay Central Hosptial of XinJiang Karamay, Karamay, Xinjiang, PR China.
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, PR China.
| | - Yongqiang Yang
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing, PR China.
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Crosstalk of TNF-α, IFN-γ, NF-kB, STAT1 and redox signaling in lipopolysaccharide/D-galactosamine/dimethylsulfoxide-induced fulminant hepatic failure in mice. Saudi Pharm J 2023; 31:370-381. [PMID: 37026046 PMCID: PMC10071328 DOI: 10.1016/j.jsps.2023.01.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 01/19/2023] [Indexed: 01/26/2023] Open
Abstract
Purpose The clinical study of fulminant hepatic failure is challenging due to its high mortality and relative rarity, necessitating reliance on pre-clinical models to gain insight into its pathophysiology and develop potential therapies. Methods and Results In our study, the combination of the commonly used solvent dimethyl sulfoxide to the current-day model of lipopolysaccharide/d-galactosamine-caused fulminant hepatic failure was found to cause significantly greater hepatic damage, as indicated by alanine aminotransferase level. The effect was dose-dependent, with the maximum increase in alanine aminotransferase observed following 200 μl/kg dimethyl sulfoxide co-administration. Co-administration of 200 μl/kg dimethyl sulfoxide also remarkably increased histopathological changes induced by lipopolysaccharide/d-galactosamine. Importantly, alanine aminotransferase levels and survival rate in the 200 μl/kg dimethyl sulfoxide co-administration groups were both greater than those in the classical lipopolysaccharide/d-galactosamine model. We found that dimethyl sulfoxide co-administration aggravated lipopolysaccharide/d-galactosamine-caused liver damage by stimulating inflammatory signaling, as indicated by tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) levels. Further, nuclear factor kappa B (NF-kB) and transcription factor activator 1 (STAT1) were upregulated, as was neutrophil recruitment, indicated by myeloperoxidase activity. Hepatocyte apoptosis was also increased, and greater nitro-oxidative stress was noted, as determined based on nitric oxide, malondialdehyde, and glutathione levels. Conclusion Co-treatment with low doses of dimethyl sulfoxide enhanced the lipopolysaccharide/d-galactosamine-caused hepatic failure in animals, with higher toxicity and greater survival rates. The current findings also highlight the potential danger of using dimethyl sulfoxide as a solvent in experiments involving the hepatic immune system, suggesting that the new lipopolysaccharide/d-galactosamine/dimethyl sulfoxide model described herein could be used for pharmacological screening with the goal to better understand hepatic failure and evaluate treatment approaches.
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11
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Li B, Hong L, Luo Y, Zhang B, Yu Z, Li W, Cao N, Huang Y, Xu D, Li Y, Tian Y. LPS-Induced Liver Injury of Magang Geese through Toll-like Receptor and MAPK Signaling Pathway. Animals (Basel) 2022; 13:ani13010127. [PMID: 36611736 PMCID: PMC9817723 DOI: 10.3390/ani13010127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/24/2022] [Accepted: 12/26/2022] [Indexed: 12/30/2022] Open
Abstract
Lipopolysaccharide (LPS) is one of the main virulence factors of Gram-negative bacteria. In the process of waterfowl breeding, an inflammatory reaction due to LPS infection is easily produced, which leads to a decline in waterfowl performance. The liver plays a vital role in the immune response and the removal of toxic components. Therefore, it is necessary to study the mechanism of liver injury induced by LPS in goose. In this study, a total of 100 1-day-old goslings were randomly divided into a control group and LPS group after 3 days of pre-feeding. On days 21, 23, and 25 of the formal experiment, the control group was intraperitoneally injected with 0.5 mL normal saline, and the LPS group was intraperitoneally injected with LPS 2 mg/(kg body weight) once a day. On day 25 of the experiment, liver samples were collected 3 h after the injection of saline and LPS. The results of histopathology and biochemical indexes showed that the livers of the LPS group had liver morphological structure destruction and inflammatory cell infiltration, and the levels of ALT and AST were increased. Next, RNA sequencing analysis was used to determine the abundances and characteristics of the transcripts, as well as the associated somatic mutations and alternative splicing. We screened 727 differentially expressed genes (DEGs) with p < 0.05 and |log2(Fold Change)| ≥ 1, as the thresholds; GO and KEGG enrichment analysis showed that LPS-induced liver injury may be involved in the Toll-like receptor signaling pathway, MAPK signaling pathway, NOD-like receptor signaling pathway, FoxO, and PPAR signaling pathway. Finally, we intersected the genes enriched in the key pathway of LPS-induced liver injury with the top 50 key genes in protein−protein interaction networks to obtain 28 more critical genes. Among them, 17 genes were enriched in Toll-like signaling pathway and MAPK signaling pathway. Therefore, these results suggest that LPS-induced liver injury in geese may be the result of the joint action of Toll-like receptor, MAPK, NOD-like receptor, FoxO, and PPAR signaling pathway. Among them, the TLR7-mediated MAPK signaling pathway plays a major role.
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Affiliation(s)
- Bingxin Li
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Longsheng Hong
- Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Yindan Luo
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Bingqi Zhang
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Ziyu Yu
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Wanyan Li
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Nan Cao
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Yunmao Huang
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Danning Xu
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Yugu Li
- Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Yunbo Tian
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
- Correspondence:
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12
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Wang X, Sun Y, Fu Y, Wu H, Chen Y, Ye Y, Zhou Q, He L, Zhou E, Wang J, Yang Z. Lysine specific demethylase 1 inhibitor alleviated lipopolysaccharide/D-galactosamine-induced acute liver injury. Eur J Pharmacol 2022; 932:175227. [PMID: 36007605 DOI: 10.1016/j.ejphar.2022.175227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 08/08/2022] [Accepted: 08/17/2022] [Indexed: 11/19/2022]
Abstract
Acute liver injury is a severe clinical syndrome with markedly high mortality and poor prognosis. An accumulating body of evidence has demonstrated that epigenetic mechanisms have essential roles in the pathogenesis of acute liver injury. Lysine-specific demethylase 1 (LSD1) belongs to the amine oxidase superfamily of flavin adenine dinucleotide (FAD)-dependent enzymes, specifically demethylates H3 lysine 4. In the study, we investigated the effects and mechanisms of LSD1 in lipopolysaccharide (LPS)/D-Galactosamine (D-Gal)-induced acute liver injury in mice. Western blot analysis showed that LSD1 phosphorylation and di-methylated histone H3 on lysine 4 (H3K4me2) protein expression were significantly increased after LPS/D-Gal treatment (2.3 and 2.4 times higher than control respectively). GSK-LSD1 2HCl is an irreversible and selective LSD1 inhibitor. Pre-treatment with LSD1 inhibitor alleviated LPS/D-Gal-induced liver damage, decreased serum levels of alanine transaminase and aspartate aminotransferase in mice. Moreover, the LSD1 phosphorylation level in low, medium, and high LSD1 inhibitor groups was lower by a factor of 1.6, 1.9, and 2.0 from the LPS/D-Gal group, respectively. Mechanistically, LSD1 inhibitor further inhibited NF-κB signaling cascades and subsequently inhibited the production of pro-inflammatory cytokine TNF-α, IL-6, and IL-1β induced by LPS/D-Gal in liver tissues. Furthermore, LSD1 inhibitor upregulated the protein expression of Nrf2/HO-1 signaling pathways, and the activities of related antioxidant enzymes were enhanced. Collectively, our data demonstrated that LSD1 inhibitor protected against the LPS/D-Gal-induced acute liver injury via inhibiting inflammation and oxidative stress, and targeting the epigenetic marker may be a potent therapeutic strategy for acute liver injury.
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Affiliation(s)
- Xia Wang
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Youpeng Sun
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Yiwu Fu
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Hanpeng Wu
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Yichun Chen
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Yingrong Ye
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Qingqing Zhou
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Li He
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Ershun Zhou
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Jingjing Wang
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China.
| | - Zhengtao Yang
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China.
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Han X, Wang Y, Huang Y, Wang X, Choo J, Chen L. Fluorescent probes for biomolecule detection under environmental stress. JOURNAL OF HAZARDOUS MATERIALS 2022; 431:128527. [PMID: 35231812 DOI: 10.1016/j.jhazmat.2022.128527] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/16/2022] [Accepted: 02/18/2022] [Indexed: 06/14/2023]
Abstract
The use of fluorescent probes in visible detection has been developed over the last several decades. Biomolecules are essential in the biological processes of organisms, and their distribution and concentration are largely influenced by environmental factors. Significant advances have occurred in the applications of fluorescent probes for the detection of the dynamic localization and quantity of biomolecules during various environmental stress-induced physiological and pathological processes. Herein, we summarize representative examples of small molecule-based fluorescent probes that provide bimolecular information when the organism is under environmental stress. The discussion includes strategies for the design of smart small-molecule fluorescent probes, in addition to their applications in biomolecule imaging under environmental stresses, such as hypoxia, ischemia-reperfusion, hyperthermia/hypothermia, organic/inorganic chemical exposure, oxidative/reductive stress, high glucose stimulation, and drug treatment-induced toxicity. We believe that comprehensive insight into the beneficial applications of fluorescent probes in biomolecule detection under environmental stress should enable the further development and effective application of fluorescent probes in the biochemical and biomedical fields.
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Affiliation(s)
- Xiaoyue Han
- CAS Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China; Present: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, UK; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yue Wang
- CAS Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yan Huang
- School of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Xiaoyan Wang
- School of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Jaebum Choo
- Department of Chemistry, Chung-Ang University, Seoul 06974, South Korea.
| | - Lingxin Chen
- CAS Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China; School of Pharmacy, Binzhou Medical University, Yantai 264003, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China.
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Pon1 Deficiency Promotes Trem2 Pathway-Mediated Microglial Phagocytosis and Inhibits Pro-inflammatory Cytokines Release In Vitro and In Vivo. Mol Neurobiol 2022; 59:4612-4629. [PMID: 35589918 DOI: 10.1007/s12035-022-02827-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 04/02/2022] [Indexed: 11/27/2022]
Abstract
Paraoxonase 1 (PON1) plays an anti-inflammatory role in the cardiovascular system. Levels of serum PON1 and polymorphisms in this gene were linked to Alzheimer's disease (AD) and Parkinson disease (PD), but its function in the neuroimmune system and AD is not clear. To address this issue, we used Pon1 knockout rats previously generated by our lab to investigate the role of Pon1 in microglia. Knockout of Pon1 in rat brain tissues protected against LPS-induced microglia activation. Pon1 deficiency in rat primary microglia increased Trem2 (triggering receptor expressed in myeloid cells 2) expression, phagocytosis, and IL-10 (M2-phenotype marker) release, but decreased production of pro-inflammatory cytokines such as IL-1β, IL-6, and IL-18 especially TNF-α (M1-phenotype markers) induced by LPS. Pon1 deficiency in rat primary microglia activated Trem2 pathway but decreased LPS-induced ERK activation. The phagocytosis-promoting effect of Pon1 knockout could be reversed by administration of recombinant PON1 protein. The interaction between PON1 and TREM2 was verified by co-immunoprecipitation (co-IP) using rat brain tissues or over-expressed BV2 cell lysates, which might be involved in lysosomal localization of TREM2. Furthermore, Pon1 knockout also enhanced microglial phagocytosis and clearance of exogenous Aβ by an intrahippocampal injection and decrease the transcription of cytokines such as IL-1β, IL-6, and TNF-α in vivo. These results suggest that Pon1 knockout facilitates microglial phagocytosis and inhibits the production of proinflammatory cytokines both in vivo and in vitro, in which the interaction between Pon1 and Trem2 may be involved. These findings provide novel insights into the role of PON1 in neuroinflammation and highlight TREM2 as a potential target for Alzheimer's disease therapy.
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15
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Li A, Li XM, Song CG, Xiao X, Yao WM, Tian HS. Fibroblast growth factor 9 attenuates sepsis-induced fulminant hepatitis in mice. Amino Acids 2022; 54:1069-1081. [PMID: 35304640 DOI: 10.1007/s00726-022-03143-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 02/21/2022] [Indexed: 11/26/2022]
Abstract
Sepsis-induced fulminant hepatitis (FH) is a fatal syndrome that has a worse prognosis in clinical practice. Hence, seeking effective agents for sepsis-induced FH treatment is urgently needed. Fibroblast growth factors (FGFs) are vital for tissue homeostasis and damage repair in various organs including the liver. Our study aims to investigate the protective effects and potential mechanisms of FGF9 on lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced FH in mice. We found that pre-treatment with FGF9 exhibited remarkable hepaprotective effects on liver damage caused by LPS/D-Gal, as manifested by the concomitant decrease in mortality and serum aminotransferase activities, and the attenuation of hepatocellular apoptosis and hepatic histopathological abnormalities in LPS/D-Gal-intoxicated mice. We further found that FGF9 alleviated the infiltration of neutrophils into the liver, and decreased the serum levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in LPS/D-Gal-challenged mice. These effects can be explained at least in part by the inhibition of NF-κB signaling pathway. Meanwhile, FGF9 enhanced the antioxidative defense system in mice livers by upregulating the expression of NRF-2-related antioxidative enzymes, including glutamate-cysteine ligase catalytic subunit (GCLC), NAD(P)H: quinone oxidoreductase 1 (NQO-1), and heme oxygenase-1 (HO-1). These data indicate that FGF9 represents a promising therapeutic drug for ameliorating sepsis-induced FH via its anti-apoptotic and anti-inflammatory capacities.
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Affiliation(s)
- Ao Li
- Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China.
| | - Xue-Mei Li
- Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China
| | - Chu-Ge Song
- Department of Respiratory Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China
| | - Xiao Xiao
- Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China
| | - Wei-Min Yao
- Department of Respiratory Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China.
| | - Hai-Shan Tian
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
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16
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Ji XF, Fan YC, Sun F, Wang JW, Wang K. Noncanonical Wnt5a/JNK Signaling Contributes to the Development of D-Gal/LPS-Induced Acute Liver Failure. Inflammation 2022; 45:1362-1373. [PMID: 35098406 DOI: 10.1007/s10753-022-01627-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/12/2021] [Accepted: 01/12/2022] [Indexed: 12/24/2022]
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17
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The Protective Effects of a Modified Xiaohua Funing Decoction against Acute Liver Failure in Mice Induced by D-Gal and LPS. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:6611563. [PMID: 35069764 PMCID: PMC8776459 DOI: 10.1155/2022/6611563] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/25/2021] [Accepted: 04/23/2021] [Indexed: 01/04/2023]
Abstract
Objective The aim of this study was to evaluate the effects of a modified Xiaohua Funing decoction (Xfd) on acute liver failure (ALF) and determine whether the protective mechanisms are related to alterations in the gut microbiota. Methods An animal model of ALF was induced by intraperitoneal injection of D-galactosamine (D-Gal, 0.5 g/kg) and lipopolysaccharide (LPS, 100 μg/kg). Male BALB/c mice were randomly divided into the following 4 groups: the control group (saline, Con), model group (D-Gal/LPS, Mod), silymarin pretreatment group (200 mg/kg, Sil), and modified Xfd pretreatment group (650 mg/kg, Xfd). The Sil and Xfd groups received the respective intervention orally for 14 days and 2 h before D-Gal/LPS treatment. The liver injury markers included alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and liver histology. 16S rRNA gene sequencing was performed to assess the effects on the caecum content. Results D-Gal/LPS treatment caused severe ALF, illustrating that the ALF model was successfully established. The administration of Sil and Xfd greatly reduced the serum ALT and AST levels and improved the pathological signs of liver injury. However, no significant difference was found between the two groups. In contrast to the Mod group, the Sil and Xfd groups showed a shift toward the Con group in terms of the gut microbiota structure. The abundances of Firmicutes and Bacteroidetes and the Bacteroidetes/Firmicutes ratio in the Mod group significantly differed from those in the Con group. The Sil and Xfd groups showed restoration of the disordered microbiota. Significantly increased relative abundances of Lachnospiraceae_NK4A136_group and Candidatus_Saccharimonas and a markedly decreased Muribaculaceae abundance were found in the Sil and Xfd mice compared with those in the Mod mice (P < 0.01, P < 0.05). Interestingly, a negative correlation was observed between the abundances of the gut microbiota constituents, specifically Clostridia_UCG-014, and ALT and AST levels. Conclusion In summary, our results indicate that Xfd may protect the liver and modify the gut microbiota in ALF mice.
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Lee S, Ha J, Park J, Kang E, Jeon SH, Han SB, Ningsih S, Paik JH, Cho S. Antioxidant and Anti-Inflammatory Effects of Bischofia javanica (Blume) Leaf Methanol Extracts through the Regulation of Nrf2 and TAK1. Antioxidants (Basel) 2021; 10:antiox10081295. [PMID: 34439543 PMCID: PMC8389227 DOI: 10.3390/antiox10081295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 11/16/2022] Open
Abstract
Bischofia javanica (Blume) has been traditionally used to treat inflammatory diseases such as tonsillitis and ulcers throughout Asia, including China, Indonesia, and the Philippines: however, the molecular mechanisms by which B. javanica exerts its antioxidant and anti-inflammatory properties remain largely unknown. In this study, we analyzed the antioxidant and anti-inflammatory mechanisms of methanol extracts of B. javanica leaves (MBJ) in vitro and in vivo. MBJ decreased nitric oxide (NO) production and the expression of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, in lipopolysaccharide (LPS)-treated RAW 264.7 cells. The observed suppression of inflammatory responses by MBJ was correlated with an inhibition of the nuclear factor-κB (NF-κB) and the mitogen-activated protein kinase (MAPK) pathways. Additionally, MBJ induced nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that upregulates the expression of anti-inflammatory and antioxidant genes. Furthermore, MBJ exhibited antioxidant and anti-inflammatory effects in an acute hepatitis mouse model. In conclusion, our results confirm the medicinal properties of B. javanica, and therefore MBJ could be applied to improve inflammatory and redox imbalances in different types of pathologies.
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Affiliation(s)
- Sewoong Lee
- Laboratory of Molecular and Pharmacological Cell Biology, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea; (S.L.); (J.H.); (J.P.); (E.K.)
| | - Jain Ha
- Laboratory of Molecular and Pharmacological Cell Biology, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea; (S.L.); (J.H.); (J.P.); (E.K.)
| | - Jiyoung Park
- Laboratory of Molecular and Pharmacological Cell Biology, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea; (S.L.); (J.H.); (J.P.); (E.K.)
| | - Eunjeong Kang
- Laboratory of Molecular and Pharmacological Cell Biology, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea; (S.L.); (J.H.); (J.P.); (E.K.)
| | - Sung-Hyun Jeon
- Biomedical Mass Spectrometry Lab, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea; (S.-H.J.); (S.B.H.)
| | - Sang Beom Han
- Biomedical Mass Spectrometry Lab, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea; (S.-H.J.); (S.B.H.)
| | - Sri Ningsih
- Center for Pharmaceutical and Medical Technology, Deputy for Agroindustrial Technology and Biotechnology, The Agency for the Assessment and Application of Technology (BPPT), Jl. Raya Puspiptek, Kota Tangerang Selatan 15310, Banten, Indonesia;
| | - Jin Hyub Paik
- International Biological Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea;
| | - Sayeon Cho
- Laboratory of Molecular and Pharmacological Cell Biology, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea; (S.L.); (J.H.); (J.P.); (E.K.)
- Correspondence: ; Tel.: +82-2-820-5595; Fax: +82-2-816-7338
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Schromm AB, Paulowski L, Kaconis Y, Kopp F, Koistinen M, Donoghue A, Keese S, Nehls C, Wernecke J, Garidel P, Sevcsik E, Lohner K, Sanchez-Gomez S, Martinez-de-Tejada G, Brandenburg K, Brameshuber M, Schütz GJ, Andrä J, Gutsmann T. Cathelicidin and PMB neutralize endotoxins by multifactorial mechanisms including LPS interaction and targeting of host cell membranes. Proc Natl Acad Sci U S A 2021; 118:e2101721118. [PMID: 34183393 PMCID: PMC8271772 DOI: 10.1073/pnas.2101721118] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Antimicrobial peptides (AMPs) contribute to an effective protection against infections. The antibacterial function of AMPs depends on their interactions with microbial membranes and lipids, such as lipopolysaccharide (LPS; endotoxin). Hyperinflammation induced by endotoxin is a key factor in bacterial sepsis and many other human diseases. Here, we provide a comprehensive profile of peptide-mediated LPS neutralization by systematic analysis of the effects of a set of AMPs and the peptide antibiotic polymyxin B (PMB) on the physicochemistry of endotoxin, macrophage activation, and lethality in mice. Mechanistic studies revealed that the host defense peptide LL-32 and PMB each reduce LPS-mediated activation also via a direct interaction of the peptides with the host cell. As a biophysical basis, we demonstrate modifications of the structure of cholesterol-rich membrane domains and the association of glycosylphosphatidylinositol (GPI)-anchored proteins. Our discovery of a host cell-directed mechanism of immune control contributes an important aspect in the development and therapeutic use of AMPs.
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Affiliation(s)
- Andra B Schromm
- Division of Immunobiophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany;
| | - Laura Paulowski
- Division of Immunobiophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany
- Division of Biophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany
| | - Yani Kaconis
- Division of Biophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany
| | - Franziska Kopp
- Division of Immunobiophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany
- Division of Biophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany
| | - Max Koistinen
- Division of Biophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany
| | - Annemarie Donoghue
- Division of Biophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany
| | - Susanne Keese
- Division of Immunobiophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany
| | - Christian Nehls
- Division of Biophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany
| | - Julia Wernecke
- Division of Biophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany
- Deutsches Elektronen-Synchrotron, D-22607 Hamburg, Germany
| | - Patrick Garidel
- Biophysikalische Chemie, Martin-Luther-Universität Halle-Wittenberg, D-06108 Halle, Germany
| | - Eva Sevcsik
- Institute of Applied Physics at TU Wien, Vienna 1040, Austria
| | - Karl Lohner
- Institute of Molecular Biosciences, Biophysics Division, University of Graz, A-8010 Graz, Austria
- BioTechMed-Graz, A-8010 Graz, Austria
| | - Susana Sanchez-Gomez
- Department of Microbiology and Parasitology, University of Navarra, E-31008 Pamplona, Spain
| | - Guillermo Martinez-de-Tejada
- Department of Microbiology and Parasitology, University of Navarra, E-31008 Pamplona, Spain
- Navarra Institute for Health Research, E-31008 Pamplona, Spain
| | - Klaus Brandenburg
- Division of Biophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany
| | | | | | - Jörg Andrä
- Division of Biophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany
- Department of Biotechnology, Faculty of Life Sciences, Hamburg University of Applied Sciences, D-21033 Hamburg, Germany
| | - Thomas Gutsmann
- Division of Biophysics, Research Center Borstel, Leibniz Lung Center, D-23845 Borstel, Germany
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20
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Yue S, Wang T, Yang Y, Fan Y, Zhou L, Li M, Fu F. Lipopolysaccharide/D-galactosamine-induced acute liver injury could be attenuated by dopamine receptor agonist rotigotine via regulating NF-κB signaling pathway. Int Immunopharmacol 2021; 96:107798. [PMID: 34162160 DOI: 10.1016/j.intimp.2021.107798] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/09/2021] [Accepted: 05/16/2021] [Indexed: 02/07/2023]
Abstract
The pathological of lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced acute liver injury is similar to what is seen clinically, and be mediated by the release of pro-inflammatory mediators. A growing body of studies have shown that dopamine (DA) and DA receptor agonist are associated with inflammation and immune response. Rotigotine, a non-ergoline dopamine receptor agonist, is a drug for the treatment of Parkinson's disease. Rotigotine-loaded microspheres (RoMS) is an intramuscular extended-release agent, which can steadily release rotigotine for more than 7 days after a single administration. The present study aimed to investigate the effects of rotigotine and RoMS on inflammation and acute liver injury induced by LPS/D-Gal in mice. The LPS/D-Gal-induced liver injury was evidenced by increases of serum aminotransferases activities and liver histological lesions. Pretreatment with rotigotine or RoMS not only ameliorated the liver histologic lesions, but also reduced the activities of serum aminotransferases and the production of TNF-α. It also showed that rotigotine and RoMS increased DA receptor 2 (DRD2) expression in LPS/D-Gal-exposed mice. Rotigotine and RoMS activated β-arrestin 2, inhibited the phosphorylation of Akt, IκB and the transposition of NF-κB. In line with the above findings, the protective effects of rotigotine and RoMS were abrogated by haloperidol, a DA receptor antagonist. In conclusion, dopamine receptor agonist can regulate NF-κB inflammatory signaling pathway and exert protective effects in LPS/D-Gal-induced liver injury.
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Affiliation(s)
- Shumin Yue
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, PR China
| | - Tian Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, PR China
| | - Yunqi Yang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, PR China
| | - Yiqian Fan
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, PR China
| | - Lin Zhou
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, PR China
| | - Mingan Li
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, PR China
| | - Fenghua Fu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, PR China.
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21
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Pan M, Liu J, Huang D, Guo Y, Luo K, Yang M, Gao W, Xu Q, Zhang W, Mai K. FoxO3 Modulates LPS-Activated Hepatic Inflammation in Turbot ( Scophthalmus maximus L.). Front Immunol 2021; 12:679704. [PMID: 34276667 PMCID: PMC8281027 DOI: 10.3389/fimmu.2021.679704] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/17/2021] [Indexed: 12/19/2022] Open
Abstract
In mammals, forkhead box O3 (foxo3) plays important roles in liver immune system. The foxo3 can regulate cell cycle, DNA repair, hypoxia, apoptosis and so on. However, as such an important transcription factor, few studies on foxo3 in fish have been reported. The present study characterized the foxo3 in turbot (Scophthalmus maximus L.). Lipopolysaccharide (LPS) incubated in vitro (hepatocytes) and injected in vivo (turbot liver) were used to construct inflammatory models. The foxo3 was interfered and overexpressed to investigate its functions in liver inflammation. The open reading frame (ORF) of foxo3 was 1998 bp (base pair), encoding 665 amino acids. Sequence analysis showed that foxo3 of turbot was highly homologous to other fishes. Tissue distribution analysis revealed that the highest expression of foxo3 was in muscle. Immunofluorescence result showed that foxo3 was expressed in cytoplasm and nucleus. Knockdown of foxo3 significantly increased mRNA levels of tumor necrosis factor-α (tnf-α), interleukin-1β (il-1β), interleukin-6 (il-6), myeloid-differentiation factor 88 (myd88), cd83, toll-like receptor 2 (tlr-2) and protein level of c-Jun N-terminal kinase (JNK) in sifoxo3 + LPS (siRNA of foxo3+ LPS) group compared with NC + LPS (negative control + LPS) group in turbot hepatocytes. Overexpressed foxo3 significantly decreased mRNA levels of tnf-α, il-6, nuclear transcription factor-kappa B (nf-κb), cd83, tlr-2 and the protein level of JNK in vitro. In vivo analysis, foxo3 knockdown significantly increased levels of GOT in serum after LPS injection compared with NC+LPS group. Overexpressed foxo3 significantly decreased levels of GPT and GOT in pcDNA3.1-foxo3+LPS group compared with pcDNA3.1+LPS group in vivo. Foxo3 knockdown significantly increased mRNA levels of tnf-α, il-1β, il-6, nf-κb, myd88 and protein level of JNK in vivo in sifoxo3+LPS group compared with NC+LPS group in turbot liver. Overexpressed foxo3 significantly decreased mRNA levels of il-1β, il-6, myd88, cd83, jnk and protein level of JNK in pcDNA3.1-foxo3+LPS group compared with pcDNA3.1+LPS group in turbot liver. The results indicated that foxo3 might modulate LPS-activated hepatic inflammation in turbot by decreasing the proinflammatory cytokines, the levels of GOT and GPT as well as activating JNK/caspase-3 and tlr-2/myd88/nf-κb pathways. Taken together, these findings indicated that FoxO3 may play important roles in liver immune responses to LPS in turbot and the research of FoxO3 in liver immunity enriches the studies on immune regulation, and provides theoretical basis and molecular targets for solving liver inflammation and liver injury in fish.
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Affiliation(s)
- Mingzhu Pan
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Jiahuan Liu
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Dong Huang
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Yanlin Guo
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Kai Luo
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Mengxi Yang
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Weihua Gao
- Department of Fisheries, College of Animal Science, Yangtze University, Jingzhou, China
| | - Qiaoqing Xu
- Department of Fisheries, College of Animal Science, Yangtze University, Jingzhou, China
| | - Wenbing Zhang
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
- Department of Fisheries, College of Animal Science, Yangtze University, Jingzhou, China
| | - Kangsen Mai
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
- Department of Fisheries, College of Animal Science, Yangtze University, Jingzhou, China
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22
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Hu B, Ge C, Zhu C. USP18 negatively regulates and inhibits lipopolysaccharides-induced sepsis by targeting TAK1 activity. Int Immunol 2021; 33:461-468. [PMID: 34423815 DOI: 10.1093/intimm/dxab029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/09/2021] [Indexed: 12/12/2022] Open
Abstract
Sepsis is an inflammatory disease with exacerbated inflammation at early stage. Inflammatory cytokines play critical roles in the pathophysiology of sepsis. Ubiquitin specific peptidase 18 (USP18), a deubiquitinating enzyme, has been shown to modulate transforming growth factor-β-activated kinase 1 (TAK1) activity. However, it is not clear about the precise role of USP18 in sepsis. Here we investigated the potential effect of USP18 on inflammation in sepsis. We generated mice with USP18 or/and TAK1 deficiency in macrophages (USP18 MKO mice, TAK1 MKO mice and USP18 MKO TAK1 MKO mice) and established lipopolysaccharides (LPS)-induced septic mice model. Bone marrow derived macrophages were isolated from wild type (WT), USP18 MKO or TAK1 MKO mice and treated with LPS or CpG, the expressions of cytokines including IL-6, IL-10, IL-1β, and TNF-α were measured. The activation of NF-κB, ERK, p38 signaling pathways and ubiquitination of TAK1 were detected. We induced sepsis in WT, USP18 MKO, TAK1 MKO or USP18 MKO TAK1 MKO mice and evaluated the survival rate, lung pathology and inflammation cytokine level in serum. Macrophages deficient in USP18 produced significantly increased IL-6, IL-1β and TNF-α post LPS or CpG stimulation. Macrophages deficient in USP18 had promoted activation of NF-κB, p38 and ERK, and increased ubiquitination of TAK1. Mice with TAK1 deficiency in macrophages had increased survival rates, decreased immune cell infiltration in lung, and decreased pro-inflammatory cytokines in serum. In contrast, mice with USP18 deficiency in macrophages had decreased survival rates, increased cell infiltration in lung and increased pro-inflammatory cytokines in serum. USP18 alleviated LPS-induced sepsis by inhibiting TAK1 activity.
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Affiliation(s)
- Bin Hu
- Department of Emergency, Heze Municipal Hospital, Heze, Shandong, China
| | - Chunhua Ge
- Department of Emergency, Heze Municipal Hospital, Heze, Shandong, China
| | - Chunqing Zhu
- Department of Emergency, Heze Municipal Hospital, Heze, Shandong, China
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23
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Olivero-Verbel J, Harkema JR, Roth RA, Ganey PE. Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, blocks steatosis and alters the inflammatory response in a mouse model of inflammation-dioxin interaction. Chem Biol Interact 2021; 345:109521. [PMID: 34052195 DOI: 10.1016/j.cbi.2021.109521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/07/2021] [Accepted: 05/14/2021] [Indexed: 12/01/2022]
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin; TCDD) is an environmental contaminant that elicits a variety of toxic effects, many of which are mediated through activation of the aryl hydrocarbon receptor (AhR). Interaction between AhR and the peroxisome proliferator-activated receptor-alpha (PPAR-α), which regulates fatty acid metabolism, has been suggested. Furthermore, with recognition of the prevalence of inflammatory conditions, there is current interest in the potential for inflammatory stress to modulate the response to environmental agents. The aim of this work was to assess the interaction of TCDD with hepatic inflammation modulated by fenofibrate, a PPAR-α agonist. Female, C57BL/6 mice were treated orally with vehicle or fenofibrate (250 mg/kg) for 13 days, and then were given vehicle or 30 μg/kg TCDD. Four days later, the animals received an i.p. injection of lipopolysaccharide-galactosamine (LPS-GalN) (0.05x107 EU/kg and 500 mg/kg, respectively) to incite inflammation, or saline as vehicle control. After 4 h, the mice were euthanized, and blood and liver samples were collected for analysis. Livers of animals treated with TCDD with or without LPS-GalN had increased lipid deposition, and this effect was blocked by fenofibrate. In TCDD/LPS-GalN-treated mice, fenofibrate caused an increase in plasma activity of alanine aminotransferase, a marker of hepatocellular injury. TCDD reduced LPS-GalN-induced apoptosis, an effect that was prevented by fenofibrate pretreatment. LPS-GalN induced an increase in the concentration of interleukin-6 in plasma and accumulation of neutrophils in liver. TCDD exposure enhanced the former response and inhibited the latter one. These results suggest that fenofibrate counteracts the changes in lipid metabolism induced by TCDD but increases inflammation and liver injury in this model of inflammation-TCDD interaction.
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Affiliation(s)
- Jesus Olivero-Verbel
- Department of Pharmacology and Toxicology. Michigan State University, East Lansing, MI, USA; Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, University of Cartagena, Cartagena, 130014, Colombia
| | - Jack R Harkema
- Department of Pathobiology and Diagnostic Investigation, Institute for Integrative Toxicology, Michigan State University, USA
| | - Robert A Roth
- Department of Pharmacology and Toxicology. Michigan State University, East Lansing, MI, USA
| | - Patricia E Ganey
- Department of Pharmacology and Toxicology. Michigan State University, East Lansing, MI, USA.
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24
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Starikova E, Mammedova J, Ozhiganova A, Lebedeva A, Malashicheva A, Semenova D, Khokhlova E, Mameli E, Caporali A, Wills J, Sokolov A. Protective Role of Mytilus edulis Hydrolysate in Lipopolysaccharide-Galactosamine Acute Liver Injury. Front Pharmacol 2021; 12:667572. [PMID: 34084140 PMCID: PMC8167060 DOI: 10.3389/fphar.2021.667572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 04/19/2021] [Indexed: 12/02/2022] Open
Abstract
Acute liver injury in its terminal phase trigger systemic inflammatory response syndrome with multiple organ failure. An uncontrolled inflammatory reaction is difficult to treat and contributes to high mortality. Therefore, to solve this problem a search for new therapeutic approaches remains urgent. This study aimed to explore the protective effects of M. edulis hydrolysate (N2-01) against Lipopolysaccharide-D-Galactosamine (LPS/D-GalN)-induced murine acute liver injure and the underlying mechanisms. N2-01 analysis, using Liquid Chromatography Mass Spectrometry (LCMS) metabolomic and proteomic platforms, confirmed composition, molecular-weight distribution, and high reproducibility between M. edulis hydrolysate manufactured batches. N2-01 efficiently protected mice against LPS/D-GalN-induced acute liver injury. The most prominent result (100% survival rate) was obtained by the constant subcutaneous administration of small doses of the drug. N2-01 decreased Vascular Cell Adhesion Molecule-1 (VCAM-1) expression from 4.648 ± 0.445 to 1.503 ± 0.091 Mean Fluorescence Intensity (MFI) and Interleukin-6 (IL-6) production in activated Human Umbilical Vein Endothelial Cells (HUVECs) from 7.473 ± 0.666 to 2.980 ± 0.130 ng/ml in vitro. The drug increased Nitric Oxide (NO) production by HUVECs from 27.203 ± 2.890 to 69.200 ± 4.716 MFI but significantly decreased inducible Nitric Oxide Synthase (iNOS) expression from 24.030 ± 2.776 to 15.300 ± 1.290 MFI and NO production by murine peritoneal lavage cells from 6.777 ± 0.373 µm to 2.175 ± 0.279 µm. The capability of the preparation to enhance the endothelium barrier function and to reduce vascular permeability was confirmed in Electrical Cell-substrate Impedance Sensor (ECIS) test in vitro and Miles assay in vivo. These results suggest N2-01 as a promising agent for treating a wide range of conditions associated with uncontrolled inflammation and endothelial dysfunction.
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Affiliation(s)
- Eleonora Starikova
- Laboratory of Immunoregulation, Department of Immunology, Institute of Experimental Medicine, St. Petersburg, Russian Federation
| | - Jennet Mammedova
- Laboratory of General Immunology, Department of Immunology, Institute of Experimental Medicine, St. Petersburg, Russian Federation
| | - Arina Ozhiganova
- Laboratory of Immunoregulation, Department of Immunology, Institute of Experimental Medicine, St. Petersburg, Russian Federation
| | - Aleksandra Lebedeva
- Laboratory of Immunoregulation, Department of Immunology, Institute of Experimental Medicine, St. Petersburg, Russian Federation
| | - Anna Malashicheva
- Laboratory of Molecular Cardiology, Almazov National Medical Research Centre, St. Petersburg, Russian Federation.,Laboratory of Regenerative Biomedicine, Institute of Cytology RAS, St. Petersburg, Russian Federation
| | - Daria Semenova
- Laboratory of Molecular Cardiology, Almazov National Medical Research Centre, St. Petersburg, Russian Federation.,Laboratory of Regenerative Biomedicine, Institute of Cytology RAS, St. Petersburg, Russian Federation
| | - Evgeniia Khokhlova
- Laboratory of Regenerative Biomedicine, Institute of Cytology RAS, St. Petersburg, Russian Federation
| | - Eleonora Mameli
- Laboratory of Vascular Biology, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Andrea Caporali
- Laboratory of Vascular Biology, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Jimi Wills
- Cancer Research United Kingdom Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Alexey Sokolov
- Laboratory of Biochemical Genetics, Department of Molecular Genetics, Institute of Experimental Medicine, St. Petersburg, Russian Federation
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25
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Guo Y, Cui Q, Ren S, Hao D, Morikawa T, Wang D, Liu X, Pan Y. The hepatoprotective efficacy and biological mechanisms of three phenylethanoid glycosides from cistanches herba and their metabolites based on intestinal bacteria and network pharmacology. J Nat Med 2021; 75:784-797. [PMID: 34003414 DOI: 10.1007/s11418-021-01508-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 03/20/2021] [Indexed: 12/16/2022]
Abstract
Echinacoside (ECH), acteoside (ACT), and isoacteoside (ISAT), the typical phenylethanoid glycosides (PhGs) in cistanches herba, have various pharmacological activities. However, the ECH, ACT and ISAT have extremely low oral bioavailability, which is related to their metabolism under the intestinal flora. Previous studies showed that intestinal metabolites were the hepatoprotective substances in vivo, but the research on whether PhGs has effects without intestinal bacteria has not been studied. In this paper, ECH, ACT and ISAT were incubated with human or rat intestinal bacteria for 36 h. After incubating with human bacteria for 36 h, three prototype compounds were not detected and were mainly biotransformed to 3-HPP and HT. In the network pharmacology, a total of 6 common targets were obtained by analysing the prototypes, the metabolites and the liver injury. It was found that the combinations of three metabolites and common targets were more stable than those of the prototypes and common targets by molecular docking. Meanwhile, hepatocellular apoptosis, proliferation, inflammation and oxidative responses might play important roles in the mechanisms of the metabolites exerting hepatoprotective activities. Then normal and pseudo-sterile mice experiments were adopted to further compare the hepatoprotective activities of prototypes and metabolites. Animal experiment results showed that the prototypes and the metabolites in the normal mice had significantly hepatoprotective activity. Interestingly, in the pseudo-germfree mice, the metabolites showed significant hepatoprotective effect, but the prototypes had not effect. It indicated that the prototype cannot exert liver protective activity without the effect of intestinal bacteria.
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Affiliation(s)
- Yongli Guo
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Qingling Cui
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Shumeng Ren
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Deguo Hao
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Toshio Morikawa
- Pharmaceutical Research and Technology Institute, Joint Research Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka, 577-8502, Japan
| | - Dongmei Wang
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Xiaoqiu Liu
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Yingni Pan
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China.
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Kim H, Yang WS, Htwe KM, Lee MN, Kim YD, Yoon KD, Lee BH, Lee S, Cho JY. Dipterocarpus tuberculatus Roxb. Ethanol Extract Has Anti-Inflammatory and Hepatoprotective Effects In Vitro and In Vivo by Targeting the IRAK1/AP-1 Pathway. Molecules 2021; 26:molecules26092529. [PMID: 33926126 PMCID: PMC8123704 DOI: 10.3390/molecules26092529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 11/28/2022] Open
Abstract
Dipterocarpus tuberculatus Roxb. has been used traditionally as a remedy for many diseases, especially inflammation. Therefore, we analyzed and explored the mechanism of the anti-inflammatory effect of a Dipterocarpus tuberculatus Roxb. ethanol extract (Dt-EE). Dt-EE clearly and dose-dependently inhibited the expression of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β in lipopolysaccharide (LPS)-treated RAW264.7 cells. Also, Dt-EE suppressed the activation of the MyD88/TRIF-mediated AP-1 pathway and the AP-1 pathway related proteins JNK2, MKK4/7, and TAK1, which occurred as a result of inhibiting the kinase activity of IRAK1 and IRAK4, the most upstream factors of the AP-1 pathway. Finally, Dt-EE displayed hepatoprotective activity in a mouse model of hepatitis induced with LPS/D-galactosamine (D-GalN) through decreasing the serum levels of alanine aminotransferase and suppressing the activation of JNK and IRAK1. Therefore, our results strongly suggest that Dt-EE could be a candidate anti-inflammatory herbal medicine with IRAK1/AP-1 inhibitory and hepatoprotective properties.
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Affiliation(s)
- Haeyeop Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Korea; (H.K.); (W.S.Y.)
| | - Woo Seok Yang
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Korea; (H.K.); (W.S.Y.)
| | - Khin Myo Htwe
- Popa Mountain Park, Forest Department, Kyaukpadaung Township, Mandalay Division, Kyaukpadaung 05241, Myanmar;
| | - Mi-Nam Lee
- Department of Hospitality and Culinary, Ansan University, Ansan 15318, Korea;
| | - Young-Dong Kim
- Department of Life Science, Hallym University, Chuncheon 200-702, Korea;
| | - Ki Dong Yoon
- College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea;
| | - Byoung-Hee Lee
- National Institute of Biological Resources, Environmental Research Complex, Incheon 22689, Korea;
| | - Sarah Lee
- National Institute of Biological Resources, Environmental Research Complex, Incheon 22689, Korea;
- Correspondence: (S.L.); (J.Y.C.); Tel.: +82-32-590-7265 (S.L.); +82-31-290-7868 (J.Y.C.); Fax: +82-32-590-7472 (S.L.); +82-31-290-7870 (J.Y.C.)
| | - Jae Youl Cho
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Korea; (H.K.); (W.S.Y.)
- Correspondence: (S.L.); (J.Y.C.); Tel.: +82-32-590-7265 (S.L.); +82-31-290-7868 (J.Y.C.); Fax: +82-32-590-7472 (S.L.); +82-31-290-7870 (J.Y.C.)
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27
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Ansari MA, Raish M, Bin Jardan YA, Ahmad A, Shahid M, Ahmad SF, Haq N, Khan MR, Bakheet SA. Sinapic acid ameliorates D-galactosamine/lipopolysaccharide-induced fulminant hepatitis in rats: Role of nuclear factor erythroid-related factor 2/heme oxygenase-1 pathways. World J Gastroenterol 2021; 27:592-608. [PMID: 33642831 PMCID: PMC7901048 DOI: 10.3748/wjg.v27.i7.592] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/30/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sinapic acid (SA) has been shown to have various pharmacological properties such as antioxidant, antifibrotic, anti-inflammatory, and anticancer activities. Its mechanism of action is dependent upon its ability to curb free radical production and protect against oxidative stress-induced tissue injuries. AIM To study the hepatoprotective effects of SA against lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver failure (ALF) in rats. METHODS Experimental ALF was induced with an intraperitoneal (i.p.) administration of 8 μg LPS and 800 mg/kg D-GalN in normal saline. SA was administered orally once daily starting 7 d before LPS/D-GalN treatment. RESULTS Data showed that SA ameliorates acute liver dysfunction, decreases serum levels of alanine transaminase (ALT), and aspartate aminotransferase (AST), as well as malondialdehyde (MDA) and NO levels in ALF model rats. However, pretreatment with SA (20 mg/kg and 40 mg/kg) reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and levels of inflammatory cytokines (tumor necrosis factor-α and interleukin 6). Also, SA increased the activity of the nuclear factor erythroid-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway. CONCLUSION In conclusion, SA offers significant protection against LPS/D-GalN-induced ALF in rats by upregulating Nrf2/HO-1 and downregulating NF-κB.
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Affiliation(s)
- Mushtaq Ahmad Ansari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad Raish
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Yousef A Bin Jardan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ajaz Ahmad
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mudassar Shahid
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sheikh Fayaz Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Nazrul Haq
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad Rashid Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Saleh A Bakheet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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Li S, Hu K, Li L, Shen Y, Huang J, Tang L, Zhang L, Shao R, Lu H, Yang Y. Stattic alleviates acute hepatic damage induced by LPS/d-galactosamine in mice. Innate Immun 2021; 27:201-209. [PMID: 33576722 PMCID: PMC7882804 DOI: 10.1177/1753425920988330] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/17/2020] [Accepted: 12/28/2020] [Indexed: 01/21/2023] Open
Abstract
Increasing evidence indicates that signal transducer and activator of transcription 3 (STAT3), a vital transcription factor, plays crucial roles in the regulation of inflammation. STAT3 has become a novel therapeutic target for intervention in inflammation-related disorders. However, it remains unclear whether STAT3 plays a part in acute hepatic damage. To investigate the effects of STAT3 here, LPS/d-GalN-induced hepatic damage was induced in mice, the STAT3 inhibitor Stattic was administered, and the degree of liver injury, inflammation, and hepatocyte apoptosis were investigated. The results showed that Stattic mitigated the hepatic morphologic abnormalities and decreased the level of aminotransferase in LPS/D-GalN-insulted mice. The results also indicated that Stattic decreased the levels of TNF-α and IL-6, prevented the activation of the caspase cascade, suppressed cleavage of PARP, and decreased the quantity of TUNEL-positive cells. These results suggest that Stattic provided protective benefits in LPS/d-GalN-induced hepatic damage, and the protective effects might be associated with its anti-inflammatory and anti-apoptotic effects. Therefore, STAT3 might become a novel target for intervening in inflammation-based and apoptosis-based hepatic disorders.
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Affiliation(s)
- Sijia Li
- Department of Pathophysiology, Chongqing Medical University, China
| | - Kai Hu
- Department of Pathophysiology, Chongqing Medical University, China
| | - Longjiang Li
- Department of Pathophysiology, Chongqing Medical University, China
| | - Yi Shen
- Department of Pathophysiology, Chongqing Medical University, China
| | - Jiayi Huang
- Department of Pathophysiology, Chongqing Medical University, China
| | - Li Tang
- Department of Pathophysiology, Chongqing Medical University, China
| | - Li Zhang
- Department of Pathophysiology, Chongqing Medical University, China
| | - Ruyue Shao
- Clinical Medical School, Chongqing Medical and Pharmaceutical College, China
- Chongqing Engineering Research Center of Pharmaceutical Sciences, China
| | - Han Lu
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Yongqiang Yang
- Department of Pathophysiology, Chongqing Medical University, China
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Schromm AB, Brandenburg K. TLR4 Ligands: Single Molecules and Aggregates. PROGRESS IN INFLAMMATION RESEARCH 2021:39-56. [DOI: 10.1007/978-3-030-56319-6_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Rasineni K, Lee SML, McVicker BL, Osna NA, Casey CA, Kharbanda KK. Susceptibility of Asialoglycoprotein Receptor-Deficient Mice to Lps/Galactosamine Liver Injury and Protection by Betaine Administration. BIOLOGY 2020; 10:biology10010019. [PMID: 33396223 PMCID: PMC7823640 DOI: 10.3390/biology10010019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 12/27/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Work from our laboratory has shown that the ethanol-induced increase in apoptotic hepatocellular death is closely related to the impairment in the ability of the asialoglycoprotein receptor (ASGP-R) to remove neighboring apoptotic cells. In this study, we assessed the role of ASGP-R in fulminant liver failure and investigated whether prior treatment with betaine (a naturally occurring tertiary amine) is protective. METHODS Lipopolysaccharide (LPS; 50 μg/kg BW) and galactosamine (GalN; 350 mg/kg BW) were injected together to wild-type and ASGP-R-deficient mice that were treated for two weeks prior with or without 2% betaine in drinking water. The mice were sacrificed 1.5, 3, or 4.5 h post-injection, and tissue samples were collected. RESULTS LPS/GalN injection generate distinct molecular processes, which includes increased production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), thus causing apoptosis as evident by increased caspase-3 activity. ASGP-R deficient animals showed increased liver caspase activities, serum TNF-α and IL-6 levels, as well as more pronounced liver damage compared with the wild-type control animals after intraperitoneal injection of LPS/GalN. In addition, prior administration of betaine was found to significantly attenuate the LPS/GalN-induced increases in liver injury parameters. CONCLUSION Our work underscores the importance of normal functioning of ASGP-R in preventing severe liver damage and signifies a therapeutic role of betaine in prevention of liver injuries from toxin-induced fulminant liver failure.
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Affiliation(s)
- Karuna Rasineni
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Serene M. L. Lee
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Benita L. McVicker
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Natalia A. Osna
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Carol A. Casey
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Correspondence: ; Tel.: +1-402-995-3752; Fax: +1-402-995-4600
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Yousif AS, Ronsard L, Shah P, Omatsu T, Sangesland M, Bracamonte Moreno T, Lam EC, Vrbanac VD, Balazs AB, Reinecker HC, Lingwood D. The persistence of interleukin-6 is regulated by a blood buffer system derived from dendritic cells. Immunity 2020; 54:235-246.e5. [PMID: 33357409 PMCID: PMC7836640 DOI: 10.1016/j.immuni.2020.12.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 10/17/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022]
Abstract
The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro-inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions.
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Affiliation(s)
- Ashraf S Yousif
- The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA
| | - Larance Ronsard
- The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA
| | - Pankaj Shah
- The Center for the Study of Inflammatory Bowel Disease, Center for Computational and Integrative Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
| | - Tatsushi Omatsu
- The Center for the Study of Inflammatory Bowel Disease, Center for Computational and Integrative Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
| | - Maya Sangesland
- The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA
| | - Thalia Bracamonte Moreno
- The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA
| | - Evan C Lam
- The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA
| | - Vladimir D Vrbanac
- The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA
| | - Alejandro B Balazs
- The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA
| | - Hans-Christian Reinecker
- The Center for the Study of Inflammatory Bowel Disease, Center for Computational and Integrative Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; The Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
| | - Daniel Lingwood
- The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA.
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Brandenburg K, Schromm AB, Weindl G, Heinbockel L, Correa W, Mauss K, Martinez de Tejada G, Garidel P. An update on endotoxin neutralization strategies in Gram-negative bacterial infections. Expert Rev Anti Infect Ther 2020; 19:495-517. [PMID: 33210958 DOI: 10.1080/14787210.2021.1834847] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Gram-negative bacterial infections represent still a severe problem of human health care, regarding the increase in multi-resistance against classical antibiotics and the lack of newly developed antimicrobials. For the fight against these germs, anti-infective agents must overcome and/or bind to the Gram-negative outer membrane consisting of a lipopolysaccharide (LPS, endotoxin) outer leaflet and an inner leaflet from phospholipids, with additional peripheral or integral membrane proteins (OMP's). AREAS COVERED The current article reviews data of existing therapeutic options and summarizes newer approaches for targeting and neutralizing endotoxins, ranging from in vitro over in vivo animal data to clinical applications by using databases such as Medline. EXPERT OPINION Conventional antibiotic treatment of the bacteria leads to their killing, but not necessary LPS neutralization, which may be a severe problem in particular for the systemic pathway. This is the reason why there is an increasing number of therapeutic approaches, which - besides combating whole bacteria - at the same time try to neutralize endotoxin within or outside the bacterial cells mainly responsible for the high inflammation induction in Gram-negative species.
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Affiliation(s)
- Klaus Brandenburg
- Brandenburg Antiinfektiva GmbH, c/o Forschungszentrum Borstel, Borstel, Germany
| | - Andra B Schromm
- FG Immunobiophysik, Forschungszentrum Borstel, Leibniz Lungenzentrum, Borstel, Germany
| | - Günther Weindl
- Brandenburg Antiinfektiva GmbH, c/o Forschungszentrum Borstel, Borstel, Germany.,Universität Bonn, Universität Bonn Pharmazeutisches Institut Pharmakologie Und Toxikologie Bonn, Germany
| | - Lena Heinbockel
- Brandenburg Antiinfektiva GmbH, c/o Forschungszentrum Borstel, Borstel, Germany
| | - Wilmar Correa
- FG Biophysik, Forschungszentrum Borstel, Leibniz Lungenzentrum, Borstel, Germany
| | - Karl Mauss
- Brandenburg Antiinfektiva GmbH, c/o Forschungszentrum Borstel, Borstel, Germany.,Asklepios-Klinik Hamburg-Altona, Hamburg, Germany
| | - Guillermo Martinez de Tejada
- Department of Microbiology and Parasitology, University of Navarra, E-31008 Pamplona, Spain and Navarra Institute for Health Research (Idisna), Pamplona, Spain.,Department de Microbiologia, Universidad De Navarra, Pamplona, Spain
| | - Patrick Garidel
- Martin-Luther-Universität Halle-Wittenberg, Institut für Chemie, Halle/Saale, Germany
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Zhang W, Tao SS, Wang T, Li YT, Chen H, Zhan YQ, Yu M, Ge CH, Li CY, Ren GM, Yin RH, Yang XM. NLRP3 is dispensable for d-galactosamine/lipopolysaccharide-induced acute liver failure. Biochem Biophys Res Commun 2020; 533:1184-1190. [PMID: 33041005 DOI: 10.1016/j.bbrc.2020.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 10/02/2020] [Indexed: 12/01/2022]
Abstract
The nucleotide-binding domain and leucine-rich repeat-containing family pyrin domain containing 3 (NLRP3) inflammasome is involved in various acute and chronic liver diseases, however, it is not clear whether NLRP3 contributes to d-Galactosamine (D-GalN) plus lipopolysaccharide (LPS)-induced acute liver failure (ALF). This study aims to investigate the role of NLRP3 inflammasome in D-GalN/LPS-induced fatal hepatitis. We found that Nlrp3-/- and WT mice showed similar mortality against a lethal dose of D-GalN/LPS treatment. Serum ALT and AST levels, as well as liver necrosis area and hepatocyte apoptosis, were not significantly different between Nlrp3-/- and WT mice at 6 h after D-GalN/LPS injection. Moreover, the numbers of intrahepatic F4/80+ cells and Ly6G+ cells were comparable in two genotype mice following D-GalN/LPS treatment. Besides, Nlrp3-/- mice had reduced IL-1β levels but similar TNF-α, IL-6, and MCP-1 levels compared with WT mice upon D-GalN/LPS administration. Our findings revealed that NLRP3 ablation does not protect mice from D-GalN/LPS-induced fatal hepatitis and has a marginal effect on intrahepatic inflammatory response upon D-GalN/LPS treatment. This suggests that NLRP3 inflammasome does not appear to be a major contributor to D-GalN/LPS-induced ALF.
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Affiliation(s)
- Wen Zhang
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Shou-Song Tao
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Ting Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China; School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Ya-Ting Li
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Hui Chen
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Yi-Qun Zhan
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Miao Yu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Chang-Hui Ge
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Chang-Yan Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Guang-Ming Ren
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
| | - Rong-Hua Yin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
| | - Xiao-Ming Yang
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China; School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui Province, China.
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The Central Role and Possible Mechanisms of Bacterial DNAs in Sepsis Development. Mediators Inflamm 2020; 2020:7418342. [PMID: 32934605 PMCID: PMC7479481 DOI: 10.1155/2020/7418342] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 07/20/2020] [Indexed: 12/20/2022] Open
Abstract
The pathological roles of bacterial DNA have been documented many decades ago. Bacterial DNAs are different from mammalian DNAs; the latter are heavily methylated. Mammalian cells have sensors such as TLR-9 to sense the DNAs with nonmethylated CpGs and distinguish them from host DNAs with methylated CpGs. Further investigation has identified many other types of DNA sensors distributed in a variety of cellular compartments. These sensors not only sense foreign DNAs, including bacterial and viral DNAs, but also sense damaged DNAs from the host cells. The major downstream signalling pathways includeTLR-9-MyD88-IKKa-IRF-7/NF-κB pathways to increase IFN/proinflammatory cytokine production, STING-TBK1-IRF3 pathway to increase IFN-beta, and AIM2-ASC-caspas-1 pathway to release IL-1beta. The major outcome is to activate host immune response by inducing cytokine production. In this review, we focus on the roles and potential mechanisms of DNA sensors and downstream pathways in sepsis. Although bacterial DNAs play important roles in sepsis development, bacterial DNAs alone are unable to cause severe disease nor lead to death. Priming animals with bacterial DNAs facilitate other pathological factors, such as LPS and other virulent factors, to induce severe disease and lethality. We also discuss compartmental distribution of DNA sensors and pathological significance as well as the transport of extracellular DNAs into cells. Understanding the roles of DNA sensors and signal pathways will pave the way for novel therapeutic strategies in many diseases, particularly in sepsis.
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Koepsell H. Glucose transporters in the small intestine in health and disease. Pflugers Arch 2020; 472:1207-1248. [PMID: 32829466 PMCID: PMC7462918 DOI: 10.1007/s00424-020-02439-5] [Citation(s) in RCA: 148] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/11/2020] [Accepted: 07/17/2020] [Indexed: 12/23/2022]
Abstract
Absorption of monosaccharides is mainly mediated by Na+-D-glucose cotransporter SGLT1 and the facititative transporters GLUT2 and GLUT5. SGLT1 and GLUT2 are relevant for absorption of D-glucose and D-galactose while GLUT5 is relevant for D-fructose absorption. SGLT1 and GLUT5 are constantly localized in the brush border membrane (BBM) of enterocytes, whereas GLUT2 is localized in the basolateral membrane (BLM) or the BBM plus BLM at low and high luminal D-glucose concentrations, respectively. At high luminal D-glucose, the abundance SGLT1 in the BBM is increased. Hence, D-glucose absorption at low luminal glucose is mediated via SGLT1 in the BBM and GLUT2 in the BLM whereas high-capacity D-glucose absorption at high luminal glucose is mediated by SGLT1 plus GLUT2 in the BBM and GLUT2 in the BLM. The review describes functions and regulations of SGLT1, GLUT2, and GLUT5 in the small intestine including diurnal variations and carbohydrate-dependent regulations. Also, the roles of SGLT1 and GLUT2 for secretion of enterohormones are discussed. Furthermore, diseases are described that are caused by malfunctions of small intestinal monosaccharide transporters, such as glucose-galactose malabsorption, Fanconi syndrome, and fructose intolerance. Moreover, it is reported how diabetes, small intestinal inflammation, parental nutrition, bariatric surgery, and metformin treatment affect expression of monosaccharide transporters in the small intestine. Finally, food components that decrease D-glucose absorption and drugs in development that inhibit or downregulate SGLT1 in the small intestine are compiled. Models for regulations and combined functions of glucose transporters, and for interplay between D-fructose transport and metabolism, are discussed.
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Affiliation(s)
- Hermann Koepsell
- Institute for Anatomy and Cell Biology, University of Würzburg, Koellikerstr 6, 97070, Würzburg, Germany.
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36
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Protective effect of diosgenin on LPS/D-Gal-induced acute liver failure in C57BL/6 mice. Microb Pathog 2020; 146:104243. [DOI: 10.1016/j.micpath.2020.104243] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 02/20/2020] [Accepted: 04/30/2020] [Indexed: 12/28/2022]
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Exacerbated LPS/GalN-Induced Liver Injury in the Stress-Sensitive Wistar Kyoto Rat Is Associated with Changes in the Endocannabinoid System. Molecules 2020; 25:molecules25173834. [PMID: 32842550 PMCID: PMC7504576 DOI: 10.3390/molecules25173834] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 08/14/2020] [Accepted: 08/20/2020] [Indexed: 02/08/2023] Open
Abstract
Acute liver injury (ALI) is a highly destructive and potentially life-threatening condition, exacerbated by physical and psychological stress. The endocannabinoid system plays a key role in modulating stress and hepatic function. The aim of this study was to examine the development of acute liver injury in the genetically susceptible stress-sensitive Wistar-Kyoto (WKY) rat compared with normo-stress-sensitive Sprague Dawley (SD) rats, and associated changes in the endocannabinoid system. Administration of the hepatotoxin lipopolysaccharide/D-Galactosamine (LPS/GalN) resulted in marked liver injury in WKY, but not SD rats, with increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH) plasma levels, significant histopathological changes, increased hepatic pro-inflammatory cytokine expression and caspase-3 activity and expression and reduced Glutathione (GSH) activity. Furthermore, compared to SD controls, WKY rats display increased anandamide and 2-Arachidonoylglycerol levels concurrent with decreased expression of their metabolic enzymes and a decrease in cannabinoid (CB)1 receptor expression following LPS/GalN. CB1 antagonism with AM6545 or CB2 agonism with JWH133 did not alter LPS/GalN-induced liver injury in SD or WKY rats. These findings demonstrate exacerbation of acute liver injury induced by LPS/GalN in a stress-sensitive rat strain, with effects associated with alterations in the hepatic endocannabinoid system. Further studies are required to determine if the endocannabinoid system mediates or modulates the exacerbation of liver injury in this stress-sensitive rat strain.
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Hu C, Zhao L, Shen M, Wu Z, Li L. Autophagy regulation is an effective strategy to improve the prognosis of chemically induced acute liver injury based on experimental studies. J Cell Mol Med 2020; 24:8315-8325. [PMID: 32627386 PMCID: PMC7412417 DOI: 10.1111/jcmm.15565] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 05/25/2020] [Accepted: 06/16/2020] [Indexed: 12/12/2022] Open
Abstract
Acute liver injury (ALI) induced by chemicals in current experimental studies is characterized by inflammation, oxidative stress and necrosis, which can greatly influence the long-term outcome and lead to liver failure. In liver cells, different autophagy forms envelop cytoplasm components, including proteins, endoplasmic reticulum (ER), mitochondria and lipids, and they effectively participate in breaking down the cargo enclosed inside lysosomes to replenish cellular energy and contents. In general, autophagy serves as a cell survival mechanism in stressful microenvironments, but it also serves as a destructive mechanism that results in cell death in vitro and in vivo. In experimental animals, multiple chemicals are used to mimic ALI in patients to clarify the potential pathological mechanisms and develop effective strategies in the clinic. In this review, we summarize related publications about autophagy modulation to attenuate chemically induced ALI in vitro and in vivo. We also analysed the underlying mechanisms of autophagy regulators and genetic modifications to clarify how to control autophagy to protect against chemically induced ALI in animal models. We anticipate that selectively controlling the dual effects of hepatic autophagy will help to protect against ALI in various animals, but the detailed mechanisms and effects should be determined further in future studies. In this way, we are more confident that modulating autophagy in liver regeneration can improve the prognosis of ALI.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious DiseasesState Key Laboratory for the Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
- National Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
| | - Lingfei Zhao
- Key Laboratory of Kidney Disease Prevention and Control TechnologyKidney Disease CenterInstitute of NephrologyFirst Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouPR China
| | - Miaoda Shen
- Department of OrthopedicsThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
| | - Zhongwen Wu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious DiseasesState Key Laboratory for the Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
- National Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
| | - Lanjuan Li
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious DiseasesState Key Laboratory for the Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
- National Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
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Zhuge A, Li B, Yuan Y, Lv L, Li Y, Wu J, Yang L, Bian X, Wang K, Wang Q, Yan R, Zhu X, Li L. Lactobacillus salivarius LI01 encapsulated in alginate-pectin microgels ameliorates D-galactosamine-induced acute liver injury in rats. Appl Microbiol Biotechnol 2020; 104:7437-7455. [PMID: 32666187 DOI: 10.1007/s00253-020-10749-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/01/2020] [Accepted: 06/16/2020] [Indexed: 12/13/2022]
Abstract
Acute liver failure is a clinical emergency associated with high mortality. Accumulating evidence indicates that gut microbiota participates in the progression of liver injury, and preventive therapies based on altering gut microbiota are of great interest. Previous studies demonstrated that Lactobacillus salivarius LI01 attenuates hepatic injury, though efficiency in curtailed in the harsh environment in the gastrointestinal tract. In this study, a system to encapsulate LI01 in alginate-pectin (AP) microgels was investigated. Encapsulation significantly enhances probiotic viability for long-term storage and heat treatment, and in simulated gastrointestinal fluids (SGF or SIF) and bile salt solutions. Acute liver injury was induced in Sprague-Dawley (SD) rats by D-galactosamine (D-GaIN) injection following pretreatment with probiotics. Liver and gut barrier function, cytokines, liver and gut histology, bacterial translocation, and gut microbiota were assessed. Administration of encapsulated LI01 more effectively upregulates hepatic anti-inflammatory cytokine IL-10 and TLR-3, restores expressions of gut barrier biomarkers Claudin-1 and MUC2 and attenuates destruction of mucosal ultrastructure compared with unencapsulated probiotics pretreatment. Pretreatment with AP-LI01 microgels altered the microbial community, decreasing the abundance of pathogenic taxa Ruminiclostridium, Dorea and Ruminococcaceae_UCG-004 and enriching beneficial taxa Ruminococcaceae_UCG-014, Eubacterium, and Prevotella_1 that produce short-chain fatty acids. These results suggest that AP encapsulation of LI01 boosts viability and attenuates liver injury by reducing inflammation and restoring intestinal barrier function. These beneficial effects are probably due to alternation of gut flora. These findings provide new insight into encapsulation technology and prevention of liver failure. KEY POINTS: • Alginate-pectin encapsulation enhances the viability of Lactobacillus salivarius LI01 under simulated commercial conditions and simulated gastrointestinal environment. • AP-LI01 microgel attenuates hepatic and intestinal inflammation and restores gut barrier function. • AP-LI01 microgel alters gut microbial community with increased SCFAs producers and decreased pathogenic microbes. • Beneficial improvements after administration of probiotics are highly associated with alternation of gut microbial community.
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Affiliation(s)
- Aoxiang Zhuge
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Bo Li
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Yin Yuan
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Longxian Lv
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Yating Li
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Jingjing Wu
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Liya Yang
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Xiaoyuan Bian
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Kaicen Wang
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Qiangqiang Wang
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Ren Yan
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Xueling Zhu
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
- Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
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Park CY, Choi E, Yang H, Ho SH, Park S, Park K, Kim S. Efficacy of Artemisia annua L. extract for recovery of acute liver failure. Food Sci Nutr 2020; 8:3738-3749. [PMID: 32724636 PMCID: PMC7382175 DOI: 10.1002/fsn3.1662] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 05/03/2020] [Accepted: 05/06/2020] [Indexed: 12/18/2022] Open
Abstract
Artemisia annua L. is an annual herb belonging to the Asteraceae family. It is commonly grown in parts of Asia, including Korea and China, and is called by its nickname Gae-ddong-ssuk, or Chung-ho. The herb is well known for its positive effects on fever and hemostasis, as well as its antibiotic effects. To evaluate the protective properties of A. annua L. on the liver, an acute liver failure animal model was set up with intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (D-galN) in C57BL/6J mice, showing increased levels of AST (aspartate transaminase) and ALT (alanine transaminase). Oral administration of the extract of A. annua L. (EAA) for 2 weeks reduced the level of AST and ALT up to 50% of the levels in the negative control group treated with water vehicle. The efficacy of EAA was more effective than that in a comparative positive control group treated with milk thistle extract. Moreover, EAA protected hepatic cells and tissues from oxidative stresses and inflammatory damages, showing downregulation of inflammatory cytokines such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). We also found that LPS stimulated the mouse macrophage cell line, Raw264.7, and secreted a tremendous level of proinflammatory cytokines and the secretion of these cytokines was reduced with EAA treatment via downregulation of mitogen-activated protein kinase phosphorylation and p65 translocation. This study demonstrated that A. annua L. extract is a promising treatment for protection against and recovery from liver damage, as well as maintenance of liver health.
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Affiliation(s)
| | | | | | | | | | - Ki‐Moon Park
- Department of Food Science & BiotechnologySungkyunkwan UniversitySuwonKorea
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Weinhage T, Wirth T, Schütz P, Becker P, Lueken A, Skryabin BV, Wittkowski H, Foell D. The Receptor for Advanced Glycation Endproducts (RAGE) Contributes to Severe Inflammatory Liver Injury in Mice. Front Immunol 2020; 11:1157. [PMID: 32670276 PMCID: PMC7326105 DOI: 10.3389/fimmu.2020.01157] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 05/11/2020] [Indexed: 12/24/2022] Open
Abstract
Background: The receptor for advanced glycation end products (RAGE) is a multiligand receptor involved in a number of processes and disorders. While it is known that RAGE-signaling can contribute to toxic liver damage and fibrosis, its role in acute inflammatory liver injury and septic multiorgan failure is yet undefined. We examined RAGE in lipopolysaccharide (LPS) induced acute liver injury of D-galN sensitized mice as a classical model for tumor necrosis factor alpha (TNF-α) dependent inflammatory organ damage. Methods: Mice (Rage–/– and C57BL/6) were intraperitoneally injected with D-galN (300 mg/kg) and LPS (10 μg/kg). Animals were monitored clinically, and cytokines, damage associated molecular pattern molecules (DAMPs) as well as liver enzymes were determined in serum. Liver histology, hepatic cytokines as well as RAGE mRNA expression were analyzed. Cellular activation and functionality were evaluated by flow cytometry both in bone marrow- and liver-derived cells. Results: Genetic deficiency of RAGE significantly reduced the mortality of mice exposed to LPS/D-galN. Hepatocyte damage markers were reduced in Rage–/– mice, and liver histopathology was less severe. Rage–/– mice produced less pro-inflammatory cytokines and DAMPs in serum and liver. While immune cell functions appeared normal, TNF-α production by hepatocytes was reduced in Rage–/– mice. Conclusions: We found that RAGE deletion attenuated the expression of pro-inflammatory cytokines and DAMPs in hepatocytes without affecting cellular immune functions in the LPS/D-galN model of murine liver injury. Our data highlight the importance of tissue-specific RAGE-signaling also in acute inflammatory liver stress contributing to sepsis and multiorgan failure.
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Affiliation(s)
- Toni Weinhage
- Department of Pediatric Rheumatology and Immunology, University of Münster, Münster, Germany
| | - Timo Wirth
- Department of Neurology With Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Paula Schütz
- Department of Pediatric Rheumatology and Immunology, University of Münster, Münster, Germany
| | - Philipp Becker
- Department of Pediatric Rheumatology and Immunology, University of Münster, Münster, Germany
| | - Aloys Lueken
- Department of Pediatric Rheumatology and Immunology, University of Münster, Münster, Germany
| | - Boris V Skryabin
- Core Facility of Transgenic Animal and Genetic Engineering Models (TRAM), University of Münster, Münster, Germany
| | - Helmut Wittkowski
- Department of Pediatric Rheumatology and Immunology, University of Münster, Münster, Germany
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University of Münster, Münster, Germany
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Schulte R, Wohlleber D, Unrau L, Geers B, Metzger C, Erhardt A, Tiegs G, van Rooijen N, Heukamp LC, Klotz L, Knolle PA, Diehl L. Pioglitazone-Mediated Peroxisome Proliferator-Activated Receptor γ Activation Aggravates Murine Immune-Mediated Hepatitis. Int J Mol Sci 2020; 21:ijms21072523. [PMID: 32260486 PMCID: PMC7177299 DOI: 10.3390/ijms21072523] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/02/2020] [Accepted: 04/03/2020] [Indexed: 12/20/2022] Open
Abstract
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) regulates target gene expression upon ligand binding. Apart from its effects on metabolism, PPARγ activity can inhibit the production of pro-inflammatory cytokines by several immune cells, including dendritic cells and macrophages. In chronic inflammatory disease models, PPARγ activation delays the onset and ameliorates disease severity. Here, we investigated the effect of PPARγ activation by the agonist Pioglitazone on the function of hepatic immune cells and its effect in a murine model of immune-mediated hepatitis. Cytokine production by both liver sinusoidal endothelial cells (IL-6) and in T cells ex vivo (IFNγ) was decreased in cells from Pioglitazone-treated mice. However, PPARγ activation did not decrease pro-inflammatory tumor necrosis factor alpha TNFα production by Kupffer cells after Toll-like receptor (TLR) stimulation ex vivo. Most interestingly, although PPARγ activation was shown to ameliorate chronic inflammatory diseases, it did not improve hepatic injury in a model of immune-mediated hepatitis. In contrast, Pioglitazone-induced PPARγ activation exacerbated D-galactosamine (GalN)/lipopolysaccharide (LPS) hepatitis associated with an increased production of TNFα by Kupffer cells and increased sensitivity of hepatocytes towards TNFα after in vivo Pioglitazone administration. These results unravel liver-specific effects of Pioglitazone that fail to attenuate liver inflammation but rather exacerbate liver injury in an experimental hepatitis model.
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Affiliation(s)
- Rike Schulte
- Institute for Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany; (R.S.); (D.W.); (C.M.); (L.K.); (P.A.K.)
| | - Dirk Wohlleber
- Institute for Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany; (R.S.); (D.W.); (C.M.); (L.K.); (P.A.K.)
- Institute of Molecular Immunology and Experimental Oncology, Technical University Munich, 81675, Munich, Germany
| | - Ludmilla Unrau
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (L.U.); (B.G); (A.E.); (G.T.)
| | - Bernd Geers
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (L.U.); (B.G); (A.E.); (G.T.)
| | - Christina Metzger
- Institute for Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany; (R.S.); (D.W.); (C.M.); (L.K.); (P.A.K.)
| | - Annette Erhardt
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (L.U.); (B.G); (A.E.); (G.T.)
| | - Gisa Tiegs
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (L.U.); (B.G); (A.E.); (G.T.)
| | - Nico van Rooijen
- Department of Molecular Cell Biology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands;
| | | | - Luisa Klotz
- Institute for Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany; (R.S.); (D.W.); (C.M.); (L.K.); (P.A.K.)
- Department of Neurology, University Hospital Münster, 48149 Münster, Germany
| | - Percy A. Knolle
- Institute for Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany; (R.S.); (D.W.); (C.M.); (L.K.); (P.A.K.)
- Institute of Molecular Immunology and Experimental Oncology, Technical University Munich, 81675, Munich, Germany
| | - Linda Diehl
- Institute for Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany; (R.S.); (D.W.); (C.M.); (L.K.); (P.A.K.)
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (L.U.); (B.G); (A.E.); (G.T.)
- Correspondence:
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Hao J, Qi T, Zhu X, Chen J. Comparative Proteomic Analyses of the Liver in D-Galactosamine-Sensitized Mice Treated with Different Toll-Like Receptor Agonists. Proteomics 2020; 20:e1900393. [PMID: 32131144 DOI: 10.1002/pmic.201900393] [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: 12/02/2019] [Revised: 02/13/2020] [Indexed: 01/03/2023]
Abstract
Acute liver failure (ALF) is a severe consequence of abrupt hepatocyte injury and has lethal outcomes. Three toll-like receptor agonists, including polyinosinic-polycytidylic acid (poly(I:C)), lipopolysaccharide (LPS), and cytosine-phosphate-guanine (CpG) DNA, cause acute and severe hepatitis, respectively, in D-galactosamine (D-GalN)-sensitized mice. However, the molecular differences among three ALF models (LPS/D-GalN, poly(I:C)/D-GalN, and CpG DNA/D-GalN), are unclear. Here, tandem mass tag based quantitative proteomic analyses of three ALF mouse models are performed. 52 common differentially expressed proteins (DEPs) are identified, in three ALF groups, compared to the control. Gene ontology analyses show that among the common DEPs, ten proteins are involved in immune system process, and 39 proteins in metabolic process. Among 80,195, and 23 specifically-expressed proteins in poly(I:C)/D-GalN, LPS/D-GalN, and CpG DNA/D-GalN groups, LPS/D-GalN-specific proteins are mostly distributed in the endoplasmic reticulum and more enriched in metabolic pathways, whereas poly (I:C)/D-GalN-specific proteins are mainly in the membrane and CpG DNA/D-GalN-specific proteins are related to the ribosome structural composition. In conclusion, the common and specific DEPs in three ALF mouse models at molecular level are identified; and determined a close-to-complete reference map of mouse liver proteins which will be useful for clinical diagnosis and treatment of liver failure in humans.
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Affiliation(s)
- Jun Hao
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Tingting Qi
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Xiaoying Zhu
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Jinjun Chen
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
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The Cardioprotective Effects of Aminoguanidine on Lipopolysaccharide Induced Inflammation in Rats. Cardiovasc Toxicol 2020; 20:474-481. [PMID: 32232724 DOI: 10.1007/s12012-020-09570-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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You Y, Cheng S, Zhang L, Zhu Y, Zhang C, Xian Y. Rational Modulation of the Luminescence of Upconversion Nanomaterials with Phycocyanin for the Sensing and Imaging of Myeloperoxidase during an Inflammatory Process. Anal Chem 2020; 92:5091-5099. [DOI: 10.1021/acs.analchem.9b05468] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Yi You
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China
| | - Shasha Cheng
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China
| | - Li Zhang
- School of Life Science, East China Normal University, Shanghai 200241, China
| | - Yingxin Zhu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China
| | - Cuiling Zhang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China
| | - Yuezhong Xian
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China
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Yang S, Kuang G, Zhang L, Wu S, Zhao Z, Wang B, Yin X, Gong X, Wan J. Mangiferin Attenuates LPS/D-GalN-Induced Acute Liver Injury by Promoting HO-1 in Kupffer Cells. Front Immunol 2020; 11:285. [PMID: 32158448 PMCID: PMC7052129 DOI: 10.3389/fimmu.2020.00285] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 02/04/2020] [Indexed: 12/21/2022] Open
Abstract
Acute liver injury and its terminal phase, hepatic failure, trigger a series of complications, including hepatic encephalopathy, systematic inflammatory response syndrome, and multiorgan failure, with relatively high morbidity and mortality. Liver transplantation is the ultimate intervention, but the shortage of donor organs has limited clinical success. Mangiferin (MF), a xanthone glucoside, has been reported to have excellent anti-inflammatory efficacy. Here, a lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver injury mouse model was established to investigate the protective role of MF and the underlying mechanisms of action. Pretreatment with MF improved survival, decreased serum aminotransferase activities, and inhibited hepatic TNF-α production in LPS/D-GalN-challenged mice. Through Kupffer cell (KC) deletion by GdCl3 and KC adoptive transfer, KCs were confirmed to be involved in these beneficial effects of MF. MF reduced LPS-mediated TNF-α production via the suppression of the TLR4/NF-κB signaling pathway in vitro. MF promoted HO-1 expression, but the knockdown of HO-1 prevented TNF-α inhibition, suggesting that the damage-resistance effects of HO-1 occurred via the suppression of TNF-α synthesis. When HO-1-silenced KCs were transferred to the liver with KC deletion, the protective effect of MF against LPS/D-GalN-induced acute liver injury was reduced, illustrating the role of KC-derived HO-1 in the anti-injury effects of MF. Collectively, MF attenuated acute liver injury induced by LPS/D-GalN via the inhibition of TNF-α production by promoting KCs to upregulate HO-1 expression.
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Affiliation(s)
- Sen Yang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Ge Kuang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Liangke Zhang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Shengwang Wu
- Department of Anatomy, Chongqing Medical University, Chongqing, China
| | - Zizuo Zhao
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bin Wang
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xinru Yin
- Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Xia Gong
- Department of Anatomy, Chongqing Medical University, Chongqing, China
| | - Jingyuan Wan
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
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Enhanced effect of recombinant human soluble thrombomodulin by ultrasound irradiation in acute liver failure. Sci Rep 2020; 10:1742. [PMID: 32015385 PMCID: PMC6997189 DOI: 10.1038/s41598-020-58624-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 01/15/2020] [Indexed: 12/13/2022] Open
Abstract
The administration of recombinant human soluble thrombomodulin (rhsTM) significantly improves liver inflammation and increases the survival rate of patients with acute liver failure (ALF). However, rhsTM is dose-dependently correlated to the risk of bleeding. Recently, ultrasound (US) was found to enhance the effect of various drugs. Thus, the present study aimed to determine the enhancement effect of US irradiation on rhsTM in ALF. rhsTM (1 mg/kg) and US (1 MHz, 0.3 W/cm2) were irradiated to the liver of lipopolysaccharide/D-galactosamine-induced ALF mice model. The post-treatment aspartate aminotransferase, alanine aminotransferase, and high-mobility group box 1 levels were significantly lower in the rhsTM + US group than in the rhsTM alone group. Histopathological findings revealed significantly reduced liver injury and apoptosis in the rhsTM + US group. By contrast, US irradiation had no effect on rhsTM and TNF-α concentration in the liver tissue. In conclusion, US irradiation enhanced the effect of rhsTM in the ALF mice model. However, further studies must be conducted to determine the exact mechanism of such enhancement effect.
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He C, Yue H, Xu L, Liu Y, Song Y, Tang C, Yin C. siRNA release kinetics from polymeric nanoparticles correlate with RNAi efficiency and inflammation therapy via oral delivery. Acta Biomater 2020; 103:213-222. [PMID: 31812844 DOI: 10.1016/j.actbio.2019.12.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 11/21/2019] [Accepted: 12/03/2019] [Indexed: 01/26/2023]
Abstract
Despite many efforts in the rational design of nanoparticles (NPs) to overcome the biological barriers to small interfering RNA (siRNA) delivery for improving gene silencing efficiency, little is known about the correlations between siRNA release kinetics and RNA interference (RNAi) efficiency and inflammation therapy via oral delivery. On the basis of mannose-modified trimethyl chitosan-cysteine (MTC) polymers, seven types of MTC NPs containing tumor necrosis factor (TNF)-α siRNA were prepared through ionic gelation. The siRNA release kinetics from MTC NPs were finely tuned by adjusting the kinds and amounts of the crosslinkers involved. These MTC NPs exhibited no disparities in siRNA protection against enzymatic degradation in physiological fluids and cellular uptake in macrophages; however, they showed distinct in vitro siRNA release profiles and intracellular unpacking kinetics. MTC NPs with relatively rapid and sustained siRNA release were responsible for efficient, prompt, and prolonged RNAi, contributing to desired therapeutic efficacy in acute and chronic inflammatory murine models following oral delivery. However, MTC NPs insufficiently releasing siRNA could not elicit effective RNAi. Collectively, the present investigation might provide broad insights into the optimization of siRNA nanocarriers with respect to their release kinetics for improving RNAi efficacies aiming at different types of inflammatory diseases. STATEMENT OF SIGNIFICANCE: siRNA release kinetics in the cytoplasm and pathological characteristics of diseases themselves determine the therapeutic efficacy of siRNA delivery. Herein, by adjusting the kinds and amounts of the crosslinkers involved, we developed seven types of MTC NPs containing TNF-α siRNA with distinct siRNA release kinetics. MTC NPs with relatively rapid and sustained siRNA release were responsible for prompt and prolonged RNAi, respectively, contributing to desired therapeutic efficacy in acute and chronic inflammation following oral delivery. These results might provide broad insights into the optimization of siRNA nanocarriers in respect to their release kinetics for improving therapeutic outcomes toward different clinical requirements.
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Dempsey JL, Cui JY. Microbiome is a functional modifier of P450 drug metabolism. CURRENT PHARMACOLOGY REPORTS 2019; 5:481-490. [PMID: 33312848 PMCID: PMC7731899 DOI: 10.1007/s40495-019-00200-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Host cytochrome P450s (P450s) play important roles in the bioactivation and detoxification of numerous therapeutic drugs, environmental toxicants, dietary factors, as well as endogenous compounds. Gut microbiome is increasingly recognized as our "second genome" that contributes to the xenobiotic biotransformation of the host, and the first pass metabolism of many orally exposed chemicals is a joint effort between host drug metabolizing enzymes including P450s and gut microbiome. Gut microbiome contributes to the drug metabolism via two distinct mechanisms: direct mechanism refers to the metabolism of drugs by microbial enzymes, among which reduction and hydrolysis (or deconjugation) are among the most important reactions; whereas indirect mechanism refers to the influence of host receptors and signaling pathways by microbial metabolites. Many types of microbial metabolites, such as secondary bile acids (BAs), short chain fatty acids (SCFAs), and tryptophan metabolites, are known regulators of human diseases through modulating host xenobiotic-sensing receptors. To study the roles of gut microbiome in regulating host drug metabolism including P450s, several models including germ free mice, antibiotics or probiotics treatments, have been widely used. The present review summarized the current information regarding the interactions between microbiome and the host P450s in xenobiotic biotransformation organs such as liver, intestine, and kidney, highlighting the remote sensing mechanisms underlying gut microbiome mediated regulation of host xenobiotic biotransformation. In addition, the roles of bacterial, fungal, and other microbiome kingdom P450s, which is an understudied area of research in pharmacology and toxicology, are discussed.
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Affiliation(s)
- Joseph L Dempsey
- Department of Environmental and Occupational Health Sciences, University of Washington
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington
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Li M, Wang S, Li X, Wang Q, Liu Z, Yu T, Kou R, Xie K. Inhibitory effects of diallyl sulfide on the activation of Kupffer cell in lipopolysaccharide/d-galactosamine-induced acute liver injury in mice. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.103550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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