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Gao F, Mu W, Fan J, Shen J. β-arrestin2 promotes angiogenesis of liver sinusoidal endothelial cells through the VEGF/VEGFR2 pathway to aggravate cirrhosis. Toxicol Lett 2024; 401:1-12. [PMID: 39197505 DOI: 10.1016/j.toxlet.2024.08.011] [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: 05/11/2024] [Revised: 07/24/2024] [Accepted: 08/21/2024] [Indexed: 09/01/2024]
Abstract
Excessive extracellular matrix deposition and increased intrahepatic angiogenesis are prominent features of cirrhosis. β-arrestin2 is thought to be involved in the pathological processes of various fibrotic diseases. This study aimed to investigate the role and possible mechanism of β-arrestin2 in the angiogenesis of cirrhosis. Firstly, β-arrestin2 expression in liver tissues of cirrhotic patients was detected, and the correlation between β-arrestin2 and α-SMA, CD-31, PDGF, and VEGF indexes was analyzed. Then, after liver cirrhosis induced by CCL4 in Arrb2-KO mice (β-arrestin2 coding gene), liver histopathological changes were observed, and the expressions of α-SMA, CD-31, PDGF, VEGF, and VEGFR2 were detected. Finally, VEGF-A was used to treat human liver sinusoidal endothelial cells (LSECs) to simulate pathological conditions. After transfection with si-ARRB2, the cell activity, MDA and GSH-PX activities, cell invasion, angiogenesis, and the expressions of α-SMA, CD-31, and VEGF/VEGFR2 pathway were detected. Results showed that β-arrestin2 expression in the liver increased significantly during cirrhosis and was positively correlated with angiogenesis. In vivo, Arrb2-KO significantly inhibited fibrosis and angiogenesis in cirrhotic mice, and decreased the expressions of α-SMA, CD31, PDGF, VEGF, and VEGFR2. Studies using LSECs in vitro showed that after intervention of ARRB2, the activity of LSECs and the number of invasions and tubule formations were significantly reduced. Similarly, after transfection with si-ARRB2, the expressions of α-SMA, CD31, PDGF, VEGF, and VEGFR2 in LSECs were significantly decreased. Collectively, β-arrestin2 aggravated cirrhosis by promoting the angiogenesis of LSECs. Blocking β-arrestin2 may be an important target against angiogenesis and fibrosis in cirrhosis.
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Affiliation(s)
- Feng Gao
- Department of Interventional Therapy, Shanxi Provincial People's Hospital, Taiyuan 030012, China
| | - Wei Mu
- Department of Interventional Therapy, Shanxi Provincial People's Hospital, Taiyuan 030012, China
| | - Jiangbo Fan
- Department of Interventional Therapy, Shanxi Provincial People's Hospital, Taiyuan 030012, China
| | - Jing Shen
- Department of Interventional Therapy, Shanxi Provincial People's Hospital, Taiyuan 030012, China.
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Wang J, Zhao F, Brouwer LA, Buist-Homan M, Wolters JC, Moshage H, Harmsen MC. Collagen-rich liver-derived extracellular matrix hydrogels augment survival and function of primary rat liver sinusoidal endothelial cells and hepatocytes. Int J Biol Macromol 2024; 278:134717. [PMID: 39142477 DOI: 10.1016/j.ijbiomac.2024.134717] [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: 04/09/2024] [Revised: 07/11/2024] [Accepted: 08/11/2024] [Indexed: 08/16/2024]
Abstract
Liver sinusoidal endothelial cells (LSECs) are key targets for addressing metabolic dysfunction-associated steatotic liver disease (MASLD). However, isolating and culturing primary LSECs is challenging due to rapid dedifferentiation, resulting in loss of function. The extracellular matrix (ECM) likely plays a crucial role in maintaining the fate and function of LSECs. In this study, we explored the influence of liver-ECM (L-ECM) on liver cells and developed culture conditions that maintain the differentiated function of liver cells in vitro for prolonged periods. Porcine liver-derived L-ECM, containing 34.9 % protein, 0.045 % glycosaminoglycans, and negligible residual DNA (41.2 ng/mg), was utilized to culture primary rat liver cells in generated hydrogels. Proteomic analyses and molecular weight distribution of proteins of solubilized L-ECM revealed the typical diverse ECM core matrisome, with abundant collagens. L-ECM hydrogels showed suitable stiffness and stress relaxation properties. Furthermore, we demonstrated that collagen-rich L-ECM hydrogels enhanced LSECs' and hepatocytes' viability, and reduced the dedifferentiation rate of LSECs. In addition, hepatocyte function was maintained longer by culture on L-ECM hydrogels compared to traditional culturing. These beneficial effects are likely attributed to the bioactive macromolecules including collagens, and mechanical and microarchitectural properties of the L-ECM hydrogels.
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Affiliation(s)
- Junyu Wang
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands.
| | - Fenghua Zhao
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands; University of Groningen, University Medical Centre Groningen, W.J. Kolff Institute for Biomedical Engineering and Materials Science, Groningen, the Netherlands; University of Groningen, University Medical Centre Groningen, Department of Biomedical Engineering, Groningen, the Netherlands.
| | - Linda A Brouwer
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands.
| | - Manon Buist-Homan
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen, the Netherlands.
| | - Justina C Wolters
- University of Groningen, University Medical Centre Groningen, Department of Pediatrics, Groningen, the Netherlands; University of Groningen, University Medical Centre Groningen, Interfaculty Mass Spectrometry Center, Groningen, the Netherlands.
| | - Han Moshage
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen, the Netherlands.
| | - Martin C Harmsen
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands; University of Groningen, University Medical Centre Groningen, W.J. Kolff Institute for Biomedical Engineering and Materials Science, Groningen, the Netherlands; University of Groningen, University Medical Centre Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands.
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Wang J, Wu Z, Xia M, Salas SS, Ospina JA, Buist-Homan M, Harmsen MC, Moshage H. Extracellular vesicles derived from liver sinusoidal endothelial cells inhibit the activation of hepatic stellate cells and Kupffer cells in vitro. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167020. [PMID: 38244390 DOI: 10.1016/j.bbadis.2024.167020] [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: 08/22/2023] [Revised: 12/22/2023] [Accepted: 01/05/2024] [Indexed: 01/22/2024]
Abstract
Liver sinusoidal endothelial cells (LSECs) play a crucial role in maintaining liver microcirculation and exchange of nutrients in the liver and are thought to be involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). The activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs) has been considered to be responsible for the onset of liver fibrosis and the aggravation of liver injury. However, the paracrine regulatory effects of LSECs in the development of MASLD, in particular the role of LSEC-derived extracellular vesicles (EVs) remains unclear. Therefore, the aim of the present study was to investigate the influence of LSEC-derived EVs on HSCs and KCs. Primary rat LSECs, HSCs and KCs were isolated from male Wistar rats. LSEC-derived EVs were isolated from conditioned medium by ultracentrifugation and analyzed by nanoparticle tracking analysis, and expression of specific markers. LSEC-derived EVs reduced the expression of activation markers in activated HSCs but did not affect quiescent HSCs. Also, LSEC-derived EVs suppressed proliferation of activated HSCs activation, as assessed by Xcelligence and BrdU assay. LSEC-derived EVs also increased the expression of inflammatory genes in HSCs that normally are lowly expression during their activation. In contrast, EVs decreased the expression of inflammatory genes in activated KCs. In summary, our results suggest that LSEC-derived EVs may attenuate the fibrogenic phenotype of activated HSCs and the inflammatory phenotype of KCs. Our results show promise for LSEC-derived EVs as therapeutic moieties to treat MASLD. In addition, these EVs might prove of diagnostic value.
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Affiliation(s)
- Junyu Wang
- University Medical Center Groningen, University of Groningen, Department of Gastroenterology and Hepatology, Groningen, the Netherlands
| | - Zongmei Wu
- University Medical Center Groningen, University of Groningen, Department of Gastroenterology and Hepatology, Groningen, the Netherlands
| | - Mengmeng Xia
- University Medical Center Groningen, University of Groningen, Department of Gastroenterology and Hepatology, Groningen, the Netherlands
| | - Sandra Serna Salas
- University Medical Center Groningen, University of Groningen, Department of Gastroenterology and Hepatology, Groningen, the Netherlands
| | - Johanna Arroyave Ospina
- University Medical Center Groningen, University of Groningen, Department of Gastroenterology and Hepatology, Groningen, the Netherlands
| | - Manon Buist-Homan
- University Medical Center Groningen, University of Groningen, Department of Gastroenterology and Hepatology, Groningen, the Netherlands; University Medical Center Groningen, University of Groningen, Department of Laboratory Medicine, Groningen, the Netherlands
| | - Martin C Harmsen
- University Medical Center Groningen, University of Groningen, Department of Gastroenterology and Hepatology, Groningen, the Netherlands; University Medical Center Groningen, University of Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands
| | - Han Moshage
- University Medical Center Groningen, University of Groningen, Department of Gastroenterology and Hepatology, Groningen, the Netherlands; University Medical Center Groningen, University of Groningen, Department of Laboratory Medicine, Groningen, the Netherlands.
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Yao Y, Satapathy SK, Fernandes EDSM, Ramírez-Fernández O, Vitale A, Chen Z. Hepatic venous pressure gradient (HVPG) predicts liver failure after transjugular intrahepatic portal shunt: a retrospective cohort study. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1122. [PMID: 36388791 PMCID: PMC9652563 DOI: 10.21037/atm-22-4737] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/14/2022] [Indexed: 08/10/2023]
Abstract
BACKGROUND Esophagogastric variceal bleeding is a serious complication of decompensated cirrhosis. Transjugular intrahepatic portal shunt (TIPS) is a salvage treatment with clear hemostatic results. However, various complications may occur after TIPS, including postoperative liver failure, and the prognosis is very poor once occurs. Liver failure is a common symptom of severe liver disease with a high mortality rate. This study investigated the incidence of liver failure after TIPS treatment for varicose bleeding. METHODS We analyzed the data of patients admitted to the First Affiliated Hospital of Soochow University between January 2013 and December 2018 with portal hypertension with an episode of acute gastroesophageal variceal bleeding. A total of 121 patients were referred to the regional liver unit for TIPS. Hepatic venous pressure gradient (HVPG) and clinical data were collected. Patients with incomplete data were excluded, and 93 patients were ultimately enrolled in the study. Primary outcomes were morbidity and hospital mortality within 4 weeks of surgery. The data were retrospectively and consecutively collected and evaluated by univariate and multivariate analyses to identify risk factors of liver failure. RESULTS The patients included 58 males (62.37%) and 35 females (37.63%), and the mean age was 58.43±11.85 years. The main cause was hepatitis B virus (HBV), which was found in 50.54% of patient. The overall surgical success rate was 83.87% (78/93). Of 15 treatment-failure patients, 9 (9.68%) died in hospital. Four patients died of liver failure, accounting for 44.44% of postoperative all-cause deaths. Univariate logistic regression analysis showed that only hepatic venous pressure gradient (HVPG) was an independent risk factor for post-TIPS morbidity [relative risk (RR) 1.156; 95% confidence interval (CI): 1.041 to 1.283; P=0.006]. In addition, HVPG was an independent risk factor for hospital mortality within 4 weeks (RR 1.133; 95% CI: 1.021 to 0.539; P=0.016). CONCLUSIONS Post-TIPS liver failure is a serious complication in patients with cirrhosis. Pre-TIPS HVPG level may be used as a predictor of potential short-term postoperative adverse events.
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Affiliation(s)
- Yunhai Yao
- Department of Infectious Disease, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Sanjaya K. Satapathy
- Division of Hepatology, Department of Medicine and Northwell Center for Liver Diseases & Transplantation, Northwell Health, Manhasset, NY, USA
| | | | - Odin Ramírez-Fernández
- Faculty of Mechanical and Electrical Engineering North Unit, Autonomous University of Coahuila, Monclova, Mexico
- Mexico University of Technology-Online Campus of Unitec Mexico-Anahuac College, Mexico City, Mexico
| | - Alessandro Vitale
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy
| | - Zutao Chen
- Department of Infectious Disease, the First Affiliated Hospital of Soochow University, Suzhou, China
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Olmesartan Improves Hepatic Sinusoidal Remodeling in Mice with Carbon Tetrachloride-Induced Liver Fibrosis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:4710993. [PMID: 36060127 PMCID: PMC9439923 DOI: 10.1155/2022/4710993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 07/04/2022] [Accepted: 07/30/2022] [Indexed: 11/24/2022]
Abstract
Aim In mice with liver fibrosis produced by carbon tetrachloride (CCl4), the effects of olmesartan on intrahepatic angiogenesis and sinusoidal remodeling will be evaluated. Methods By injecting CCl4 into the peritoneal cavity, we established a mouse model of liver fibrosis. Using Sirius red and Masson trichrome staining, the extent of liver fibrosis in the animals was determined. Using immunohistochemical labeling and western blotting, the level of α-smooth muscle actin (α-SMA) expression, a characteristic of hepatic stellate cell activation, was assessed. Electron microscopy was used to determine the effect of olmesartan on hepatic sinusoidal capillarization, and immunohistochemical labeling was used to determine the expression levels of endothelial and basement membrane proteins in mouse liver tissues. Platelet-derived growth factor (PDGF), IL-10, vascular endothelial growth factor (VEGF), and angiotensin II levels in mouse serum were measured by Luminex multifactor analysis and ELISA. Olmesartan's effect on the angiotensin II type 1 receptor (AT1R) and the VEGF receptor (VEGFR) was evaluated using western blotting. Results Olmesartan reduced CCl4-induced inflammatory cell infiltration and collagen deposition to alleviate liver fibrosis. α-SMA expression was decreased, and HSC activation was inhibited in mouse liver tissues by olmesartan treatment. In addition, hepatic sinusoidal capillarization was improved under the action of olmesartan. The expression of collagen IV, fibronectin, CD31, and von Willebrand factor (VWF) in the olmesartan group was also markedly downregulated. In fibrotic mice, olmesartan medication decreased the levels of PDGF, VEGF, and angiotensin II, but it increased the level of IL-10. Moreover, olmesartan reduced the expression of VEGFR-1, VEGFR-2, and AT1R relative to CCl4-induced liver fibrosis. Conclusions In mice with CCl4-induced fibrosis, olmesartan lowers angiogenesis and improves hepatic sinusoidal remodeling, according to our findings. By acting on the angiotensin II-AT1R-VEGF axis, this is achieved.
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Li H. Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis, cirrhosis and hepatocellular carcinoma. Dig Liver Dis 2022; 54:598-613. [PMID: 34344577 DOI: 10.1016/j.dld.2021.07.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022]
Abstract
Intercellular crosstalk among various liver cells plays an important role in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Capillarization of liver sinusoidal endothelial cells (LSECs) precedes fibrosis and accumulating evidence suggests that the crosstalk between LSECs and other liver cells is critical in the development and progression of liver fibrosis. LSECs dysfunction, a key event in the progression from fibrosis to cirrhosis, and subsequently obstruction of hepatic sinuses and increased intrahepatic vascular resistance (IHVR) contribute to development of portal hypertension (PHT) and cirrhosis. More importantly, immunosuppressive tumor microenvironment (TME), which is closely related to the crosstalk between LSECs and immune liver cells like CD8+ T cells, promotes advances tumorigenesis, especially HCC. However, the connections within the crosstalk between LSECs and other liver cells during the progression from liver fibrosis to cirrhosis to HCC have yet to be discussed. In this review, we first summarize the current knowledge of how different crosstalk between LSECs and other liver cells, including hepatocytes, hepatic stellate cells (HSCs), macrophoges, immune cells in liver and extra cellular matrix (ECM) contribute to the physiological function and the progrssion from liver fibrosis to cirrhosis, or even to HCC. Then we examine current treatment strategies for LSECs crosstalk in liver fibrosis, cirrhosis and HCC.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, NO. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan Province, PR China.
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Naltrexone protects against BDL-induced cirrhosis in Wistar rats by attenuating thrombospondin-1 and enhancing antioxidant defense system via Nrf-2. Life Sci 2022; 300:120576. [PMID: 35487305 DOI: 10.1016/j.lfs.2022.120576] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 04/17/2022] [Accepted: 04/20/2022] [Indexed: 11/23/2022]
Abstract
AIMS It is well-established that thrombospondin-1 (THBS-1), vascular endothelial growth factor-A (VEGF-A), nuclear factor-erythroid 2-related factor 2 (Nrf-2), Kelch-like ECH-associated protein 1 (Keap-1), and transforming growth factor-beta 1 (TGF-β1) are the pivotal players of liver fibrosis. Recent studies have shown that endogenous opioid levels increase during liver cirrhosis. Therefore, the present study aimed to clarify the effect of naltrexone (NTX), an opioid antagonist, on the alteration of these factors following bile duct ligation (BDL)-induced liver cirrhosis. MAIN METHODS Wistar male rats (n = 50) were categorized equally into 5 groups (baseline, sham+saline, BDL + saline, sham+NTX (10 mg/kg of body weight (BW)), and BDL + NTX (10 mg/kg of BW)). At the end of the experiment, H&E staining was used to assess necrosis and lobular damage of hepatic tissue. The gene expression of THBS-1 and NADPH oxidase 1 (NOX-1) was measured by real time-PCR and VEGF-A, Nrf-2, Keap-1, and TGF-β1 protein levels were assessed by western blot. The antioxidant enzymes activity, total oxidant status (TOS) and MDA level were measured by commercial kits. KEY FINDINGS Hepatic necrosis and lobular damage increased substantially and NTX reduced them markedly in the BDL group. Gene expression of hepatic THBS-1 and NOX-1, TOS and MDA levels increased markedly in the BDL + saline group, and Nrf-2 and VEGF-A values decreased significantly in the BDL + NTX group. NTX recovered THBS-1, NOX-1 and Nrf-2 in the BDL + NTX group, substantially (p-value ≤ 0.05). SIGNIFICANCE Data showed that NTX treatment attenuates liver fibrosis mainly by lowering THBS-1 and NOX-1 and increasing Nrf-2 protein level and antioxidant enzymes.
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Zheng Y, Wang J, Zhao T, Wang L, Wang J. Modulation of the VEGF/AKT/eNOS signaling pathway to regulate liver angiogenesis to explore the anti-hepatic fibrosis mechanism of curcumol. JOURNAL OF ETHNOPHARMACOLOGY 2021; 280:114480. [PMID: 34358654 DOI: 10.1016/j.jep.2021.114480] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/20/2021] [Accepted: 07/30/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Curcuma is a common Chinese herbal medicine that is used in the clinical treatment of chronic liver disease. Studies have found that curcumol is the main active ingredient of curcuma and has good hepatoprotective and anti-inflammatory effects. However, there are few reports on the molecular mechanism underlying the anti-liver fibrosis effect of curcumol. AIM To explore the effect of curcumol on liver angiogenesis, and to reveal the mechanism of curcumol against liver fibrosis. MATERIALS AND METHODS We used liver collagenase perfusion combined with Percoll density gradient sedimentation to separate primary liver sinusoidal endothelial cells, and then applied a leptin-activated cell pathological model. The cells were divided into four treatment groups as follows: blank group, model group, curcumol group, and solafini group. MTT was used to detect the cell proliferation rate in each group, and RT-PCR and western blotting were used to detect the expressions of VEGF, AKT, eNOS, CD31, and vWF. A fluorescent probe was used to detect NO expression, and scanning electron microscopy was used to observe changes in the cell fenestration structure. Angiogenesis assays were used to observe blood vessel formation in each group. RESULTS The results of the MTT test found that the proliferation rate of each group was higher. The results of the molecular biology tests found that curcumol inhibited the activity of the VEGF/AKT/eNOS pathway, thereby increasing fenestration of sinusoidal endothelial cells and inhibiting liver angiogenesis. These differences were statistically significant compared with the model group. CONCLUSIONS Curcumol inhibits the activity of the VEGF/AKT/eNOS signaling pathway, regulates the structure of hepatic sinusoidal endothelial cells, and inhibits liver angiogenesis, which together may explain its anti-liver fibrosis mechanism.
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Affiliation(s)
- Yang Zheng
- Department of Medicine, Faculty of Chinese Medicine Science Guangxi University of Chinese, Medicine, Nanning, Guangxi, 530222, China
| | - Jiaru Wang
- College of Nursing,Guangdong Medical University, Dongguan, Guangdong, 523000, China
| | - Tiejian Zhao
- Department of Physiology, College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, 530222, China
| | - Lei Wang
- Department of Medicine, Faculty of Chinese Medicine Science Guangxi University of Chinese, Medicine, Nanning, Guangxi, 530222, China
| | - Jiahui Wang
- Department of Medicine, Faculty of Chinese Medicine Science Guangxi University of Chinese, Medicine, Nanning, Guangxi, 530222, China.
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Sun X, Tan Y, Lyu J, Liu HL, Zhao ZM, Liu CH. Active Components Formulation Developed from Fuzheng Huayu Recipe () for Anti-Liver Fibrosis. Chin J Integr Med 2021; 28:538-544. [PMID: 34581939 DOI: 10.1007/s11655-021-3293-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/03/2020] [Indexed: 01/22/2023]
Abstract
OBJECTIVE To screen the active components from Fuzheng Huayu Recipe (, FZHY) and redesign a new recipe composed of the active components, and validate the effect of active components formulation from FZHY against liver fibrosis. METHODS Thirty-two components from FZHY were evaluated for their activities against liver fibrosis respectively, with 6 kinds of cell models in vitro, including oxidative stressed hepatocyte in L-02, hypoxia injured/proliferative hepatic sinusoidal endothelial cells in SK-HEP-1 and human hepatic sinusoidal endothelial cells (HHSEC), and activated hepatic stellate cell in LX-2. The comprehensive activity of each component against liver fibrosis was scored according to the role of original herbs in FZHY and cell functions in fibrogenesis. Totally 7 active components were selected and combined with equal proportion to form a novel active components formulation (ACF). The efficacy of ACF on liver fibrosis were evaluated on activation of LX-2 and proliferation of HHSEC in vitro and in liver fibrosis model mice induced by dimethylnitrosamine (DMN). Totally 72 mice were divided into 6 groups using a random number table, including normal, high-dose ACF control (20 µ mol/L × 7 components/kg body weight), model, low-, medium-, high-dose ACF groups (5, 10, 20 µ mol/L × 7 components/kg body weight, respectively). Hematoxylin eosin and Sirius red stainings were used to observe inflammation and fibrosis change of liver tissue; scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were utilized to observe the effect of ACF on ultrastructure of hepatic sinusoids. RESULTS Fifteen components from FZHY showed higher scores for their activity on against liver fibrosis. Among them, 7 components including tanshinone II A, salvianolic acid B, cordycepin, amygdalin, quercetin, protopanaxatriol, and schizandrin B were recombined with equal proportions to form ACF. ACF at 1,2, 4 µ mol/L showed strong inhibitory effects on activation of LX-2 and proliferation of HHSEC in vitro (all P<0.01). Compared with the model group, ACF attenuated liver collagen deposition, improved sinusoidal capillarization in a dose-dependent manner (all P<0.05). CONCLUSION ACF exerts a satisfactory effect against experimental liver fibrosis and attenuates sinusoidal capillarization, which warrant a further research and development for herbal components formulation on liver fibrosis.
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Affiliation(s)
- Xin Sun
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ye Tan
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jing Lyu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hong-Liang Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhi-Min Zhao
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China
| | - Cheng-Hai Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. .,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China.
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Han X, Ding C, Sang X, Peng M, Yang Q, Ning Y, Lv Q, Shan Q, Hao M, Wang K, Wu X, Zhang H, Cao G. Targeting Sirtuin1 to treat aging-related tissue fibrosis: From prevention to therapy. Pharmacol Ther 2021; 229:107983. [PMID: 34480962 DOI: 10.1016/j.pharmthera.2021.107983] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/18/2021] [Accepted: 08/18/2021] [Indexed: 12/19/2022]
Abstract
Fibrosis, which is characterized by excessive extracellular matrix (ECM) deposition, is a wound-healing response to organ injury and may promote cancer and failure in various organs, such as the heart, liver, lung, and kidney. Aging associated with oxidative stress and inflammation exacerbates cellular dysfunction, tissue failure, and body function disorders, all of which are closely related to fibrosis. Sirtuin-1 (SIRT1) is a class III histone deacetylase that regulates growth, transcription, aging, and metabolism in various organs. This protein is downregulated in organ injury and fibrosis associated with aging. Its expression and distribution change with age in different organs and play critical roles in tissue oxidative stress and inflammation. This review first described the background on fibrosis and regulatory functions of SIRT1. Second, we summarized the relationships of SIRT1 with other proteins and its protective action during fibrosis in the heart, liver, lung and kidney. Third, the activation of SIRT1 in therapies of tissue fibrosis, especially in liver fibrosis and aging-related tissue injury, was analyzed. In conclusion, SIRT1 targeting may be a new therapeutic strategy in fibrosis.
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Affiliation(s)
- Xin Han
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Chuan Ding
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - XiaNan Sang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - MengYun Peng
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiao Yang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yan Ning
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiang Lv
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - QiYuan Shan
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Min Hao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - KuiLong Wang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xin Wu
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Hongyan Zhang
- Cancer Hospital of The University of Chinese Academy of Sciences, Hangzhou, China
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
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Petrillo S, Manco M, Altruda F, Fagoonee S, Tolosano E. Liver Sinusoidal Endothelial Cells at the Crossroad of Iron Overload and Liver Fibrosis. Antioxid Redox Signal 2021; 35:474-486. [PMID: 32689808 DOI: 10.1089/ars.2020.8168] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Significance: Liver fibrosis results from different etiologies and represents one of the most serious health issues worldwide. Fibrosis is the outcome of chronic insults on the liver and is associated with several factors, including abnormal iron metabolism. Recent Advances: Multiple mechanisms underlying the profibrogenic role of iron have been proposed. The pivotal role of liver sinusoidal endothelial cells (LSECs) in iron-level regulation, as well as their morphological and molecular dedifferentiation occurring in liver fibrosis, has encouraged research on LSECs as prime regulators of very early fibrotic events. Importantly, normal differentiated LSECs may act as gatekeepers of fibrogenesis by maintaining the quiescence of hepatic stellate cells, while LSECs capillarization precedes the onset of liver fibrosis. Critical Issues: In the present review, the morphological and molecular alterations occurring in LSECs after liver injury are addressed in an attempt to highlight how vascular dysfunction promotes fibrogenesis. In particular, we discuss in depth how a vicious loop can be established in which iron dysregulation and LSEC dedifferentiation synergize to exacerbate and promote the progression of liver fibrosis. Future Directions: LSECs, due to their pivotal role in early liver fibrosis and iron homeostasis, show great promises as a therapeutic target. In particular, new strategies can be devised for restoring LSECs differentiation and thus their role as regulators of iron homeostasis, hence preventing the progression of liver fibrosis or, even better, promoting its regression. Antioxid. Redox Signal. 35, 474-486.
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Affiliation(s)
- Sara Petrillo
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Marta Manco
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Fiorella Altruda
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, CNR c/o Molecular Biotechnology Center, Torino, Italy
| | - Emanuela Tolosano
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
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12
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Peng W, Cheng S, Bao Z, Wang Y, Zhou W, Wang J, Yang Q, Chen C, Wang W. Advances in the research of nanodrug delivery system for targeted treatment of liver fibrosis. Biomed Pharmacother 2021; 137:111342. [DOI: 10.1016/j.biopha.2021.111342] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 01/23/2021] [Accepted: 01/27/2021] [Indexed: 02/08/2023] Open
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13
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Sanz-García C, Fernández-Iglesias A, Gracia-Sancho J, Arráez-Aybar LA, Nevzorova YA, Cubero FJ. The Space of Disse: The Liver Hub in Health and Disease. LIVERS 2021; 1:3-26. [DOI: 10.3390/livers1010002] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Since it was first described by the German anatomist and histologist, Joseph Hugo Vincenz Disse, the structure and functions of the space of Disse, a thin perisinusoidal area between the endothelial cells and hepatocytes filled with blood plasma, have acquired great importance in liver disease. The space of Disse is home for the hepatic stellate cells (HSCs), the major fibrogenic players in the liver. Quiescent HSCs (qHSCs) store vitamin A, and upon activation they lose their retinol reservoir and become activated. Activated HSCs (aHSCs) are responsible for secretion of extracellular matrix (ECM) into the space of Disse. This early event in hepatic injury is accompanied by loss of the pores—known as fenestrations—of the endothelial cells, triggering loss of balance between the blood flow and the hepatocyte, and underlies the link between fibrosis and organ dysfunction. If the imbalance persists, the expansion of the fibrotic scar followed by the vascularized septae leads to cirrhosis and/or end-stage hepatocellular carcinoma (HCC). Thus, researchers have been focused on finding therapeutic targets that reduce fibrosis. The space of Disse provides the perfect microenvironment for the stem cells niche in the liver and the interchange of nutrients between cells. In the present review article, we focused on the space of Disse, its components and its leading role in liver disease development.
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Affiliation(s)
- Carlos Sanz-García
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Anabel Fernández-Iglesias
- Liver Vascular Biology Research Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Hepatology, Department of Biomedical Research, University of Bern, 3012 Bern, Switzerland
| | - Luis Alfonso Arráez-Aybar
- Department of Anatomy and Embriology, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Yulia A. Nevzorova
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
- 12 de Octubre Health Research Institute (imas12), 28040 Madrid, Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), 28040 Madrid, Spain
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14
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Hagino Y, Khalil IA, Kimura S, Kusumoto K, Harashima H. GALA-Modified Lipid Nanoparticles for the Targeted Delivery of Plasmid DNA to the Lungs. Mol Pharm 2021; 18:878-888. [PMID: 33492961 DOI: 10.1021/acs.molpharmaceut.0c00854] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
This study describes the development of lipid nanoparticles (LNPs) for the efficient and selective delivery of plasmid DNA (pDNA) to the lungs. The GALA peptide was used as a ligand to target the lung endothelium and as an endosomal escape device. Transfection activity in the lungs was significantly improved when pDNA was encapsulated in double-coated LNPs. The inner coat was composed of dioleoylphsophoethanolamine and a stearylated octaarginine (STR-R8) peptide, while the outer coat was largely a cationic lipid, di-octadecenyl-trimethylammonium propane, mixed with YSK05, a pH-sensitive lipid, and cholesterol. Optimized amounts of YSK05 and GALA were used to achieve an efficient and lung-selective system. The optimized system produced a high gene expression level in the lungs (>107 RLU/mg protein) with high lung/liver and lung/spleen ratios. GALA/R8 modification and the double-coating design were indispensable for efficient gene expression in the lungs. Despite the fact that NPs prepared with 1-step or 2-step coating have the same lipid amount and composition and the same pDNA dose, the transfection activity was dramatically higher in the lungs in the case of 2-step coating. Surprisingly, 1-step or 2-step coatings had no effect on the amount of nanoparticles that were delivered to the lungs, suggesting that the double-coating strategy substantially improved the efficiency of gene expression at the intracellular level.
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Affiliation(s)
- Yuta Hagino
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
| | - Ikramy A Khalil
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.,Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
| | - Seigo Kimura
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
| | - Kenji Kusumoto
- Formulation Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan
| | - Hideyoshi Harashima
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.,Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
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15
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Peroxisome proliferator-activated receptors in the pathogenesis and therapies of liver fibrosis. Pharmacol Ther 2020; 222:107791. [PMID: 33321113 DOI: 10.1016/j.pharmthera.2020.107791] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022]
Abstract
Liver fibrosis is a dynamic wound-healing process associated with the deposition of extracellular matrix produced by myofibroblasts. HSCs activation, inflammation, oxidative stress, steatosis and aging play critical roles in the progression of liver fibrosis, which is correlated with the regulation of the peroxisome proliferator-activated receptor (PPAR) pathway. As nuclear receptors, PPARs reduce inflammatory response, regulate lipid metabolism, and inhibit fibrogenesis in the liver associated with aging. Thus, PPAR ligands have been investigated as possible therapeutic agents. Mounting evidence indicated that some PPAR agonists could reverse steatohepatitis and liver fibrosis. Consequently, targeting PPARs might be a promising and novel therapeutic option against liver fibrosis. This review summarizes recent studies on the role of PPARs on the pathogenesis and treatment of liver fibrosis.
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16
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Zheng Y, Wang J, Wang J, Xie H, Zhao T. Effect of Curcumol on the Fenestrae of Liver Sinusoidal Endothelial Cells Based on NF- κB Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2020; 2020:8590638. [PMID: 32595742 PMCID: PMC7275224 DOI: 10.1155/2020/8590638] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/23/2020] [Accepted: 04/08/2020] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To study the effect of curcumol on liver sinusoidal endothelial cells (LSECs) and to analyze the mechanism of antihepatic fibrosis. METHODS The effects of drug intervention on cell proliferation rates were detected by MTT assay. The expression of NF-κB was detected by RT-PCR and WB. The NF-κB expression and entry into the nucleus were detected by immunofluorescence; scanning electron microscopy was used to observe the changes of LSECs fenestrae. RESULTS MTT results showed that the interference of cell proliferation in each group was small. RT-PCR showed that the expression of NF-κB in the curcumol intervention group was significantly lower than that in the positive control group (P < 0.05). The WB detection found that, in the curcumol intervention group, the expression of pNF-κB in the NF-κB signaling pathway was significantly lower than that in the positive control group (P < 0.05). Scanning electron microscopy showed that the LSEC fenestrae were significantly improved compared with the positive control group. CONCLUSION Curcumol may be one of the mechanisms of antihepatic fibrosis by inhibiting the activity of the NF-κB signaling pathway and increasing the fenestrae of LSECs.
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Affiliation(s)
- Yang Zheng
- Department of Medicine, Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning, Guangxi 530021, China
| | - Jiahui Wang
- Department of Medicine, Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning, Guangxi 530021, China
| | - Jiaru Wang
- College of Nursing, Guangdong Medical University, Dongguan, Guangdong 523000, China
| | - Haiyuan Xie
- Department of Physiology, College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi 530021, China
| | - Tiejian Zhao
- Department of Physiology, College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi 530021, China
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17
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Abstract
Alcoholic liver diseases (ALD) are a wide spectrum of liver diseases caused by excessive alcohol consumption, from steatosis to cirrhosis. The pathogenesis of ALD is insufficiently understood, but mainly involves oxidative stress, inflammation, bacterial translocation, cell death, and impaired regeneration. Despite numerous attempts to improve patient prognosis, the treatment of advanced ALD is still based on abstinence, brief exposure to corticosteroids, or liver transplantation. However, poor response to corticosteroids and the shortage of liver donors leaves patients helpless towards the end stages. Advances in basic research have contributed to a better understanding of ALD pathophysiology, which offers new options for treatment. In recent years, several therapies related to liver regeneration have been tested with promising prospects, including molecule-induced liver regeneration, stem cell transplantation, and full-function 3D artificial liver assembly. This review discusses mechanisms underlying ALD that can be considered therapeutic targets for regeneration-based treatments.
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Affiliation(s)
- Yi Lv
- Laboratory of Neuroendocrinology, Fujian Key Laboratory of Developmental and Neurobiology, College of Life Sciences, Fujian Normal University, Fuzhou 350108, China
| | - Kwok Fai So
- Laboratory of Neuroendocrinology, Fujian Key Laboratory of Developmental and Neurobiology, College of Life Sciences, Fujian Normal University, Fuzhou 350108, China
| | - Jia Xiao
- Laboratory of Neuroendocrinology, Fujian Key Laboratory of Developmental and Neurobiology, College of Life Sciences, Fujian Normal University, Fuzhou 350108, China.,Institute of Clinical Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
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18
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Chen F, Wang H, Xiao J. Regulated differentiation of stem cells into an artificial 3D liver as a transplantable source. Clin Mol Hepatol 2020; 26:163-179. [PMID: 32098013 PMCID: PMC7160355 DOI: 10.3350/cmh.2019.0022n] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 02/02/2020] [Indexed: 02/07/2023] Open
Abstract
End-stage liver disease is one of the leading causes of death around the world. Since insufficient sources of transplantable liver and possible immune rejection severely hinder the wide application of conventional liver transplantation therapy, artificial three-dimensional (3D) liver culture and assembly from stem cells have become a new hope for patients with end-stage liver diseases, such as cirrhosis and liver cancer. However, the induced differentiation of single-layer or 3D-structured hepatocytes from stem cells cannot physiologically support essential liver functions due to the lack of formation of blood vessels, immune regulation, storage of vitamins, and other vital hepatic activities. Thus, there is emerging evidence showing that 3D organogenesis of artificial vascularized liver tissue from combined hepatic cell types derived from differentiated stem cells is practical for the treatment of end-stage liver diseases. The optimization of novel biomaterials, such as decellularized matrices and natural macromolecules, also strongly supports the organogenesis of 3D tissue with the desired complex structure. This review summarizes new research updates on novel differentiation protocols of stem cell-derived major hepatic cell types and the application of new supportive biomaterials. Future biological and clinical challenges of this concept are also discussed.
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Affiliation(s)
- Feng Chen
- National Key Disciplines for Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jia Xiao
- Clinical Medicine Research Institute, The First Affiliated Hospital of Jinan University, Guangzhou, China
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19
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Jiayuan S, Junyan Y, Xiangzhen W, Zuping L, Jian N, Baowei H, Lifang J. Gant61 ameliorates CCl 4-induced liver fibrosis by inhibition of Hedgehog signaling activity. Toxicol Appl Pharmacol 2019; 387:114853. [PMID: 31816328 DOI: 10.1016/j.taap.2019.114853] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/27/2019] [Accepted: 12/05/2019] [Indexed: 02/08/2023]
Abstract
As an intercellular signaling molecule, Hedgehog (Hh) plays a critical role in liver fibrosis/regeneration. Transcription effectors Gli1 and Gli2 are key components of the Hh signaling pathway. However, whether inhibition of Gli1/2 activity can affect liver fibrogenesis is largely unknown. In the present study, we investigated the effect of Gant61 (a Gli1/2 transcription factor inhibitor) on liver fibrosis and its possible mechanism. Wild-type and Shh-EGFP-Cre male mice were exposed to CCl4, and then treated with or without Gant61 for four weeks. The level of liver injury/fibrosis and expression levels of mRNA and protein related to the Hh ligand/pathway were assessed. In our study, CCl4 treatment induced liver injury/fibrosis and promoted activation of hepatic stellate cells (HSCs). In addition, CCl4 induced the expression of Shh ligands in and around the fibrotic lesion, accompanied by induction of mRNA and protein expression of Hh components (Smo, Gli1 and Gli2). However, administration of Gant61 decreased liver fibrosis by reduction in HSC number, down-regulation of mRNA and protein expression of Hh components (Smo, Gli1 and Gli2), and cell-cycle arrest of HSCs. Our data highlight the importance of the Shh pathway for the development of liver fibrosis, and also suggest Glis as potential therapeutic targets for the treatment of liver fibrosis.
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Affiliation(s)
- Shen Jiayuan
- College of Life Science, Shaoxing University, Shaoxing, Zhejiang, China; Department of pathology, Affliliated hospital of Shaoxing University, Shaoxing, Zhejiang, China
| | - Yan Junyan
- College of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | | | - Liu Zuping
- College of Life Science, Shaoxing University, Shaoxing, Zhejiang, China; Department of pathology, Affliliated hospital of Shaoxing University, Shaoxing, Zhejiang, China
| | - Ni Jian
- College of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Hu Baowei
- College of Life Science, Shaoxing University, Shaoxing, Zhejiang, China.
| | - Jin Lifang
- College of Life Science, Shaoxing University, Shaoxing, Zhejiang, China.
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20
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Ma Z, Zhang B, Fan Y, Wang M, Kebebe D, Li J, Liu Z. Traditional Chinese medicine combined with hepatic targeted drug delivery systems: A new strategy for the treatment of liver diseases. Biomed Pharmacother 2019; 117:109128. [PMID: 31234023 DOI: 10.1016/j.biopha.2019.109128] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/12/2019] [Accepted: 06/12/2019] [Indexed: 12/18/2022] Open
Abstract
Liver diseases are clinically common and present a substantial public health issue. Many of the currently available drugs for the treatment of liver diseases suffer from limitations that include low hepatic distribution, lack of target effects, poor in vivo stability and adverse effects on other organs. Consequently, conventional treatment of hepatic diseases is ineffective. TCM is commonly used in the treatment of liver diseases worldwide, particularly in China, and has advantages over conventional therapy. HTDDS can be designed to enhance clinical efficacy in the treatment of liver diseases. We have conducted an extensive review of 335 studies reported since 1964. These included about 166 references involving the treatment of liver diseases with TCM (covering active components of TCM, single TCM and Chinese medicine formulas), 169 reports on HTDDS and background studies on liver-related diseases. Here we review the long history of TCM in the treatment of liver diseases.We have also reviewed the status of studies on active components of TCM using nanotechnology-based targeted delivery systems to provide support for further research and development of TCM-based targeted preparations for the treatment of liver disease.
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Affiliation(s)
- Zhe Ma
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Bing Zhang
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Yuqi Fan
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Meng Wang
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Dereje Kebebe
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; School of Pharmacy, Institute of Health Sciences, Jimma University, Jimma, Ethiopia
| | - Jiawei Li
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.
| | - Zhidong Liu
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.
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21
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Fc gamma RIIb expression levels in human liver sinusoidal endothelial cells during progression of non-alcoholic fatty liver disease. PLoS One 2019; 14:e0211543. [PMID: 30695042 PMCID: PMC6350999 DOI: 10.1371/journal.pone.0211543] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 01/16/2019] [Indexed: 12/15/2022] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) play a pivotal role in hepatic function and homeostasis. LSEC dysfunction has been recognized to be closely involved in various liver diseases, including non-alcoholic steatohepatitis (NASH), but not much is known about the fate of the scavenger receptors in LSECs during NASH. Fc gamma receptor IIb (FcγRIIb), known as a scavenger receptor, contributes to receptor-mediated endocytosis and immune complexes clearance. In this study, to elucidate the fate of FcγRIIb in the progression of non-alcoholic fatty liver disease (NAFLD), we examined FcγRIIb levels in NAFLD biopsy specimens by immunohistochemistry, and investigated their correlation with the exacerbation of biological indexes and clinicopathological scores of NASH. The FcγRIIb expression levels indicated significant negative correlations with serum levels of blood lipids (triglyceride, total cholesterol, high-density lipoprotein-cholesterol), type 4 collagen and hyaluronic acid, which are involved in hepatic lipid metabolism disorder, fibrosis, and inflammation, respectively. However, there was no significant difference of FcγRIIb expression levels among the pathological grades of NAFLD. During NAFLD progression, inflammation and fibrosis may influence the expression of FcγRIIb and their scavenger functions to maintain hepatic homeostasis.
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22
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Di Martino J, Mascalchi P, Legros P, Lacomme S, Gontier E, Bioulac-Sage P, Balabaud C, Moreau V, Saltel F. Actin Depolymerization in Dedifferentiated Liver Sinusoidal Endothelial Cells Promotes Fenestrae Re-Formation. Hepatol Commun 2018; 3:213-219. [PMID: 30766959 PMCID: PMC6357827 DOI: 10.1002/hep4.1301] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 11/14/2018] [Indexed: 12/18/2022] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) possess fenestrae, which are key for the exchange between blood and hepatocytes. Alterations in their number or diameter have important implications for hepatic function in liver diseases. They are lost early in the development of hepatic fibrosis through a process called capillarization. In this study, we aimed to demonstrate whether in vitro dedifferentiated LSECs that have lost fenestrae are able to re-form these structures. Using stimulated emission depletion super-resolution microscopy in combination with transmission electron microscopy, we analyzed fenestrae formation in a model mimicking the capillarization process in vitro. Actin is known to be involved in fenestrae regulation in differentiated LSECs. Using cytochalasin D, an actin-depolymerizing agent, we demonstrated that dedifferentiated LSECs remain capable of forming fenestrae. Conclusion: We provide a new insight into the complex role of actin in fenestrae formation and in the control of their size and show that LSEC fenestrae re-formation is possible, suggesting that this process could be used during fibrosis regression to try to restore exchanges and hepatocyte functions.
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Affiliation(s)
- Julie Di Martino
- INSERM, UMR1053 Bariton-Bordeaux Research in Translational Oncology Bordeaux France.,Université de Bordeaux Bordeaux France
| | - Patrice Mascalchi
- Université de Bordeaux Bordeaux France.,Bordeaux Imaging Center Bordeaux France
| | - Philippe Legros
- Plateforme Aquitaine de Caractérisation des Matériaux Pessac France
| | - Sabrina Lacomme
- Université de Bordeaux Bordeaux France.,Bordeaux Imaging Center Bordeaux France
| | - Etienne Gontier
- Université de Bordeaux Bordeaux France.,Bordeaux Imaging Center Bordeaux France
| | | | - Charles Balabaud
- INSERM, UMR1053 Bariton-Bordeaux Research in Translational Oncology Bordeaux France
| | - Violaine Moreau
- INSERM, UMR1053 Bariton-Bordeaux Research in Translational Oncology Bordeaux France.,Université de Bordeaux Bordeaux France
| | - Frédéric Saltel
- INSERM, UMR1053 Bariton-Bordeaux Research in Translational Oncology Bordeaux France.,Université de Bordeaux Bordeaux France
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23
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Tee JK, Ng LY, Koh HY, Leong DT, Ho HK. Titanium Dioxide Nanoparticles Enhance Leakiness and Drug Permeability in Primary Human Hepatic Sinusoidal Endothelial Cells. Int J Mol Sci 2018; 20:35. [PMID: 30577655 PMCID: PMC6337147 DOI: 10.3390/ijms20010035] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 11/26/2018] [Accepted: 11/26/2018] [Indexed: 02/06/2023] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) represent the permeable interface that segregates the blood compartment from the hepatic cells, regulating hepatic vascular tone and portal pressure amidst changes in the blood flow. In the presence of pathological conditions, phenotypic changes in LSECs contribute to the progression of chronic liver diseases, including the loss of endothelial permeability. Therefore, modulating LSECs offers a possible way to restore sinusoidal permeability and thereby improve hepatic recovery. Herein, we showed that titanium dioxide nanoparticles (TiO₂ NPs) could induce transient leakiness in primary human hepatic sinusoidal endothelial cells (HHSECs). Interestingly, HHSECs exposed to these NPs exhibited reduced protein kinase B (Akt) phosphorylation, an important protein kinase which regulates cell attachment. Using a 3D co-culture system, we demonstrated that TiO₂ NPs diminished the attachment of HHSECs onto normal human hepatic cell LO2. To further illustrate the significance of leakiness in liver sinusoids, we showed that NP-induced leakiness promoted Sunitinib transport across the HHSEC layer, resulting in increased drug uptake and efficacy. Hence, TiO₂ NPs have the potential to modulate endothelial permeability within the specialized sinusoidal endothelium, especially during events of fibrosis and occlusion. This study highlighted the possible use of inorganic NPs as a novel strategy to promote drug delivery targeting the diseased liver.
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Affiliation(s)
- Jie Kai Tee
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
- NUS Graduate School for Integrative Sciences & Engineering, Centre for Life Sciences, 28 Medical Drive, Singapore 117456, Singapore.
| | - Li Yang Ng
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
| | - Hannah Yun Koh
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
| | - David Tai Leong
- NUS Graduate School for Integrative Sciences & Engineering, Centre for Life Sciences, 28 Medical Drive, Singapore 117456, Singapore.
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore.
| | - Han Kiat Ho
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
- NUS Graduate School for Integrative Sciences & Engineering, Centre for Life Sciences, 28 Medical Drive, Singapore 117456, Singapore.
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24
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Li Y, Pan Q, Zhao H. Investigation of the values of CT perfusion imaging and ultrasound elastography in the diagnosis of liver fibrosis. Exp Ther Med 2018; 16:896-900. [PMID: 30116343 PMCID: PMC6090262 DOI: 10.3892/etm.2018.6269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Accepted: 06/01/2018] [Indexed: 12/12/2022] Open
Abstract
This study intended to investigate the clinical application values of computed tomography (CT) perfusion imaging and ultrasound elastography in the diagnosis of liver fibrosis, and to analyze the characteristics and diagnostic values of the two methods in liver fibrosis. A total of 320 patients diagnosed with suspected liver fibrosis in Qingdao Municipal Hospital from April 2014 to May 2016 were selected. The patients were diagnosed by ultrasound elastography and CT perfusion imaging, respectively, and the influencing characteristics and diagnostic accuracies of the two methods were compared. Among 320 patients, there were 315 definitely diagnosed with liver fibrosis through liver biopsy. The accuracy of CT perfusion imaging was 95.63% (306/325), while that of ultrasound elastography was 91.88% (294/320); there was a significant difference in accuracy between the two methods (P>0.05). CT perfusion imaging was superior to ultrasound elastography in the degree of liver fibrosis (P<0.05). Receiver operating characteristic (ROC) curve analysis showed that the areas under the curve (AUC) of patients were 0.841 and 0.865 in S1 (P>0.05), 0.830 and 0.887 in S2 (P>0.05), 0.851 and 0.931 in S3 (P>0.05), and 0.951 and 0.970 in S4, respectively (P>0.05). AUC values of ROC curves of CT perfusion imaging and ultrasound elastography in diagnosing liver fibrosis were 0.833 and 0.857, respectively (P>0.05). Both CT perfusion imaging and ultrasound elastography have relatively high accuracies in the clinical diagnosis of liver fibrosis, and they are worth promoting and applying. However, the best imaging method needs to be selected according to the actual situation of patients and research purpose.
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Affiliation(s)
- Yansong Li
- Department of Ultrasound, Qingdao Municipal Hospital, Qingdao, Shandong 266071, P.R. China
| | - Qing Pan
- Department of Ultrasound, Qingdao Municipal Hospital, Qingdao, Shandong 266071, P.R. China
| | - Hong Zhao
- Department of Radiology, Eastern Hospital, Qingdao Municipal Hospital, Qingdao, Shandong 266071, P.R. China
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25
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Altered AKAP12 expression in portal fibroblasts and liver sinusoids mediates transition from hepatic fibrogenesis to fibrosis resolution. Exp Mol Med 2018; 50:1-13. [PMID: 29700280 PMCID: PMC5938025 DOI: 10.1038/s12276-018-0074-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 02/20/2018] [Accepted: 02/22/2018] [Indexed: 12/11/2022] Open
Abstract
Liver fibrosis can be reversed by removing its causative injuries; however, the molecular mechanisms mediating the resolution of liver fibrogenesis are poorly understood. We investigate the role of a scaffold protein, A-Kinase Anchoring Protein 12 (AKAP12), during liver fibrosis onset, and resolution. Biliary fibrogenesis and fibrosis resolution was induced in wild-type (WT) or AKAP12-deficient C57BL/6 mice through different feeding regimens with 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing chow. AKAP12 expression in portal fibroblasts (PFs) and liver sinusoidal endothelial cells (LSECs) gradually decreased as fibrosis progressed but was restored after cessation of the fibrotic challenge. Histological analysis of human liver specimens with varying degrees of fibrosis of different etiologies revealed that AKAP12 expression diminishes in hepatic fibrosis from its early stages onward. AKAP12 KO mice displayed reduced fibrosis resolution in a DDC-induced biliary fibrosis model, which was accompanied by impaired normalization of myofibroblasts and capillarized sinusoids. RNA sequencing of the liver transcriptome revealed that genes related to ECM accumulation and vascular remodeling were mostly elevated in AKAP12 KO samples. Gene ontology (GO) and bioinformatic pathway analyses identified that the differentially expressed genes were significantly enriched in GO categories and pathways, such as the adenosine 3′,5′-cyclic monophosphate (cAMP) pathway. Knockdown of the AKAP12 gene in cultured primary PFs revealed that AKAP12 inhibited PF activation in association with the adenosine 3′,5′-cyclic monophosphate (cAMP) pathway. Moreover, AKAP12 knockdown in LSECs led to enhanced angiogenesis, endothelin-1 expression and alterations in laminin composition. Collectively, this study demonstrates that AKAP12-mediated regulation of PFs and LSECs has a central role in resolving hepatic fibrosis. A scaffolding protein that modulates cell signaling pathways contributes to reverse liver scarring. Liver fibrosis is caused by a build-up of scar tissue that interferes with liver function. However, the damage is reversed when the cause of injury is removed. Kyu-Won Kim at Seoul National University, South Korea, and colleagues examined the levels of A-Kinase Anchoring Protein 12 (AKAP12), a scaffolding protein that regulates the subcellular location of signaling proteins, in mouse and human livers. Levels of AKAP12 were reduced in fibrotic livers but restored when fibrosis was reversed. Mice lacking AKAP12 were unable to effectively repair the damage caused by fibrosis. Genetic analyses suggest that AKAP12 stimulates signaling through the adenosine 3′,5′-cyclic monophosphate (cAMP) pathway, which can inhibit fibrosis. These findings highlight a key role for AKAP12 in accelerating liver recovery.
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26
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Ni Y, Li JM, Liu MK, Zhang TT, Wang DP, Zhou WH, Hu LZ, Lv WL. Pathological process of liver sinusoidal endothelial cells in liver diseases. World J Gastroenterol 2017; 23:7666-7677. [PMID: 29209108 PMCID: PMC5703927 DOI: 10.3748/wjg.v23.i43.7666] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Revised: 09/13/2017] [Accepted: 09/28/2017] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis develops from liver fibrosis and is the severe pathological stage of all chronic liver injury. Cirrhosis caused by hepatitis B virus and hepatitis C virus infection is especially common. Liver fibrosis and cirrhosis involve excess production of extracellular matrix, which is closely related to liver sinusoidal endothelial cells (LSECs). Damaged LSECs can synthesize transforming growth factor-beta and platelet-derived growth factor, which activate hepatic stellate cells and facilitate the synthesis of extracellular matrix. Herein, we highlight the angiogenic cytokines of LSECs related to liver fibrosis and cirrhosis at different stages and focus on the formation and development of liver fibrosis and cirrhosis. Inhibition of LSEC angiogenesis and antiangiogenic therapy are described in detail. Targeting LSECs has high therapeutic potential for liver diseases. Further understanding of the mechanism of action will provide stronger evidence for the development of anti-LSEC drugs and new directions for diagnosis and treatment of liver diseases.
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MESH Headings
- Angiogenesis Inhibitors/pharmacology
- Angiogenesis Inhibitors/therapeutic use
- Animals
- Cytokines/metabolism
- Disease Models, Animal
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Endothelial Cells/virology
- Extracellular Matrix/metabolism
- Extracellular Matrix/pathology
- Hepacivirus/pathogenicity
- Hepatic Stellate Cells/metabolism
- Hepatic Stellate Cells/pathology
- Hepatic Stellate Cells/virology
- Hepatitis B virus/pathogenicity
- Hepatitis, Viral, Human/diagnosis
- Hepatitis, Viral, Human/drug therapy
- Hepatitis, Viral, Human/pathology
- Hepatitis, Viral, Human/virology
- Humans
- Liver/blood supply
- Liver/cytology
- Liver/pathology
- Liver/virology
- Liver Cirrhosis/diagnosis
- Liver Cirrhosis/drug therapy
- Liver Cirrhosis/pathology
- Liver Cirrhosis/virology
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/pathology
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Affiliation(s)
- Yao Ni
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Juan-Mei Li
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ming-Kun Liu
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ting-Ting Zhang
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Dong-Ping Wang
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Wen-Hui Zhou
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ling-Zi Hu
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Wen-Liang Lv
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
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27
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Zhang C, Bian M, Chen X, Jin H, Zhao S, Yang X, Shao J, Chen A, Guo Q, Zhang F, Zheng S. Oroxylin A prevents angiogenesis of LSECs in liver fibrosis via inhibition of YAP/HIF-1α signaling. J Cell Biochem 2017; 119:2258-2268. [PMID: 28857294 DOI: 10.1002/jcb.26388] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 08/23/2017] [Indexed: 12/19/2022]
Abstract
Angiogenesis of liver sinusoidal endothelial cells (LSECs) accompanies with hypoxia in liver fibrosis and they are of mutual promotion, which has raised wide concern. Here we established murine model of liver fibrosis and found that oroxylin A (40 mg/kg) could ameliorate angiogenesis in liver fibrosis may related to hypoxia inducible factor 1α (HIF-1α). The underlying mechanism was further investigated by isolating and culturing murine primary LSECs. Hypoxia induced vascular endothelial growth factor A (VEGF-A), angiopoietin 2 (Ang-2), and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) elevated in LSECs were reduced by oroxylin A or acriflavine (ACF, an HIF-1α inhibitor), indicating HIF-1α involved the angiogenesis of LSECs. Additionally, interference with Yes-associated protein (YAP) significant downregulated the protein expression of HIF-1α and VEGF-A, while YAP plasmid exhibited an opposite effect. We next found that oroxylin A inhibited hypoxia-induced nuclear translocation of YAP, which may influence the accumulation of HIF-1α and subsequently decrease transcription of downstream target gene including VEGF-A and Ang-2, thereby exerting an anti-angiogenic activity.
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Affiliation(s)
- Chenxi Zhang
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Mianli Bian
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xingran Chen
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Huanhuan Jin
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Shifeng Zhao
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xiang Yang
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jiangjuan Shao
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Anping Chen
- Department of Pathology, School of Medicine, Saint Louis University, St Louis, Missouri
| | - Qinglong Guo
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Feng Zhang
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Shizhong Zheng
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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