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Wu G, Fan Q, Chen M, Luo G, Wu Z, Zhao J, Lin J, Zhang C, Li H, Qi X, Huo H, Zheng L, Luo M. Activation of AMP-activated Protein Kinase by Metformin Inhibits Dedifferentiation of Platelet-derived Growth Factor-BB-induced Vascular Smooth Muscle Cells to Improve Arterial Remodeling in Cirrhotic Portal Hypertension. Cell Mol Gastroenterol Hepatol 2025; 19:101487. [PMID: 40024535 PMCID: PMC12008675 DOI: 10.1016/j.jcmgh.2025.101487] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 02/21/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND & AIMS Portal hypertension (PHT) is the potentially deadly complication of liver cirrhosis. Intrahepatic vascular resistance and the splanchnic hyperdynamic circulation are 2 principal driving factors contributing to the maintenance and exacerbation of PHT. However, in the advanced stages of cirrhosis, the fibrotic process in the liver becomes irreversible, leading to persistent and intractable increases in intrahepatic vascular resistance. Arterial remodeling emerges as a crucial mechanism driving the hyperdynamic splanchnic circulation. Therefore, ameliorating the hyperdynamic splanchnic circulation has become an indispensable component of PHT therapeutic strategies. METHODS Liver cirrhosis with PHT was induced in the rats by common bile duct ligation (BDL). Based on the transcriptomic sequencing of the mesenteric arteries, we investigated the effects and mechanisms of metformin on the arterial remodeling at different stages of cirrhosis. We further validated potential molecular mechanisms through in vitro experiments using the A7r5 smooth muscle cell line and primary vascular smooth muscle cells (VSMCs). RESULTS Our findings revealed the beneficial effects of metformin on liver cirrhosis and PHT in rats following BDL for 4 and 6 weeks. Metformin was observed to ameliorate PHT and splanchnic hyperdynamic circulation in BDL rats, even in the advanced stages of liver cirrhosis. This effect was evidenced by reduced portal pressure and cardiac output, decreased superior mesenteric artery (SMA) flow, accompanied by improvements in systemic vascular resistance and SMA resistance. Moreover, chronic inflammation in BDL rats was alleviated by metformin, which might inhibit the driving factors of angiogenesis and arterial remodeling. Notably, SMA dilation and arterial remodeling in BDL rats were potent alleviated following metformin treatment. Metformin ameliorated arterial remodeling in BDL rats by inhibiting the dedifferentiation of contractile VSMCs, resulting in the upregulation of contractile protein expressions such as alpha-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α). Platelet-derived growth factor-BB (PDGF-BB)/platelet-derived growth factor receptor beta (PDGFR-β) signaling exerted crucial roles in regulating the VSMCs cell phenotype. Activation of AMP-activated protein kinase (AMPK) by metformin blocked the downstream pathway of PDGF-BB/PDGFRβ. Furthermore, in vitro cell experiments, VSMCs were respectively treated with AMPK activator metformin or AMPK inhibitor Compound C. We revealed the molecular mechanism that metformin inhibited the phenotypic switching of A7r5 cells induced by PDGF-BB and primary VSMCs from BDL rats, which was mediated by activating AMPK to enhance the expression of contractile protein α-SMA. These findings suggest that AMPK can ameliorate the progression of arterial remodeling during PHT via suppressing the PDGF-BB/PDGFRβ signaling pathway, thereby offering novel insights into seek PHT treatment approaches. CONCLUSIONS Our findings revealed that metformin exerts its effects by activating the AMPK pathway, inhibiting the dedifferentiation of contractile VSMCs in the splanchnic arteries, and improving arterial remodeling, thereby ameliorating PHT and splanchnic hyperdynamic circulation in cirrhotic rats.
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MESH Headings
- Animals
- Metformin/pharmacology
- Metformin/therapeutic use
- Hypertension, Portal/drug therapy
- Hypertension, Portal/etiology
- Hypertension, Portal/pathology
- Vascular Remodeling/drug effects
- Rats
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/cytology
- Male
- Cell Dedifferentiation/drug effects
- Becaplermin/pharmacology
- Becaplermin/metabolism
- AMP-Activated Protein Kinases/metabolism
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Liver Cirrhosis/complications
- Liver Cirrhosis/drug therapy
- Liver Cirrhosis/pathology
- Rats, Sprague-Dawley
- Splanchnic Circulation/drug effects
- Cell Line
- Mesenteric Arteries/drug effects
- Enzyme Activation/drug effects
- Disease Models, Animal
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Affiliation(s)
- Guangbo Wu
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiang Fan
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Chen
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guqing Luo
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenghao Wu
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinbo Zhao
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiayun Lin
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chihao Zhang
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongjie Li
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoliang Qi
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haizhong Huo
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Lei Zheng
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Meng Luo
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Pun CK, Huang HC, Chang CC, Chuang CL, Hsu SJ, Hou MC, Lee FY. Fructooligosaccharides reverses hepatic vascular dysfunction and dysbiosis in rats with liver cirrhosis and portal hypertension. Eur J Clin Invest 2024; 54:e14287. [PMID: 39017981 DOI: 10.1111/eci.14287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 07/08/2024] [Indexed: 07/18/2024]
Abstract
BACKGROUND Portal hypertension leads to lethal complications in liver cirrhosis. Oxidative stress induced hepatic vascular dysfunction, which exaggerated vasoconstriction and increases hepatic vascular resistance (HVR). Gut dysbiosis further exacerbates portal hypertension. Fructooligosaccharides are prebiotics with potent antioxidant effect. This study aimed to evaluate the roles of fructooligosaccharides in portal hypertension-related vascular dysregulation and gut microbiome. METHODS Sprague-Dawley rats received bile duct ligation to induce cirrhosis or sham operation as controls. The rats then randomly received fructooligosaccharides or vehicle for 4 weeks. Experiments were performed on the 29th day after operations. RESULTS Fructooligosaccharides did not affect portal pressure. Interestingly, fructooligosaccharides significantly attenuated HVR (p = .03). Malondialdehyde, an oxidative stress marker, reduced significantly in the liver in fructooligosaccharides-treated group. In addition, superoxide dismutase and trolox equivalent antioxidant capacity increased in the treatment group. On the other hand, vasodilatation-related protein expressions, GTPCH and phospho-eNOS, enhanced significantly. Fructooligosaccharides had no adverse vasodilatation effects on splanchnic vascular system or porto-systemic collateral systems. Locomotor function was not affected by fructooligosaccharides. Faecal microbiota analysis showed that Negativicutes, Selenomonadales and Lactobacillus salivarius reduced in the fructooligosaccharides-treated group. CONCLUSION In conclusion, fructooligosaccharides attenuate hepatic vascular dysfunction in cirrhotic rats via at least partly, ameliorate of dysbiosis and oxidative stress.
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Affiliation(s)
- Chon Kit Pun
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Therapeutic and Research Center of Liver Cirrhosis and Portal Hypertension, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hui-Chun Huang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Therapeutic and Research Center of Liver Cirrhosis and Portal Hypertension, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ching-Chih Chang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Holistic and Multidisciplinary Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chiao-Lin Chuang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shao-Jung Hsu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Therapeutic and Research Center of Liver Cirrhosis and Portal Hypertension, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Chih Hou
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Therapeutic and Research Center of Liver Cirrhosis and Portal Hypertension, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Therapeutic and Research Center of Liver Cirrhosis and Portal Hypertension, Taipei Veterans General Hospital, Taipei, Taiwan
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Pun C, Huang HC, Chang CC, Hsu SJ, Chuang CL, Huang YH, Hou MC, Lee FY. Low-dose alcohol exacerbates hyperdynamic circulation and shunting in non-alcoholic cirrhotic rats. Biosci Rep 2024; 44:BSR20240354. [PMID: 38967060 PMCID: PMC11263042 DOI: 10.1042/bsr20240354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 06/18/2024] [Accepted: 07/02/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND Portal hypertension affects hepatic, splanchnic and portosystemic collateral systems. Although alcohol is a well-known risk factor for liver cirrhosis, it also affects vascular contractility. However, the relevant effects on portal hypertension have not been evaluated in non-alcoholic cirrhosis. The present study aimed to investigate the impacts of low-dose alcohol on portal hypertension-related derangements in non-alcoholic cirrhotic rats. METHODS Sprague-Dawley rats received bile duct ligation to induce cirrhosis or sham operation as controls. The chronic or acute effects of low-dose alcohol (2.4 g/kg/day, oral gavage, approximately 1.3 drinks/day in humans) were evaluated. RESULTS The chronic administration of low-dose alcohol did not precipitate liver fibrosis in the sham or cirrhotic rats; however, it significantly increased splanchnic blood inflow (P=0.034) and portosystemic collaterals (P=0.001). Mesenteric angiogenesis and pro-angiogenic proteins were up-regulated in the alcohol-treated cirrhotic rats, and poorer collateral vasoresponsiveness to vasoconstrictors (P<0.001) was noted. Consistently, acute alcohol administration reduced splenorenal shunt resistance. Collateral vasoresponsiveness to vasoconstrictors also significantly decreased (P=0.003). CONCLUSIONS In non-alcoholic cirrhosis rats, a single dose of alcohol adversely affected portosystemic collateral vessels due to vasodilatation. Long-term alcohol use precipitated splanchnic hyperdynamic circulation, in which mesenteric angiogenesis played a role. Further studies are warranted to evaluate the benefits of avoiding low-dose alcohol consumption in patients with non-alcoholic cirrhosis.
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Affiliation(s)
- Chon Kit Pun
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hui-Chun Huang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ching-Chih Chang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Holistic and Multidisciplinary Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shao-Jung Hsu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chiao-Lin Chuang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Chih Hou
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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Fan Q, Wu G, Chen M, Luo G, Wu Z, Huo H, Li H, Zheng L, Luo M. Cediranib ameliorates portal hypertensive syndrome via inhibition of VEGFR-2 signaling in cirrhotic rats. Eur J Pharmacol 2024; 964:176278. [PMID: 38158116 DOI: 10.1016/j.ejphar.2023.176278] [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: 08/07/2023] [Revised: 12/04/2023] [Accepted: 12/13/2023] [Indexed: 01/03/2024]
Abstract
Portal hypertension (PHT) is a syndrome caused by systemic and portal hemodynamic disturbances with the progression of cirrhosis. However, the exact mechanisms regulating angiogenesis-related responses in PHT remain unclear. Cediranib is a potent inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, exhibiting a greater affinity for VEGFR-2. Liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague-Dawley rats. Sham-operated rats were controls. BDL and sham rats were randomly allocated to receive Cediranib or vehicle after BDL. On the 28th day, portal hypertension related parameters were surveyed. Cediranib treatment could significantly reduce the portal pressure (PP) in BDL rats, while it did not affect the mean arterial pressure (MAP) in sham groups and BDL groups. Cediranib treatment could significantly affect the stroke volume (SV), cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), superior mesenteric artery (SMA) flow and SMA resistance in BDL groups and BDL with Cediranib groups. Cediranib treatment could improve the mesenteric vascular remodeling and contractility. Cediranib treatment significantly reduced mesenteric vascular density. And phospho-VEGFR-2 was significantly downregulated by Cediranib. On the other hand, phospho-endothelial Nitric Oxide Synthases (phospho-eNOS) expressions were upregulated. Cediranib not only improved splanchnic hemodynamics, extrahepatic vascular remodeling and vasodilation, but also alleviated intrahepatic fibrosis and collagen deposition significantly. Cediranib treatment could reduce intrahepatic angiogenesis between BDL-vehicle and BDL-Cediranib rats. In conclusion, Cediranib could improve extrahepatic hyperdynamic circulation by inhibiting extrahepatic angiogenesis through inhibition of the VEGFR-2 signaling pathway, portal collateral circulation formation, as well as eNOS-mediated vasodilatation and vascular remodeling, and at the same time, Cediranib improved intrahepatic fibrogenesis and angiogenesis, which together alleviate cirrhotic PHT syndrome.
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Affiliation(s)
- Qiang Fan
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guangbo Wu
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Chen
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guqing Luo
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenghao Wu
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haizhong Huo
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongjie Li
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Lei Zheng
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Meng Luo
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Huang CJ, Hsu SJ, Hsu YC, Chen LK, Li C, Huang HC, Lee YH. Synthesis, characterization, and biological verification of asialoglycoprotein receptor-targeted lipopolysaccharide-encapsulated PLGA nanoparticles for the establishment of a liver fibrosis animal model. Biomater Sci 2023; 11:6650-6662. [PMID: 37609825 DOI: 10.1039/d3bm01058a] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
Liver fibrosis is generally preceded by various liver injuries and often leads to chronic liver diseases and even cirrhosis. Therefore, a liver fibrosis animal model is the cornerstone for the development of therapeutic strategies for hepatic diseases. Although administration of hepatotoxic substances and/or bile duct ligation have been widely performed to construct the in vivo model over the last decades, they are seriously hindered by time-consuming protocols, high mortality, and instability, indicating that an effective and safe approach for the induction of liver fibrosis is still urgently needed nowadays. In this study, we have developed asialoglycoprotein receptor (ASGPR)-targeted lipopolysaccharide (LPS)-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles named ALPNPs for establishing an animal model of liver fibrosis. The ALPNPs are characterized as having a spherical nanostructure with size of 182.9 ± 8.89 nm and surface charge of -8.3 ± 1.48 mV. An anti-ASGPR antibody bound to the surface of the nanoparticles with a crosslinking efficiency of 95.03% allows ALPNPs to have hepatocyte-binding specificity. In comparison to free LPSs, the ALPNPs can induce higher aspartate aminotransferase and total bilirubin concentrations in plasma, reduce the blood flow rate in the portal system and the kidneys, and increase vascular resistance in the liver, kidneys, and collateral shunting vasculature. Based on histological and RNA-seq analyses, the ALPNPs can provide similar capability on inducing hepatic inflammation and fibrosis compared to free LPS but possess higher liver targetability than the naked drug. In addition, the ALPNPs are less toxic in organs other than the liver in comparison to free LPS, demonstrating that the ALPNPs do not elicit off-target effects in vivo. Given the aforementioned efficacies with other merits such as biocompatibility and drug release controllability provided by PLGA, we anticipate that the developed ALPNPs are highly applicable in establishing animal models of liver fibrosis in pre-clinical studies.
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Affiliation(s)
- Ching-Ju Huang
- Department of Biomedical Sciences and Engineering, National Central, University, Taoyuan 32001, Taiwan R.O.C.
| | - Shao-Jung Hsu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan R.O.C.
- School of Medicine, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan R.O.C
| | - Yi-Chiung Hsu
- Department of Biomedical Sciences and Engineering, National Central, University, Taoyuan 32001, Taiwan R.O.C.
| | - Liang-Kun Chen
- Department of Biomedical Sciences and Engineering, National Central, University, Taoyuan 32001, Taiwan R.O.C.
| | - Chuan Li
- Department of Biomedical Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan R.O.C
| | - Hui-Chun Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan R.O.C.
- School of Medicine, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan R.O.C
| | - Yu-Hsiang Lee
- Department of Biomedical Sciences and Engineering, National Central, University, Taoyuan 32001, Taiwan R.O.C.
- Department of Chemical and Materials Engineering, National Central University, Taoyuan, Taiwan R.O.C
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Pun CK, Chang CC, Chuang CL, Huang HC, Hsu SJ, Huang YH, Hou MC, Lee FY. Dual angiotensin receptor and neprilysin inhibitor reduced portal pressure through peripheral vasodilatation and decreasing systemic arterial pressure in cirrhotic rats. J Chin Med Assoc 2023; 86:786-794. [PMID: 37462441 DOI: 10.1097/jcma.0000000000000959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/09/2023] Open
Abstract
BACKGROUND Portal hypertension develops along with the progression of liver cirrhosis. Natriuretic peptides have been shown to reduce portal pressure but concomitantly activate the renin-angiotensin-aldosterone system (RAAS). Angiotensin receptor-neprilysin inhibitors (ARNIs) upregulate natriuretic peptides and avoid the adverse effects of RAAS activation. ARNIs have been shown to reduce portal pressure in rats with pre-hepatic portal hypertension, which involves relatively little liver injury. This study aimed to evaluate the relevant effects of an ARNI in rats with both liver cirrhosis and portal hypertension. METHODS Male Sprague-Dawley rats received common bile duct ligation to induce liver cirrhosis and portal hypertension. Sham-operated rats served as surgical controls. All rats were randomly allocated into three groups to receive distilled water (vehicle), LCZ696 (an ARNI), or valsartan for 4 weeks. Portal hypertension and relevant derangements were assessed after treatment. RESULTS Portal hypertension and hyperdynamic circulation developed in the cirrhotic rats. In the rats with cirrhosis and portal hypertension, both LCZ696 and valsartan reduced portal hypertension, mean arterial pressure, and systemic vascular resistance. The decrease in portal pressure was highly associated with the reduction in arterial pressure and systemic vascular resistance. Blood flow in hepatic, splanchnic, and portosystemic collateral systems was not altered. LCZ696 did not significantly influence liver injury or plasma cytokine levels. Liver fibrosis and splanchnic angiogenesis were not affected. CONCLUSION ARNI treatment exerted portal pressure lowering effects via peripheral vasodilatation and decreasing systemic arterial pressure in the rats with liver cirrhosis and portal hypertension. Caution should be taken when using ARNIs in liver cirrhosis.
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Affiliation(s)
- Chon Kit Pun
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ching-Chih Chang
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Holistic and Multidisciplinary Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chiao-Lin Chuang
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Hui-Chun Huang
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shao-Jung Hsu
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Hsiang Huang
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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Coelho M, Patarrão RS, Sousa-Lima I, Ribeiro RT, Meneses MJ, Andrade R, Mendes VM, Manadas B, Raposo JF, Macedo MP, Jones JG. Increased Intake of Both Caffeine and Non-Caffeine Coffee Components Is Associated with Reduced NAFLD Severity in Subjects with Type 2 Diabetes. Nutrients 2022; 15:nu15010004. [PMID: 36615664 PMCID: PMC9824649 DOI: 10.3390/nu15010004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Coffee may protect against non-alcoholic fatty liver disease (NAFLD), but the roles of the caffeine and non-caffeine components are unclear. Coffee intake by 156 overweight subjects (87% with Type-2-Diabetes, T2D) was assessed via a questionnaire, with 98 subjects (all T2D) also providing a 24 h urine sample for quantification of coffee metabolites by LC-MS/MS. NAFLD was characterized by the fatty liver index (FLI) and by Fibroscan® assessment of fibrosis. No associations were found between self-reported coffee intake and NAFLD parameters; however, total urine caffeine metabolites, defined as Σcaffeine (caffeine + paraxanthine + theophylline), and adjusted for fat-free body mass, were significantly higher for subjects with no liver fibrosis than for those with fibrosis. Total non-caffeine metabolites, defined as Σncm (trigonelline + caffeic acid + p-coumaric acid), showed a significant negative association with the FLI. Multiple regression analyses for overweight/obese T2D subjects (n = 89) showed that both Σcaffeine and Σncm were negatively associated with the FLI, after adjusting for age, sex, HbA1c, ethanol intake and glomerular filtration rate. The theophylline fraction of Σcaffeine was significantly increased with both fibrosis and the FLI, possibly reflecting elevated CYP2E1 activity-a hallmark of NAFLD worsening. Thus, for overweight/obese T2D patients, higher intake of both caffeine and non-caffeine coffee components is associated with less severe NAFLD. Caffeine metabolites represent novel markers of NAFLD progression.
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Affiliation(s)
- Margarida Coelho
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-531 Coimbra, Portugal
- III Institute for Interdisciplinary Research, University of Coimbra (IIIUC), 3030-789 Coimbra, Portugal
| | - Rita S. Patarrão
- iNOVA4Health, NOVA Medical School-Faculdade de Ciências Médicas, NMS-FCM, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal
| | - Inês Sousa-Lima
- iNOVA4Health, NOVA Medical School-Faculdade de Ciências Médicas, NMS-FCM, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal
| | - Rogério T. Ribeiro
- APDP-Diabetes Portugal, Education and Research Center, 1250-189 Lisbon, Portugal
| | - Maria João Meneses
- iNOVA4Health, NOVA Medical School-Faculdade de Ciências Médicas, NMS-FCM, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal
| | - Rita Andrade
- APDP-Diabetes Portugal, Education and Research Center, 1250-189 Lisbon, Portugal
| | - Vera M. Mendes
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-531 Coimbra, Portugal
- III Institute for Interdisciplinary Research, University of Coimbra (IIIUC), 3030-789 Coimbra, Portugal
| | - Bruno Manadas
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-531 Coimbra, Portugal
- III Institute for Interdisciplinary Research, University of Coimbra (IIIUC), 3030-789 Coimbra, Portugal
| | - João Filipe Raposo
- APDP-Diabetes Portugal, Education and Research Center, 1250-189 Lisbon, Portugal
| | - M. Paula Macedo
- iNOVA4Health, NOVA Medical School-Faculdade de Ciências Médicas, NMS-FCM, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal
- APDP-Diabetes Portugal, Education and Research Center, 1250-189 Lisbon, Portugal
| | - John G. Jones
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-531 Coimbra, Portugal
- III Institute for Interdisciplinary Research, University of Coimbra (IIIUC), 3030-789 Coimbra, Portugal
- Correspondence:
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8
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Shan L, Wang F, Zhai D, Meng X, Liu J, Lv X. Caffeine in liver diseases: Pharmacology and toxicology. Front Pharmacol 2022; 13:1030173. [PMID: 36324678 PMCID: PMC9618645 DOI: 10.3389/fphar.2022.1030173] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/05/2022] [Indexed: 11/29/2022] Open
Abstract
We have previously shown that adenosine A1AR antagonists, adenosine A2aAR antagonists, and caffeine have significant inhibitory effects on the activation and proliferation of hepatic stellate cells in alcoholic liver fibrosis. Many recent studies have found that moderate coffee consumption is beneficial for various liver diseases. The main active ingredient of coffee is caffeine, which is a natural non-selective adenosine receptor antagonist. Moreover, numerous preclinical epidemiological studies and clinical trials have examined the association between frequent coffee consumption and the risk of developing different liver diseases. In this review, we summarize and analyze the prophylactic and therapeutic effects of caffeine on various liver diseases, with an emphasis on cellular assays, animal experiments, and clinical trials. To review the prevention and treatment effects of caffeine on different liver diseases, we searched all literature before 19 July 2022, using “caffeine” and “liver disease” as keywords from the PubMed and ScienceDirect databases. We found that moderate coffee consumption has beneficial effects on various liver diseases, possibly by inhibiting adenosine binding to its receptors. Caffeine is a potential drug for the prevention and treatment of various liver diseases.
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Affiliation(s)
- Liang Shan
- Department of Pharmacy, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
- The Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, China
| | - Fengling Wang
- Department of Pharmacy, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
| | - Dandan Zhai
- Department of Pharmacy, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
| | - Xiangyun Meng
- Department of Pharmacy, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
| | - Jianjun Liu
- Department of Pharmacy, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
- *Correspondence: Jianjun Liu, ; Xiongwen Lv,
| | - Xiongwen Lv
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
- The Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, China
- *Correspondence: Jianjun Liu, ; Xiongwen Lv,
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9
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Xie J, Xu L. Coffee Consumption and Lower Liver Stiffness: The Risk for Residual Confounders Should be Considered. Clin Gastroenterol Hepatol 2022; 20:2152-2153. [PMID: 34775081 DOI: 10.1016/j.cgh.2021.11.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 11/05/2021] [Indexed: 02/07/2023]
Affiliation(s)
- Jiarong Xie
- Department of Gastroenterology, Ningbo First Hospital, Ningbo, China
| | - Lei Xu
- Department of Gastroenterology, Ningbo First Hospital, Ningbo, China
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10
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Ryu J. New Aspects on the Treatment of Retinopathy of Prematurity: Currently Available Therapies and Emerging Novel Therapeutics. Int J Mol Sci 2022; 23:8529. [PMID: 35955664 PMCID: PMC9369302 DOI: 10.3390/ijms23158529] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 02/05/2023] Open
Abstract
Retinopathy of prematurity (ROP) is a rare proliferative ocular disorder in preterm infants. Because of the advancements in neonatal care, the incidence of ROP has increased gradually. Now, ROP is one of the leading causes of blindness in children. Preterm infants with immature retinal development are exposed to supplemental oxygen inside an incubator until their cardiopulmonary system is adequately developed. Once they are returned to room air, the relatively low oxygen level stimulates various angiogenesis factors initiating retinal neovascularization. If patients with ROP are not offered adequate and timely treatment, they can experience vision loss that may ultimately lead to permanent blindness. Although laser therapy and anti-vascular endothelial growth factor agents are widely used to treat ROP, they have limitations. Thus, it is important to identify novel therapeutics with minimal adverse effects for the treatment of ROP. To date, various pharmacologic and non-pharmacologic therapies have been assessed as treatments for ROP. In this review, the major molecular factors involved in the pathogenesis of ROP, currently offered therapies, therapies under investigation, and emerging novel therapeutics of ROP are discussed.
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Affiliation(s)
- Juhee Ryu
- Vessel-Organ Interaction Research Center, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea; ; Tel.: +82-539508583
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea
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11
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Huang HC, Hsu SJ, Chang CC, Kao YC, Chuang CL, Hou MC, Lee FY. Lycopene treatment improves intrahepatic fibrosis and attenuates pathological angiogenesis in biliary cirrhotic rats. J Chin Med Assoc 2022; 85:414-420. [PMID: 35120355 DOI: 10.1097/jcma.0000000000000699] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Liver cirrhosis is characterized by liver fibrosis and pathological angiogenesis, which results in hyperdynamic circulation, portal-systemic collateral vascular formation, and abnormal angiogenesis. Lycopene is a nutrient mostly found in tomatoes. The beneficial effects of lycopene include anti-inflammation, anti-oxidation, anti-fibrosis, and anti-angiogenesis; however, the association between liver cirrhosis and pathological angiogenesis has yet to be studied. This study aimed to investigate the effects of lycopene on biliary cirrhotic rats. METHODS The efficacy of lycopene treatment in common bile duct ligation (BDL)-induced biliary cirrhotic rats was evaluated. Sham-operated rats served as surgical controls. Lycopene (20 mg/kg/day, oral gavage) or vehicle was administered to BDL or sham-operated rats for 4 weeks, after which the hemodynamics, liver biochemistry, portal-systemic shunting, liver and mesenteric angiogenesis, and hepatic angiogenesis-related protein expressions were examined. RESULTS Lycopene alleviated hyperdynamic circulation as evidenced by decreased cardiac index and increased peripheral vascular resistance (p < 0.05), but it did not affect portal pressure or liver biochemistry in the BDL rats (p > 0.05). Lycopene significantly diminished the shunting degree of portal-systemic collaterals (p = 0.04) and mesenteric vascular density (p = 0.01), and also ameliorated intrahepatic angiogenesis and liver fibrosis. In addition, lycopene upregulated endothelial nitric oxide synthase, protein kinase B (Akt) and phosphatidylinositol 3-kinases (PI3K), and downregulated vascular endothelial growth factor receptor 2 (VEGFR-2) protein expressions (p < 0.05) in the livers of the BDL rats. CONCLUSION Lycopene ameliorated liver fibrosis, hyperdynamic circulation, and pathological angiogenesis in biliary cirrhotic rats, possibly through the modulation of intrahepatic Akt/PI3K/eNOS and VEGFR-2 pathways.
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Affiliation(s)
- Hui-Chun Huang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shao-Jung Hsu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ching-Chih Chang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yun-Chieh Kao
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chiao-Lin Chuang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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12
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Huang HC, Tsai MH, Chang CC, Pun CK, Huang YH, Hou MC, Lee FY, Hsu SJ. Microbiota transplants from feces or gut content attenuated portal hypertension and portosystemic collaterals in cirrhotic rats. Clin Sci (Lond) 2021; 135:2709-2728. [PMID: 34870313 DOI: 10.1042/cs20210602] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 11/28/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022]
Abstract
Liver cirrhosis and portal hypertension is the end of chronic liver injury with hepatic, splanchnic and portosystemic collateral systems dysregulation. Liver injury is accompanied by gut dysbiosis whereas dysbiosis induces liver fibrosis, splanchnic angiogenesis and dysregulated vascular tones vice versa, making portal hypertension aggravated. It has been proved that intestinal microbiota transplantation alleviates dysbiosis. Nevertheless, the influences of microbiota transplantation on cirrhosis-related portal hypertension are not so clear. Liver cirrhosis with portal hypertension was induced by bile duct ligation (BDL) in rats. Sham rats were surgical controls. Rats randomly received vehicle, fecal or gut (terminal ileum) material transplantation. The results showed that microbiota transplantation from feces or gut material significantly reduced portal pressure in cirrhotic rats (P=0.010, 0.044). Hepatic resistance, vascular contractility, fibrosis and relevant protein expressions were not significantly different among cirrhotic rats. However, microbiota transplantation ameliorated splanchnic hyperdynamic flow and vasodilatation. Mesenteric angiogenesis, defined by whole mesenteric window vascular density, decreased in both transplantation groups and phosphorylated endothelial nitric-oxide synthase (eNOS) was down-regulated. Portosystemic shunts determined by splenorenal shunt (SRS) flow decreased in both transplantation groups (P=0.037, 0.032). Shunting severity assessed by microsphere distribution method showed consistent results. Compared with sham rats, cirrhotic rats lacked Lachnospiraceae. Both microbiota transplants increased Bifidobacterium. In conclusion, microbiota transplantation in cirrhotic rats reduced portal pressure, alleviated splanchnic hyperdynamic circulation and portosystemic shunts. The main beneficial effects may be focused on portosystemic collaterals-related events, such as hepatic encephalopathy and gastroesophageal variceal hemorrhage. Further clinical investigations are mandatory.
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Affiliation(s)
- Hui-Chun Huang
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Hung Tsai
- Division of Gastroenterology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Ching-Chih Chang
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chon Kit Pun
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shao-Jung Hsu
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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13
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Hanidziar D, Robson SC. Synapomorphic features of hepatic and pulmonary vasculatures include comparable purinergic signaling responses in host defense and modulation of inflammation. Am J Physiol Gastrointest Liver Physiol 2021; 321:G200-G212. [PMID: 34105986 PMCID: PMC8410108 DOI: 10.1152/ajpgi.00406.2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatosplanchnic and pulmonary vasculatures constitute synapomorphic, highly comparable networks integrated with the external environment. Given functionality related to obligatory requirements of "feeding and breathing," these organs are subject to constant environmental challenges entailing infectious risk, antigenic and xenobiotic exposures. Host responses to these stimuli need to be both protective and tightly regulated. These functions are facilitated by dualistic, high-low pressure blood supply of the liver and lungs, as well as tolerogenic characteristics of resident immune cells and signaling pathways. Dysregulation in hepatosplanchnic and pulmonary blood flow, immune responses, and microbiome implicate common pathogenic mechanisms across these vascular networks. Hepatosplanchnic diseases, such as cirrhosis and portal hypertension, often impact lungs and perturb pulmonary circulation and oxygenation. The reverse situation is also noted with lung disease resulting in hepatic dysfunction. Others, and we, have described common features of dysregulated cell signaling during liver and lung inflammation involving extracellular purines (e.g., ATP, ADP), either generated exogenously or endogenously. These metabokines serve as danger signals, when released by bacteria or during cellular stress and cause proinflammatory and prothrombotic signals in the gut/liver-lung vasculature. Dampening of these danger signals and organ protection largely depends upon activities of vascular and immune cell-expressed ectonucleotidases (CD39 and CD73), which convert ATP and ADP into anti-inflammatory adenosine. However, in many inflammatory disorders involving gut, liver, and lung, these protective mechanisms are compromised, causing perpetuation of tissue injury. We propose that interventions that specifically target aberrant purinergic signaling might prevent and/or ameliorate inflammatory disorders of the gut/liver and lung axis.
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Affiliation(s)
- Dusan Hanidziar
- 1Department of Anesthesia, Critical Care and Pain Medicine, grid.32224.35Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Simon C. Robson
- 2Department of Anesthesia, Critical Care and Pain Medicine, Center for Inflammation Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts,3Department of Medicine, Division of Gastroenterology/Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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14
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Glycyrrhizin Attenuates Portal Hypertension and Collateral Shunting via Inhibition of Extrahepatic Angiogenesis in Cirrhotic Rats. Int J Mol Sci 2021; 22:ijms22147662. [PMID: 34299285 PMCID: PMC8304322 DOI: 10.3390/ijms22147662] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 01/14/2023] Open
Abstract
Portal hypertension develops along with liver cirrhosis then induces the formation of portal-systemic collaterals and lethal complications. Extrahepatic angiogenesis plays an important role. Glycyrrhizin has been found to exhibit anti-angiogenic features, which leads to its extensive use. However, the relevant effects of glycyrrhizin on liver cirrhosis and portal hypertension have not been evaluated. This study thus aimed to investigate the impact of glycyrrhizin on portal hypertension-related derangements in cirrhotic rats. Male Sprague-Dawley rats received bile duct ligation (BDL) to induce cirrhosis or sham operation as control. The rats were subdivided to receive glycyrrhizin (150 mg/kg/day, oral gavage) or vehicle beginning on the 15th day post operation, when BDL-induced liver fibrosis developed. The effects of glycyrrhizin were determined on the 28th day, the typical timing of BDL-induced cirrhosis. Glycyrrhizin significantly reduced portal pressure (p = 0.004). The splanchnic inflow as measured by superior mesenteric arterial flow decreased by 22% (p = 0.029). The portal-systemic collateral shunting degree reduced by 30% (p = 0.024). The mesenteric angiogenesis and phospho-VEGFR2 protein expression were also downregulated (p = 0.038 and 0.031, respectively). Glycyrrhizin did not significantly influence the liver biochemistry data. Although glycyrrhizin tended to reverse liver fibrosis, statistical significance was not reached (p = 0.069). Consistently, hepatic inflow from portal side, hepatic vascular resistance, and liver fibrosis-related protein expressions were not affected. Glycyrrhizin treatment at the stage of hepatic fibrosis still effectively attenuated portal hypertension and portosystemic collateral shunting. These beneficial effects were attributed to, at least in part, the suppression of mesenteric angiogenesis by VEGF signaling pathway downregulation.
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15
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Alshabi AM, Alkahtani SA, Shaikh IA, Habeeb MS. Caffeine modulates pharmacokinetic and pharmacodynamic profiles of pioglitazone in diabetic rats: Impact on therapeutics. Saudi Med J 2021; 42:151-160. [PMID: 33563733 PMCID: PMC7989285 DOI: 10.15537/smj.2021.2.25695] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 01/06/2021] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVES To determine the influence of caffeine on pharmacokinetics and pharmacodynamics of pioglitazone (PIO) in diabetic rats. METHODS This was a preclinical study conducted in the College of Pharmacy, Najran University, Saudi Arabia, using 5 groups of Wistar rats: normal rats, untreated diabetic rats, diabetic rats + caffeine (20 mg/kg), diabetic rats + PIO (10 mg/kg), and diabetic rats + PIO (10 mg/kg) + caffeine (20 mg/kg). The drugs were administered for 14 days, and fasting plasma glucose concentrations were determined on the first day, and thereafter at weekly intervals. On day 14, rat sacrifice was followed with assay of levels of biomarkers. To estimate the pharmacokinetic parameters, the diabetic animals were assigned to 2 groups: one group received PIO (10 mg/kg), while the other received PIO + caffeine (20 mg/kg). Blood samples were drawn from the retro-orbital plexus at different time intervals, and pharmacokinetic parameters were measured using high performance liquid chromatography. RESULTS Caffeine caused statistically marked increases in area under the curve, Cmax, Tmax, and half-life of PIO, and decreased clearance. Combination of PIO and caffeine produced a synergistic effect on percentage reduction in blood glucose, with 67.1% reductions observed on day 7 and 68.9% reductions observed on day 14. Liver and cardiac biomarkers were significantly decreased, suggesting cardioprotective and hepatoprotective effects. CONCLUSION Co-administration of PIO with caffeine enhances its antidiabetic effect, probably due to enhanced bioavailability of PIO, leading to clinical benefits in diabetic patients.
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Affiliation(s)
- Ali M. Alshabi
- From the Department of Clinical Pharmacy (Alshabi, Alkahtani), and from the Department of Pharmacology (Shaikh, Habeeb), College of Pharmacy, Najran University, Najran, Kingdom of Saudi Arabia.
| | - Saad A. Alkahtani
- From the Department of Clinical Pharmacy (Alshabi, Alkahtani), and from the Department of Pharmacology (Shaikh, Habeeb), College of Pharmacy, Najran University, Najran, Kingdom of Saudi Arabia.
| | - Ibrahim A. Shaikh
- From the Department of Clinical Pharmacy (Alshabi, Alkahtani), and from the Department of Pharmacology (Shaikh, Habeeb), College of Pharmacy, Najran University, Najran, Kingdom of Saudi Arabia.
| | - Mohammed S. Habeeb
- From the Department of Clinical Pharmacy (Alshabi, Alkahtani), and from the Department of Pharmacology (Shaikh, Habeeb), College of Pharmacy, Najran University, Najran, Kingdom of Saudi Arabia.
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16
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Gunarathne LS, Rajapaksha H, Shackel N, Angus PW, Herath CB. Cirrhotic portal hypertension: From pathophysiology to novel therapeutics. World J Gastroenterol 2020; 26:6111-6140. [PMID: 33177789 PMCID: PMC7596642 DOI: 10.3748/wjg.v26.i40.6111] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/28/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin II type receptor 1 blockers, which target the components of the classical renin angiotensin system (RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant off-target effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective -blockers (NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs. Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.
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Affiliation(s)
- Lakmie S Gunarathne
- Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia
| | - Harinda Rajapaksha
- School of Molecular Science, College of Science, Health and Engineering, La Trobe University, Bundoora, VIC 3086, Australia
| | | | - Peter W Angus
- Department of Gastroenterology, Austin Health, Heidelberg, VIC 3084, Australia
| | - Chandana B Herath
- Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia
- South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Ingham Institute for Applied Medical Research, 1 Campbell Street, Liverpool, NSW 2170, Australia
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17
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Mai ZH, Huang Y, Huang D, Huang ZS, He ZX, Li PL, Zhang S, Weng JF, Gu WL. Reversine and herbal Xiang-Sha-Liu-Jun-Zi decoction ameliorate thioacetamide-induced hepatic injury by regulating the RelA/NF-κB/caspase signaling pathway. Open Life Sci 2020; 15:696-710. [PMID: 33817258 PMCID: PMC7747499 DOI: 10.1515/biol-2020-0059] [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: 02/29/2020] [Revised: 05/30/2020] [Accepted: 05/30/2020] [Indexed: 02/07/2023] Open
Abstract
This study investigated the anti-fibrotic effects of reversine and Chinese medicine Xiang–Sha–Liu–Jun–Zi decoction (XSLJZD) on thioacetamide (TAA)-induced hepatic injury. Sprague-Dawley rats were intraperitoneally administered with TAA, then injected with reversine intraperitoneally, and/or orally provided with XSLJZD. TAA resulted in liver injury with increases in the liver index and levels of serum aspartate aminotransferase (AST) and alanine aminotransferase. Reversine alleviated the liver index and AST level and improved TAA-induced pathological changes but decreased TAA-induced collagen deposition, and α-smooth muscle actin and transforming growth factor-β1 expression. Reversine also modulated the mRNA levels of inflammatory cytokines, such as RelA, interleukin (IL)-17A, IL-22, IL-1β, IL-6, NLR family pyrin domain containing 3, platelet-derived growth factor, and monocyte chemoattractant protein, and suppressed nuclear factor (NF)-κB (p65) phosphorylation and caspase 1 activation. Meanwhile, XSLJZD protected TAA-injured liver without increasing fibrosis and enhanced the regulating effect of reversine on RelA, IL-17A, IL-1β, and MCP-1 cytokines. In conclusion, reversine ameliorates liver injury and inhibits inflammation reaction by regulating NF-κB, and XSLJZD protects the liver through its synergistic effect with reversine on regulating inflammatory cytokines.
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Affiliation(s)
- Zhen-Hao Mai
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Medical University, Guangzhou, Guangdong 510180, People's Republic of China
| | - Yu Huang
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, People's Republic of China
| | - Di Huang
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, People's Republic of China
| | - Zi-Sheng Huang
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Medical University, Guangzhou, Guangdong 510180, People's Republic of China
| | - Zhi-Xiang He
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China
| | - Pei-Lin Li
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China
| | - Shuai Zhang
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, People's Republic of China
| | - Jie-Feng Weng
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, People's Republic of China
| | - Wei-Li Gu
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, People's Republic of China
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18
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Romualdo GR, Prata GB, da Silva TC, Evangelista AF, Reis RM, Vinken M, Moreno FS, Cogliati B, Barbisan LF. The combination of coffee compounds attenuates early fibrosis-associated hepatocarcinogenesis in mice: involvement of miRNA profile modulation. J Nutr Biochem 2020; 85:108479. [PMID: 32795656 DOI: 10.1016/j.jnutbio.2020.108479] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 06/19/2020] [Accepted: 08/03/2020] [Indexed: 12/12/2022]
Abstract
Aberrant microRNA expression implicates on hepatocellular carcinoma (HCC) development. Conversely, coffee consumption reduces by ~40% the risk for fibrosis/cirrhosis and HCC, while decaffeinated coffee does not. It is currently unknown whether these protective effects are related to caffeine (CAF), or to its combination with other common and/or highly bioavailable coffee compounds, such as trigonelline (TRI) and chlorogenic acid (CGA). We evaluated whether CAF individually or combined with TRI and/or CGA alleviates fibrosis-associated hepatocarcinogenesis, examining the involvement of miRNA profile modulation. Then, male C3H/HeJ mice were submitted to a diethylnitrosamine/carbon tetrachloride-induced model. Animals received CAF (50 mg/kg), CAF+TRI (50 and 25 mg/kg), CAF+CGA (50 and 25 mg/kg) or CAF+TRI+CGA (50, 25 and 25 mg/kg), intragastrically, 5×/week, for 10 weeks. Only CAF+TRI+CGA combination reduced the incidence, number and proliferation (Ki-67) of hepatocellular preneoplastic foci while enhanced apoptosis (cleaved caspase-3) in adjacent parenchyma. CAF+TRI+CGA treatment also decreased hepatic oxidative stress and enhanced the antioxidant Nrf2 axis. CAF+TRI+CGA had the most pronounced effects on decreasing hepatic pro-inflammatory IL-17 and NFκB, contributing to reduce CD68-positive macrophage number, stellate cell activation, and collagen deposition. In agreement, CAF+TRI+CGA upregulated tumor suppressors miR-144-3p, miR-376a-3p and antifibrotic miR-15b-5p, frequently deregulated in human HCC. CAF+TRI+CGA reduced the hepatic protein levels of pro-proliferative EGFR (miR-144-3p target), antiapoptotic Bcl-2 family members (miR-15b-5p targets), and the number of PCNA (miR-376a-3p target) positive hepatocytes in preneoplastic foci. Our results suggest that the combination of most common and highly bioavailable coffee compounds, rather than CAF individually, attenuates fibrosis-associated hepatocarcinogenesis by modulating miRNA expression profile.
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Affiliation(s)
- Guilherme Ribeiro Romualdo
- Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), Botucatu, - SP, Brazil
| | - Gabriel Bacil Prata
- Department of Structural and Functional Biology, Biosciences Institute, São Paulo State University (UNESP), Botucatu, - SP, Brazil
| | - Tereza Cristina da Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo (USP), São Paulo, - SP, Brazil
| | | | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, - SP, Brazil; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; 3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Fernando Salvador Moreno
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, - SP, Brazil
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo (USP), São Paulo, - SP, Brazil
| | - Luís Fernando Barbisan
- Department of Structural and Functional Biology, Biosciences Institute, São Paulo State University (UNESP), Botucatu, - SP, Brazil.
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19
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Ho HL, Tsai MH, Hsieh YH, Huo TI, Chang CC, Lee FY, Huang HC, Hou MC, Lee SD. Folic acid ameliorates homocysteine-induced angiogenesis and portosystemic collaterals in cirrhotic rats. Ann Hepatol 2020; 18:633-639. [PMID: 31078441 DOI: 10.1016/j.aohep.2018.12.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 12/06/2018] [Accepted: 11/23/2018] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Liver cirrhosis is characterized by increased intrahepatic resistance, splanchnic vasodilation/angiogenesis, and formation of portosystemic collateral vessels. Collaterals can cause lethal complications such as gastroesophageal variceal hemorrhage. Homocysteine is linked to vascular dysfunction and angiogenesis and higher levels have been reported in cirrhotic patients. It is also known that folic acid supplementation reverses the effects of homocysteine. However, the treatment effect in cirrhosis has yet to be investigated. MATERIAL AND METHODS Liver cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation (CBDL). The CBDL rats randomly received (1) vehicle; (2) dl-homocysteine thiolactone (1g/kg/day); (3) dl-homocysteine thiolactone plus folic acid (100mg/kg/day); or (4) folic acid. On the 29th day, hemodynamic parameters, liver and renal biochemistry, protein expressions of proangiogenic factors, mesenteric vascular density and portosystemic shunting were evaluated. RESULTS In the cirrhotic rats, homocysteine increased mesenteric vascular density and the severity of shunting. It also up-regulated the protein expressions of mesenteric vascular endothelial growth factor (VEGF) and phosphorylated-endothelial nitric oxide synthase (p-eNOS). These effects were reversed by folic acid treatment (P<0.05). CONCLUSION Folic acid ameliorated the adverse effects of homocysteine in the cirrhotic rats, which may be related to down-regulation of the VEGF-NO signaling pathway.
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Affiliation(s)
- Hsin-Ling Ho
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
| | - Ming-Hung Tsai
- Division of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Lin-Kuo Medical Center, Chang Gung University, College of Medicine, Taoyuan, Taiwan
| | - Yu-Hsin Hsieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Teh-Ia Huo
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ching-Chih Chang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
| | - Hui-Chun Huang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan
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20
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Abstract
Terlipressin, somatostatin, or octreotide are recommended as pharmacologic treatment of acute variceal hemorrhage. Nonselective β-blockers decrease the risk of variceal hemorrhage and hepatic decompensation, particularly in those 30% to 40% of patients with good hemodynamic response. Carvedilol, statins, and anticoagulants are promising agents in the management of portal hypertension. Recent advances in the pharmacologic treatment of portal hypertension have mainly focused on modifying an increased intrahepatic resistance through nitric oxide and/or modulation of vasoactive substances. Several novel pharmacologic agents for portal hypertension are being evaluated in humans.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand; Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA.
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21
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Chang T, Ho HL, Hsu SJ, Chang CC, Tsai MH, Huo TI, Huang HC, Lee FY, Hou MC, Lee SD. Glucobrassicin Metabolites Ameliorate the Development of Portal Hypertension and Cirrhosis in Bile Duct-Ligated Rats. Int J Mol Sci 2019; 20:ijms20174161. [PMID: 31454890 PMCID: PMC6747388 DOI: 10.3390/ijms20174161] [Citation(s) in RCA: 3] [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: 06/27/2019] [Revised: 08/11/2019] [Accepted: 08/24/2019] [Indexed: 01/24/2023] Open
Abstract
Patients suffering from liver cirrhosis are often complicated with the formation of portosystemic collateral vessels, which is associated with the progression of a splanchnic hyperdynamic circulatory state. Alleviating pathological angiogenesis has thus been proposed to be a feasible treatment strategy. Indole-3-carbinol (C9H9NO, I3C) and 3,3'-diindolymethane (DIM), formed by the breakdown of glucosinolate glucobrassicin, are prevalent in cruciferous vegetables and have anti-angiogenesis properties. We aimed to evaluate their influences on portal hypertension, the severity of mesenteric angiogenesis, and portosystemic collaterals in cirrhosis. Sprague-Dawley rats with common bile duct ligation (CBDL)-induced liver cirrhosis or sham operation (surgical control) were randomly allocated to receive I3C (20 mg/kg/3 day), DIM (5 mg/kg/day) or vehicle for 28 days. The systemic and portal hemodynamics, severity of portosystemic shunting, mesenteric angiogenesis, and mesenteric proangiogenic factors protein expressions were evaluated. Compared to vehicle, both DIM and I3C significantly reduced portal pressure, ameliorated liver fibrosis, and down-regulated mesenteric protein expressions of vascular endothelial growth factor and phosphorylated Akt. DIM significantly down-regulated pErk, and I3C down-regulated NFκB, pIκBα protein expressions, and reduced portosystemic shunting degree. The cruciferous vegetable byproducts I3C and DIM not only exerted a portal hypotensive effect but also ameliorated abnormal angiogenesis and portosystemic collaterals in cirrhotic rats.
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Affiliation(s)
- Ting Chang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Hsin-Ling Ho
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Lotong Poh-Ai Hospital, Yilan 26546, Taiwan
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
| | - Shao-Jung Hsu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Ching-Chih Chang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
- Division of Gastroenterology and Hepatology, Department of Medicine, Lotong Poh-Ai Hospital, Yilan 26546, Taiwan.
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan.
| | - Ming-Hung Tsai
- Chang Gung University College of Medicine and Division of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Teh-Ia Huo
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Hui-Chun Huang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Fa-Yauh Lee
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei 11217, Taiwan
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22
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Urotensin II receptor antagonist reduces hepatic resistance and portal pressure through enhanced eNOS-dependent HSC vasodilatation in CCl4-induced cirrhotic rats. Front Med 2019; 13:398-408. [DOI: 10.1007/s11684-019-0689-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 12/27/2018] [Indexed: 12/11/2022]
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23
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Effects of Caffeine Treatment on Hepatopulmonary Syndrome in Biliary Cirrhotic Rats. Int J Mol Sci 2019; 20:ijms20071566. [PMID: 30925782 PMCID: PMC6480428 DOI: 10.3390/ijms20071566] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 03/22/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatopulmonary syndrome (HPS) is a lethal complication of cirrhosis characterized by hypoxia and overt intrapulmonary shunting. In this study, we investigated the effect of caffeine in rats with common bile duct ligation (CBDL)-induced liver cirrhosis and HPS. CBDL rats were randomly allocated to receive caffeine or vehicle for 14 days. On the 28th day after CBDL, mortality rate, hemodynamics, liver, and renal biochemistry parameters and arterial blood gas analysis were evaluated. Lung and liver were dissected for the evaluation of inflammation, angiogenesis and protein expressions. In another series with parallel groups, the intrapulmonary shunting was determined. Caffeine significantly reduced portal pressure (caffeine vs. control: 10.0 ± 3.7 vs. 17.0 ± 8.1 mmHg, p < 0.05) in CBDL rats. The mortality rate, mean arterial pressure, biochemistry data and hypoxia were similar between caffeine-treated and control groups. Caffeine alleviated liver fibrosis and intrahepatic angiogenesis but intrapulmonary inflammation and angiogenesis were not ameliorated. The hepatic VEGF/Rho-A protein expressions were down-regulated but the pulmonary inflammation- and angiogenesis-related protein expressions were not significantly altered by caffeine. Caffeine did not reduce the intrapulmonary shunting, either. Caffeine has been shown to significantly improve liver fibrosis, intrahepatic angiogenesis and portal hypertension in cirrhotic rats, however, it does not ameliorate HPS.
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24
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Vilaseca M, Guixé-Muntet S, Fernández-Iglesias A, Gracia-Sancho J. Advances in therapeutic options for portal hypertension. Therap Adv Gastroenterol 2018; 11:1756284818811294. [PMID: 30505350 PMCID: PMC6256317 DOI: 10.1177/1756284818811294] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 10/15/2018] [Indexed: 02/04/2023] Open
Abstract
Portal hypertension represents one of the major clinical consequences of chronic liver disease, having a deep impact on patients' prognosis and survival. Its pathophysiology defines a pathological increase in the intrahepatic vascular resistance as the primary factor in its development, being subsequently aggravated by a paradoxical increase in portal blood inflow. Although extensive preclinical and clinical research in the field has been developed in recent decades, no effective treatment targeting its primary mechanism has been defined. The present review critically summarizes the current knowledge in portal hypertension therapeutics, focusing on those strategies driven by the disease pathophysiology and underlying cellular mechanisms.
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Affiliation(s)
- Marina Vilaseca
- Hepatic Hemodynamic Laboratory, IDIBAPS
Biomedical Research Institute, Barcelona, Spain
| | - Sergi Guixé-Muntet
- Department of Biomedical Research, University of
Bern, Bern, Switzerland
| | | | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona
Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute,
CIBEREHD, Rosselló 149, 4th floor, 08036 Barcelona, Spain
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25
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Insulin reverses major portal hypertension-related derangements in rats with liver cirrhosis and diabetes. Clin Sci (Lond) 2018; 132:2391-2405. [DOI: 10.1042/cs20180557] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 10/11/2018] [Accepted: 10/20/2018] [Indexed: 12/11/2022]
Abstract
Liver cirrhosis is accompanied by increased intrahepatic resistance and angiogenesis-related portosystemic collaterals formation. Diabetic patients suffer from abnormal vasoresponsiveness and angiogenesis that can be ameliorated by glucose control. However, the relevant presentation is not clear in those with cirrhosis and diabetes, in whom insulin is the treatment of choice. Liver cirrhosis was induced in Sprague–Dawley rats with common bile duct ligation (BDL) and sham rats were used as controls. Streptozotocin 60 mg/kg (STZ, i.p., to induce diabetes) or vehicle was injected. The rats received BDL and STZ injections were injected with insulin or vehicle. On the 29th day after the procedure, the groups were surveyed for (1) systemic and portal hemodynamics; (2) mesenteric vascular density; (3) severity of portosystemic collaterals; (4) hepatic resistance using in situ liver perfusion; (5) histology survey of mesentery and liver; and (6) mesentery angiogenesis- and liver fibrogenesis-related protein expressions. Compared with the cirrhotic rats, the cirrhotic diabetic rats had lower body weight, cardiac output, superior mesenteric arterial (SMA) resistance and portal venous (PV) resistance, and higher SMA and PV flow, which were mostly reversed by insulin. The cirrhotic diabetic rats also had increased mesenteric vascular density, and enhanced pERK, pAkt, VEGF, VEGFR2 protein expressions that were reversed by insulin. Insulin decreased the degree of shunting in the diabetic cirrhotic rats. Hepatic perfusion pressure and severity of liver fibrosis were not significantly influenced by diabetes and insulin treatment in the cirrhotic rats. In conclusion, diabetes aggravated hemodynamic derangements, mesenteric angiogenesis and collaterals in the cirrhotic rats, which were mostly ameliorated by insulin. Further clinical investigations are warranted.
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26
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Xu W, Liu P, Mu YP. Research progress on signaling pathways in cirrhotic portal hypertension. World J Clin Cases 2018; 6:335-343. [PMID: 30283796 PMCID: PMC6163134 DOI: 10.12998/wjcc.v6.i10.335] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 07/27/2018] [Accepted: 08/04/2018] [Indexed: 02/05/2023] Open
Abstract
Portal hypertension (PHT) is an important consequence of liver cirrhosis, which can lead to complications that adversely affect a patient’s quality of life and survival, such as upper gastrointestinal bleeding, ascites, and portosystemic encephalopathy. In recent years, advances in molecular biology have led to major discoveries in the pathological processes of PHT, including the signaling pathways that may be involved: PI3K-AKT-mTOR, RhoA/Rho-kinase, JAK2/STAT3, and farnesoid X receptor. However, the pathogenesis of PHT is complex and there are numerous pathways involved. Therefore, the targeting of signaling pathways for medical management is lagging. This article summarizes the progress that has been made in understanding the signaling pathways in PHT, and provides ideas for treatment of the disorder.
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Affiliation(s)
- Wen Xu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Shanghai 201203, China
- Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Shanghai University of TCM, Shanghai 201203, China
- Clinical key laboratory of TCM of Shanghai, Shanghai 201203, China
| | - Ping Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Shanghai 201203, China
- Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Shanghai University of TCM, Shanghai 201203, China
- Clinical key laboratory of TCM of Shanghai, Shanghai 201203, China
| | - Yong-Ping Mu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Shanghai 201203, China
- Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Shanghai University of TCM, Shanghai 201203, China
- Clinical key laboratory of TCM of Shanghai, Shanghai 201203, China
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27
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Evaluation of antifibrotic effects of coffee and cocoa extracts in rats with thioacetamide-induced fibrosis. Eur Food Res Technol 2018. [DOI: 10.1007/s00217-018-3119-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Ebrahimi H, Naderian M, Sohrabpour AA. New Concepts on Reversibility and Targeting of Liver Fibrosis; A Review Article. Middle East J Dig Dis 2018; 10:133-148. [PMID: 30186577 PMCID: PMC6119836 DOI: 10.15171/mejdd.2018.103] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 06/10/2018] [Indexed: 12/12/2022] Open
Abstract
Currently, liver fibrosis and its complications are regarded as critical health problems.
With the studies showing the reversible nature of liver fibrogenesis, scientists have focused
on understanding the underlying mechanism of this condition in order to develop new
therapeutic strategies. Although hepatic stellate cells are known as the primary cells
responsible for liver fibrogenesis, studies have shown contributing roles for other cells,
pathways, and molecules in the development of fibrosis depending on the etiology of
liver fibrosis. Hence, interventions could be directed in the proper way for each type of
liver diseases to better address this complication. There are two main approaches in clinical
reversion of liver fibrosis; eliminating the underlying insult and targeting the fibrosis
process, which have variable clinical importance in the treatment of this disease. In this
review, we present recent concepts in molecular pathways of liver fibrosis reversibility
and their clinical implications.
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Affiliation(s)
- Hedyeh Ebrahimi
- The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Naderian
- The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Sohrabpour
- Associate Professor, The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Eraky SM, El-Mesery M, El-Karef A, Eissa LA, El-Gayar AM. Silymarin and caffeine combination ameliorates experimentally-induced hepatic fibrosis through down-regulation of LPAR1 expression. Biomed Pharmacother 2018; 101:49-57. [PMID: 29477472 DOI: 10.1016/j.biopha.2018.02.064] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/14/2018] [Accepted: 02/15/2018] [Indexed: 01/08/2023] Open
Abstract
AIMS Lysophosphatidic acid is a lipid mediator that is supposed to be implicated in hepatic fibrosis. Silymarin and caffeine are natural compounds known for their anti-inflammatory and antioxidant effects. Our study aimed to explore the effect of silymarin, caffeine, and their combination on lysophosphatidic acid receptor 1 (LPAR1) pathway in thioacetamide (TAA)-induced hepatic fibrosis. MAIN METHODS Hepatic fibrosis was induced in male Sprague-Dawley rats by intraperitoneal injection of 200 mg/kg of TAA twice a week for 8 weeks. Silymarin (50 mg/kg), caffeine (50 mg/kg), and their combination (50 mg/kg silymarin + 50 mg/kg caffeine) were orally given to rats every day for 8 weeks along with TAA injection. Liver functions were measured. Histopathological examination of liver tissues was performed using hematoxylin and eosin and Masson's trichrome staining. mRNA expressions of LPAR1, transforming growth factor beta 1 (TGF-β1), connective tissue growth factor (CTGF), and alpha smooth muscle actin (α-SMA) were measured using RT-PCR. LPAR1 tissue expression was scored using immunohistochemistry. KEY FINDINGS Silymarin, caffeine, and their combination significantly improved liver function. They caused significant decrease in fibrosis and necro-inflammatory scores. Combination of silymain and caffeine caused a significant decrease in the necro-inflammatory score than the single treatment with silymarin or caffeine. In addition, silymarin, caffeine, and their combination significantly decreased hepatic LPAR1, TGF-β1, CTGF, and α-SMA gene expressions and LPAR1 tissue expression. SIGNIFICANCE Silymarin, caffeine, and their combination protect against liver fibrosis through down-regulation of LPAR1, TGF-β1, and CTGF.
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Affiliation(s)
- Salma M Eraky
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Mohamed El-Mesery
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Amro El-Karef
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Laila A Eissa
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Amal M El-Gayar
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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30
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Extrahepatic angiogenesis hinders recovery of portal hypertension and collaterals in rats with cirrhosis resolution. Clin Sci (Lond) 2018; 132:669-683. [PMID: 29449343 DOI: 10.1042/cs20171370] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 02/09/2018] [Accepted: 02/15/2018] [Indexed: 12/20/2022]
Abstract
Liver cirrhosis is characterized by portal hypertension. However, the alteration of portal hypertension-related derangements during cirrhosis resolution is not well known. The present study aimed to establish animal models with cirrhosis resolution and to investigate the relevant changes during this process. Male Sprague-Dawley rats were applied. In reverse thioacetamide (rTAA) model, rats were randomly allocated into four groups with control, thioacetamide (TAA) cirrhosis and rTAA groups that discontinued TAA for 4 or 8 weeks after cirrhosis induction. In reverse bile duct ligation (rBDL) model, rats received choledochoduodenal shunt surgery upon the establishment of cirrhosis and 4, 8, or 16 weeks were allowed after the surgery. At the end, portal hypertension-related parameters were evaluated. Cirrhosis resolution was observed in rTAA groups. Portal pressure (PP) decreased after cirrhosis resolution but remained higher than control group (control, TAA, rTAA4, rTAA8 (mmHg): 5.4 ± 0.3, 12.9 ± 0.3, 8.6 ± 0.4, 7.6 ± 0.6). Further survey found the increased splanchnic blood flow did not reduce during cirrhosis resolution. The extrahepatic pathological angiogenesis was not ameliorated (% of mesenteric window area: 1.2 ± 0.3, 7.3 ± 1.1, 8.3 ± 1.0, 11.3 ± 2.7). In collateral system, the shunting degree reduced while the vessels structure remained. The vascular contractility of all systems and nitric oxide (NO) production were normalized. In rBDL series, PP decreased in rBDL16 groups but the extrahepatic angiogenesis persisted. In conclusion, cirrhosis resolution attenuates but not completely normalizes portal hypertension because of persistently high splanchnic inflow and angiogenesis. In clinical setting, vascular complications such as varices could persist after cirrhosis resolution and further investigation to define the follow-up and treatment strategies is anticipated.
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Abstract
Critical illness is accompanied by hypothalamic-pituitary-adrenal axis activation, but adrenal insufficiency characterized by inadequate glucocorticoid synthesis is common in critically ill cirrhotic patients, the "hepato-adrenal syndrome." Adrenal cortex also synthesizes androgen (dehydroepiandrosterone, DHEA). DHEA maintains microcirculation by enhancing vascular endothelial nitric oxide synthase (eNOS) activity. In critical patients of other disease entities, a shift of adrenal steroidogenesis away from androgens toward glucocorticoid has been noted, arousing interests in androgen replacement in critical settings. Nevertheless, this has not been surveyed in cirrhosis with hemorrhage. In this study, liver cirrhosis was induced with common bile duct ligation (BDL) in Spraque-Dawley rats. Sham rats were controls. DHEA or vehicle was injected at the beginning of hemorrhage-transfused procedure, followed by terlipressin injection. Hemodynamic parameters were measured. Then abdominal aorta, superior mesenteric arteries (SMA) and splenorenal shunt (prominent portosystemic collateral vessel in rodents) eNOS and inducible NOS protein expressions were evaluated. In bleeding BDL groups without terlipressin injection, adrenocorticotropic hormone (ACTH) stimulation test was performed to evaluate the DHEA response. The results showed that DHEA significantly elevated mean arterial pressure, cardiac output, and stroke volume of bleeding cirrhotic rats treated with terlipressin and reduced systemic vascular resistance without affecting SMA flow, resistance, and portal pressure. DHEA upregulated abdominal aorta and SMA eNOS expressions. ACTH did not stimulate DHEA synthesis in bleeding BDL rats. In conclusion, androgen deficiency exists in bleeding cirrhotic rats. DHEA augments terlipressin-induced amelioration of shock without influencing splanchnic hemodynamics, possibly rendering it a feasible adjunct to vasoconstrictors in variceal hemorrhage.
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32
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The beneficial effects of curcumin in cirrhotic rats with portal hypertension. Biosci Rep 2017; 37:BSR20171015. [PMID: 29162665 PMCID: PMC6435472 DOI: 10.1042/bsr20171015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 12/11/2017] [Accepted: 11/14/2017] [Indexed: 12/21/2022] Open
Abstract
In liver cirrhosis with portal hypertension, the uneven distribution of vasoactive substances leads to increased intrahepatic vascular resistance and splanchnic vasodilatation. Angiogenesis also induces increased portal inflow and portosystemic collaterals. The collaterals may induce lethal complications such as gastroesophageal variceal hemorrhage, but the therapeutic effect of vasoconstrictors is still suboptimal due to poor collateral vasoresponsivenss. Curcumin has aroused much attention for its antifibrosis, vasoactive, and anti-angiogenesis actions. However, whether it affects the aforementioned aspects is unknown. Liver cirrhosis was induced by common bile duct ligation (CBDL) in Sprague-Dawley rats. Sham-operated rats were controls. CBDL and sham rats were randomly allocated to receive curcumin (600 mg/kg per day) or vehicle since the 15th day after BDL. On the 29th day, portal hypertension related parameters were surveyed. Portosystemic collateral in situ perfusion was performed to evaluate vascular activity. Chronic curcumin treatment decreased portal pressure (PP), cardiac index (CI) and increased systemic vascular resistance (SVR) in cirrhotic rats. In splanchnic system, curcumin decreased superior mesenteric artery (SMA) flow and increased SMA resistance. Mesenteric angiogenesis was attenuated by curcumin. Acute administration of curcumin significantly induced splanchnic vasoconstriction. The mesenteric protein expressions of p-endothelial nitric oxide synthase (eNOS), cyclooxygenase (COX) 2 (COX2), vascular endothelial growth factor (VEGF), p-VEGF receptor 2 (VEGFR2), and p-Erk were down-regulated. In collateral system, curcumin decreased portosystemic shunting and induced vasoconstriction. In conclusion, chronic curcumin administration in cirrhotic rats ameliorated portal hypertension related hemodynamic derangements and portosystemic collaterals. Curcumin also attenuated splanchnic hyperdynamic circulation by inducing vasoconstriction through inhibition of eNOS activation and by decreasing mesenteric angiogenesis via VEGF pathway blockade.
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33
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Fausther M, Lavoie EG, Goree JR, Dranoff JA. An Elf2-like transcription factor acts as repressor of the mouse ecto-5'-nucleotidase gene expression in hepatic myofibroblasts. Purinergic Signal 2017; 13:417-428. [PMID: 28667437 PMCID: PMC5714833 DOI: 10.1007/s11302-017-9570-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 05/12/2017] [Indexed: 01/20/2023] Open
Abstract
Hepatic fibrosis represents a pathological wound healing and tissue repair process triggered in response to chronic liver injury. A heterogeneous population of activated non-parenchymal liver cells, known as liver myofibroblasts, functions as the effector cells in hepatic fibrosis. Upon activation, liver myofibroblasts become fibrogenic, acquiring contractile properties and increasing collagen production capacity, while developing enhanced sensitivity to endogenous molecules and factors released in the local microenvironment. Hepatic extracellular adenosine is a bioactive small molecule, increasingly recognized as an important regulator of liver myofibroblast functions, and an important mediator in the pathogenesis of liver fibrosis overall. Remarkably, ecto-5'-nucleotidase/Nt5e/Cd73 enzyme, which accounts for the dominant adenosine-generating activity in the extracellular medium, is expressed by activated liver myofibroblasts. However, the molecular signals regulating Nt5e gene expression in liver myofibroblasts remain poorly understood. Here, we show that activated mouse liver myofibroblasts express Nt5e gene products and characterize the putative Nt5e minimal promoter in the mouse species. We describe the existence of an enhancer sequence upstream of the mouse Nt5e minimal promoter and establish that the mouse Nt5e minimal promoter transcriptional activity is negatively regulated by an Elf2-like Ets-related transcription factor in activated mouse liver myofibroblasts.
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Affiliation(s)
- Michel Fausther
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR, 72205, USA.
- Research Service, Central Arkansas Veterans Administration Health System, Little Rock, AR, 72205, USA.
| | - Elise G Lavoie
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR, 72205, USA
- Research Service, Central Arkansas Veterans Administration Health System, Little Rock, AR, 72205, USA
| | - Jessica R Goree
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR, 72205, USA
- Research Service, Central Arkansas Veterans Administration Health System, Little Rock, AR, 72205, USA
| | - Jonathan A Dranoff
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR, 72205, USA
- Research Service, Central Arkansas Veterans Administration Health System, Little Rock, AR, 72205, USA
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34
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Li Y, Chen Y, Huang H, Shi M, Yang W, Kuang J, Yan J. Autophagy mediated by endoplasmic reticulum stress enhances the caffeine-induced apoptosis of hepatic stellate cells. Int J Mol Med 2017; 40:1405-1414. [PMID: 28949381 PMCID: PMC5627881 DOI: 10.3892/ijmm.2017.3145] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Accepted: 09/18/2017] [Indexed: 12/28/2022] Open
Abstract
Caffeine has been identified to have beneficial effects against chronic liver diseases, particularly liver fibrosis. Many studies have reported that caffeine ameliorates liver fibrosis by directly inducing hepatic stellate cell (HSC) apoptosis; however, the molecular mechanisms involved in this process remain unclear. The presents study aimed to detect the underlying mechanisms by which caffeine mediates HSC apoptosis and eliminates activated HSCs. For this purpose, the LX-2 cell line was applied in this study and the cells were exposed to various concentrations of caffeine for the indicated times. The effects of caffeine on cell viability and apoptosis were assessed by Cell Counting Kit-8 assay and flow cytometry, respectively. Autophagy and endoplasmic reticulum (ER) stress were explored by morphological assessment and western blotting. In the present study, caffeine was found to inhibit the viability and increase the apoptosis of the LX-2 cells in dose- and time-dependent manners. ER stress was stimulated by caffeine as demonstrated by increased levels of GRP78/BiP, CHOP and inositol-requiring enzyme 1 (IRE1)-α as well as many enlarged ERs detected by electron microscopy. Caffeine induced autophagy as shown by increased p62 and LC3II accumulation and the number of GFP/RFP-LC3 puncta and autophagosomes/autolysosomes. Moreover, IRE1-α knockdown decreased the level of autophagic flux, and inhibition of autophagy protected LX-2 cells from apoptotic death. In conclusion, our study showed that the caffeine-enhanced autophagic flux in HSCs was stimulated by ER stress via the IRE1-α signaling pathway, which further weakened HSC viability via the induction of apoptosis. These findings provide new insight into the mechanism of caffeine's anti-fibrotic effects.
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Affiliation(s)
- Yongjian Li
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
| | - Yunyang Chen
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
| | - Haiyan Huang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
| | - Minmin Shi
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
| | - Weiping Yang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
| | - Jie Kuang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
| | - Jiqi Yan
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
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35
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Schwabl P, Laleman W. Novel treatment options for portal hypertension. Gastroenterol Rep (Oxf) 2017; 5:90-103. [PMID: 28533907 PMCID: PMC5421460 DOI: 10.1093/gastro/gox011] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 03/12/2017] [Indexed: 12/13/2022] Open
Abstract
Portal hypertension is most frequently associated with cirrhosis and is a major driver for associated complications, such as variceal bleeding, ascites or hepatic encephalopathy. As such, clinically significant portal hypertension forms the prelude to decompensation and impacts significantly on the prognosis of patients with liver cirrhosis. At present, non-selective β-blockers, vasopressin analogues and somatostatin analogues are the mainstay of treatment but these strategies are far from satisfactory and only target splanchnic hyperemia. In contrast, safe and reliable strategies to reduce the increased intrahepatic resistance in cirrhotic patients still represent a pending issue. In recent years, several preclinical and clinical trials have focused on this latter component and other therapeutic avenues. In this review, we highlight novel data in this context and address potentially interesting therapeutic options for the future.
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Affiliation(s)
- Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Wim Laleman
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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36
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Zhang S, Zhou R, Li B, Li H, Wang Y, Gu X, Tang L, Wang C, Zhong D, Ge Y, Huo Y, Lin J, Liu XL, Chen JF. Caffeine preferentially protects against oxygen-induced retinopathy. FASEB J 2017; 31:3334-3348. [PMID: 28420694 DOI: 10.1096/fj.201601285r] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 04/05/2017] [Indexed: 12/16/2022]
Abstract
Retinopathy of prematurity (ROP) is the leading cause of childhood blindness, but current anti-VEGF therapy is concerned with delayed retinal vasculature, eye, and brain development of preterm infants. The clinical observation of reduced ROP severity in premature infants after caffeine treatment for apnea suggests that caffeine may protect against ROP. Here, we demonstrate that caffeine did not interfere with normal retinal vascularization development but selectively protected against oxygen-induced retinopathy (OIR) in mice. Moreover, caffeine attenuated not only hypoxia-induced pathologic angiogenesis, but also hyperoxia-induced vaso-obliteration, which suggests a novel protection window by caffeine. At the hyperoxic phase, caffeine reduced oxygen-induced neural apoptosis by adenosine A2A receptor (A2AR)-dependent mechanism, as revealed by combined caffeine and A2AR-knockout treatment. At the hypoxic phase, caffeine reduced microglial activation and enhanced tip cell formation by A2AR-dependent and -independent mechanisms, as combined caffeine and A2AR knockout produced additive and nearly full protection against OIR. Together with clinical use of caffeine in neonates, our demonstration of the selective protection against OIR, effective therapeutic window, adenosine receptor mechanisms, and neuroglial involvement provide the direct evidence of the novel effects of caffeine therapy in the prevention and treatment of ROP.-Zhang, S., Zhou, R., Li, B., Li, H., Wang, Y., Gu, X., Tang, L., Wang, C., Zhong, D., Ge, Y., Huo, Y., Lin, J., Liu, X.-L., Chen, J.-F. Caffeine preferentially protects against oxygen-induced retinopathy.
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Affiliation(s)
- Shuya Zhang
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Rong Zhou
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Bo Li
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Haiyan Li
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Yanyan Wang
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Xuejiao Gu
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Lingyun Tang
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Cun Wang
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Dingjuan Zhong
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Yuanyuan Ge
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Yuqing Huo
- Department of Cellular Biology and Anatomy, Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Key Laboratory of Chemical Genomics, Drug Discovery Center, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Jing Lin
- Department of Neonatology, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Xiao-Ling Liu
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China; .,State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Jiang-Fan Chen
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China; .,State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
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37
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Salomone F, Galvano F, Li Volti G. Molecular Bases Underlying the Hepatoprotective Effects of Coffee. Nutrients 2017; 9:nu9010085. [PMID: 28124992 PMCID: PMC5295129 DOI: 10.3390/nu9010085] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/29/2016] [Accepted: 01/09/2017] [Indexed: 12/29/2022] Open
Abstract
Coffee is the most consumed beverage worldwide. Epidemiological studies with prospective cohorts showed that coffee intake is associated with reduced cardiovascular and all-cause mortality independently of caffeine content. Cohort and case-control studies reported an inverse association between coffee consumption and the degree of liver fibrosis as well as the development of liver cancer. Furthermore, the beneficial effects of coffee have been recently confirmed by large meta-analyses. In the last two decades, various in vitro and in vivo studies evaluated the molecular determinants for the hepatoprotective effects of coffee. In the present article, we aimed to critically review experimental evidence regarding the active components and the molecular bases underlying the beneficial role of coffee against chronic liver diseases. Almost all studies highlighted the beneficial effects of this beverage against liver fibrosis with the most solid results indicating a pivot role for both caffeine and chlorogenic acids. In particular, in experimental models of fibrosis, caffeine was shown to inhibit hepatic stellate cell activation by blocking adenosine receptors, and emerging evidence indicated that caffeine may also favorably impact angiogenesis and hepatic hemodynamics. On the other side, chlorogenic acids, potent phenolic antioxidants, suppress liver fibrogenesis and carcinogenesis by reducing oxidative stress and counteract steatogenesis through the modulation of glucose and lipid homeostasis in the liver. Overall, these molecular insights may have translational significance and suggest that coffee components need clinical evaluation.
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Affiliation(s)
- Federico Salomone
- Division of Gastroenterology, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, 95124 Catania, Italy.
| | - Fabio Galvano
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy.
| | - Giovanni Li Volti
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy.
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38
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Chen JF, Zhang S, Zhou R, Lin Z, Cai X, Lin J, Huo Y, Liu X. Adenosine receptors and caffeine in retinopathy of prematurity. Mol Aspects Med 2017; 55:118-125. [PMID: 28088487 DOI: 10.1016/j.mam.2017.01.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Revised: 12/28/2016] [Accepted: 01/10/2017] [Indexed: 01/26/2023]
Abstract
Retinopathy of prematurity (ROP) is a major cause of childhood blindness in the world and is caused by oxygen-induced damage to the developing retinal vasculature, resulting in hyperoxia-induced vaso-obliteration and subsequent delayed retinal vascularization and hypoxia-induced pathological neovascularization driven by vascular endothelial growth factor (VEGF) signaling pathway in retina. Current anti-VEGF therapy has shown some effective in a clinical trial, but is associated with the unintended effects on delayed eye growth and retinal vasculature development of preterm infants. Notably, cellular responses to hypoxia are characterized by robust increases in extracellular adenosine production and the markedly induced adenosine receptors, which provide a novel target for preferential control of pathological angiogenesis without affecting normal vascular development. Here, we review the experimental evidence in support of adenosine receptor-based therapeutic strategy for ROP, including the aberrant adenosine signaling in oxygen-induced retinopathy and the role of three adenosine receptor subtypes (A1R, A2AR, A2BR) in development and treatment of ROP using oxygen-induced retinopathy models. The clinical and initial animal evidence that implicate the therapeutic effect of caffeine (a non-selective adenosine receptor antagonist) in treatment of ROP are highlighted. Lastly, we discussed the translational potential as well therapeutic advantage of adenosine receptor- and caffeine-based therapy for ROR and possibly other proliferative retinopathy.
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Affiliation(s)
- Jiang-Fan Chen
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of China, Wenzhou, Zhejiang, China.
| | - Shuya Zhang
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of China, Wenzhou, Zhejiang, China
| | - Rong Zhou
- State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of China, Wenzhou, Zhejiang, China
| | - Zhenlang Lin
- Department of Neonatology, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaohong Cai
- Department of Neonatology, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jing Lin
- Department of Neonatology, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yuqing Huo
- Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China
| | - Xiaoling Liu
- State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of China, Wenzhou, Zhejiang, China
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39
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Tung HC, Hsu SJ, Tsai MH, Lin TY, Hsin IF, Huo TI, Lee FY, Huang HC, Ho HL, Lin HC, Lee SD. Homocysteine deteriorates intrahepatic derangement and portal-systemic collaterals in cirrhotic rats. Clin Sci (Lond) 2017; 131:69-86. [DOI: 10.1042/cs20160470] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
In liver cirrhosis, the altered levels of vasoactive substances, especially endothelin-1 (ET-1) and nitric oxide (NO) lead to elevated intrahepatic resistance, increased portal-systemic collaterals and abnormal intra- and extra-hepatic vascular responsiveness. These derangements aggravate portal hypertension-related complications such as gastro-oesophageal variceal bleeding. Homocysteine, a substance implicated in cardiovascular diseases, has been found with influences on vasoresponsiveness and angiogenesis. However, their relevant effects in liver cirrhosis have not been investigated. In the present study, liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague–Dawley rats. In acute study, the results showed that homocysteine enhanced hepatic vasoconstriction to ET-1 but decreased portal-systemic collateral vasocontractility to arginine vasopressin (AVP). Homocysteine down-regulated hepatic phosphorylated endothelial NO synthase (p-eNOS) and p-Akt protein expressions. Inducible NOS (iNOS) and cyclooxygenase (COX)-2 expressions were up-regulated by homocysteine in splenorenal shunt (SRS), the most prominent intra-abdominal collateral vessel. In chronic study, BDL or thioacetamide (TAA) rats received homocysteine or vehicle for 14 days. The results revealed that homocysteine increased hepatic collagen fibre deposition and fibrotic factors expressions in both BDL- and TAA-induced liver fibrotic rats. Portal-systemic shunting and expressions of mesenteric angiogenetic factors [vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), PDGF receptor β (PDGFRβ) and p-eNOS] were also increased in BDL rats. In conclusion, homocysteine is harmful to vascular derangements and liver fibrosis in cirrhosis.
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Affiliation(s)
- Hung-Chun Tung
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Shao-Jung Hsu
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Ming-Hung Tsai
- Chang Gung University College of Medicine and Division of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Te-Yueh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - I-Fang Hsin
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
- Division of Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Te-Ia Huo
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Hui-Chun Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hsin-Ling Ho
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
- Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan
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Hsu SJ, Lin TY, Wang SS, Chuang CL, Lee FY, Huang HC, Hsin IF, Lee JY, Lin HC, Lee SD. Endothelin receptor blockers reduce shunting and angiogenesis in cirrhotic rats. Eur J Clin Invest 2016; 46:572-80. [PMID: 27091078 DOI: 10.1111/eci.12636] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Accepted: 04/17/2016] [Indexed: 12/21/2022]
Abstract
BACKGROUND Angiogenesis plays a pivotal role in splanchnic hyperaemia and portosystemic collateral formation in cirrhosis. Endothelin-1 (ET-1), an endothelium-derived vasoconstrictor, has also been implicated in the pathogenesis of cirrhosis and portal hypertension. DESIGN This study aimed to survey the influences of ET-1 in cirrhosis-related angiogenesis. Common bile duct ligation was performed on Spraque-Dawley rats to induce cirrhosis. Since the 14th day after the operation, rats randomly received distilled water (DW, control), bosentan [a nonselective ET receptor (ETR) blocker] or ambrisentan (a selective ETA R blocker) for 4 weeks. On the 43rd day, portal and systemic haemodynamics, liver biochemistry, portosystemic shunting degree, mesenteric vascular density, mRNA and/or protein expressions of relevant angiogenic factors were evaluated. RESULTS In cirrhotic rats, bosentan significantly reduced portal pressure. Ambrisentan did not influence haemodynamics and liver biochemistry. Both of them significantly improved the severity of portosystemic collaterals and decreased the mesenteric vascular density. Compared with the DW-treated cirrhotic rats, splenorenal shunt and mesenteric inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), vascular endothelial growth factor mRNA expressions and mesenteric iNOS, COX2, VEGF, phospho-VEGF receptor 2, Akt and phospho-Akt protein expressions were down-regulated in both groups. CONCLUSIONS In rats with liver cirrhosis, both nonselective and selective ETA R blockade ameliorate the severity of portosystemic shunting and mesenteric angiogenesis via the down-regulation of VEGF pathway and relevant angiogenic factors. ET receptors may be targeted to control the severity of portosystemic collaterals and associated complications in cirrhosis.
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Affiliation(s)
- Shao-Jung Hsu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterologyand Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Te-Yueh Lin
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Sun-Sang Wang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Department of Medical Affair and Planning, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chiao-Lin Chuang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterologyand Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hui-Chun Huang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterologyand Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - I-Fang Hsin
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jing-Yi Lee
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Han-Chieh Lin
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterologyand Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan
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Hsin IF, Lee JY, Huo TI, Lee FY, Huang HC, Hsu SJ, Wang SS, Ho HL, Lin HC, Lee SD. 2'-Hydroxyflavanone ameliorates mesenteric angiogenesis and portal-systemic collaterals in rats with liver fibrosis. J Gastroenterol Hepatol 2016; 31:1045-51. [PMID: 26474184 DOI: 10.1111/jgh.13197] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 09/16/2015] [Accepted: 09/22/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Portal-systemic collaterals lead to dreadful consequences in patients with cirrhosis. Angiogenesis participates in the development of liver fibrosis, hyperdynamic circulation, and portal-systemic collaterals. 2'-Hydroxyflavanone (2'-HF), one of the citrus fruits flavonoids, is known to have antiangiogenesis effect without adverse response. However, the relevant effects in liver fibrosis have not been surveyed. METHODS Male Wistar rats received thioacetamide (TAA, 100 mg/kg tiw, i.p.) for 6 weeks to induce liver fibrosis. On the 29th to 42nd day, rats randomly received 2'-HF (100 mg/kg, qod, i.p.) or vehicle (corn oil). On the 43rd day, after hemodynamic measurements, the followings were surveyed: (i) severity of collaterals; (ii) mesenteric angiogenesis; (iii) mesenteric proangiogenic factors protein expressions; (iv) Mesenteric vascular endothelial cells apoptosis; and (v) Mesenteric expressions of proteins regulating apoptosis. RESULTS Compared with the vehicle group, 2'-HF did not significantly change body weight, mean arterial pressure, heart rate, and portal pressure in TAA rats. 2'-HF significantly alleviated the severity of collaterals, but the mesenteric phospho-ERK, ERK, phospho-Akt, Akt, COX1, COX2, VEGF, and VEGFR-2 protein expressions were not altered. The apoptotic index of 2'-HF group was significantly higher and the mesenteric protein expressions of pro-apoptotic factors, NFkB 50, NFkB 65, Bax, phospho-p53, 17 kD cleaved caspase 3, and 17 kD casepase 3 were up-regulated. CONCLUSIONS 2'-HF does not influence the hemodynamics but alleviated the severity of collaterals in rats with liver fibrosis and early portal hypertension. This is, at least partly, attributed to enhanced apoptosis of mesenteric vascular endothelial cells.
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Affiliation(s)
- I-Fang Hsin
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Endoscopy Center for Diagnosis and Treatment, Taipei, Taiwan
| | - Jing-Yi Lee
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Teh-Ia Huo
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hui-Chun Huang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shao-Jung Hsu
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Sun-Sang Wang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Department of Medical Affair and Planning, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hsin-Ling Ho
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Han-Chieh Lin
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan
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Wang D, Wang Q, Yin J, Dong R, Wang Q, Du X, Lu J. Combined administration of propranolol + AG490 offers better effects on portal hypertensive rats with cirrhosis. J Gastroenterol Hepatol 2016; 31:1037-44. [PMID: 26487394 DOI: 10.1111/jgh.13207] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 10/07/2015] [Accepted: 10/07/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS AG490, the specific inhibitor of JAK2/STAT3 signaling, has been shown to decrease portal pressure, splanchnic hyperdynamic circulation and liver fibrosis in cirrhotic rats. Nonselective betablockers such as propranolol are the only drugs recommended in the treatment of portal hypertension. The aim of this study was to explore the combinative effect of treatment with propranolol and AG490 on portal hypertension. METHODS Rats induced by common bile duct ligation were treated with vehicle, AG490, propranolol, or AG490 + propranolol for 2 weeks. Hemodynamics parameters were assessed. Expressions of phospho-STAT3 protein and its down-regulated cytokines in splanchnic organs were detected by ELISA or western blot. Lipopolysaccharide binding protein (LBP) and IL-6 were assessed by ELISA or western blot. Characterization of liver and mesentery was performed by histological analyses. RESULTS Highly expressed phospho-STAT3 protein in cirrhotic rats could successfully be inhibited by AG490 or AG490 + propranolol treatments but not by propranolol alone. Both AG490 and propranolol significantly reduced portal pressure and hyperdynamic splanchnic circulation, and combination of AG490 and propranolol achieved an additive effect than with either drug alone. AG490, alone or in combination with propranolol, inhibited liver fibrosis, splenomegaly and splanchnic angiogenesis. Increased markers of bacterial translocation (LBP and IL6) were greatly reduced by propranolol but not by AG490. CONCLUSIONS The combination of propranolol and AG490 caused a greater improvement of portal hypertension and might therefore offer a potentially promising therapy in the portal hypertension treatment.
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Affiliation(s)
- Dong Wang
- Departments of General Surgery, TangDu Hospital, Xi'an, China
| | - Qin Wang
- Pharmacogenomics, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Jikai Yin
- Departments of General Surgery, TangDu Hospital, Xi'an, China
| | - Rui Dong
- Departments of General Surgery, TangDu Hospital, Xi'an, China
| | - Qing Wang
- Departments of General Surgery, TangDu Hospital, Xi'an, China
| | - Xilin Du
- Departments of General Surgery, TangDu Hospital, Xi'an, China
| | - Jianguo Lu
- Departments of General Surgery, TangDu Hospital, Xi'an, China
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Beharry KD, Valencia G, Lazzaro D, Aranda J. Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity. Semin Perinatol 2016; 40:189-202. [PMID: 26831641 PMCID: PMC4808450 DOI: 10.1053/j.semperi.2015.12.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Retinopathy of prematurity (ROP), a significant morbidity in prematurely born infants, is the most common cause of visual impairment and blindness in children and persists till adulthood. Strict control of oxygen therapy and prevention of intermittent hypoxia are the keys in the prevention of ROP, but pharmacologic interventions have decreased risk of ROP. Various drug classes such as methylxanthines (caffeine), VEGF inhibitors, antioxidants, and others have decreased ROP occurrence. The timing of pharmacologic intervention remains unsettled, but early prevention rather than controlling disease progression may be preferred. These drugs act through different mechanisms, and synergistic approaches should be considered to maximize efficacy and safety.
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Zhang Y, Ding HG. Prevention and treatment of cirrhotic portal hypertension: New cellular and molecular targets. Shijie Huaren Xiaohua Zazhi 2016; 24:2950. [DOI: 10.11569/wcjd.v24.i19.2950] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Hsu SJ, Wang SS, Huo TI, Lee FY, Huang HC, Chang CC, Hsin IF, Ho HL, Lin HC, Lee SD. The Impact of Spironolactone on the Severity of Portal-Systemic Collaterals and Hepatic Encephalopathy in Cirrhotic Rats. J Pharmacol Exp Ther 2015; 355:117-24. [PMID: 26260462 DOI: 10.1124/jpet.115.225516] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 08/03/2015] [Indexed: 12/23/2022] Open
Abstract
Liver cirrhosis and portal hypertension are accompanied by portal-systemic collaterals formation and lethal complications. Angiogenesis participates in the development of collaterals. Spironolactone is an aldosterone receptor antagonist used to control fluid overload in cirrhotic patients although recent studies suggest that it also inhibits angiogenesis. This study investigated the effect of spironolactone on abnormal angiogenesis and portal-systemic collaterals in cirrhosis. Liver cirrhosis was induced in Sprague-Dawley rats by common bile duct ligation (BDL), and sham-operated rats were the controls. The BDL and sham rats received spironolactone (20 mg/kg/d, oral gavage) or vehicle from day 15 to 28 after the operations. Spironolactone did not influence the portal and systemic hemodynamic, and the renal and hepatic biochemistry data, but it significantly ameliorated hepatic fibrosis, portal-systemic shunting, and mesenteric angiogenesis. Plasma vascular endothelial growth factor (VEGF) levels and the mesenteric protein expression of VEGF and phosphor-vascular endothelial growth factor receptor 2 (VEGFR-2) decreased in the spironolactone group. Spironolactone did not affect motor activity or plasma ammonia levels. The down-regulation of VEGF pathway participates, albeit partly, in the antiangiogenic effect of spironolactone. Thus, spironolactone treatment in patients with liver cirrhosis may provide additional benefits aside from ascites control.
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Affiliation(s)
- Shao-Jung Hsu
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Sun-Sang Wang
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Teh-Ia Huo
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Fa-Yauh Lee
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Hui-Chun Huang
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Ching-Chih Chang
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - I-Fang Hsin
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Hsin-Ling Ho
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Han-Chieh Lin
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Shou-Dong Lee
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
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Outstanding research paper awards of the 2014 Taiwanese Journal of Obstetrics and Gynecology. Taiwan J Obstet Gynecol 2015; 54:215-6. [DOI: 10.1016/j.tjog.2015.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2015] [Indexed: 10/23/2022] Open
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Feld JJ, Lavoie ÉG, Fausther M, Dranoff JA. I drink for my liver, Doc: emerging evidence that coffee prevents cirrhosis. F1000Res 2015; 4:95. [PMID: 25977756 PMCID: PMC4416533 DOI: 10.12688/f1000research.6368.2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/20/2015] [Indexed: 01/10/2023] Open
Abstract
Evidence demonstrating that regular ingestion of coffee has salutary effects on patients with chronic liver disease is accumulating rapidly. Specifically, it appears that coffee ingestion can slow the progression of liver fibrosis, preventing cirrhosis and hepatocellular carcinoma (HCC). This should excite clinicians and scientists alike, since these observations, if true, would create effective, testable hypotheses that should lead to improved understanding on fibrosis pathogenesis and thus may generate novel pharmacologic treatments of patients with chronic liver disease. This review is designed to examine the relevant clinical and epidemiological data in critical fashion and to examine the putative pharmacological effects of coffee relevant to the pathogenesis of liver fibrosis and cirrhosis. We hope that this will inspire relevant critical analyses, especially among “coffee skeptics”. Of note, one major assumption made by this review is that the bulk of the effects of coffee consumption are mediated by caffeine, rather than by other chemical constituents of coffee. Our rationales for this assumption are threefold: first, caffeine’s effects on adenosinergic signaling provide testable hypotheses; second, although there are myriad chemical constituents of coffee, they are present in very low concentrations, and perhaps more importantly, vary greatly between coffee products and production methods (it is important to note that we do not dismiss the “botanical” hypothesis here; rather, we do not emphasize it at present due to the limitations of the studies examined); lastly, some (but not all) observational studies have examined both coffee and non-coffee caffeine consumption and found consistent effects, and when examined, no benefit to decaffeinated coffee has been observed. Further, in the interval since we examined this phenomenon last, further evidence has accumulated supporting caffeine as the effector molecule for coffee’s salutary effects.
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Affiliation(s)
- Jordan J Feld
- Toronto Western Hospital Liver Center, Toronto, ON, M5G 2M9, Canada
| | - Élise G Lavoie
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Michel Fausther
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Jonathan A Dranoff
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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Littlejohn GO. Fibrositis/fibromyalgia syndrome in the workplace. J Biol Chem 1989; 290:28286-28298. [PMID: 2644678 DOI: 10.1074/jbc.m115.683813] [Citation(s) in RCA: 125] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Indexed: 12/20/2022] Open
Abstract
A recent major epidemic of localized fibrositis/fibromyalgia syndrome occurring in the workplaces of Australia is reviewed. The clinical features are described and the important provoking factors are detailed. A neurogenic model is proposed to explain this localized phenomena and also encompass primary generalized fibrositis/fibromyalgia syndrome.
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Affiliation(s)
- G O Littlejohn
- Rheumatology Unit, Prince Henry's Hospital, Melbourne, Australia
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