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Wang X, Li J, Nong J, Deng X, Chen Y, Wu P, Huang X. Curcumol Attenuates Portal Hypertension and Collateral Shunting Via Inhibition of Extrahepatic Angiogenesis in Cirrhotic Rats. Biochem Genet 2025; 63:281-297. [PMID: 38438779 DOI: 10.1007/s10528-024-10684-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 01/03/2024] [Indexed: 03/06/2024]
Abstract
Liver cirrhosis can cause disturbances in blood circulation in the liver, resulting in impaired portal blood flow and ultimately increasing portal venous pressure. Portal hypertension induces portal-systemic collateral formation and fatal complications. Extrahepatic angiogenesis plays a crucial role in the development of portal hypertension. Curcumol is a sesquiterpenoid derived from the rhizome of Curcumae Rhizoma and has been confirmed to alleviate liver fibrosis by inhibiting angiogenesis. Therefore, our study was designed to explore the effects of curcumol on extrahepatic angiogenesis and portal hypertension. To induce cirrhosis, Sprague Dawley rats underwent bile duct ligation (BDL) surgery. Rats received oral administration with curcumol (30 mg/kg/d) or vehicle (distilled water) starting on day 15 following surgery, when BDL-induced liver fibrosis had developed. The effect of curcumol was assessed on day 28, which is the typical time of BDL-induced cirrhosis. The results showed that curcumol markedly reduced portal pressure in cirrhotic rats. Curcumol inhibited abnormal splanchnic inflow, mitigated liver injury, improved liver fibrosis, and attenuated portal-systemic collateral shunting in cirrhotic rats. These protective effects were partially attributed to the inhibition on mesenteric angiogenesis by curcumol. Mechanically, curcumol partially reversed the BDL-induced activation of the JAK2/STAT3 signaling pathway in cirrhotic rats. Collectively, curcumol attenuates portal hypertension in liver cirrhosis by suppressing extrahepatic angiogenesis through inhibiting the JAK2/STAT3 signaling pathway.
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Affiliation(s)
- Xinyuan Wang
- Development of Planning Division, Guangxi University of Chinese Medicine, Nanning, 530000, China
| | - Juan Li
- Development of Pediatric, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, 530000, China
| | - Jiao Nong
- Development of Education, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, 530000, China
| | - Xin Deng
- Basic Medical College, Guangxi University of Chinese Medicine, Nanning, 530000, China
| | - Yiping Chen
- Development of Emergency, The First Affiliated Hospital of Guangxi University of Chinese Medicine, No.28 Wangyuan Road, Qingxiu District, Nanning, 530000, China
| | - Peibin Wu
- Achievement Transformation and Social Service Office, Guangxi University of Chinese Medicine, Nanning, 530000, China
| | - Xiabing Huang
- Development of Emergency, The First Affiliated Hospital of Guangxi University of Chinese Medicine, No.28 Wangyuan Road, Qingxiu District, Nanning, 530000, China.
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Fu C, Zhang Y, Xi WJ, Xu K, Meng F, Ma T, Li W, Wu L, Chen Z. Dahuang Zhechong pill attenuates hepatic sinusoidal capillarization in liver cirrhosis and hepatocellular carcinoma rat model via the MK/integrin signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2023; 308:116191. [PMID: 36731809 DOI: 10.1016/j.jep.2023.116191] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/08/2023] [Accepted: 01/17/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Dahuang Zhechong pill (DHZCP), a traditional Chinese medicine, was derived from the famous book Unk "Synopsis of Prescriptions of the Golden Chamber" during the Han dynasty. Owing to its ability to invigorate the circulation of blood in Chinese medicine, DHZCP is usually used for treating liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Clinical application have shown that DHZCP exhibits satisfactory therapeutic effects in HCC adjuvant therapy; however, little is known about its underlying mechanisms. AIM OF THE STUDY We aimed to clarify the mechanism of DHZCP against hepatic sinusoidal capillarization in rats with LC and HCC by inhibiting the MK/integrin signaling pathway of liver sinusoidal endothelial cells (LSECs). MATERIALS AND METHODS The contents of 29 characteristic components in DHZCP were determined by ultraperformance liquid chromatography-tandem mass spectrometry. DEN (Diethylnitrosamine)-induced LC and HCC rat models were constructed, and DHZCP was administered when the disease entered the LC stage. After 4 or 12 weeks of administration, hematoxylin and eosin staining, Masson staining, Metavir score, and SSCP (Single strand conformation polymorphism) gene mutation detection were used to confirm tissue fibrosis and cancer. The levels of NO, ET-1 and TXA2, which can regulate vasomotor functions and activate the MK/Itgα6/Src signaling pathway were evaluated by using immunohistochemistry, chemiluminescence, immunofluorescence, Western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Similar methods were also used to evaluate the levels of VEGF, VEGFR, Ang-2 and Tie, which can promote pathological angiogenesis and activate the MK/Itgα4/NF-κB signaling pathway. In vitro cell experiments were performed using potential pharmacodynamic molecules targeting integrins in DHZCP were selected by molecular docking, and the effects of these molecules on the function of LSECs were studied by Itgα4+ and Itgα6+ cell models. RESULTS At the stage of LC, the animal experiments demonstrated that DHZCP mainly inhibited the MK/Itgα6 signaling pathway to increase the number and size of hepatic sinus fenestration, reversed the ET-1/NO and TXA2/NO ratios, regulated hepatic sinus relaxation and contraction balance, reduced the portal vein pressure, and inhibited cirrhotic carcinogenesis. At the HCC stage, DHZCP could also significantly inhibit the MK/Itgα4 signaling pathway, reduce pathological angiogenesis, and alleviate disease progression. The results of the cell experiments showed that Rhein, Naringenin, Liquiritin and Emodin-8-O-β-D-glucoside (PMEG) were involved in vascular regulation by affecting the MK/integrin signaling pathway. Liquiritin and PMEG mainly blocked the MK/α6 signal, which is important in regulating the vasomotor function of the liver sinus. Naringenin and Rhein mainly acted by blocked the signaling of MK/α4 action signal, which are potent molecules that inhibit pathological angiogenesis. CONCLUSIONS DHZCP could improve the hepatic sinusoidal capillarization of LC and HCC by inhibiting the MK/Itgα signaling pathway and inhibited disease progression. Rhein, Naringenin, Liquiritin and PMEG were the main active molecules that affected the MK/Itgα signaling pathway.
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Affiliation(s)
- Chuankui Fu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Yiheng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Wen Jie Xi
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Kejia Xu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Fansheng Meng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Tianle Ma
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Weidong Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Li Wu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Zhipeng Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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Lee EJ, Kim Y, Kim JE, Yoon EL, Lee SR, Jun DW. ALS-L1023 from Melissa officinalis Alleviates Liver Fibrosis in a Non-Alcoholic Fatty Liver Disease Model. LIFE (BASEL, SWITZERLAND) 2022; 13:life13010100. [PMID: 36676050 PMCID: PMC9863634 DOI: 10.3390/life13010100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 11/30/2022] [Accepted: 12/28/2022] [Indexed: 12/31/2022]
Abstract
ALS-L1023 is an ingredient extracted from Melissa officinalis L. (Labiatae; lemon balm), which is known as a natural medicine that suppresses angiogenesis. Herein, we aimed to determine whether ALS-L1023 could alleviate liver fibrosis in the non-alcoholic fatty liver disease (NAFLD) model. C57BL/6 wild-type male mice (age, 6 weeks old) were fed a choline-deficient high-fat diet (CDHFD) for 10 weeks to induce NAFLD. For the next 10 weeks, two groups of mice received the test drug along with CDHFD. Two doses (a low dose, 800 mg/kg/day; and a high dose, 1200 mg/kg/day) of ALS-L1023 were selected and mixed with feed for administration. Obeticholic acid (OCA; 10 mg/kg/day) was used as the positive control. Biochemical analysis revealed that the ALS-L1023 low-dose group had significantly decreased alanine transaminase and aspartate transaminase. The area of fibrosis significantly decreased due to the administration of ALS-L1023, and the anti-fibrotic effect of ALS-L1023 was greater than that of OCA. RNA sequencing revealed that the responder group had lower expression of genes related to the hedgehog-signaling pathway than the non-responder group. ALS-L1023 may exert anti-fibrotic effects in the NAFLD model, suggesting that it may provide potential benefits for the treatment of liver fibrosis.
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Affiliation(s)
- Eun Jeoung Lee
- Department of Translational Medical Science, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul 04763, Republic of Korea
| | - Yun Kim
- Hanyang Medicine-Engineering-Bio Collaborative & Comprehensive Center for Drug Development, Hanyang University, Seoul 04763, Republic of Korea
- College of Pharmacy, Daegu Catholic University, Gyeongsan 38430, Republic of Korea
| | - Ji Eun Kim
- Department of Translational Medical Science, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul 04763, Republic of Korea
| | - Eileen Laurel Yoon
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul 04763, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul 04763, Republic of Korea
| | - Sung Ryol Lee
- Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
- Correspondence: (S.R.L.); (D.W.J.)
| | - Dae Won Jun
- Department of Translational Medical Science, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul 04763, Republic of Korea
- Hanyang Medicine-Engineering-Bio Collaborative & Comprehensive Center for Drug Development, Hanyang University, Seoul 04763, Republic of Korea
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul 04763, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul 04763, Republic of Korea
- Correspondence: (S.R.L.); (D.W.J.)
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Sauer TJ, Abadi E, Segars P, Samei E. Anatomically and physiologically informed computational model of hepatic contrast perfusion for virtual imaging trials. Med Phys 2022; 49:2938-2951. [PMID: 35195901 PMCID: PMC9547339 DOI: 10.1002/mp.15562] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 02/02/2022] [Accepted: 02/02/2022] [Indexed: 12/10/2022] Open
Abstract
PURPOSE Virtual (in silico) imaging trials (VITs), involving computerized phantoms and models of the imaging process, provide a modern alternative to clinical imaging trials. VITs are faster, safer, and enable otherwise-impossible investigations. Current phantoms used in VITs are limited in their ability to model functional behavior such as contrast perfusion which is an important determinant of dose and image quality in CT imaging. In our prior work with the XCAT computational phantoms, we determined and modeled inter-organ (organ to organ) intravenous contrast concentration as a function of time from injection. However, intra-organ concentration, heterogeneous distribution within a given organ, was not pursued. We extend our methods in this work to model intra-organ concentration within the XCAT phantom with a specific focus on the liver. METHODS Intra-organ contrast perfusion depends on the organ's vessel network. We modeled the intricate vascular structures of the liver, informed by empirical and theoretical observations of anatomy and physiology. The developed vessel generation algorithm modeled a dual-input-single-output vascular network as a series of bifurcating surfaces to optimally deliver flow within the bounding surface of a given XCAT liver. Using this network, contrast perfusion was simulated within voxelized versions of the phantom by using knowledge of the blood velocities in each vascular structure, vessel diameters and length, and the time since the contrast entered the hepatic artery. The utility of the enhanced phantom was demonstrated through a simulation study with the phantom voxelized prior to CT simulation with the relevant liver vasculature prepared to represent blood and iodinated contrast media. The spatial extent of the blood-contrast mixture was compared to clinical data. RESULTS The vascular structures of the liver were generated with size and orientation which resulted in minimal energy expenditure required to maintain blood flow. Intravenous contrast was simulated as having known concentration and known total volume in the liver as calibrated from time-concentration curves. Measurements of simulated CT ROIs were found to agree with clinically observed values of early arterial phase contrast enhancement of the parenchyma (∼ 5 $ \sim 5$ HU). Similarly, early enhancement in the hepatic artery was found to agree with average clinical enhancement( 180 $(180$ HU). CONCLUSIONS The computational methods presented here furthered the development of the XCAT phantoms allowing for multi-timepoint contrast perfusion simulations, enabling more anthropomorphic virtual clinical trials intended for optimization of current clinical imaging technologies and applications.
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Affiliation(s)
- Thomas J. Sauer
- Center for Virtual Imaging Trials (CVIT), Carl E. Ravin Advanced Imaging Laboratories, Department of Radiology, Duke University Medical Center
| | - Ehsan Abadi
- Center for Virtual Imaging Trials (CVIT), Carl E. Ravin Advanced Imaging Laboratories, Department of Radiology, Duke University Medical Center
| | - Paul Segars
- Center for Virtual Imaging Trials (CVIT), Carl E. Ravin Advanced Imaging Laboratories, Department of Radiology, Duke University Medical Center
| | - Ehsan Samei
- Center for Virtual Imaging Trials (CVIT), Carl E. Ravin Advanced Imaging Laboratories, Department of Radiology, Duke University Medical Center
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Garbuzenko DV. Pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. World J Clin Cases 2022; 10:3662-3676. [PMID: 35647163 PMCID: PMC9100727 DOI: 10.12998/wjcc.v10.i12.3662] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/17/2021] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a complex pathological process controlled by a variety of cells, mediators and signaling pathways. Hepatic stellate cells play a central role in the development of liver fibrosis. In chronic liver disease, hepatic stellate cells undergo dramatic phenotypic activation and acquire fibrogenic properties. This review focuses on the pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. They enter the cell cycle under the influence of various triggers. The "Initiation" phase of hepatic stellate cells activation overlaps and continues with the "Perpetuation" phase, which is characterized by a pronounced inflammatory and fibrogenic reaction. This is followed by a resolution phase if the injury subsides. Knowledge of these pathophysiological mechanisms paved the way for drugs aimed at preventing the development and progression of liver fibrosis. In this respect, impairments in intracellular signaling, epigenetic changes and cellular stress response can be the targets of therapy where the goal is to deactivate hepatic stellate cells. Potential antifibrotic therapy may focus on inducing hepatic stellate cells to return to an inactive state through cellular aging, apoptosis, and/or clearance by immune cells, and serve as potential antifibrotic therapy. It is especially important to prevent the formation of liver cirrhosis since the only radical approach to its treatment is liver transplantation which can be performed in only a limited number of countries.
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Takano C, Grubbs BH, Ishige M, Ogawa E, Morioka I, Hayakawa S, Miki T. Clinical perspective on the use of human amniotic epithelial cells to treat congenital metabolic diseases with a focus on maple syrup urine disease. Stem Cells Transl Med 2021; 10:829-835. [PMID: 33547875 PMCID: PMC8133340 DOI: 10.1002/sctm.20-0225] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 12/18/2020] [Accepted: 12/20/2020] [Indexed: 12/16/2022] Open
Abstract
Congenital metabolic diseases are a group of hereditary disorders caused by the deficiency of a single specific enzyme activity. Without appropriate therapy, affected patients suffer severe neurologic disability and eventual death. The current mainstays of management attempt to slow disease progression, but are not curative. Several of these diseases have demonstrated significant benefits from liver transplantation; however, this approach is limited by the morbidity associated with this invasive procedure and a shortage of donor organs. Therefore, there is a need to establish a new strategy for improving the quality of a life for these patients. One potential solution is regenerative therapy using hepatocytes generated from stem cells. Herein, we discuss pertinent issues necessary for clinical application of the human amniotic epithelial cell, a type of placental stem cell. Focusing on maple syrup urine disease as an example, where liver replacement is an effective therapy, we explore this approach from a clinician's perspective.
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Affiliation(s)
- Chika Takano
- Division of Microbiology, Department of Pathology and MicrobiologyNihon University School of MedicineTokyoJapan
- Department of Pediatrics and Child HealthNihon University School of MedicineTokyoJapan
| | - Brendan H. Grubbs
- Department of Obstetrics and GynecologyKeck School of Medicine, University of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Mika Ishige
- Department of Pediatrics and Child HealthNihon University School of MedicineTokyoJapan
| | - Erika Ogawa
- Department of Pediatrics and Child HealthNihon University School of MedicineTokyoJapan
| | - Ichiro Morioka
- Department of Pediatrics and Child HealthNihon University School of MedicineTokyoJapan
| | - Satoshi Hayakawa
- Division of Microbiology, Department of Pathology and MicrobiologyNihon University School of MedicineTokyoJapan
| | - Toshio Miki
- Department of PhysiologyNihon University School of MedicineTokyoJapan
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Garbuzenko DV, Arefyev NO. Primary prevention of bleeding from esophageal varices in patients with liver cirrhosis: An update and review of the literature. J Evid Based Med 2020; 13:313-324. [PMID: 33037792 DOI: 10.1111/jebm.12407] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 06/19/2020] [Indexed: 12/12/2022]
Abstract
All patients with liver cirrhosis and portal hypertension should be stratified by risk groups to individualize different therapeutic strategies to increase the effectiveness of treatment. In this regard, the development of primary prophylaxis of variceal bleeding and its management according to the severity of portal hypertension may be promising. This paper is to describe the modern principles of primary prophylaxis of esophageal variceal bleeding in patients with liver cirrhosis. The PubMed and EMbase databases, Web of Science, Google Scholar, and the Cochrane Database of Systematic Reviews were used to search for relevant publications from 1999 to 2019. The results suggested that depending on the severity of portal hypertension, patients with cirrhosis should be divided into those who need preprimary prophylaxis, which aims to prevent the formation of esophageal varices, and those who require measures that aim to prevent esophageal variceal bleeding. In subclinical portal hypertension, therapy should be etiological and pathogenetic. Cirrhosis with clinically significant portal hypertension should receive nonselective β-blockers if they have small esophageal varices and risk factors for variceal bleeding. Nonselective β-blockers are the first-line drugs for the primary prevention of bleeding from medium to large-sized esophageal varices. Endoscopic band ligation is indicated for the patients who are intolerant to nonselective β-blockers or in the case of contraindications to pharmacological therapy. In summary, the stratification of cirrhotic patients by the severity of portal hypertension and an individual approach to the choice of treatment may increase the effectiveness of therapy as well as improve survival rate of these patients.
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Affiliation(s)
| | - Nikolay Olegovich Arefyev
- Department of Pathological Anatomy and Forensic Medicine, South Ural State Medical University, Chelyabinsk, Russia
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Nouri-Vaskeh M, Malek Mahdavi A, Afshan H, Alizadeh L, Zarei M. Effect of curcumin supplementation on disease severity in patients with liver cirrhosis: A randomized controlled trial. Phytother Res 2020; 34:1446-1454. [PMID: 32017253 DOI: 10.1002/ptr.6620] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 01/03/2020] [Accepted: 01/13/2020] [Indexed: 01/15/2023]
Abstract
Recent reports indicated that curcumin had beneficial effects in animal models of liver injury and cirrhosis. Current study aimed to investigate the effects of curcumin supplementation in patients with liver cirrhosis. In this randomized double-blind placebo-controlled trial, 70 patients with liver cirrhosis aged 20-70 years were randomly divided into two groups to receive 1,000 mg/day curcumin (n = 35) or placebo (n = 35) for 3 months. Model for end-stage liver disease (MELD) (i), MELD, MELD-Na, and Child-Pugh scores were used to assess the severity of cirrhosis. Sixty patients (29 in the curcumin group and 31 in the placebo group) completed the study. MELD(i) (15.55 ± 3.78 to 12.41 ± 3.07), MELD (15.31 ± 3.07 to 12.03 ± 2.79), MELD-Na (15.97 ± 4.02 to 13.55 ± 3.51), and Child-Pugh (7.17 ± 1.54 to 6.72 ± 1.31) scores decreased significantly in the curcumin group after 3-month intervention (p < .001, p < .001, p = .001, and p = .051, respectively), whereas they increased significantly in the placebo group (p < .001, p < .001, p < .001, p = .001, respectively). Significant differences were only observed between the two groups in MELD(i), MELD, MELD-Na, and Child-Pugh scores after 3-month intervention (p < .001 for all of them). In this pilot study, beneficial effects of curcumin supplementation were observed in decreasing disease activity scores and severity of cirrhosis in patients with cirrhosis.
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Affiliation(s)
- Masoud Nouri-Vaskeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aida Malek Mahdavi
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Afshan
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Alizadeh
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Zarei
- Department of Pathology and Laboratory Medicine, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
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Pharmacogenetic-Based Interactions between Nutraceuticals and Angiogenesis Inhibitors. Cells 2019; 8:cells8060522. [PMID: 31151284 PMCID: PMC6627675 DOI: 10.3390/cells8060522] [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: 04/16/2019] [Revised: 05/20/2019] [Accepted: 05/24/2019] [Indexed: 12/19/2022] Open
Abstract
Background: Angiogenesis inhibitors (AIs) have become established as an effective cancer treatment. Whereas their interactions with antineoplastic drugs have extensively been investigated, little is known of the effect of their co-administration with nutraceuticals/dietary supplements (N/DSs), which are often self-prescribed. N/DSs comprise a wide range of products such as herbs, nutrients, vitamins, minerals, and probiotics. Assessment of their interactions with cancer drugs, particularly AIs, is hampered by the difficulty of gauging the amount of active substances patients actually take. Moreover, there is no agreement on which approach should be used to determine which N/DSs are most likely to influence AI treatment efficacy. We present a comprehensive review of the metabolic routes of the major AIs and their possible interactions with N/DSs. Methods: The PubMed and Cochrane databases were searched for papers describing the metabolic routes of the main AIs and N/DSs. Results: Data from the 133 studies thus identified were used to compile a diagnostic table reporting known and expected AI-N/DS interactions based on their metabolization pathways. AIs and N/DSs sharing the cytochrome P450 pathway are at risk of negative interactions. Conclusions: Recent advances in pharmacogenetics offer exceptional opportunities to identify prognostic and predictive markers to enhance the efficacy of individualized AI treatments. The table provides a guide to genotyping patients who are due to receive AIs and is a promising tool to prevent occult AI-N/DS interactions in poor metabolizers. N/DS use by cancer patients receiving AIs is a topical problem requiring urgent attention from the scientific community.
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Portal hypertension: The desperate search for the placenta. Curr Res Transl Med 2018; 67:56-61. [PMID: 30503816 DOI: 10.1016/j.retram.2018.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 09/17/2018] [Accepted: 09/30/2018] [Indexed: 12/10/2022]
Abstract
We propose that the circulatory impairments produced, in both portal hypertension and liver cirrhosis, to a certain degree resemble those characterizing prenatal life in the fetus. In fact, the left-right circulatory syndrome is common in cirrhotic patients and in the fetus. Thus, in patients with portal hypertension and chronic liver failure, the re-expression of a blood circulation comparable to fetal circulation is associated with the development of similar amniotic functions, i.e., ascites production and placenta functions, and portal vascular enteropathy. Therefore, these re-expressed embryonic functions are extra-embryonic and responsible for prenatal trophism and development.
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Ling L, Li G, Meng D, Wang S, Zhang C. Carvedilol Ameliorates Intrahepatic Angiogenesis, Sinusoidal Remodeling and Portal Pressure in Cirrhotic Rats. Med Sci Monit 2018; 24:8290-8297. [PMID: 30448852 PMCID: PMC6253986 DOI: 10.12659/msm.913118] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Accepted: 11/01/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Carvedilol is the first-line drug for the primary prophylaxis of variceal bleeding due to portal hypertension (PHT) in liver cirrhosis. This study aimed to investigate the effects of carvedilol on intrahepatic angiogenesis and sinusoidal remodeling in cirrhotic rats and explore the underlying mechanisms of carvedilol in PHT. MATERIAL AND METHODS For in vivo experiments, carbon tetrachloride was used to induce liver cirrhosis in rats, and carvedilol was simultaneously administered by gavage. The portal pressure was measured in rats, and liver tissues were examined by immunohistochemistry. Sinusoidal remodeling was observed by transmission electron microscopy. For in vitro experiments, the effects of carvedilol on fibronectin (FN) synthesis in human umbilical vein endothelial cells (HUVECs) were explored by quantitative real-time polymerase chain reaction and western blot analysis. RESULTS Portal vein pressure measurements showed that carvedilol reduced portal pressure in cirrhotic rats. Immunohistochemistry assays indicated that carvedilol ameliorated intrahepatic angiogenesis. Transmission electron microscopy examination demonstrated that carvedilol improved sinusoidal remodeling. In the in vitro experiments, carvedilol suppressed transforming growth factor β1 (TGFβ1)-induced FN synthesis in HUVECs by inhibition of the TGFβ1/Smads pathway. CONCLUSIONS Carvedilol ameliorated intrahepatic angiogenesis, sinusoidal remodeling and portal pressure in cirrhotic rats. Carvedilol improved sinusoidal remodeling by suppressing FN synthesis in endothelial cells. Carvedilol has potential utility for treating early-stage liver cirrhosis.
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Affiliation(s)
- Liping Ling
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, P.R. China
| | - Guangqi Li
- Department of Oncology, Binzhou People’s Hospital, Binzhou, Shandong, P.R. China
| | - Dongxiao Meng
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, P.R. China
| | - Sining Wang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, P.R. China
| | - Chunqing Zhang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, P.R. China
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Garbuzenko DV, Arefyev NO, Kazachkov EL. Antiangiogenic therapy for portal hypertension in liver cirrhosis: Current progress and perspectives. World J Gastroenterol 2018; 24:3738-3748. [PMID: 30197479 PMCID: PMC6127663 DOI: 10.3748/wjg.v24.i33.3738] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 07/09/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
Developing medicines for hemodynamic disorders that are characteristic of cirrhosis of the liver is a relevant problem in modern hepatology. The increase in hepatic vascular resistance to portal blood flow and subsequent hyperdynamic circulation underlie portal hypertension (PH) and promote its progression, despite the formation of portosystemic collaterals. Angiogenesis and vascular bed restructurization play an important role in PH pathogenesis as well. In this regard, strategic directions in the therapy for PH in cirrhosis include selectively decreasing hepatic vascular resistance while preserving or increasing portal blood flow, and correcting hyperdynamic circulation and pathological angiogenesis. The aim of this review is to describe the mechanisms of angiogenesis in PH and the methods of antiangiogenic therapy. The PubMed database, the Google Scholar retrieval system, and the reference lists from related articles were used to search for relevant publications. Articles corresponding to the aim of the review were selected for 2000-2017 using the keywords: "liver cirrhosis", "portal hypertension", "pathogenesis", "angiogenesis", and "antiangiogenic therapy". Antiangiogenic therapy for PH was the inclusion criterion. In this review, we have described angiogenesis inhibitors and their mechanism of action in relation to PH. Although most of them were studied only in animal experiments, this selective therapy for abnormally growing newly formed vessels is pathogenetically reasonable to treat PH and associated complications.
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Affiliation(s)
| | - Nikolay Olegovich Arefyev
- Department of Pathological Anatomy and Forensic Medicine, South Ural State Medical University, Chelyabinsk 454092, Russia
| | - Evgeniy Leonidovich Kazachkov
- Department of Pathological Anatomy and Forensic Medicine, South Ural State Medical University, Chelyabinsk 454092, Russia
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Evaluation of Hepatoprotective Effect of Curcumin on Liver Cirrhosis Using a Combination of Biochemical Analysis and Magnetic Resonance-Based Electrical Conductivity Imaging. Mediators Inflamm 2018; 2018:5491797. [PMID: 29887757 PMCID: PMC5985075 DOI: 10.1155/2018/5491797] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 04/11/2018] [Indexed: 12/20/2022] Open
Abstract
In oriental medicine, curcumin is used to treat inflammatory diseases, and its anti-inflammatory effect has been reported in recent research. In this feasibility study, the hepatoprotective effect of curcumin was investigated using a rat liver cirrhosis model, which was induced with dimethylnitrosamine (DMN). Together with biochemical analysis, we used a magnetic resonance-based electrical conductivity imaging method to evaluate tissue conditions associated with a protective effect. The effects of curcumin treatment and lactulose treatment on liver cirrhosis were compared. Electrical conductivity images indicated that liver tissues damaged by DMN showed decreased conductivity compared with normal liver tissues. In contrast, cirrhotic liver tissues treated with curcumin or lactulose showed increased conductivity than tissues in the DMN-only group. Specifically, conductivity of cirrhotic liver after curcumin treatment was similar to that of normal liver tissues. Histological staining and immunohistochemical examination showed significant levels of attenuated fibrosis and decreased inflammatory response after both curcumin and lactulose treatments compared with damaged liver tissues by DMN. The conductivity imaging and biochemical examination results indicate that curcumin's anti-inflammatory effect can prevent the progression of irreversible liver dysfunction.
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Zhang F, Lu S, He J, Jin H, Wang F, Wu L, Shao J, Chen A, Zheng S. Ligand Activation of PPARγ by Ligustrazine Suppresses Pericyte Functions of Hepatic Stellate Cells via SMRT-Mediated Transrepression of HIF-1α. Am J Cancer Res 2018; 8:610-626. [PMID: 29344293 PMCID: PMC5771080 DOI: 10.7150/thno.22237] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Accepted: 10/22/2017] [Indexed: 12/31/2022] Open
Abstract
Rationale: Hepatic stellate cells (HSCs) are liver-specific pericytes regulating vascular remodeling during hepatic fibrosis. Here, we investigated how ligustrazine affects HSC pericyte functions. Methods: Rat HSC-T6 and human HSC-LX2 cells were cultured, and multiple molecular experiments including real-time PCR, Western blot, flow cytometry, immunofluorescence, electrophoretic mobility shift assay and co-immunoprecipitation were used to elucidate the underlying mechanisms. Molecular simulation and site-directed mutagenesis were performed to uncover the target molecule of ligustrazine. Rats were intoxicated with CCl4 for evaluating ligustrazine's effects in vivo. Results: Ligustrazine inhibited angiogenic cytokine production, migration, adhesion and contraction in HSCs, and activated PPARγ. Selective PPARγ inhibitor GW9662 potently abrogated ligustrazine suppression of HSC pericyte functions. Additionally, HIF-1α inhibitor PX-478 repressed HSC pericyte functions, and ligustrazine inhibited the transcription of HIF-1α, which was diminished by GW9662. Moreover, ligustrazine downregulation of HIF-1α was rescued by knockdown of SMRT, and ligustrazine increased PPARγ physical interaction with SMRT, which was abolished by GW9662. These findings collectively indicated that activation of PPARγ by ligustrazine led to transrepression of HIF-1α via a SMRT-dependent mechanism. Furthermore, molecular docking evidence revealed that ligustrazine bound to PPARγ in a unique double-molecule manner via hydrogen bonding with the residues Ser289 and Ser342. Site-directed mutation of Ser289 and/or Ser342 resulted in the loss of ligustrazine transrepression of HIF-1α in HSCs, indicating that interactions with both the residues were indispensable for ligustrazine effects. Finally, ligustrazine improved hepatic injury, angiogenesis and vascular remodeling in CCl4-induced liver fibrosis in rats. Conclusions: We discovered a novel ligand activation pattern for PPARγ transrepression of the target gene with therapeutic implications in HSC pericyte biology and liver fibrosis.
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Ni Y, Li JM, Liu MK, Zhang TT, Wang DP, Zhou WH, Hu LZ, Lv WL. Pathological process of liver sinusoidal endothelial cells in liver diseases. World J Gastroenterol 2017; 23:7666-7677. [PMID: 29209108 PMCID: PMC5703927 DOI: 10.3748/wjg.v23.i43.7666] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Revised: 09/13/2017] [Accepted: 09/28/2017] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis develops from liver fibrosis and is the severe pathological stage of all chronic liver injury. Cirrhosis caused by hepatitis B virus and hepatitis C virus infection is especially common. Liver fibrosis and cirrhosis involve excess production of extracellular matrix, which is closely related to liver sinusoidal endothelial cells (LSECs). Damaged LSECs can synthesize transforming growth factor-beta and platelet-derived growth factor, which activate hepatic stellate cells and facilitate the synthesis of extracellular matrix. Herein, we highlight the angiogenic cytokines of LSECs related to liver fibrosis and cirrhosis at different stages and focus on the formation and development of liver fibrosis and cirrhosis. Inhibition of LSEC angiogenesis and antiangiogenic therapy are described in detail. Targeting LSECs has high therapeutic potential for liver diseases. Further understanding of the mechanism of action will provide stronger evidence for the development of anti-LSEC drugs and new directions for diagnosis and treatment of liver diseases.
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MESH Headings
- Angiogenesis Inhibitors/pharmacology
- Angiogenesis Inhibitors/therapeutic use
- Animals
- Cytokines/metabolism
- Disease Models, Animal
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Endothelial Cells/virology
- Extracellular Matrix/metabolism
- Extracellular Matrix/pathology
- Hepacivirus/pathogenicity
- Hepatic Stellate Cells/metabolism
- Hepatic Stellate Cells/pathology
- Hepatic Stellate Cells/virology
- Hepatitis B virus/pathogenicity
- Hepatitis, Viral, Human/diagnosis
- Hepatitis, Viral, Human/drug therapy
- Hepatitis, Viral, Human/pathology
- Hepatitis, Viral, Human/virology
- Humans
- Liver/blood supply
- Liver/cytology
- Liver/pathology
- Liver/virology
- Liver Cirrhosis/diagnosis
- Liver Cirrhosis/drug therapy
- Liver Cirrhosis/pathology
- Liver Cirrhosis/virology
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/pathology
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Affiliation(s)
- Yao Ni
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Juan-Mei Li
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ming-Kun Liu
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ting-Ting Zhang
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Dong-Ping Wang
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Wen-Hui Zhou
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ling-Zi Hu
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Wen-Liang Lv
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
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Cervantes-Garcia D, Cuellar-Juarez AG, Borrego-Soto G, Rojas-Martinez A, Aldaba-Muruato LR, Salinas E, Ventura-Juarez J, Muñoz-Ortega MH. Adenoviral‑bone morphogenetic protein‑7 and/or doxazosin therapies promote the reversion of fibrosis/cirrhosis in a cirrhotic hamster model. Mol Med Rep 2017; 16:9431-9440. [PMID: 29039539 PMCID: PMC5780000 DOI: 10.3892/mmr.2017.7785] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 09/15/2017] [Indexed: 12/13/2022] Open
Abstract
Liver fibrosis occurs in the presence of continuous insults, including toxic or biological agents. Novel treatments must focus on ceasing the progression of cellular damage, promoting the regeneration of the parenchyma and inhibition of the fibrotic process. The present study analyzed the effect of bone morphogenetic protein (BMP)-7 gene therapy with or without co-treatment with doxazosin in a model of liver cirrhosis in hamsters. The serum alanine aminotransferase, aspartate aminotransferase and albumin levels were analyzed spectrophotometrically. Tissue hepatic samples were analyzed by hematoxylin and eosin for parenchymal structure and Sirius red for collagen fiber content. BMP-7 and α-smooth muscle actin (SMA)-positive cells were detected by immunohistochemistry. BMP-7 and collagen type I content in hepatic tissue were analyzed by western blotting, and tissue inhibitor of metalloproteinases (TIMP)-2 and matrix metalloproteinase (MMP)-13 expression levels were detected by reverse transcription-quantitative polymerase chain reaction. The present study detected a significant reduction of collagen type I deposits in the group treated with adenoviral-transduction with BMP-7 and doxazosin. In animals with BMP-7 and doxazosin therapy, α-SMA-positive cells were 31.7 and 29% significantly decreased compared with animals with placebo, respectively. Adenoviral-BMP-7 transduction and/or doxazosin treatments actively induced decrement in type I collagen deposition via increased MMP-13 and reduced TIMP-2 expression. In conclusion, the adenovirus-BMP-7 gene therapy and the doxazosin therapy are potential candidates for the diminution of fibrosis in the liver, although combination of both therapies does not improve the individual anti-fibrotic effect once cirrhosis is established.
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Affiliation(s)
- Daniel Cervantes-Garcia
- Department of Microbiology, Basic Sciences Center, Autonomous University of Aguascalientes, 20131 Aguascalientes, Mexico
| | | | - Gissela Borrego-Soto
- Tecnologico de Monterrey, School of Medicine and Health Sciences, Monterrey, 64710 Nuevo Leon, Mexico
| | - Augusto Rojas-Martinez
- Tecnologico de Monterrey, School of Medicine and Health Sciences, Monterrey, 64710 Nuevo Leon, Mexico
| | - Liseth Rubi Aldaba-Muruato
- Department of Morphology, Basic Sciences Center, Autonomous University of Aguascalientes, 20131 Aguascalientes, Mexico
| | - Eva Salinas
- Department of Microbiology, Basic Sciences Center, Autonomous University of Aguascalientes, 20131 Aguascalientes, Mexico
| | - Javier Ventura-Juarez
- Department of Morphology, Basic Sciences Center, Autonomous University of Aguascalientes, 20131 Aguascalientes, Mexico
| | - Martin Humberto Muñoz-Ortega
- Department of Chemistry, Basic Sciences Center, Autonomous University of Aguascalientes, 20131 Aguascalientes, Mexico
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Garg M, Kaur S, Banik A, Kumar V, Rastogi A, Sarin SK, Mukhopadhyay A, Trehanpati N. Bone marrow endothelial progenitor cells activate hepatic stellate cells and aggravate carbon tetrachloride induced liver fibrosis in mice via paracrine factors. Cell Prolif 2017; 50:e12355. [PMID: 28682508 PMCID: PMC6529081 DOI: 10.1111/cpr.12355] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 05/02/2017] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES Bone marrow derived endothelial progenitor cells (BM-EPCs) are increased in chronic liver disease (CLD). Their role in hepatic fibrosis and regeneration remains an area of intense studies. We investigated the migration and secretory functions of BM-EPCs in fibrotic mice liver. MATERIALS AND METHODS Bone marrow cells from C57BL6-GFP mice were transplanted into the femur of irradiated C57BL6 mice, followed by CCl4 doses for 8 weeks, to develop hepatic fibrosis (n = 36). Transplanted C57BL6 mice without CCl4 treatment were used as controls. EPCs were analyzed in BM, blood and liver by flow cytometry and immunofluorescence. VEGF and TGF-β were analysed in the hepatic stellate cells (HSCs) and BM-EPCs co-cultures using ELISAs. RESULTS There was a significant migration of EPCs from BM to blood and to the liver (P ≤ 0.01). Percentage of GFP+ CD31+ EPCs and collagen proportionate area was substantially increased in the liver at 4th week of CCl4 dosage compared to the controls (19.8% vs 1.9%, P ≤ 0.05). Levels of VEGF (533.6 pg/ml) and TGF-β (327.44 pg/ml) also increased significantly, when HSCs were treated with the EPC conditioned medium, as compared to controls (25.66 pg/ml and 5.87 pg/ml, respectively; P ≤ 0.001). CONCLUSIONS Present findings suggest that BM-EPCs migrate to the liver during CCl4-induced liver injury and contribute to fibrosis.
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Affiliation(s)
- Manali Garg
- Institute of Liver and Biliary SciencesDepartment of Molecular and Cellular MedicineNew DelhiIndia
| | - Savneet Kaur
- Gautam Buddha UniversityGreater NoidaUttar PradeshIndia
| | - Arpita Banik
- Institute of Liver and Biliary SciencesDepartment of Molecular and Cellular MedicineNew DelhiIndia
| | | | - Archana Rastogi
- Institute of Liver and Biliary SciencesDepartment of PathologyNew DelhiIndia
| | - Shiv K. Sarin
- Institute of Liver and Biliary SciencesDepartment of HepatologyNew DelhiIndia
| | | | - Nirupma Trehanpati
- Institute of Liver and Biliary SciencesDepartment of Molecular and Cellular MedicineNew DelhiIndia
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Garbuzenko DV, Arefyev NO, Belov DV. Restructuring of the vascular bed in response to hemodynamic disturbances in portal hypertension. World J Hepatol 2016; 8:1602-1609. [PMID: 28083082 PMCID: PMC5192551 DOI: 10.4254/wjh.v8.i36.1602] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 09/23/2016] [Accepted: 11/01/2016] [Indexed: 02/06/2023] Open
Abstract
In recent years, defined progress has been made in understanding the mechanisms of hemodynamic disturbances occurring in liver cirrhosis, which are based on portal hypertension. In addition to pathophysiological disorders related to endothelial dysfunction, it was revealed: There is the restructuring of the vasculature, which includes vascular remodeling and angiogenesis. In spite of the fact that these changes are the compensatory-adaptive response to the deteriorating conditions of blood circulation, taken together, they contribute to the development and progression of portal hypertension causing severe complications such as bleeding from esophageal varices. Disruption of systemic and organ hemodynamics and the formation of portosystemic collaterals in portal hypertension commence with neovascularization and splanchnic vasodilation due to the hypoxia of the small intestine mucosa. In this regard, the goal of comprehensive treatment may be to influence on the chemokines, proinflammatory cytokines, and angiogenic factors (vascular endothelial growth factor, placental growth factor, platelet-derived growth factor and others) that lead to the development of these disorders. This review is to describe the mechanisms of restructuring of the vascular bed in response to hemodynamic disturbances in portal hypertension. Development of pathogenetic methods, which allow correcting portal hypertension, will improve the efficiency of conservative therapy aimed at prevention and treatment of its inherent complications.
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Affiliation(s)
- Dmitry Victorovich Garbuzenko
- Dmitry Victorovich Garbuzenko, Nikolay Olegovich Arefyev, Department of Faculty Surgery, South Ural State Medical University, 454092 Chelyabinsk, Russia
| | - Nikolay Olegovich Arefyev
- Dmitry Victorovich Garbuzenko, Nikolay Olegovich Arefyev, Department of Faculty Surgery, South Ural State Medical University, 454092 Chelyabinsk, Russia
| | - Dmitry Vladimirovich Belov
- Dmitry Victorovich Garbuzenko, Nikolay Olegovich Arefyev, Department of Faculty Surgery, South Ural State Medical University, 454092 Chelyabinsk, Russia
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Berretta M, Rinaldi L, Di Benedetto F, Lleshi A, De Re V, Facchini G, De Paoli P, Di Francia R. Angiogenesis Inhibitors for the Treatment of Hepatocellular Carcinoma. Front Pharmacol 2016; 7:428. [PMID: 27881963 PMCID: PMC5101236 DOI: 10.3389/fphar.2016.00428] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 10/26/2016] [Indexed: 12/12/2022] Open
Abstract
Background: Angiogenesis inhibitors have become an important therapeutic approach in the treatment of hepatocellular carcinoma (HCC) patients. The therapeutic inhibition of angiogenesis of Sorafenib in increasing overall survival of patients with HCC is a fundamental element of the treatment of this disease. Considering the heterogeneous aspects of HCC and to boost therapeutic efficacy, prevail over drug resistance and lessen toxicity, adding antiangiogenic drugs to antiblastic chemotherapy (AC), radiation therapy or other targeted drugs have been evaluated. The matter is additionally complicated by the combination of antiangiogenesis with further AC or biologic drugs. To date, no planned approach to understand which patients are more responsive to a given type of antiangiogenic treatment is available. Conclusion: Large investments in the clinical research are essential to improve treatment response and minimize toxicities for patients with HCC. Future investigations will need to focus on utilizing patterns of genetic information to classify HCC into groups that display similar prognosis and treatment sensitivity, and combining targeted therapies with AC producing enhanced anti-tumor effect. In this review the current panel of available antiangiogenic therapies for the treatment of HCC have been analyzed. In addition current clinical trials are also reported herein.
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Affiliation(s)
| | - Luca Rinaldi
- Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Second University of Naples Naples, Italy
| | - Fabrizio Di Benedetto
- Liver and Multivisceral Transplant Center, University of Modena and Reggio Emilia Modena, Italy
| | - Arben Lleshi
- Department of Medical Oncology, National Cancer Institute Aviano, Italy
| | - Vallì De Re
- Bioimmunotherapy of Human Cancers Unit, Centro di Riferimento Oncologico (CRO) National Cancer Institute Aviano, Italy
| | - Gaetano Facchini
- Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS Naples Naples, Italy
| | - Paolo De Paoli
- Scientific Directorate, Centro di Riferimento Oncologico (CRO) National Cancer Institute Aviano, Italy
| | - Raffaele Di Francia
- Department of Hematology, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS Naples Naples, Italy
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