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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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Ding JY, Meng TT, Du RL, Song XB, Li YX, Gao J, Ji R, He QY. Bibliometrics of trends in global research on the roles of stem cells in myocardial fibrosis therapy. World J Stem Cells 2024; 16:1086-1105. [PMID: 39734477 PMCID: PMC11669986 DOI: 10.4252/wjsc.v16.i12.1086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 10/05/2024] [Accepted: 11/11/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Myocardial fibrosis, a condition linked to several cardiovascular diseases, is associated with a poor prognosis. Stem cell therapy has emerged as a potential treatment option and the application of stem cell therapy has been studied extensively. However, a comprehensive bibliometric analysis of these studies has yet to be conducted. AIM To map thematic trends, analyze research hotspots, and project future directions of stem cell-based myocardial fibrosis therapy. METHODS We conducted a bibliometric and visual analysis of studies in the Web of Science Core Collection using VOSviewer and Microsoft Excel. The dataset included 1510 articles published between 2001 and 2024. Countries, organizations, authors, references, keywords, and co-citation networks were examined to identify evolving research trends. RESULTS Our findings revealed a steady increase in the number of publications, with a projected increase to over 200 publications annually by 2030. Initial research focused on stem cell-based therapy, particularly for myocardial infarction and heart failure. More recently, there has been a shift toward cell-free therapy, involving extracellular vesicles, exosomes, and microRNAs. Key research topics include angiogenesis, inflammation, apoptosis, autophagy, and oxidative stress. CONCLUSION This analysis highlights the evolution of stem cell therapies for myocardial fibrosis, with emerging interest in cell-free approaches. These results are expected to guide future scientific exploration and decision-making.
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Affiliation(s)
- Jing-Yi Ding
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Tian-Tian Meng
- Department of Rehabilitation, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100071, China
| | - Ruo-Lin Du
- Department of Emergency Medicine, South Branch of Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Xin-Bin Song
- Department of Intensive Care Unit, Zhumadian Hospital of Traditional Chinese Medicine, Zhumadian 463000, Henan Province, China
| | - Yi-Xiang Li
- Department of Chinese Medicine, The Third People's Hospital of Henan Province, Zhengzhou 450000 Henan Province, China
| | - Jing Gao
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ran Ji
- Department of Intensive Care Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Qing-Yong He
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
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Süer Mickler H, Erkan MM. The Investigation of Somatostatin Receptors as a Potential Target in Breast Phyllodes Tumours. Diagnostics (Basel) 2024; 14:2841. [PMID: 39767203 PMCID: PMC11675630 DOI: 10.3390/diagnostics14242841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 12/04/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Somatostatin receptors (SSTRs) are expressed in most neuroendocrine neoplasms, particularly in gastroenteropancreatic neuroendocrine tumours, and have been utilised as diagnostic markers and therapeutic targets. The radioiodinated somatostatin analogue 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid- Tyr3-octreotate (DOTATATE) has been employed for SSTR targeting for either diagnostic or therapeutic purposes depending on the labelling with 68Gallium or 177Lutetium, respectively. SSTR expression is reported in a subset of breast adenocarcinoma and breast neuroendocrine carcinomas; however, minimal knowledge exists regarding their expression in fibroepithelial (biphasic) breast lesions such as fibroadenoma and phyllodes tumours. Aggressive ends of the spectrum, i.e., "cystosarcoma phyllodes", may present a management challenge with recurrences and metastases, and SSTRs could be a promising therapeutic target for these types of tumours. METHODS Gene and protein expressions of SSTRs in primary human fibroepithelial lesions of the breast are investigated using RT-PCR and immunoblotting. Localisation of the SSTR-positive cells was determined with immunohistochemistry and immunofluorescence. RESULTS AND CONCLUSIONS Both fibroadenoma and phyllodes tumours express SSTRs. Immunohistochemical analyses suggested that this expression is in the stromal, not epithelial, component by demonstrating that SSTR stained in the areas overlapping with α-smooth muscle actin-positive myoepithelial cells around blood vessels and capillary structures. This study is the first in the literature to demonstrate SSTR positivity in mammary fibroepithelial neoplasms. Once validated, these findings may also have significant implications for managing the treatment of these tumours.
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Affiliation(s)
- Hande Süer Mickler
- Graduate School of Health Sciences, Acıbadem Mehmet Ali Aydınlar University, 34752 Istanbul, Turkey;
| | - Murat Mert Erkan
- Department of Surgery, School of Medicine, Acıbadem Mehmet Ali Aydınlar University, 34752 Istanbul, Turkey
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Gao J, Lan T, Kostallari E, Guo Y, Lai E, Guillot A, Ding B, Tacke F, Tang C, Shah VH. Angiocrine signaling in sinusoidal homeostasis and liver diseases. J Hepatol 2024; 81:543-561. [PMID: 38763358 PMCID: PMC11906189 DOI: 10.1016/j.jhep.2024.05.014] [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: 12/29/2023] [Revised: 04/29/2024] [Accepted: 05/10/2024] [Indexed: 05/21/2024]
Abstract
The hepatic sinusoids are composed of liver sinusoidal endothelial cells (LSECs), which are surrounded by hepatic stellate cells (HSCs) and contain liver-resident macrophages called Kupffer cells, and other patrolling immune cells. All these cells communicate with each other and with hepatocytes to maintain sinusoidal homeostasis and a spectrum of hepatic functions under healthy conditions. Sinusoidal homeostasis is disrupted by metabolites, toxins, viruses, and other pathological factors, leading to liver injury, chronic liver diseases, and cirrhosis. Alterations in hepatic sinusoids are linked to fibrosis progression and portal hypertension. LSECs are crucial regulators of cellular crosstalk within their microenvironment via angiocrine signaling. This review discusses the mechanisms by which angiocrine signaling orchestrates sinusoidal homeostasis, as well as the development of liver diseases. Here, we summarise the crosstalk between LSECs, HSCs, hepatocytes, cholangiocytes, and immune cells in health and disease and comment on potential novel therapeutic methods for treating liver diseases.
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Affiliation(s)
- Jinhang Gao
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Tian Lan
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China; Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Yangkun Guo
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Enjiang Lai
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Bisen Ding
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
| | - Chengwei Tang
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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Chen M, Yang Z, Gong H, Wu H, Liu L, Jiang JS, Gao JH, Tang CW, Huang ZY. Long-term intermittent oral administration of selective COX-2 inhibitor improved the clinical outcomes of COVID-19 in patients with cirrhosis. J Dig Dis 2024; 25:517-524. [PMID: 39350571 DOI: 10.1111/1751-2980.13313] [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: 02/21/2024] [Revised: 09/01/2024] [Accepted: 09/03/2024] [Indexed: 10/25/2024]
Abstract
OBJECTIVES Patients with cirrhosis are more susceptible to coronavirus disease 2019 (COVID-19) due to immune dysfunction. In this retrospective study we aimed to investigate whether suppression of mild systemic inflammation with selective cyclooxygenase-2 inhibitor (COX-2-I) during chronic care of cirrhotic patients would reduce the occurrence of acute decompensated events and improve patient prognosis of COVID-19. METHODS Medical records of cirrhotic patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were sequentially reviewed. The patients were divided into the COX-2-I and control groups depending on whether they took oral selective COX-2-I for over 3 months or not. The primary outcomes included the occurrence of severe/critical COVID-19, acute decompensated events, and acute-on-chronic liver failure (ACLF). RESULTS After propensity score matching analysis, there were 314 cases in the control group and 118 cases in the COX-2-I group. Compared with the control group, the risk of severe/critical COVID-19 in the COX-2-I group was significantly decreased by 83.1% (p = 0.004). Acute decompensated events and ACLF occurred in 23 (7.32%) and nine (2.87%) cases in the control group, but none in the COX-2-I group (p = 0.003 and 0.122). The rate of hospitalization in the COX-2-I group was significantly lower than that of the control group (3.39% vs 13.06%, p = 0.003). No patient in the COX-2-I group required intensive care unit admission. CONCLUSIONS Long-term intermittent oral administration of selective COX-2-I in cirrhotic patients significantly reduces the occurrence of severe/critical COVID-19, acute decompensated events, and ACLF. It may also be used for systemic inflammation caused by other pathogens.
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Affiliation(s)
- Ming Chen
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhu Yang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Hui Gong
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Hao Wu
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Ling Liu
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jing Sun Jiang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jin Hang Gao
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Cheng Wei Tang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhi Yin Huang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
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Saad HM, Oda SS, Alexiou A, Papadakis M, Mahmoud MH, Batiha GE, Khalifa E. Hepatoprotective activity of Lactéol® forte and quercetin dihydrate against thioacetamide-induced hepatic cirrhosis in male albino rats. J Cell Mol Med 2024; 28:e18196. [PMID: 38534093 PMCID: PMC10967145 DOI: 10.1111/jcmm.18196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 11/20/2023] [Accepted: 02/04/2024] [Indexed: 03/28/2024] Open
Abstract
Liver cirrhosis is a silent disease in humans and is experimentally induced by many drugs and toxins as thioacetamide (TAA) in particular, which is the typical model for experimental induction of hepatic fibrosis. Thus, the objective of the present study was to elucidate the possible protective effects of lactéol® forte (LF) and quercetin dihydrate (QD) against TAA-induced hepatic damage in male albino rats. Induction of hepatotoxicity was performed by TAA injection (200 mg/kg I/P, twice/ week) in rats. LF (1 × 109 CFU/rat 5 times/week) and QD (50 mg/kg 5 times/week) treated groups were administered concurrently with TAA injection (200 mg/kg I/P, twice/ week). The experimental treatments were conducted for 12 weeks. Hepatotoxicity was evaluated biochemically by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) in the serum and histopathologically with the scoring of histopathological changes besides histochemical assessment of collagen by Masson's trichrome and immunohistochemical analysis for α-smooth muscle actin (α-SMA), Ki67 and caspase-3 expression in liver sections. Our results indicated that LF and QD attenuated some biochemical changes and histochemical markers in TAA-mediated hepatotoxicity in rats by amelioration of biochemical markers and collagen, α-SMA, Ki67 and caspase3 Immunoexpression. Additionally, LF and QD supplementation downregulated the proliferative, necrotic, fibroblastic changes, eosinophilic intranuclear inclusions, hyaline globules and Mallory-like bodies that were detected histopathologically in the TAA group. In conclusion, LF showed better hepatic protection than QD against TAA-induced hepatotoxicity in rats by inhibiting inflammatory reactions with the improvement of some serum hepatic transaminases, histopathological picture and immunohistochemical markers.
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Affiliation(s)
- Hebatallah M. Saad
- Department of Pathology, Faculty of Veterinary MedicineMatrouh UniversityMatrouhEgypt
| | - Samah S. Oda
- Department of Pathology, Faculty of Veterinary MedicineAlexandria UniversityAbeesAlexandria ProvinceEgypt
| | - Athanasios Alexiou
- University Centre for Research & DevelopmentChandigarh UniversityMohaliPunjabIndia
- Department of Research & DevelopmentFunogenAthensGreece
- Department of Research & DevelopmentAFNP MedWienAustria
- Department of Science and EngineeringNovel Global Community Educational FoundationHebershamNew South WalesGermany
| | - Marios Papadakis
- Department of Surgery IIUniversity Hospital Witten‐Herdecke, Heusnerstrasse 40, University of Witten‐HerdeckeWuppertalGermany
| | - Mohamed H. Mahmoud
- Department of Biochemistry, College of ScienceKing Saud UniversityRiyadhKingdom of Saudi Arabia
| | - Gaber El‐Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary MedicineDamanhour UniversityDamanhourAlBeheiraEgypt
| | - Eman Khalifa
- Department of Microbiology, Faculty of Veterinary MedicineMatrouh UniversityMatrouhEgypt
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Ye Y, Tang S, Tai Y, Zhao C, Tang C, Huang Z, Gao J. The transcriptomic profile shows the protective effects of celecoxib on cirrhotic splenomegaly. Immunopharmacol Immunotoxicol 2024; 46:117-127. [PMID: 38047472 DOI: 10.1080/08923973.2023.2281282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 11/04/2023] [Indexed: 12/05/2023]
Abstract
BACKGROUND Splenomegaly can exacerbate liver cirrhosis and portal hypertension. We have previously demonstrated that cyclooxygenase-2 (COX-2) inhibitor can attenuate cirrhotic splenomegaly. However, the mechanism of cirrhotic splenomegaly remains unclear, thus becoming the focus of the present study. MATERIALS AND METHODS Thioacetamide (TAA) intraperitoneal injection was used to induce cirrhotic splenomegaly. Rats were randomized into the control, TAA and TAA + celecoxib groups. Histological analysis and high-throughput RNA sequencing of the spleen were conducted. Splenic collagen III, α-SMA, Ki-67, and VEGF were quantified. RESULTS A total of 1461 differentially expressed genes (DEGs) were identified in the spleens of the TAA group compared to the control group. The immune response and immune cell activation might be the major signaling pathways involved in the pathogenesis of cirrhotic splenomegaly. With its immunoregulatory effect, celecoxib presents to ameliorate cirrhotic splenomegaly and liver cirrhosis. Furthermore, 304 coexisting DEGs were obtained between TAA vs. control and TAA + celecoxib vs. TAA. Gene ontology (GO) and KEGG analyses collectively indicated that celecoxib may attenuate cirrhotic splenomegaly through the suppression of splenic immune cell proliferation, inflammation, immune regulation, and fibrogenesis. The impacts on these factors were subsequently validated by the decreased splenic Ki-67-positive cells, macrophages, fibrotic areas, and mRNA levels of collagen III and α-SMA. CONCLUSIONS Celecoxib attenuates cirrhotic splenomegaly by inhibiting splenic immune cell proliferation, inflammation, and fibrogenesis. The current study sheds light on the therapeutic strategy of liver cirrhosis by targeting splenic abnormalities and provides COX-2 inhibitors as a novel medical treatment for cirrhotic splenomegaly.
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Affiliation(s)
- Yanting Ye
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Shihang Tang
- Department of Gastroenterology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yang Tai
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chong Zhao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiyin Huang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Gao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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Deng C, Lu C, Wang K, Chang M, Shen Y, Yang X, Sun H, Yao X, Qiu C, Xu F. Celecoxib ameliorates diabetic sarcopenia by inhibiting inflammation, stress response, mitochondrial dysfunction, and subsequent activation of the protein degradation systems. Front Pharmacol 2024; 15:1344276. [PMID: 38313305 PMCID: PMC10834620 DOI: 10.3389/fphar.2024.1344276] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 01/05/2024] [Indexed: 02/06/2024] Open
Abstract
Aim: Diabetic sarcopenia leads to disability and seriously affects the quality of life. Currently, there are no effective therapeutic strategies for diabetic sarcopenia. Our previous studies have shown that inflammation plays a critical role in skeletal muscle atrophy. Interestingly, the connection between chronic inflammation and diabetic complications has been revealed. However, the effects of non-steroidal anti-inflammatory drug celecoxib on diabetic sarcopenia remains unclear. Materials and Methods: The streptozotocin (streptozotocin)-induced diabetic sarcopenia model was established. Rotarod test and grip strength test were used to assess skeletal muscle function. Hematoxylin and eosin and immunofluorescence staining were performed to evaluate inflammatory infiltration and the morphology of motor endplates in skeletal muscles. Succinate dehydrogenase (SDH) staining was used to determine the number of succinate dehydrogenase-positive muscle fibers. Dihydroethidium staining was performed to assess the levels of reactive oxygen species (ROS). Western blot was used to measure the levels of proteins involved in inflammation, oxidative stress, endoplasmic reticulum stress, ubiquitination, and autophagic-lysosomal pathway. Transmission electron microscopy was used to evaluate mitophagy. Results: Celecoxib significantly ameliorated skeletal muscle atrophy, improving skeletal muscle function and preserving motor endplates in diabetic mice. Celecoxib also decreased infiltration of inflammatory cell, reduced the levels of IL-6 and TNF-α, and suppressed the activation of NF-κB, Stat3, and NLRP3 inflammasome pathways in diabetic skeletal muscles. Celecoxib decreased reactive oxygen species levels, downregulated the levels of Nox2 and Nox4, upregulated the levels of GPX1 and Nrf2, and further suppressed endoplasmic reticulum stress by inhibiting the activation of the Perk-EIF-2α-ATF4-Chop in diabetic skeletal muscles. Celecoxib also inhibited the levels of Foxo3a, Fbx32 and MuRF1 in the ubiquitin-proteasome system, as well as the levels of BNIP3, Beclin1, ATG7, and LC3Ⅱ in the autophagic-lysosomal system, and celecoxib protected mitochondria and promoted mitochondrial biogenesis by elevating the levels of SIRT1 and PGC1-α, increased the number of SDH-positive fibers in diabetic skeletal muscles. Conclusion: Celecoxib improved diabetic sarcopenia by inhibiting inflammation, oxidative stress, endoplasmic reticulum stress, and protecting mitochondria, and subsequently suppressing proteolytic systems. Our study provides evidences for the molecular mechanism and treatment of diabetic sarcopenia, and broaden the way for the new use of celecoxib in diabetic sarcopenia.
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Affiliation(s)
- Chunyan Deng
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Chunfeng Lu
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China
| | - Kexin Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Mengyuan Chang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Xiaoming Yang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Hualin Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Xinlei Yao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Chunjian Qiu
- Department of Endocrinology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Feng Xu
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China
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Zhang L, Zhao C, Dai W, Tong H, Yang W, Huang Z, Tang C, Gao J. Disruption of cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis alleviates liver fibrosis. Cell Mol Life Sci 2023; 80:379. [PMID: 38010435 PMCID: PMC11072584 DOI: 10.1007/s00018-023-05032-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/05/2023] [Accepted: 11/01/2023] [Indexed: 11/29/2023]
Abstract
B cells can promote liver fibrosis, but the mechanism of B cell infiltration and therapy against culprit B cells are lacking. We postulated that the disruption of cholangiocyte-B-cell crosstalk could attenuate liver fibrosis by blocking the CXCL12-CXCR4 axis via a cyclooxygenase-2-independent effect of celecoxib. In wild-type mice subjected to thioacetamide, celecoxib ameliorated lymphocytic infiltration and liver fibrosis. By single-cell RNA sequencing and flow cytometry, CXCR4 was established as a marker for profibrotic and liver-homing phenotype of B cells. Celecoxib reduced liver-homing B cells without suppressing CXCR4. Cholangiocytes expressed CXCL12, attracting B cells to fibrotic areas in human and mouse. The proliferation and CXCL12 expression of cholangiocytes were suppressed by celecoxib. In CXCL12-deficient mice, liver fibrosis was also attenuated with less B-cell infiltration. In the intrahepatic biliary epithelial cell line HIBEpiC, bulk RNA sequencing indicated that both celecoxib and 2,5-dimethyl-celecoxib (an analog of celecoxib that does not show a COX-2-dependent effect) regulated the TGF-β signaling pathway and cell cycle. Moreover, celecoxib and 2,5-dimethyl-celecoxib decreased the proliferation, and expression of collagen I and CXCL12 in HIBEpiC cells stimulated by TGF-β or EGF. Taken together, liver fibrosis can be ameliorated by disrupting cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis with a COX-2-independent effect of celecoxib.
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Affiliation(s)
- Linhao Zhang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1, 4th Keyuan Road, Chengdu, 610041, China
| | - Chong Zhao
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1, 4th Keyuan Road, Chengdu, 610041, China
| | - Wenting Dai
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1, 4th Keyuan Road, Chengdu, 610041, China
| | - Huan Tong
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Wenjuan Yang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhiyin Huang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chengwei Tang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1, 4th Keyuan Road, Chengdu, 610041, China.
| | - Jinhang Gao
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1, 4th Keyuan Road, Chengdu, 610041, China.
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10
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Wang C, Bai Y, Li T, Liu J, Wang Y, Ju S, Yao W, Xiong B, Zhou G. Beneficial effects of ginkgetin on improving nonalcoholic steatohepatitis characterized by bulk and single-cell RNA sequencing analysis. Front Pharmacol 2023; 14:1267445. [PMID: 37860111 PMCID: PMC10582714 DOI: 10.3389/fphar.2023.1267445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 09/22/2023] [Indexed: 10/21/2023] Open
Abstract
Background and aims: Nonalcoholic steatohepatitis (NASH) has become one of the major causes of cirrhosis and liver failure. However, there are currently no approved medications for managing NASH. Our study was designed to assess the effects of ginkgetin on NASH and the involved mechanisms. Methods: We constructed a mouse model of NASH by high-fat diet for 24 weeks. The effects of ginkgetin on NASH were evaluated by histological study, Western blot, and biochemical analysis. RNA Sequencing (RNA-Seq) analysis was used to investigate the alteration in gene expression and signaling pathways at bulk and single-cell levels. Results: Administration of ginkgetin resulted in a marked improvement in hepatic lipid accumulation, inflammation, and fibrosis in the NASH model. And these results were supported by bulk RNA-Seq analysis, in which the related signaling pathways and gene expression were markedly downregulated. Furthermore, single-cell RNA-Seq (scRNA-Seq) analysis revealed that the effects of ginkgetin on NASH were associated with the reprogramming of macrophages, hepatic stellate cells, and endothelial cells. Especially, ginkgetin induced a marked decrease in macrophages and a shift from pro-inflammatory to anti-inflammatory phenotype in NASH mice. And the NASH-associated macrophages (NAMs), which emerge during NASH, were also significantly downregulated by ginkgetin. Conclusion: Ginkgetin exhibits beneficial effects on improving NASH, supported by bulk and single-cell RNA-Seq. Our study may promote pharmacological therapy for NASH and raise the existent understanding of NASH.
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Affiliation(s)
- Chaoyang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaowei Bai
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tongqiang Li
- Department of Interventional Radiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiacheng Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuguang Ju
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Yao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin Xiong
- Department of Interventional Radiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Guofeng Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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11
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Dudley AC, Griffioen AW. Pathological angiogenesis: mechanisms and therapeutic strategies. Angiogenesis 2023; 26:313-347. [PMID: 37060495 PMCID: PMC10105163 DOI: 10.1007/s10456-023-09876-7] [Citation(s) in RCA: 185] [Impact Index Per Article: 92.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 03/26/2023] [Indexed: 04/16/2023]
Abstract
In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different mechanisms such as vasculogenesis, sprouting, intussusceptive, and coalescent angiogenesis, as well as vessel co-option, vasculogenic mimicry and lymphangiogenesis, underlie the formation of new vasculature. In many pathological conditions, such as cancer, atherosclerosis, arthritis, psoriasis, endometriosis, obesity and SARS-CoV-2(COVID-19), developmental angiogenic processes are recapitulated, but are often done so without the normal feedback mechanisms that regulate the ordinary spatial and temporal patterns of blood vessel formation. Thus, pathological angiogenesis presents new challenges yet new opportunities for the design of vascular-directed therapies. Here, we provide an overview of recent insights into blood vessel development and highlight novel therapeutic strategies that promote or inhibit the process of angiogenesis to stabilize, reverse, or even halt disease progression. In our review, we will also explore several additional aspects (the angiogenic switch, hypoxia, angiocrine signals, endothelial plasticity, vessel normalization, and endothelial cell anergy) that operate in parallel to canonical angiogenesis mechanisms and speculate how these processes may also be targeted with anti-angiogenic or vascular-directed therapies.
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Affiliation(s)
- Andrew C Dudley
- Department of Microbiology, Immunology and Cancer Biology, The University of Virginia, Charlottesville, VA, 22908, USA.
| | - Arjan W Griffioen
- Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam UMC, Cancer Center Amsterdam, Amsterdam, The Netherlands.
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12
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Lan T, Tai Y, Zhao C, Xiao Y, Yang Z, Zhang L, Gan C, Dai W, Tong H, Tang C, Huang Z, Gao J. Atypical cholangiocytes derived from hepatocyte-cholangiocyte transdifferentiation mediated by COX-2: a kind of misguided liver regeneration. Inflamm Regen 2023; 43:37. [PMID: 37452426 PMCID: PMC10347763 DOI: 10.1186/s41232-023-00284-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 05/31/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Hepatocyte-cholangiocyte transdifferentiation (HCT) is a potential origin of proliferating cholangiocytes in liver regeneration after chronic injury. This study aimed to determine HCT after chronic liver injury, verify the impacts of HCT on liver repair, and avoid harmful regeneration by understanding the mechanism. METHODS A thioacetamide (TAA)-induced liver injury model was established in wild-type (WT-TAA group) and COX-2 panknockout (KO-TAA group) mice. HCT was identified by costaining of hepatocyte and cholangiocyte markers in vivo and in isolated mouse hepatocytes in vitro. The biliary tract was injected with ink and visualized by whole liver optical clearing. Serum and liver bile acid (BA) concentrations were measured. Either a COX-2 selective inhibitor or a β-catenin pathway inhibitor was administered in vitro. RESULTS Intrahepatic ductular reaction was associated with COX-2 upregulation in chronic liver injury. Immunofluorescence and RNA sequencing indicated that atypical cholangiocytes were characterized by an intermediate genetic phenotype between hepatocytes and cholangiocytes and might be derived from hepatocytes. The structure of the biliary system was impaired, and BA metabolism was dysregulated by HCT, which was mediated by the TGF-β/β-catenin signaling pathway. Genetic deletion or pharmaceutical inhibition of COX-2 significantly reduced HCT in vivo. The COX-2 selective inhibitor etoricoxib suppressed HCT through the TGF-β-TGFBR1-β-catenin pathway in vitro. CONCLUSIONS Atypical cholangiocytes can be derived from HCT, which forms a secondary strike by maldevelopment of the bile drainage system and BA homeostasis disequilibrium during chronic liver injury. Inhibition of COX-2 could ameliorate HCT through the COX-2-TGF-β-TGFBR1-β-catenin pathway and improve liver function.
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Affiliation(s)
- Tian Lan
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yang Tai
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chong Zhao
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yang Xiao
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhu Yang
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Linhao Zhang
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Can Gan
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Wenting Dai
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Huan Tong
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chengwei Tang
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhiyin Huang
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Jinhang Gao
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Khaleel A, El-Sheakh AR, Suddek GM. Celecoxib abrogates concanavalin A-induced hepatitis in mice: Possible involvement of Nrf2/HO-1, JNK signaling pathways and COX-2 expression. Int Immunopharmacol 2023; 121:110442. [PMID: 37352567 DOI: 10.1016/j.intimp.2023.110442] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/31/2023] [Accepted: 05/31/2023] [Indexed: 06/25/2023]
Abstract
Concanavalin A (ConA) is an established model for inducing autoimmune hepatitis (AIH) in mice, mimicking clinical features in human. The aimof the current study is to explore the possible protective effect of celecoxib, a cyclooxygenase-2 inhibitor,on immunological responses elicited in the ConA model of acute hepatitis. ConA (20 mg/kg) was administered intravenously to adult male mice for 6 h. Prior to ConA intoxication, mice in the treatedgroups received daily doses of celecoxib (30 and 60 mg/kg in CMC) for 7 days. Results revealed that administration of celecoxib 60 mg/kg for 7 days significantly protected the liver from ConA-induced liver damage revealed by significant decrease in ALT and AST serum levels. Celecoxib 30 and 60 mg/kg pretreatment enhanced oxidant/antioxidant hemostasis by significantreduction of MDA and NO content and increase hepatic GSH contents and SOD activity. In addition, celecoxib 30 and 60 mg/kg caused significant increase in hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) and the stress protein heme oxygenase-1 (HO-1) levels. Moreover, celecoxib 30 and 60 mg/kg inhibited the release of proinflammatory markers including IL-1β and TNF-α along with significant decrease in p-JNK, AKT phosphorylation ratio and caspase-3 expression. Besides, Con A was correlated to high expression of cyclooxygenase COX-2 and this increasing was improved by administration of celecoxib. These changes were in good agreement with improvement in histological deterioration. The protective effect of celecoxib was also associated with significant reduction of autophagy biomarkers (Beclin-1 and LC3II). In conclusion, celecoxib showed antioxidant, anti-inflammatory, anti-apoptotic and anti-autophagy activity against Con A-induced immune-mediated hepatitis. These effects could be produced by modulation of Nrf2/HO-1, IL-1B /p-JNK/p-AKT, JNK/caspase-3, and Beclin-1/LC3II signaling pathways.
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Affiliation(s)
- Aya Khaleel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Ahmed R El-Sheakh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa, Egypt; Future Studies and Risks Management' National Committee of Drugs, Academy of Scientific Research, Ministry of Higher Education, Elsayeda Zeinab, Egypt
| | - Ghada M Suddek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
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14
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Zhao C, Qian S, Tai Y, Guo Y, Tang C, Huang Z, Gao J. Proangiogenic role of circRNA-007371 in liver fibrosis. Cell Prolif 2023:e13432. [PMID: 36854930 DOI: 10.1111/cpr.13432] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 02/06/2023] [Accepted: 02/15/2023] [Indexed: 03/02/2023] Open
Abstract
Circular RNAs (circRNAs) are crucially involved in cancers as competing endogenous RNA (ceRNA) or microRNA (miRNA) sponges. However, the function and mechanism of circRNAs in liver fibrosis remain unknown and are the focus of this study. Murine fibrotic models were induced by thioacetamide (TAA) or carbon tetrachloride (CCl4 ). Increased angiogenesis is accompanied by liver fibrosis in TAA- and CCl4 -induced murine fibrotic livers. circRNA microarray and argonaute 2 (AGO2)-RNA immunoprecipitation (RIP) sequencing (AGO2-RIP sequencing) were performed in murine livers to screen for functional circRNAs. Compared to control livers, 86 differentially expressed circRNAs were obtained in TAA-induced murine fibrotic livers using circRNA microarray. In addition, 551 circRNAs were explored by AGO2-RIP sequencing of murine fibrotic livers. The circRNA-007371 was then selected and verified for back-spliced junction, resistance to RNase R, and loop formation. In vitro, murine hemangioendothelioma endothelial (EOMA) cells were transfected with circRNA-007371 overexpressing plasmid or empty plasmid. circRNA-007371 overexpression promoted tube formation, migration, and cell proliferation of EOMA cells. RNA sequencing and miRNA sequencing were then performed to explore the mechanism of the proangiogenic effects of circRNA-007371. circRNA-007371 promotes liver fibrosis via miRNA sponges or ceRNA mechanisms. Stag1, the parent gene of circRNA-007371, may play a significant role in proangiogenic progression. In conclusion, circRNA-007371 enhances angiogenesis via a miRNA sponge mechanism in liver fibrosis. The antiangiogenic effect of circRNA-007371 inhibition may provide a new strategy for treating patients with liver cirrhosis.
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Affiliation(s)
- Chong Zhao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Shuaijie Qian
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Tai
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yangkun Guo
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiyin Huang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Gao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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15
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Lv L, Wang D, Yin J, Yang T, Huang B, Cao Y, Lu J. Downregulation of miR-20b-5p Contributes to the Progression of Liver Fibrosis via the STAT3 Signaling Pathway In Vivo and In Vitro. Dig Dis Sci 2023; 68:487-496. [PMID: 35947307 DOI: 10.1007/s10620-022-07660-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 08/02/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Activated hepatic stellate cells (HSCs) are primarily involved in liver fibrosis and portal hypertension (PHT). We aimed to investigate the effect of miR-20b-5p on HSCs, liver fibrosis, and PHT. METHODS MiR-20b-5p expression in HSCs and in mouse liver fibrosis was determined by qPCR. Further, the effects of miR-20b-5p mimic on HSCs migration, proliferation, and apoptosis were investigated in vitro. A dual-luciferase reporter assay was performed to confirm the direct interaction between miR-20b-5p and STAT3. In vivo, mouse liver fibrosis was established by common bile duct ligation and intervened by agomiR-20b-5p. Sirius red staining and hydroxyproline content were used to evaluate collagen deposition. The α-SMA expression in the liver was detected by IHC and Western blotting. The STAT3 signaling pathway and its downregulated cytokines as well as portal pressure and angiogenesis were explored. RESULTS MiR-20b-5p was significantly downregulated during HSCs activation and in mouse liver fibrosis. The functional analyses demonstrated that miR-20b-5p inhibited cell proliferation, activation, and promoted apoptosis in HSCs in vitro. Moreover, miR-20b-5p regulated STAT3 expression by binding to the 3'UTR of its miRNA directly. Overexpression of miR-20b-5p facilitated HSC activation and proliferation by inhibiting the STAT3 signaling pathway. MiR-20b-5p overexpression suppressed the STAT3 and its downstream cytokines and ameliorated liver fibrosis in mice. The intra- and inter-hepatic angiogenesis were also effectively inhibited. The inhibition of liver fibrosis and neoangiogenesis contributed to the decrease of portal pressure. CONCLUSIONS MiR-20b-5p plays an important role in the fibrosis and angiogenesis of liver fibrosis by targeting the STAT3 signaling pathway.
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Affiliation(s)
- Ling Lv
- Department of Disease Control and Prevention, Tangdu Hospital, Fourth Military Medical University, 569 Xin Si Road, Xi'an, 710038, China
| | - Dong Wang
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
| | - Jikai Yin
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Tao Yang
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Bo Huang
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yanlong Cao
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Jianguo Lu
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
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16
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Is There a Place for Somatostatin Analogues for the Systemic Treatment of Hepatocellular Carcinoma in the Immunotherapy Era? LIVERS 2022. [DOI: 10.3390/livers2040024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Patients with advanced hepatocellular carcinoma (HCC) have a very limited survival rate even after the recent inclusion of kinase inhibitors or immune checkpoint inhibitors in the therapeutic armamentarium. A significant problem with the current proposed therapies is the considerable cost of treatment that may be a serious obstacle in low- and middle-income countries. Implementation of somatostatin analogues (SSAs) has the potential to overcome this obstacle, but due to some negative studies their extensive evaluation came to a halt. However, experimental evidence, both in vitro and in vivo, has revealed various mechanisms of the anti-tumor effects of these analogues, including inhibition of cancer cell proliferation and angiogenesis and induction of apoptosis. Favorable indirect effects such as inhibition of liver inflammation and fibrosis and influence on macrophage-mediated innate immunity have also been noted and are presented in this review. Furthermore, the clinical application of SSAs is both presented and compared with clinical trials of kinase and immune checkpoint inhibitors (ICIs). No direct trials have been performed to compare survival in the same cohort of patients, but the cost of treatment with SSAs is a fraction compared to the other modalities and with significantly less serious side effects. As in immunotherapy, patients with viral HCC (excluding alcoholics), as well as Barcelona stage B or C and Child A patients, are the best candidates, since they usually have a survival prospect of at least 6 months, necessary for optimum results. Reasons for treatment failures are also discussed and further research is proposed.
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17
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Gan C, Cai Q, Tang C, Gao J. Inflammasomes and Pyroptosis of Liver Cells in Liver Fibrosis. Front Immunol 2022; 13:896473. [PMID: 35707547 PMCID: PMC9189314 DOI: 10.3389/fimmu.2022.896473] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/04/2022] [Indexed: 01/18/2023] Open
Abstract
Inflammasomes are multiprotein complexes that can sense danger signals and activate caspase-1 to mediate pro-inflammatory cytokines release and pyroptotic cell death. There are two main canonical and non-canonical signaling pathways that trigger inflammasome activation. Inflammasomes are expressed and assembled in parenchymal and nonparenchymal cells in response to liver injury in the liver. Additionally, the hepatocytes, biliary epithelial cells (cholangiocytes), hepatic stellate cells (HSCs), hepatic macrophages, and liver sinusoidal endothelial cells (LSECs) contribute to liver fibrosis via different mechanisms. However, the underlying mechanism of the inflammasome and pyroptosis in these liver cells in liver fibrosis remains elusive. This review summarizes the activation and function of inflammasome complexes and then discusses the association between inflammasomes, pyroptosis, and liver fibrosis. Unlike other similar reviewers, we will focus on the effect of inflammasome activation and pyroptosis in the various liver cells during the development of liver fibrosis. We will also highlight the latest progress of pharmacological intervention in inflammasome-mediated liver fibrosis.
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Affiliation(s)
- Can Gan
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Qiuyu Cai
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Jinhang Gao, ; ; Chengwei Tang,
| | - Jinhang Gao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Jinhang Gao, ; ; Chengwei Tang,
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18
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Zhang L, Huang Z, Cai Q, Zhao C, Xiao Y, Quan X, Tang C, Gao J. Inhibition of Transketolase Improves the Prognosis of Colorectal Cancer. Front Med (Lausanne) 2022; 9:837143. [PMID: 35280908 PMCID: PMC8905541 DOI: 10.3389/fmed.2022.837143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/25/2022] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) remains a heavy health burden worldwide. Transketolase (TKT) is a crucial enzyme in the non-oxidative phase of the Pentose Phosphate Pathway (PPP), and is up-regulated in multiple cancer types. However, the role of TKT in the prognosis of CRC remains unclear. We aimed to explore whether TKT expression is altered in CRC, how TKT is associated with the prognosis of CRC, and whether the regulation of TKT might have an impact on CRC. Differentially expressed genes (DEGs) were identified using bioinformatics analysis. TKT expression was examined in the human colon adenocarcinoma tissue microarray and xenografts. Cell viability, proliferation, migration, and apoptosis assays in vitro were applied to evaluate the protumoral effects of TKT on CRC. TKT was found to be a risk factor for the poor prognosis of CRC by bioinformatics analysis among the DEGs. TKT was significantly up-regulated in colon adenocarcinoma tissues compared with normal colon tissues in patients. Moreover, similar results were found in HCT116 and RKO human colon adenocarcinoma xenografts in nude mice. TKT expression was positively associated with advanced TNM stage, positive lymph nodes, and poor 5 or 10-year overall survival of CRC patients. In vitro, inhibition of TKT reduced cell viability, proliferation, and migration, and induced cell apoptosis. In addition, inhibition of TKT decreased the protein levels of NICD and Hes1. In conclusion, high TKT expression was associated with the poor prognosis of CRC patients. The protumoral effects of downregulating TKT may be realized by suppressing the Notch signaling pathway. TKT may be a new prognostic biomarker and therapeutic target for CRC.
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Affiliation(s)
- Linhao Zhang
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiyin Huang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Qiuyu Cai
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chong Zhao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Xiao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Quan
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Gao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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19
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Li X, Zhang Q, Wang Z, Zhuang Q, Zhao M. Immune and Metabolic Alterations in Liver Fibrosis: A Disruption of Oxygen Homeostasis? Front Mol Biosci 2022; 8:802251. [PMID: 35187072 PMCID: PMC8850363 DOI: 10.3389/fmolb.2021.802251] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/17/2021] [Indexed: 12/06/2022] Open
Abstract
According to the WHO, “cirrhosis of the liver” was the 11th leading cause of death globally in 2019. Many kinds of liver diseases can develop into liver cirrhosis, and liver fibrosis is the main pathological presentation of different aetiologies, including toxic damage, viral infection, and metabolic and genetic diseases. It is characterized by excessive synthesis and decreased decomposition of extracellular matrix (ECM). Hepatocyte cell death, hepatic stellate cell (HSC) activation, and inflammation are crucial incidences of liver fibrosis. The process of fibrosis is also closely related to metabolic and immune disorders, which are usually induced by the destruction of oxygen homeostasis, including mitochondrial dysfunction, oxidative stress, and hypoxia pathway activation. Mitochondria are important organelles in energy generation and metabolism. Hypoxia-inducible factors (HIFs) are key factors activated when hypoxia occurs. Both are considered essential factors of liver fibrosis. In this review, the authors highlight the impact of oxygen imbalance on metabolism and immunity in liver fibrosis as well as potential novel targets for antifibrotic therapies.
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Affiliation(s)
- Xinyu Li
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Quyan Zhang
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Zeyu Wang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Quan Zhuang
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Quan Zhuang, ; Mingyi Zhao,
| | - Mingyi Zhao
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Quan Zhuang, ; Mingyi Zhao,
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20
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Baghaei K, Mazhari S, Tokhanbigli S, Parsamanesh G, Alavifard H, Schaafsma D, Ghavami S. Therapeutic potential of targeting regulatory mechanisms of hepatic stellate cell activation in liver fibrosis. Drug Discov Today 2021; 27:1044-1061. [PMID: 34952225 DOI: 10.1016/j.drudis.2021.12.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/11/2021] [Accepted: 12/17/2021] [Indexed: 11/03/2022]
Abstract
Hepatic fibrosis is a manifestation of different etiologies of liver disease with the involvement of multiple mediators in complex network interactions. Activated hepatic stellate cells (aHSCs) are the central driver of hepatic fibrosis, given their potential to induce connective tissue formation and extracellular matrix (ECM) protein accumulation. Therefore, identifying the cellular and molecular pathways involved in the activation of HSCs is crucial in gaining mechanistic and therapeutic perspectives to more effectively target the disease. In addition to a comprehensive summary of our current understanding of the role of HSCs in liver fibrosis, we also discuss here the proposed therapeutic strategies based on targeting HSCs.
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Affiliation(s)
- Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Sogol Mazhari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Samaneh Tokhanbigli
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Gilda Parsamanesh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Helia Alavifard
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | | | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
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21
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Antitumoral and Anti-inflammatory Roles of Somatostatin and Its Analogs in Hepatocellular Carcinoma. Anal Cell Pathol (Amst) 2021; 2021:1840069. [PMID: 34873567 PMCID: PMC8643256 DOI: 10.1155/2021/1840069] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 11/12/2021] [Indexed: 11/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and affects about 8% of cirrhotic patients, with a recurrence rate of over 50%. There are numerous therapies available for the treatment of HCC, depending on cancer staging and condition of the patient. The complexity of the treatment is also justified by the unique pathogenesis of HCC that involves intricate processes such as chronic inflammation, fibrosis, and multiple molecular carcinogenesis events. During the last three decades, multiple in vivo and in vitro experiments have used somatostatin and its analogs (SSAs) to reduce the proliferative and metastatic potential of hepatoma cells by inducing their apoptosis and reducing angiogenesis and the inflammatory component of HCC. Most experiments have proven successful, revealing several different pathways and mechanisms corresponding to the aforementioned functions. Moreover, a correlation between specific effects and expression of somatostatin receptors (SSTRs) was observed in the studied cells. Clinical trials have tested either somatostatin or an analog, alone or in combination with other drugs, to explore the potential effects on HCC patients, in various stages of the disease. While the majority of these clinical trials exhibited minor to moderate success, some other studies were inconclusive or even reported negative outcomes. A complete evaluation of the efficacy of somatostatin and SSAs is still the matter of intense debate, and, if deemed useful, these substances may play a beneficial role in the management of HCC patients.
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22
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Kronborg TM, Ytting H, Hobolth L, Møller S, Kimer N. Novel Anti-inflammatory Treatments in Cirrhosis. A Literature-Based Study. Front Med (Lausanne) 2021; 8:718896. [PMID: 34631742 PMCID: PMC8495012 DOI: 10.3389/fmed.2021.718896] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/26/2021] [Indexed: 12/11/2022] Open
Abstract
Liver cirrhosis is a disease characterised by multiple complications and a poor prognosis. The prevalence is increasing worldwide. Chronic inflammation is ongoing in liver cirrhosis. No cure for the inflammation is available, and the current treatment of liver cirrhosis is only symptomatic. However, several different medical agents have been suggested as potential healing drugs. The majority are tested in rodents, but few human trials are effectuated. This review focuses on medical agents described in the literature with supposed alleviating and curing effects on liver cirrhosis. Twelve anti-inflammatory, five antioxidative, and three drugs with effects on gut microflora and the LPS pathway were found. Two drugs not categorised by the three former categories were found in addition. In total, 42 rodent studies and seven human trials were found. Promising effects of celecoxib, aspirin, curcumin, kahweol, pentoxifylline, diosmin, statins, emricasan, and silymarin were found in cirrhotic rodent models. Few indices of effects of etanercept, glycyrrhizin arginine salt, and mitoquinone were found. Faecal microbiota transplantation is in increasing searchlight with a supposed potential to alleviate cirrhosis. However, human trials are in demand to verify the findings in this review.
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Affiliation(s)
- Thit Mynster Kronborg
- Gastro Unit, Medical Division, Amager-Hvidovre University Hospital, Hvidovre, Denmark
| | - Henriette Ytting
- Gastro Unit, Medical Division, Amager-Hvidovre University Hospital, Hvidovre, Denmark
| | - Lise Hobolth
- Gastro Unit, Medical Division, Amager-Hvidovre University Hospital, Hvidovre, Denmark
| | - Søren Møller
- Department of Clinical Physiology and Nuclear Medicine 260, Center for Functional and Diagnostic Imaging and Research, Amager-Hvidovre Hospital, Hvidovre, Denmark.,Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nina Kimer
- Gastro Unit, Medical Division, Amager-Hvidovre University Hospital, Hvidovre, Denmark.,Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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23
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Tai Y, Zhao C, Zhang L, Tang S, Jia X, Tong H, Liu R, Tang C, Gao J. Celecoxib reduces hepatic vascular resistance in portal hypertension by amelioration of endothelial oxidative stress. J Cell Mol Med 2021; 25:10389-10402. [PMID: 34609050 PMCID: PMC8581330 DOI: 10.1111/jcmm.16968] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 09/16/2021] [Accepted: 09/21/2021] [Indexed: 02/05/2023] Open
Abstract
The balance between endothelial nitric oxide (NO) synthase (eNOS) activation and production of reactive oxygen species (ROS) is very important for NO homeostasis in liver sinusoidal endothelial cells (LSECs). Overexpression of cyclooxygenase‐2 (COX‐2), a major intravascular source of ROS production, has been observed in LSECs of cirrhotic liver. However, the links between low NO bioavailability and COX‐2 overexpression in LSECs are unknown. This study has confirmed the link between low NO bioavailability and COX‐2 overexpression by COX‐2‐dependent PGE2‐EP2‐ERK1/2‐NOX1/NOX4 signalling pathway in LSECs in vivo and in vitro. In addition, the regulation of COX‐2‐independent LKB1‐AMPK‐NRF2‐HO‐1 signalling pathway on NO homeostasis in LSECs was also elucidated. The combinative effects of celecoxib on diminishment of ROS via COX‐2‐dependent and COX‐2‐independent signalling pathways greatly decreased NO scavenging. As a result, LSECs capillarisation was reduced, and endothelial dysfunction was corrected. Furthermore, portal hypertension of cirrhotic liver was ameliorated with substantial decreasing hepatic vascular resistance and great increase of portal blood flow. With the advance understanding of the mechanisms of LSECs protection, celecoxib may serve as a potential therapeutic candidate for patients with cirrhotic portal hypertension.
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Affiliation(s)
- Yang Tai
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Chong Zhao
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Linhao Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Shihang Tang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xintong Jia
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Huan Tong
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Liu
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Gao
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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24
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Liang S, Zhao T, Xu Q, Duan J, Sun Z. Evaluation of fine particulate matter on vascular endothelial function in vivo and in vitro. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 222:112485. [PMID: 34246944 DOI: 10.1016/j.ecoenv.2021.112485] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 05/09/2023]
Abstract
Ambient fine particulate matter (PM2.5) and high-fat diet (HFD) are linked to the development of atherosclerosis. However, there is still unknown about the PM2.5-induced atherosclerosis formation on vascular endothelial injury after co-exposed to PM2.5 and HFD. Thus, the aim of this study was to evaluate the effects of PM2.5 on atherogenesis in C57BL/6 mice and endothelial cells, as well as the co-exposure effect of PM2.5 and HFD. In vivo study, C57BL/6 mice exposed to PM2.5 and fed with standard chow diet (STD) or HFD for 1 month. PM2.5 could increase vascular stiffness accessed by Doppler ultrasound, and more serious in co-exposure group. PM2.5 impaired vascular endothelial layer integrity, exfoliated endothelial cells, and inflammatory cells infiltration through H&E staining. PM2.5 reduced the expression of platelet/endothelial cell adhesion molecule-1 (PECAM-1) in vessel. Moreover, PM2.5 could induce systemic inflammation detected by Mouse Inflammation Array. In vitro study, PM2.5 triggered markedly mitochondrial damage by transmission electron microscope (TEM) and flow cytometer. Inflammatory cytokines were significantly increased in PM2.5-exposed group. The cell viability and migration of endothelial cells were significantly suppressed. In addition, PM2.5 remarkably declined the expression of vascular endothelial growth factor receptor 2 (VEGFR2) and increased the expression of somatostatin (SST) and its receptor. In conclusion, co-exposure of PM2.5 and HFD might induce systemic inflammation and endothelial dysfunction in normal mice. Moreover, PM2.5 could reduce vascular endothelial repair capacity through inhibiting the proliferation and migration of endothelial cells.
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Affiliation(s)
- Shuang Liang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Tong Zhao
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Qing Xu
- Core Facility Centre, Capital Medical University, Beijing 100069, PR China
| | - Junchao Duan
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China.
| | - Zhiwei Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China.
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25
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Zhang L, Tai Y, Zhao C, Ma X, Tang S, Tong H, Tang C, Gao J. Inhibition of cyclooxygenase-2 enhanced intestinal epithelial homeostasis via suppressing β-catenin signalling pathway in experimental liver fibrosis. J Cell Mol Med 2021; 25:7993-8005. [PMID: 34145945 PMCID: PMC8358882 DOI: 10.1111/jcmm.16730] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/25/2021] [Accepted: 05/29/2021] [Indexed: 02/05/2023] Open
Abstract
The intestinal barrier dysfunction is crucial for the development of liver fibrosis but can be disturbed by intestinal chronic inflammation characterized with cyclooxygenase‐2 (COX‐2) expression. This study focused on the unknown mechanism by which COX‐2 regulates intestinal epithelial homeostasis in liver fibrosis. The animal models of liver fibrosis induced with TAA were established in rats and in intestinal epithelial–specific COX‐2 knockout mice. The impacts of COX‐2 on intestinal epithelial homeostasis via suppressing β‐catenin signalling pathway were verified pharmacologically and genetically in vivo. A similar assumption was tested in Ls174T cells with goblet cell phenotype in vitro. Firstly, disruption of intestinal epithelial homeostasis in cirrhotic rats was ameliorated by celecoxib, a selective COX‐2 inhibitor. Then, β‐catenin signalling pathway in cirrhotic rats was associated with the activation of COX‐2. Furthermore, intestinal epithelial–specific COX‐2 knockout could suppress β‐catenin signalling pathway and restore the disruption of ileal epithelial homeostasis in cirrhotic mice. Moreover, the effect of COX‐2/PGE2 was dependent on the β‐catenin signalling pathway in Ls174T cells. Therefore, inhibition of COX‐2 may enhance intestinal epithelial homeostasis via suppression of the β‐catenin signalling pathway in liver fibrosis.
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Affiliation(s)
- Linhao Zhang
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Tai
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chong Zhao
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao Ma
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Shihang Tang
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Huan Tong
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Gao
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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26
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Tang S, Huang Z, Jiang J, Gao J, Zhao C, Tai Y, Ma X, Zhang L, Ye Y, Gan C, Su W, Jia X, Liu R, Wu H, Tang C. Celecoxib ameliorates liver cirrhosis via reducing inflammation and oxidative stress along spleen-liver axis in rats. Life Sci 2021; 272:119203. [PMID: 33577848 DOI: 10.1016/j.lfs.2021.119203] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/13/2021] [Accepted: 01/31/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Splenomegaly is usually taken as a consequence of liver cirrhosis. However, as a risk factor for cirrhosis, the impacts of spleen-liver axis on the development of cirrhosis are largely unknown. This study focused on the impacts of splenomegaly on the development of cirrhosis and assessment of the effects of celecoxib, a selective COX-2 inhibitor, on the splenomegaly and cirrhotic liver. MATERIALS AND METHODS Liver cirrhosis was induced by thioacetamide (TAA). Sixty rats were randomly divided into control, TAA-16w, TAA + celecoxib groups and normal, TAA + sham, TAA + splenectomy groups. Hepatic stellate cells (HSCs) or hepatocytes were co-cultured with splenocytes from those groups. RESULTS Splenocytes of cirrhotic rats stimulated the HSCs activation and induced hepatocyte apoptosis via enhancing oxidative stress. The hepatic levels of NOX-4 and the in situ O2- were profoundly reduced in TAA + splenectomy group by 50.6% and 18.5% respectively, p < 0.05. Celecoxib significantly decreased the hepatic fibrotic septa induced with TAA by 50.8%, p < 0.05. Splenic lymphoid tissue proliferation and proinflammatory cytokines of the cirrhotic rats were also obviously suppressed by celecoxib, p < 0.05. Compared with the HSC or hepatocyte cell line co-cultured with the cirrhotic splenocytes, the expression of alpha-SMA, NOX-4, in situ O2- or the levels of cleaved caspase3 and NOX-4 were significantly decreased in those cell lines co-cultured with cirrhotic splenocytes treated by celecoxib, p < 0.05. CONCLUSION Splenomegaly contributed to the development of liver cirrhosis through enhancing oxidative stress in liver. Celecoxib could effectively ameliorate liver cirrhosis via reducing inflammatory cytokines and immune cells derived from spleen and suppressing oxidative stress.
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Affiliation(s)
- Shihang Tang
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiyin Huang
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jingsun Jiang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Gao
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chong Zhao
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Tai
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao Ma
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Linhao Zhang
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yanting Ye
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Can Gan
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Su
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xintong Jia
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Liu
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Hao Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
| | - Chengwei Tang
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
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27
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Chen H, Qian Z, Zhang S, Tang J, Fang L, Jiang F, Ge D, Chang J, Cao J, Yang L, Cao X. Silencing COX-2 blocks PDK1/TRAF4-induced AKT activation to inhibit fibrogenesis during skeletal muscle atrophy. Redox Biol 2021; 38:101774. [PMID: 33152664 PMCID: PMC7645269 DOI: 10.1016/j.redox.2020.101774] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 10/26/2020] [Accepted: 10/27/2020] [Indexed: 02/08/2023] Open
Abstract
Skeletal muscle atrophy with high prevalence can induce weakness and fatigability and place huge burden on both health and quality of life. During skeletal muscle degeneration, excessive fibroblasts and extracellular matrix (ECM) accumulated to replace and impair the resident muscle fiber and led to loss of muscle mass. Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in synthesis of prostaglandin, has been identified as a positive regulator in pathophysiological process like inflammation and oxidative stress. In our study, we found injured muscles of human subjects and mouse model overexpressed COX-2 compared to the non-damaged region and COX-2 was also upregulated in fibroblasts following TGF-β stimulation. Then we detected the effect of selective COX-2 inhibitor celecoxib on fibrogenesis. Celecoxib mediated anti-fibrotic effect by inhibiting fibroblast differentiation, proliferation and migration as well as inactivating TGF-β-dependent signaling pathway, non-canonical TGF-β pathways and suppressing generation of reactive oxygen species (ROS) and oxidative stress. In vivo pharmacological inhibition of COX-2 by celecoxib decreased tissue fibrosis and increased skeletal muscle fiber preservation reflected by less ECM formation and myofibroblast accumulation with decreased p-ERK1/2, p-Smad2/3, TGF-βR1, VEGF, NOX2 and NOX4 expression. Expression profiling further found that celecoxib could suppress PDK1 expression. The interaction between COX-2 and PDK1/AKT signaling remained unclear, here we found that COX-2 could bind to PDK1/AKT to form compound. Knockdown of COX-2 in fibroblasts by pharmacological inactivation or by siRNA restrained PDK1 expression and AKT phosphorylation induced by TGF-β treatment. Besides, si-COX-2 prevented TGF-β-induced K63-ubiquitination of AKT by blocking the interaction between AKT and E3 ubiquitin ligase TRAF4. In summary, we found blocking COX-2 inhibited fibrogenesis after muscle atrophy induced by injury and suppressed AKT signaling pathway by inhibiting upstream PDK1 expression and preventing the recruitment of TRAF4 to AKT, indicating that COX-2/PDK1/AKT signaling pathway promised to be target for treating muscle atrophy in the future.
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Affiliation(s)
- Hongtao Chen
- Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhanyang Qian
- Department of Orthopedics, Zhongda Hospital of Southeast University, Nanjing, Jiangsu, China
| | - Sheng Zhang
- Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jian Tang
- Department of Plastic and Burn Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Le Fang
- Department of Critical Care Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Fan Jiang
- Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dawei Ge
- Department of Orthopedics, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jie Chang
- Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jiang Cao
- Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lei Yang
- Department of Orthopedics, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Xiaojian Cao
- Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Hu JW, Chen B, Zhang J, Qi YP, Liang JH, Zhong JH, Xiang BD. Novel combination of celecoxib and metformin improves the antitumor effect by inhibiting the growth of Hepatocellular Carcinoma. J Cancer 2020; 11:6437-6444. [PMID: 33033527 PMCID: PMC7532521 DOI: 10.7150/jca.47532] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 08/27/2020] [Indexed: 01/27/2023] Open
Abstract
Objective: To explore the effect of COX-2 inhibitor celecoxib in combination with metformin on the prevention of Hepatocellular carcinoma (HCC) and the mechanisms involved. Methods: HCC cell lines and an HCC rat model were treated with celecoxib, metformin or a combination of both. Cell viability and tumor formation were measured. Results: In vitro and in vivo studies showed that treatment with a combination of celecoxib and metformin inhibited proliferation of HCC to a greater extent than either treatment alone, by reducing the phosphorylation of MTOR. Conclusion: The study suggested that celecoxib combined with metformin would be more effective for the preventing occurrence of HCC than either treatment alone and this combination of therapy is worthy of further study.
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Affiliation(s)
| | | | | | | | | | - Jian-Hong Zhong
- Hepatobiliary Surgery Department, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Key Laboratory for High-Incidence Tumor Prevention and Treatment, Ministry of Education, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Bang-De Xiang
- Hepatobiliary Surgery Department, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Key Laboratory for High-Incidence Tumor Prevention and Treatment, Ministry of Education, Guangxi Medical University Cancer Hospital, Nanning, China
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29
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Hassan M, Moghadamrad S, Sorribas M, Muntet SG, Kellmann P, Trentesaux C, Fraudeau M, Nanni P, Wolski W, Keller I, Hapfelmeier S, Shroyer NF, Wiest R, Romagnolo B, De Gottardi A. Paneth cells promote angiogenesis and regulate portal hypertension in response to microbial signals. J Hepatol 2020; 73:628-639. [PMID: 32205193 DOI: 10.1016/j.jhep.2020.03.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 02/27/2020] [Accepted: 03/13/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Paneth cells (PCs) synthesize and secrete antimicrobial peptides that are key mediators of host-microbe interactions, establishing a balance between intestinal microflora and enteric pathogens. We observed that their number increases in experimental portal hypertension and aimed to investigate the mechanisms by which these cells can contribute to the regulation of portal pressure. METHODS We first treated Math1Lox/LoxVilcreERT2 mice with tamoxifen to induce the complete depletion of intestinal PCs. Subsequently, we performed partial portal vein or bile duct ligation. We then studied the effects of these interventions on hemodynamic parameters, proliferation of blood vessels and the expression of genes regulating angiogenesis. Intestinal organoids were cultured and exposed to different microbial products to study the composition of their secreted products (by proteomics) and their effects on the proliferation and tube formation of endothelial cells (ECs). In vivo confocal laser endomicroscopy was used to confirm the findings on blood vessel proliferation. RESULTS Portal hypertension was significantly attenuated in PC-depleted mice compared to control mice and was associated with a decrease in portosystemic shunts. Depletion of PCs also resulted in a significantly decreased density of blood vessels in the intestinal wall and mesentery. Furthermore, we observed reduced expression of intestinal genes regulating angiogenesis in Paneth cell depleted mice using arrays and next generation sequencing. Tube formation and wound healing responses were significantly decreased in ECs treated with conditioned media from PC-depleted intestinal organoids exposed to intestinal microbiota-derived products. Proteomic analysis of conditioned media in the presence of PCs revealed an increase in factors regulating angiogenesis and additional metabolic processes. In vivo endomicroscopy showed decreased vascular proliferation in the absence of PCs. CONCLUSIONS These results suggest that in response to intestinal flora and microbiota-derived factors, PCs secrete not only antimicrobial peptides, but also pro-angiogenic signaling molecules, thereby promoting intestinal and mesenteric angiogenesis and regulating portal hypertension. LAY SUMMARY Paneth cells are present in the lining of the small intestine. They prevent the passage of bacteria from the intestine into the blood circulation by secreting substances to fight bacteria. In this paper, we discovered that these substances not only act against bacteria, but also increase the quantity of blood vessels in the intestine and blood pressure in the portal vein. This is important, because high blood pressure in the portal vein may result in several complications which could be targeted with novel approaches.
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Affiliation(s)
- Mohsin Hassan
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland
| | - Sheida Moghadamrad
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland; Inselspital, Hepatology, University of Bern, Switzerland (Clinic of Visceral Surgery and Medicine, Inselspital, Berne, Switzerland)
| | - Marcel Sorribas
- Department for Biomedical Research, Gastroenterology, University of Bern, Switzerland
| | - Sergi G Muntet
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland
| | - Philipp Kellmann
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland
| | - Coralie Trentesaux
- INSERM, U106, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université paris Descartes Sorbonne paris Cité, Paris, France
| | - Marie Fraudeau
- INSERM, U106, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université paris Descartes Sorbonne paris Cité, Paris, France
| | - Paolo Nanni
- Functional Genomic Centre, Swiss Federal Institute of Technology, Zurich, Switzerland
| | - Witold Wolski
- Functional Genomic Centre, Swiss Federal Institute of Technology, Zurich, Switzerland
| | - Irene Keller
- Department for Biomedical Research and Swiss Institute of Bioinformatics, University of Bern, Switzerland
| | | | - Noah F Shroyer
- Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
| | - Reiner Wiest
- Department for Biomedical Research, Gastroenterology, University of Bern, Switzerland; Inselspital, Hepatology, University of Bern, Switzerland (Clinic of Visceral Surgery and Medicine, Inselspital, Berne, Switzerland)
| | - Beatrice Romagnolo
- INSERM, U106, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université paris Descartes Sorbonne paris Cité, Paris, France
| | - Andrea De Gottardi
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland; Inselspital, Hepatology, University of Bern, Switzerland (Clinic of Visceral Surgery and Medicine, Inselspital, Berne, Switzerland); Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Università della Svizzera Italiana, Lugano, Switzerland.
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Pan T, Zhou D, Shi Z, Qiu Y, Zhou G, Liu J, Yang Q, Cao L, Zhang J. Centromere protein U (CENPU) enhances angiogenesis in triple-negative breast cancer by inhibiting ubiquitin-proteasomal degradation of COX-2. Cancer Lett 2019; 482:102-111. [PMID: 31705927 DOI: 10.1016/j.canlet.2019.11.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 10/30/2019] [Accepted: 11/01/2019] [Indexed: 01/07/2023]
Abstract
Triple-negative breast cancer (TNBC) is characterized by high vascularity, but anti-angiogenic therapies show poor efficacy. Centromere protein U (CENPU), a centromere component essential for mitosis, is associated with tumorigenesis in multiple cancers; however, little is known of its role in breast cancer. Here, we investigate its expression and function of promoting angiogenesis in TNBC. Immunohistochemical staining revealed high CENPU expression in TNBC tissue and high CENPU levels correlated significantly with poor distant metastasis-free and overall survival. Knockdown of CENPU in TNBC cells inhibited vascular endothelial growth factor A (VEGFA) production and significantly reduced tube formation and migration of human umbilical vein endothelial cells in vitro. In a mouse xenograft model, CENPU knockdown reduced TNBC tumor growth concomitant with a reduction in CD31 + microvessel density. Mechanistic studies revealed that CENPU promoted angiogenesis by inhibiting the ubiquitination and proteasomal degradation of cyclooxygenase-2 (COX-2), leading to increased activation of the COX-2-p-ERK-HIF-1α-VEGFA signaling pathway. Taken together, our results demonstrate a critical role for CENPU in COX-2-mediated signaling for angiogenesis, and identify a role of CENPU in regulating angiogenesis in TNBC.
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Affiliation(s)
- Teng Pan
- 3rd Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China; Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education, Tianjin, PR China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China; Tianjin's Clinical Research Center for Cancer, Tianjin, PR China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, PR China
| | - Dongdong Zhou
- 3rd Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China; Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education, Tianjin, PR China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China; Tianjin's Clinical Research Center for Cancer, Tianjin, PR China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, PR China
| | - Zhendong Shi
- 3rd Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China
| | - Yufan Qiu
- 3rd Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China; Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education, Tianjin, PR China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China; Tianjin's Clinical Research Center for Cancer, Tianjin, PR China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, PR China
| | - Guanglin Zhou
- 3rd Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China
| | - Jingjing Liu
- 3rd Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China
| | - Qianxi Yang
- 3rd Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China; Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education, Tianjin, PR China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China; Tianjin's Clinical Research Center for Cancer, Tianjin, PR China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, PR China
| | - Lixia Cao
- 3rd Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China; Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education, Tianjin, PR China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China; Tianjin's Clinical Research Center for Cancer, Tianjin, PR China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, PR China
| | - Jin Zhang
- 3rd Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China; Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education, Tianjin, PR China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China; Tianjin's Clinical Research Center for Cancer, Tianjin, PR China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, PR China.
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Dai H, Zhang S, Ma R, Pan L. Celecoxib Inhibits Hepatocellular Carcinoma Cell Growth and Migration by Targeting PNO1. Med Sci Monit 2019; 25:7351-7360. [PMID: 31568401 PMCID: PMC6784684 DOI: 10.12659/msm.919218] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background Celecoxib has shown anti-tumor activities against several types of cancer. Although the majority of research focuses on its mechanism via cyclooxygenase-2 (COX-2) enzyme inhibition, we identified a distinct mechanism behind celecoxib anti-cancer abilities. Material/Methods We treated hepatocellular carcinoma (HCC) Huh-7 cells and tumor xenograft mice models with celecoxib to test its effects on the tumor. Using gene chip method to identify the differential expressed genes after celecoxib treatment and using pathway enrichment analysis to predict the potential pathways for further study. We transfected cells with lentiviral shRNA to detect the effect of RNA binding gene partner of NOB1 (PNO1) on tumor growth in vitro and in vivo. Further we performed western blot to detect the effect of PNO1 on the protein kinase B (AKT) pathway. Results Celecoxib inhibited HCC cell growth in vitro and in vivo, and gene chip and pathway enrichment analysis revealed that PNO1 may be the potential target of celecoxib in HCC cells. Celecoxib significantly reduced levels of PNO1 in tumor tissue. Knockdown of PNO1 remarkably suppressed tumor growth and metastasis in vitro and in vivo. Disruption of PNO1 expression significantly reduced protein kinase B (AKT)/rapamycin (mTOR) signaling, indicating that this pathway may be involved in PNO1-mediated tumorigenic activity. Conclusions Celecoxib may exert its anti-tumor activity by inhibiting PNO1, and that AKT/mTOR signaling helps mediate the oncogenic effects of PNO1. This work offers the first evidence for a role of PNO1 as an HCC oncogene, which may open new avenues for prevention and treatment of HCC.
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Affiliation(s)
- Huijun Dai
- Department of Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China (mainland).,Perioperative Medical Research Center, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China (mainland)
| | - Suisui Zhang
- Department of Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China (mainland)
| | - Riliang Ma
- Department of Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China (mainland)
| | - Linghui Pan
- Department of Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China (mainland).,Perioperative Medical Research Center, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China (mainland)
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Tai Y, Zhang LH, Gao JH, Zhao C, Tong H, Ye C, Huang ZY, Liu R, Tang CW. Suppressing growth and invasion of human hepatocellular carcinoma cells by celecoxib through inhibition of cyclooxygenase-2. Cancer Manag Res 2019; 11:2831-2848. [PMID: 31114336 PMCID: PMC6497485 DOI: 10.2147/cmar.s183376] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 01/23/2019] [Indexed: 02/05/2023] Open
Abstract
Purpose: Biomarkers are lacking in hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) and its metabolites play crucial roles in the process of inflammation-tumor transformation. This study was aimed to detect COX-2 expression in HCC tissues and evaluate the effects of a COX-2 inhibitor, celecoxib, on biological behaviors of HCC cell lines in vitro. Methods: COX-2 expression was detected by immunohistochemistry on a human HCC tissue microarray. The correlations of COX-2 expression with tumor clinicopathological variables and overall survival were analyzed. The proliferation, apoptosis, cell cycle distribution, invasion capacity, and related signaling molecules of HCC cells after incubated with COX-2 inhibitor celecoxib were evaluated in vitro. Results: Expression levels of COX-2 in HCC tissues were significantly higher than those in paracancerous tissues. The TNM stage III-IV, tumor size >5 cm, lymphovascular invasion and distant metastasis was higher in high COX-2 expression group compared with that in low COX-2 expression group. Patients with low COX-2 expression achieved better 5-year overall survival than those with high COX-2 expression. Treatment with celecoxib was sufficient to inhibit cell proliferation, promote apoptosis, and induce G0/G1 cell cycle arrest in HCC cells with concentration- and time-dependent manners. Celecoxib up-regulated E-cadherin protein through inhibiting COX-2-prostaglandin E2 (PGE2)-PGE2 receptor 2 (EP2)-p-Akt/p-ERK signaling pathway to suppress HCC cells migration and invasion. Conclusion: High COX-2 expression was associated with advanced TNM stage, larger tumor size, increased lymphovascular invasion and short survival. Targeting inhibition of COX-2 by celecoxib exhibited anti-tumor activities by suppressing proliferation, promoting apoptosis, and inhibiting the aggressive properties of HCC cells.
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Affiliation(s)
- Yang Tai
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China
| | - Lin-Hao Zhang
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China
| | - Jin-Hang Gao
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China
| | - Chong Zhao
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China
| | - Huan Tong
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China
| | - Cheng Ye
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China
| | - Zhi-Yin Huang
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China
| | - Rui Liu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China
| | - Cheng-Wei Tang
- Laboratory of Gastroenterology & Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China
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Lee KC, Hsu WF, Hsieh YC, Chan CC, Yang YY, Huang YH, Hou MC, Lin HC. Dabigatran Reduces Liver Fibrosis in Thioacetamide-Injured Rats. Dig Dis Sci 2019; 64:102-112. [PMID: 30288660 DOI: 10.1007/s10620-018-5311-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 09/28/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Liver fibrosis can progress to cirrhosis, hepatocellular carcinoma, or liver failure. Unfortunately, the antifibrotic agents are limited. Thrombin activates hepatic stellate cells (HSCs). Therefore, we investigated the effects of a direct thrombin inhibitor, dabigatran, on liver fibrosis. METHODS Adult male Sprague-Dawley rats were injected intraperitoneally with thioacetamide (TAA, 200 mg/kg twice per week) for 8 or 12 weeks to induce liver fibrosis. The injured rats were assigned an oral gavage of dabigatran etexilate (30 mg/kg/day) or vehicle in the last 4 weeks of TAA administration. Rats receiving an injection of normal saline and subsequent oral gavage of dabigatran etexilate or vehicle served as controls. RESULTS In the 8-week TAA-injured rats, dabigatran ameliorated fibrosis, fibrin deposition, and phosphorylated ERK1/2 in liver, without altering the transcript expression of thrombin receptor protease-activated receptor-1. In vitro, dabigatran inhibited thrombin-induced HSC activation. Furthermore, dabigatran reduced intrahepatic angiogenesis and portal hypertension in TAA-injured rats. Similarly, in the 12-week TAA-injured rats, a 4-week treatment with dabigatran reduced liver fibrosis and portal hypertension. CONCLUSIONS By inhibiting thrombin action, dabigatran reduced liver fibrosis and intrahepatic angiogenesis. Dabigatran may be a promising therapeutic agent for treatment of liver fibrosis.
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Affiliation(s)
- Kuei-Chuan Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan.,Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Wei-Fan Hsu
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yun-Cheng Hsieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan.,Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Che-Chang Chan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan.,Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ying-Ying Yang
- Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan.,Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan.,Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. .,Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
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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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35
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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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36
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Afzal E, Alinezhad S, Khorsand M, Khoshnood MJ, Takhshid MA. Effects of Two-by-Two Combination Therapy with Valproic Acid, Lithium Chloride, and Celecoxib on the Angiogenesis of the Chicken Chorioallantoic Membrane. IRANIAN JOURNAL OF MEDICAL SCIENCES 2018; 43:506-513. [PMID: 30214103 PMCID: PMC6123555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
BACKGROUND The synergistic effects of valproic acid (VPA), lithium (Li), and celecoxib (CX) have been shown in combination therapy against the proliferation and metastasis of numerous cancers. Angiogenesis plays a critical role in the pathogenesis of tumor growth and metastasis. The aim of the present study was to evaluate the antiangiogenic effects of VPA, lithium chloride (LiCl), and CX, alone or in 2-by-2 combinations, using the chicken chorioallantoic membrane (CAM) assay. METHODS Fertilized chicken eggs were randomly divided into 10 groups: control, VPA (1.8 and 3.6 µmol/CAM), Li (0.15 and 0.60 µmol/CAM), CX (0.02 and 0.08 µmol/CAM), VPA+Li, VPA+CX, and CX+Li (n=10 per group). A window was made on the eggshells and the CAMs were exposed to a filter disk containing VPA, LiCl, and CX, alone or in 2-by-2 combinations. The control CAMs were treated with distilled water (vehicle). Three days after the treatment, the number of vessel branch points was counted in each CAM. The data were analyzed using SPSS, version 15.One-way ANOVA, followed by the Tukey tests, was used to compare the groups. A P<0.05 was considered a statistically significant difference between the groups. RESULTS According to the results, all the tested drugs decreased the number of the vessel branch points in a dose-dependent manner compared to the control group (P<0.001). In addition, combinations of the drugs were more effective in decreasing angiogenesis than the use of each drug alone. CONCLUSION These findings suggest that 2-by-2 combinations of VPA, CX, and LiCl can be considered an effective antiangiogenesis therapeutic modality.
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Affiliation(s)
- Ehsan Afzal
- Diagnostic Laboratory Sciences and Technology Research Center, Paramedical School, Shiraz University of Medical Sciences, Shiraz, Iran;
| | | | - Marjan Khorsand
- Diagnostic Laboratory Sciences and Technology Research Center, Paramedical School, Shiraz University of Medical Sciences, Shiraz, Iran;
| | | | - Mohammad Ali Takhshid
- Diagnostic Laboratory Sciences and Technology Research Center, Paramedical School, Shiraz University of Medical Sciences, Shiraz, Iran;
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Nowak-Sliwinska P, Alitalo K, Allen E, Anisimov A, Aplin AC, Auerbach R, Augustin HG, Bates DO, van Beijnum JR, Bender RHF, Bergers G, Bikfalvi A, Bischoff J, Böck BC, Brooks PC, Bussolino F, Cakir B, Carmeliet P, Castranova D, Cimpean AM, Cleaver O, Coukos G, Davis GE, De Palma M, Dimberg A, Dings RPM, Djonov V, Dudley AC, Dufton NP, Fendt SM, Ferrara N, Fruttiger M, Fukumura D, Ghesquière B, Gong Y, Griffin RJ, Harris AL, Hughes CCW, Hultgren NW, Iruela-Arispe ML, Irving M, Jain RK, Kalluri R, Kalucka J, Kerbel RS, Kitajewski J, Klaassen I, Kleinmann HK, Koolwijk P, Kuczynski E, Kwak BR, Marien K, Melero-Martin JM, Munn LL, Nicosia RF, Noel A, Nurro J, Olsson AK, Petrova TV, Pietras K, Pili R, Pollard JW, Post MJ, Quax PHA, Rabinovich GA, Raica M, Randi AM, Ribatti D, Ruegg C, Schlingemann RO, Schulte-Merker S, Smith LEH, Song JW, Stacker SA, Stalin J, Stratman AN, Van de Velde M, van Hinsbergh VWM, Vermeulen PB, Waltenberger J, Weinstein BM, Xin H, Yetkin-Arik B, Yla-Herttuala S, Yoder MC, Griffioen AW. Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis 2018; 21:425-532. [PMID: 29766399 PMCID: PMC6237663 DOI: 10.1007/s10456-018-9613-x] [Citation(s) in RCA: 457] [Impact Index Per Article: 65.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.
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Affiliation(s)
- Patrycja Nowak-Sliwinska
- Molecular Pharmacology Group, School of Pharmaceutical Sciences, Faculty of Sciences, University of Geneva, University of Lausanne, Rue Michel-Servet 1, CMU, 1211, Geneva 4, Switzerland.
- Translational Research Center in Oncohaematology, University of Geneva, Geneva, Switzerland.
| | - Kari Alitalo
- Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
| | - Elizabeth Allen
- Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, VIB-Center for Cancer Biology, KU Leuven, Louvain, Belgium
| | - Andrey Anisimov
- Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
| | - Alfred C Aplin
- Department of Pathology, University of Washington, Seattle, WA, USA
| | | | - Hellmut G Augustin
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
- Division of Vascular Oncology and Metastasis Research, German Cancer Research Center, Heidelberg, Germany
- German Cancer Consortium, Heidelberg, Germany
| | - David O Bates
- Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
| | - Judy R van Beijnum
- Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - R Hugh F Bender
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA
| | - Gabriele Bergers
- Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, VIB-Center for Cancer Biology, KU Leuven, Louvain, Belgium
- Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Andreas Bikfalvi
- Angiogenesis and Tumor Microenvironment Laboratory (INSERM U1029), University Bordeaux, Pessac, France
| | - Joyce Bischoff
- Vascular Biology Program and Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Barbara C Böck
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
- Division of Vascular Oncology and Metastasis Research, German Cancer Research Center, Heidelberg, Germany
- German Cancer Consortium, Heidelberg, Germany
| | - Peter C Brooks
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA
| | - Federico Bussolino
- Department of Oncology, University of Torino, Turin, Italy
- Candiolo Cancer Institute-FPO-IRCCS, 10060, Candiolo, Italy
| | - Bertan Cakir
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
| | - Daniel Castranova
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Anca M Cimpean
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Ondine Cleaver
- Department of Molecular Biology, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - George Coukos
- Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne, Lausanne, Switzerland
| | - George E Davis
- Department of Medical Pharmacology and Physiology, University of Missouri, School of Medicine and Dalton Cardiovascular Center, Columbia, MO, USA
| | - Michele De Palma
- School of Life Sciences, Swiss Federal Institute of Technology, Lausanne, Switzerland
| | - Anna Dimberg
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Ruud P M Dings
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | | | - Andrew C Dudley
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
- Emily Couric Cancer Center, The University of Virginia, Charlottesville, VA, USA
| | - Neil P Dufton
- Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, London, UK
| | - Sarah-Maria Fendt
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute, Leuven, Belgium
| | | | - Marcus Fruttiger
- Institute of Ophthalmology, University College London, London, UK
| | - Dai Fukumura
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Bart Ghesquière
- Metabolomics Expertise Center, VIB Center for Cancer Biology, VIB, Leuven, Belgium
- Department of Oncology, Metabolomics Expertise Center, KU Leuven, Leuven, Belgium
| | - Yan Gong
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Robert J Griffin
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Adrian L Harris
- Molecular Oncology Laboratories, Oxford University Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
| | - Christopher C W Hughes
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA
| | - Nan W Hultgren
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA
| | | | - Melita Irving
- Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne, Lausanne, Switzerland
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joanna Kalucka
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
| | - Robert S Kerbel
- Department of Medical Biophysics, Biological Sciences Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
| | - Jan Kitajewski
- Department of Physiology and Biophysics, University of Illinois, Chicago, IL, USA
| | - Ingeborg Klaassen
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Hynda K Kleinmann
- The George Washington University School of Medicine, Washington, DC, USA
| | - Pieter Koolwijk
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Elisabeth Kuczynski
- Department of Medical Biophysics, Biological Sciences Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
| | - Brenda R Kwak
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | | | - Juan M Melero-Martin
- Department of Cardiac Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Lance L Munn
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Roberto F Nicosia
- Department of Pathology, University of Washington, Seattle, WA, USA
- Pathology and Laboratory Medicine Service, VA Puget Sound Health Care System, Seattle, WA, USA
| | - Agnes Noel
- Laboratory of Tumor and Developmental Biology, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Jussi Nurro
- Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland
| | - Anna-Karin Olsson
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Tatiana V Petrova
- Department of oncology UNIL-CHUV, Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | - Kristian Pietras
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund, Sweden
| | - Roberto Pili
- Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA
| | - Jeffrey W Pollard
- Medical Research Council Centre for Reproductive Health, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
| | - Mark J Post
- Department of Physiology, Maastricht University, Maastricht, The Netherlands
| | - Paul H A Quax
- Einthoven Laboratory for Experimental Vascular Medicine, Department Surgery, LUMC, Leiden, The Netherlands
| | - Gabriel A Rabinovich
- Laboratory of Immunopathology, Institute of Biology and Experimental Medicine, National Council of Scientific and Technical Investigations (CONICET), Buenos Aires, Argentina
| | - Marius Raica
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Anna M Randi
- Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, London, UK
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
- National Cancer Institute "Giovanni Paolo II", Bari, Italy
| | - Curzio Ruegg
- Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Reinier O Schlingemann
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Stefan Schulte-Merker
- Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU, Münster, Germany
| | - Lois E H Smith
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Jonathan W Song
- Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, OH, USA
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Steven A Stacker
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre and The Sir Peter MacCallum, Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
| | - Jimmy Stalin
- Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU, Münster, Germany
| | - Amber N Stratman
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Maureen Van de Velde
- Laboratory of Tumor and Developmental Biology, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Victor W M van Hinsbergh
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Peter B Vermeulen
- HistoGeneX, Antwerp, Belgium
- Translational Cancer Research Unit, GZA Hospitals, Sint-Augustinus & University of Antwerp, Antwerp, Belgium
| | - Johannes Waltenberger
- Medical Faculty, University of Münster, Albert-Schweitzer-Campus 1, Münster, Germany
| | - Brant M Weinstein
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Hong Xin
- University of California, San Diego, La Jolla, CA, USA
| | - Bahar Yetkin-Arik
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Seppo Yla-Herttuala
- Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland
| | - Mervin C Yoder
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Arjan W Griffioen
- Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
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Salama SM, Ibrahim IAA, Shahzad N, Al-Ghamdi S, Ayoub N, AlRashdi AS, Abdulla MA, Salehen N, Bilgen M. Hepatoprotectivity of Panduratin A against liver damage: In vivo demonstration with a rat model of cirrhosis induced by thioacetamide. APMIS 2018; 126:710-721. [PMID: 30058214 DOI: 10.1111/apm.12878] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 06/22/2018] [Indexed: 12/16/2022]
Abstract
This experiment evaluated Panduratin A (PA), a chalcone isolated from Boesenbergia rotunda rhizomes, for its hepatoprotectivity. Rats were subjected to liver damage induced by intra-peritoneal injection of thioacetamide (TAA). PA was tested first for its acute toxicity and then administered by oral gavage at doses 5, 10, and 50 mg/kg to rats. At the end of the 8th week, livers from all rats were excised and evaluated ex vivo. Measurements included alkaline phosphatase (AP), alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl transferase (GGT), serum platelet-derived growth factor (PDGF) and transforming growth factor (TGF-β1), and hepatic metalloproteinase enzyme (MMP-2) and its inhibitor extracellular matrix protein (TIMP-1). Oxidative stress was measured by liver malondialdehyde (MDA) and nitrotyrosine levels, urinary 8-hydroxy 2- deoxyguanosine (8-OH-dG), and hepatic antioxidant enzyme activities. The immunohistochemistry of TGF-β1 was additionally performed. PA revealed safe dose of 250 mg/kg on experimental rats and positive effect on the liver. The results suggested reduced hepatic stellate cells (HSCs) activity as verified from the attenuation of serum PDGF and TGF-β1, hepatic MMP-2 and TIMP-1, and oxidative stress. The extensive data altogether conclude that PA treatment could protect the liver from the progression of cirrhosis through a possible mechanism inhibiting HSCs activity.
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Affiliation(s)
- Suzy M Salama
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Ibrahim Abdel Aziz Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Naiyer Shahzad
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Saeed Al-Ghamdi
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Nahla Ayoub
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Ahmed Salim AlRashdi
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Mahmood Ameen Abdulla
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Nur'Ain Salehen
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Mehmet Bilgen
- Biophysics Department, Faculty of Medicine, Adnan Menderes University, Aydin, Turkey
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Lu YY, Gao JH, Zhao C, Wen SL, Tang CW, Wang YF. Cyclooxygenase-2 up-regulates hepatic somatostatin receptor 2 expression. Sci Rep 2018; 8:11033. [PMID: 30038293 PMCID: PMC6056476 DOI: 10.1038/s41598-018-29349-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 07/09/2018] [Indexed: 02/05/2023] Open
Abstract
Somatostatin and its analogues, which function by binding to somatostatin receptors (SSTRs) 1-5, play a protective role in liver cirrhosis. Hepatic SSTR-2 expression is up-regulated in subjects with liver cirrhosis. However, little is known about the mechanisms underlying this process. In the present study, we observed the up-regulation of hepatic SSTR-2 expression in thioacetamide (TAA)-induced cirrhotic rats and further showed that cyclooxygenase-2 (COX-2) might play a role in this process via the protein kinase C (PKC)-cAMP response element binding protein (CREB) signaling pathway. In vivo, the up-regulated SSTR-2 in liver cirrhosis was inhibited by the addition of a selective COX-2 inhibitor, such as celecoxib. In vitro, the up-regulation of COX-2 by either transfection with COX-2 plasmids or treatment with TAA increased levels of SSTR-2 and phosphorylated CREB (p-CREB) in the human hepatocyte cell line L02. Furthermore, the increase in SSTR-2 expression was inhibited by the addition of celecoxib and a PKC inhibitor. Moreover, for comparable DNA methylation levels in the region upstream of the hepatic SSTR-2 gene in normal and cirrhotic livers, DNA methylation may not contribute to the up-regulation of SSTR-2 expression in cirrhotic livers. In conclusion, the up-regulation of hepatic SSTR-2 might be induced by COX-2 via the PKC-CREB signaling pathway but is probably not induced by DNA methylation.
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Affiliation(s)
- Yao-Yao Lu
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Jin-Hang Gao
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.,Division of Digestive Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Chong Zhao
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Division of Digestive Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Shi-Lei Wen
- Department of Human Anatomy, Academy of Preclinical and Forensic Medicine, West China Medicine College, Sichuan University, Chengdu, China
| | - Cheng-Wei Tang
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. .,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China. .,Division of Digestive Diseases, West China Hospital, Sichuan University, Chengdu, China.
| | - Yu-Fang Wang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
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Tai Y, Gao JH, Zhao C, Tong H, Zheng SP, Huang ZY, Liu R, Tang CW, Li J. SK-Hep1: not hepatocellular carcinoma cells but a cell model for liver sinusoidal endothelial cells. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:2931-2938. [PMID: 31938418 PMCID: PMC6958242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 03/18/2018] [Indexed: 06/10/2023]
Abstract
SK-Hep1 cells serve as a cell model of hepatocellular carcinoma and hepatocyte biology. However, SK-Hep1 cells are markedly different from normal hepatocytes and other hepatocellular carcinoma cells in their gene expression and protein levels. Furthermore, endothelial-specific makers and morphological characteristics are found in SK-Hep1 cells, indicating an endothelial origin. To confirm their cell phenotype, we investigated and compared the surface ultrastructure, endothelial function, and molecular markers of SK-Hep1 cells in vitro and in vivo. The results revealed that SK-Hep1 cells expressed endothelial-specific makers and exhibited the endothelial function of endocytosis and tubular formation. Capillary-like structures with CD31 expression were also observed in SK-Hep1 allografts in nude mice. Moreover, SK-Hep1 cells possessed fenestrae without diaphragms, consistent with liver sinusoidal endothelial cells, as seen by electron microscopy. In conclusion, SK-Hep1 cells would be better considered a cell model for liver sinusoidal endothelial cells instead of hepatocellular carcinoma cells.
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Affiliation(s)
- Yang Tai
- Department of Gastroenterology, West China Hospital, Sichuan UniversityChengdu, China
| | - Jin-Hang Gao
- Department of Gastroenterology, West China Hospital, Sichuan UniversityChengdu, China
- Division of Peptides Related with Human Diseases, West China Hospital, Sichuan UniversityChengdu, China
- Division of Digestive Diseases, West China Hospital, Sichuan UniversityChengdu, China
| | - Chong Zhao
- Division of Peptides Related with Human Diseases, West China Hospital, Sichuan UniversityChengdu, China
- Division of Digestive Diseases, West China Hospital, Sichuan UniversityChengdu, China
| | - Huan Tong
- Department of Gastroenterology, West China Hospital, Sichuan UniversityChengdu, China
| | - Shu-Ping Zheng
- Division of Scanning Electron Microscopy, Analytical and Testing Center, Sichuan UniversityChengdu, China
| | - Zhi-Yin Huang
- Department of Gastroenterology, West China Hospital, Sichuan UniversityChengdu, China
| | - Rui Liu
- Division of Peptides Related with Human Diseases, West China Hospital, Sichuan UniversityChengdu, China
- Division of Digestive Diseases, West China Hospital, Sichuan UniversityChengdu, China
| | - Cheng-Wei Tang
- Department of Gastroenterology, West China Hospital, Sichuan UniversityChengdu, China
- Division of Peptides Related with Human Diseases, West China Hospital, Sichuan UniversityChengdu, China
- Division of Digestive Diseases, West China Hospital, Sichuan UniversityChengdu, China
| | - Jing Li
- Department of Gastroenterology, West China Hospital, Sichuan UniversityChengdu, China
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Tong H, Wei B, Chen S, Xie YM, Zhang MG, Zhang LH, Huang ZY, Tang CW. Adjuvant celecoxib and lanreotide following transarterial chemoembolisation for unresectable hepatocellular carcinoma: a randomized pilot study. Oncotarget 2017; 8:48303-48312. [PMID: 28430638 PMCID: PMC5564648 DOI: 10.18632/oncotarget.15684] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 02/15/2017] [Indexed: 02/05/2023] Open
Abstract
Recurrence of hepatocellular carcinoma (HCC) after transarterial chemoembolisation (TACE) is common due to neoangiogenesis. Cyclooxygenase-2 inhibitors and somatostatin analogues were reported to inhibit tumour angiogenesis. The pilot randomized controlled trial was aimed to prospectively evaluate the protocol of TACE combined with celecoxib and lanreotide (TACE+C+L) in patients with unresectable and advanced HCC. A total of 71 patients with HCC were enrolled and randomly assigned to either TACE (n=35) or TACE+C+L (n=36) group. Overall survival, disease control rate (DCR), and adverse events were assessed during a 3-year follow-up period. The median overall survival of the TACE+C+L group (15.0 months) was doubled compared to that of TACE group (7.5 months), p = 0.012. DCR of the TACE+C+L group was significantly higher than that of the TACE group either at 6 months (72.2% vs 42.9%, p = 0.012) or at 12 months (61.1% vs 28.6%, p = 0.006). The median overall survivals (13 months vs 4.5 months, p = 0.013) and DCR at 12 months (50% vs 13.6%, p = 0.008) of patients with advanced HCC in TACE+C+L groups were significantly higher than those in TACE group. No significant difference of adverse events was observed between the two groups. The occurrence of post-embolisation syndrome in TACE+C+L group was significantly lower than that in TACE group (16.7% vs 60.0%, p = 0.001). In conclusion, the regimen of TACE+C+L prolonged overall survival, enhanced tumour response, reduced post-embolisation syndrome and was well-tolerable in the patients with unresectable HCC. It may be more beneficial for advanced HCC.
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Affiliation(s)
- Huan Tong
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Bo Wei
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Shuang Chen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yong-Mei Xie
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Ming-Guang Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Lin-Hao Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhi-Yin Huang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Cheng-Wei Tang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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