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Pinter M, Fulgenzi CAM, Pinato DJ, Scheiner B. Systemic treatment in patients with hepatocellular carcinoma and advanced liver dysfunction. Gut 2025:gutjnl-2025-334928. [PMID: 40301119 DOI: 10.1136/gutjnl-2025-334928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 04/12/2025] [Indexed: 05/01/2025]
Abstract
Systemic therapy represents the standard of care treatment for patients with advanced hepatocellular carcinoma (HCC). Given the increased risk of death from cirrhosis-related complications in patients with advanced liver dysfunction, pivotal phase III trials traditionally limited inclusion to patients with Child-Pugh class A, where death is more likely to be attributed to HCC progression. Therefore, Western guidelines recommend the use of systemic therapies primarily in patients with preserved liver function. However, patients with HCC and Child-Pugh class B are commonly encountered in clinical practice, but due to limited prospective evidence, there is no clear guidance on their optimal management.In this recent advances article, we discuss how the clinical course of cirrhosis can affect eligibility to treatment in the modern era of systemic therapy for HCC, elaborate on strategies to improve liver function in HCC patients by targeting cirrhosis-related and tumour-related factors and summarise the current literature on systemic therapy in HCC patients with Child-Pugh class B. Based on this information, we finally propose a clinical algorithm on how to systematically approach patients with HCC and advanced liver dysfunction in clinical practice.
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Affiliation(s)
- Matthias Pinter
- Division of Gastroenterology & Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Claudia A M Fulgenzi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Department of Translational Medicine, Division of Oncology, University of Piemonte Orientale, Novara, Italy
| | - Bernhard Scheiner
- Division of Gastroenterology & Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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2
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Liu J, Bai Y, Yao W, Sun P, Zhou B, Liu X, Liang B, Zheng C. Using intra-voxel incoherent motion MRI to dynamically evaluate the attenuating effects of donafenib combined with carvedilol in a thioacetamide-induced hepatic fibrosis rat model. MAGMA (NEW YORK, N.Y.) 2025:10.1007/s10334-025-01241-7. [PMID: 40095171 DOI: 10.1007/s10334-025-01241-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 02/07/2025] [Accepted: 02/24/2025] [Indexed: 03/19/2025]
Abstract
OBJECTIVE This study aimed to dynamically evaluate the attenuating effects of donafenib combined with carvedilol using intra-voxel incoherent motion (IVIM) MRI at different time points of disease course in a thioacetamide (TAA)-induced hepatic fibrosis rat model. METHODS In this study, 40 male Sprague-Dawley rats received TAA for 6 weeks to induce liver fibrosis and were divided into four groups randomly (N = 10). From week 3 to week 6 of modeling, each group of rats received daily gavage of vehicle, carvedilol (CARV), donafenib (DON), and donafenib plus carvedilol (DON + CARV), respectively. IVIM MRI was used to assess the degree of liver fibrosis in the above groups at 0, 2, 4, and 6 weeks after modeling. Liver fibrosis was classified according to the METAVIR scoring system (F0-F4). IVIM parameters were calculated using a biexponential fitting model, and a least-squares fitting approach was applied for parameter estimation. RESULTS The mean pathological collagen areas and the expression of α-SMA and collagen I in the CARV, DON, and DON + CARV groups were significantly less than that in the vehicle group (P < 0.001). IVIM-derived parameters (D, D*, and f) and ADC values were negatively correlated with the fibrosis levels (D: r2 = 0.594, P < 0.001; D*: r2 = 0.556, P < 0.001; f: r2 = 0.737, P < 0.001; ADC: r2 = 0.694, P < 0.001). At 4 and 6 weeks after modeling, the mean IVIM parameters and ADC values of the DON + CARV group were significantly higher than those of the vehicle group. CONCLUSION IVIM MRI is a noninvasive and valuable dynamic monitoring tool for liver fibrosis, and it was useful to monitor the dynamic inhibition process of donafenib and carvedilol on liver fibrosis in a TAA-induced rat model.
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Affiliation(s)
- Jiacheng Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yaowei Bai
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Wei Yao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Peng Sun
- MSC Clinical & Technical Solutions, Philips Healthcare, Wuhan, China
| | - Binqian Zhou
- Department of Ultrasound, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China
| | - Xiaoming Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China.
| | - Bin Liang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China.
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China.
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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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Porada M, Bułdak Ł. From Pathophysiology to Practice: Evolving Pharmacological Therapies, Clinical Complications, and Pharmacogenetic Considerations in Portal Hypertension. Metabolites 2025; 15:72. [PMID: 39997697 PMCID: PMC11857179 DOI: 10.3390/metabo15020072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/07/2025] [Accepted: 01/18/2025] [Indexed: 02/26/2025] Open
Abstract
Background: Portal hypertension is a major complication of chronic liver diseases, leading to serious issues such as esophageal variceal bleeding. The increase in portal vein pressure is driven by both an organic component and a functional component, including tonic contraction of hepatic stellate cells. These processes result in a pathological rise in intrahepatic vascular resistance, stemming from partial impairment of hepatic microcirculation, which is further exacerbated by abnormalities in extrahepatic vessels, including increased portal blood flow. Objectives: This review aims to provide a comprehensive overview of the evolving pharmacological therapies for portal hypertension, with consideration and discussion of pathophysiological mechanisms, clinical complications, and pharmacogenetic considerations, highlighting potential directions for future research. Methods: A review of recent literature was performed to evaluate current knowledge and potential therapeutic strategies in portal hypertension. Results: For over 35 years, non-selective beta-blockers have been the cornerstone therapy for portal hypertension by reducing portal vein inflow as an extrahepatic target, effectively preventing decompensation and variceal hemorrhages. However, since not all patients exhibit an adequate response to non-selective beta-blockers (NSBBs), and some may not tolerate NSBBs, alternative or adjunctive therapies that enhance the effects of NSBBs on portal pressure are being investigated in preclinical and early clinical studies. Conclusions: A better understanding of pharmacogenetic factors and pathophysiological mechanisms could lead to more individualized and effective treatments for portal hypertension. These insights highlight potential directions for future research.
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Affiliation(s)
- Michał Porada
- Students’ Scientific Society, Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland;
| | - Łukasz Bułdak
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland
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Wang C, Gu Y, Zhou G, Chen P, Zhao G, Ren J, Zhang W, Niu H. Association between overt hepatic encephalopathy and liver pathology after transjugular intrahepatic portosystemic shunt creation in cirrhotic patients. Sci Rep 2025; 15:1548. [PMID: 39789163 PMCID: PMC11718106 DOI: 10.1038/s41598-025-86176-8] [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: 09/19/2024] [Accepted: 01/08/2025] [Indexed: 01/12/2025] Open
Abstract
To investigate the association between overt hepatic encephalopathy (OHE) and liver pathology after transjugular intrahepatic portosystemic shunt (TIPS) creation in cirrhotic patients. From July 2015 to April 2024, 73 patients from 4 hospitals in China who received TIPS creation and liver biopsy were retrospectively enrolled in this study. Based on whether OHE occurred within 3 months after TIPS creation, the patients were categorized into OHE (n = 29) and non-OHE (n = 44) groups. The liver pathology was assessed by hematoxylin-eosin (H&E), Sirius red staining, immunohistochemistry, and immunofluorescence. Liver pathology by H&E staining showed typical features of liver cirrhosis (including disordered structure and pseudolobule formation) in all the patients. No marked difference was observed in extracellular matrix (ECM) deposition between the OHE and non-OHE groups. However, the patients in the OHE group had a higher level of liver and systemic inflammation than in the non-OHE group. And there was a strong correction between intrahepatic macrophage infiltration and serum inflammatory indicators. Additionally, the OHE group had more liver neovascularization, which was consistent with liver inflammation. The emergence of OHE after TIPS creation is closely associated with liver pathology, especially in liver inflammation and angiogenesis, but not in ECM deposition.
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Affiliation(s)
- Chaoyang Wang
- Department of Interventional Radiology, The First Affiliated Hospital, College of Clinical Medicine of Henan, University of Science and Technology, Jinghua Road #24, Luoyang, 471003, China
| | - Yuyang Gu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Jianshe Road #1, Zhengzhou, 450000, China
| | - Guofeng Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Pengfei Chen
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Jianshe Road #1, Zhengzhou, 450000, China
| | - Guorui Zhao
- Department of Interventional Radiology, The Sixth People's Hospital of Zhengzhou, Zhengzhou, 450000, China
| | - Jianzhuang Ren
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Jianshe Road #1, Zhengzhou, 450000, China
| | - Wenguang Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Jianshe Road #1, Zhengzhou, 450000, China.
| | - Huanzhang Niu
- Department of Interventional Radiology, The First Affiliated Hospital, College of Clinical Medicine of Henan, University of Science and Technology, Jinghua Road #24, Luoyang, 471003, China.
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Abou Taha MA, Ali FEM, Saleh IG, Akool ES. Sorafenib and edaravone protect against renal fibrosis induced by unilateral ureteral obstruction via inhibition of oxidative stress, inflammation, and RIPK-3/MLKL pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:8961-8977. [PMID: 38874805 PMCID: PMC11522075 DOI: 10.1007/s00210-024-03146-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 05/05/2024] [Indexed: 06/15/2024]
Abstract
Renal fibrosis is the common endpoint of nearly all chronic and progressive nephropathies. Cell death and sterile inflammation are the main characteristics of renal fibrosis, which can lead to end-stage renal failure. The inflammatory reaction triggered by tissue damage is strongly related to necroptosis, a type of caspase-independent, regulated cell death. Using an animal model of unilateral ureteral obstruction (UUO), the anti-fibrotic effects of sorafenib (SOF), a multi-kinase inhibitor, and edaravone (EDV), a potent antioxidant and free radical scavenger, were examined in rats with obstructive nephropathy. Experimentally, animals were divided randomly into five groups: sham; UUO; UUO + SOF (5 mg/kg/day, P.O.); UUO + EDV (20 mg/kg/day, P.O.); and UUO + SOF + EDV groups. The kidney function biomarkers, oxidant/antioxidant status, renal mRNA expressions of TNF-α, collagen-1α, protein expressions of RIPK-1, RIPK-3, MLKL, caspase-8, HYP, MPO, and TNF-α were all significantly modulated by UUO. Administration of either SOF or EDV significantly attenuated cellular and molecular changes induced by UUO. Also, histopathological changes were improved. Moreover, SOF in combination with EDV, significantly improved UUO-induced renal fibrosis compared with each drug alone. Collectively, administration of either SOF or EDV or both of them significantly attenuated the rats with obstructive nephropathy, possibly by blocking the RIPK-3/MLKL necroptotic pathway and suppressing renal oxidative stress and inflammation.
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Affiliation(s)
- Mohamed A Abou Taha
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University Assiut Branch, Assiut, 71524, Egypt
| | - Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University Assiut Branch, Assiut, 71524, Egypt.
| | - Ibrahim G Saleh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
- Department of Pharmacy Practice, Faculty of Pharmacy, Sinai University, Kantara, Ismailia, Egypt
| | - El-Sayed Akool
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
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Zhou Y, Liang P, Bi T, Tang B, Zhu X, Liu X, Wang H, Shen H, Sun Q, Yang S, Ren W. Angiotensin II depends on hippo/YAP signaling to reprogram angiogenesis and promote liver fibrosis. Cell Signal 2024; 123:111355. [PMID: 39173854 DOI: 10.1016/j.cellsig.2024.111355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 08/08/2024] [Accepted: 08/18/2024] [Indexed: 08/24/2024]
Abstract
Liver fibrosis is a chronic pathological process in which the abnormal proliferation of connective tissue is induced by various pathogenic factors. During the process of fibrosis, excessive angiogenesis is observed. Physiological angiogenesis has the potential to impede the progression of liver fibrosis through augmenting matrix metalloenzyme activity; however, pathological angiogenesis can exacerbate liver fibrosis by promoting collagen accumulation. Therefore, a key scientific research focus in the treatment of liver diseases is to search for the "on-off" mechanism that regulates angiogenesis from normal proliferation to pathological proliferation. In this study, we found that excessive angiogenesis appeared during the initial phase of hepatic fibrosis without mesenchymal characteristics. In addition, angiogenesis accompanied by significant endothelial-to-mesenchymal transition (EndMT) was observed in mice after the intraperitoneal injection of angiotensin II (Ang II). Interestingly, the changes in Yes-associated protein (YAP) activity in endothelial cells (ECs) can affect the regulation of angiogenesis by Ang II. The results of in vitro experiments revealed that the regulatory influence of Ang II on ECs was significantly attenuated upon suppression of YAP activity. Furthermore, the function of Ang II in regulating angiogenesis during fibrosis was investigated in liver-specific transgenic mice. The results revealed that Ang II gene deletion could restrain liver fibrosis and EndMT. Meanwhile, Ang II deletion downregulated the profibrotic YAP signaling pathway in ECs. The small molecule AT1R agonist olmesartan targeting Ang II-YAP signaling could also alleviate liver fibrosis. In conclusion, this study identified Ang II as a pivotal regulator of EndMT during the progression of liver fibrosis and evaluated the therapeutic effect of the Ang II-targeted drug olmesartan on liver fibrosis.
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Affiliation(s)
- Yanan Zhou
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China
| | - Pan Liang
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China; State Key Laboratories for Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 853, China
| | - Tao Bi
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China
| | - Bo Tang
- Department of Pathology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China
| | - Xiaoning Zhu
- Department of Hepatobiliary, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China
| | - Xinyue Liu
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China
| | - Hong Wang
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China
| | - Hongping Shen
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China
| | - Qin Sun
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China
| | - Sijin Yang
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China; State Key Laboratories for Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 853, China.
| | - Wei Ren
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China.
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Wang M, Cheng J, Qian N. Transcatheter arterial chemoembolization plus Sorafenib versus transcatheter arterial chemoembolization plus Lenvatinib for intermediate hepatocellular carcinoma. Sci Rep 2024; 14:25616. [PMID: 39463401 PMCID: PMC11514231 DOI: 10.1038/s41598-024-74801-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 09/30/2024] [Indexed: 10/29/2024] Open
Abstract
BACKGROUND Recent studies have highlighted that TACE in conjunction with Lenvatinib (TACE-L) offers a promising adjunct therapy for advanced HCC patients, outperforming TACE plus Sorafenib (TACE-S). However, there has been a lack of research comparing these two regimens for intermediate HCC. AIMS This study aims to address the research gap by evaluating the efficacy of TACE-L versus TACE-S in intermediate HCC patients. METHODS A retrospective analysis was conducted on a cohort of consecutive intermediate HCC patients who received either TACE-L or TACE-S from November 2018 to December 2022. Portal vein width was assessed using abdominal NMRI or Doppler ultrasonography, and inflammatory markers were derived from routine blood counts. The primary outcomes of interest were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse drug reactions (ADRs). RESULTS The study included 117 patients, with 56 in the TACE-S group and 61 in the TACE-L group. The TACE-S group demonstrated superior OS (HR = 1.704, 95% CI: 1.012-2.870, p = 0.045) compared to the TACE-L group. No significant difference was observed in PFS (HR:1.512, 95% CI: 0.988-2.313, p = 0.057) between the two groups. Subgroup analyses revealed that male patients, those with cirrhosis, and those with more than four tumors had better OS and PFS in the TACE-S group than in the TACE-L group. Inflammatory markers were comparable between the groups. The TACE-S group experienced a higher incidence of palmar-plantar erythrodysesthesia syndrome (PPE) (14/56 [25%] vs. 5/61 [8.1%], p = 0.014) but a lower incidence of hypertension (3/56 [5.3%] vs. 11/61 [18%], p = 0.035) compared to the TACE-L group. CONCLUSIONS In patients with intermediate HCC, TACE-S was found to be more effective in terms of OS than TACE-L. No significant disparity was noted in PFS between the two treatment groups.
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Affiliation(s)
- Moxuan Wang
- Department of Respiratory, The Eighth Medical Center of Chinese PLA General Hospital, Beijing, 100091, China
| | - Jiamin Cheng
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100853, China.
| | - Niansong Qian
- Department of Respiratory, The Eighth Medical Center of Chinese PLA General Hospital, Beijing, 100091, China.
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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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Guixé-Muntet S, Quesada-Vázquez S, Gracia-Sancho J. Pathophysiology and therapeutic options for cirrhotic portal hypertension. Lancet Gastroenterol Hepatol 2024; 9:646-663. [PMID: 38642564 DOI: 10.1016/s2468-1253(23)00438-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 04/22/2024]
Abstract
Portal hypertension represents the primary non-neoplastic complication of liver cirrhosis and has life-threatening consequences, such as oesophageal variceal bleeding, ascites, and hepatic encephalopathy. Portal hypertension occurs due to increased resistance of the cirrhotic liver vasculature to portal blood flow and is further aggravated by the hyperdynamic circulatory syndrome. Existing knowledge indicates that the profibrogenic phenotype acquired by sinusoidal cells is the initial factor leading to increased hepatic vascular tone and fibrosis, which cause increased vascular resistance and portal hypertension. Data also suggest that the phenotype of hepatic cells could be further impaired due to the altered mechanical properties of the cirrhotic liver itself, creating a deleterious cycle that worsens portal hypertension in the advanced stages of liver disease. In this Review, we discuss recent discoveries in the pathophysiology and treatment of cirrhotic portal hypertension, a condition with few pharmacological treatment options.
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Affiliation(s)
- Sergi Guixé-Muntet
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Sergio Quesada-Vázquez
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
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11
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Gopal A, Gangadaran P, Rajendran RL, Oh JM, Lee HW, Hong CM, Kalimuthu S, Han MH, Lee J, Ahn BC. Extracellular vesicle mimetics engineered from mesenchymal stem cells and curcumin promote fibrosis regression in a mouse model of thioacetamide-induced liver fibrosis. Regen Ther 2024; 26:911-921. [PMID: 39502438 PMCID: PMC11535984 DOI: 10.1016/j.reth.2024.10.005] [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: 07/11/2024] [Revised: 09/30/2024] [Accepted: 10/10/2024] [Indexed: 11/08/2024] Open
Abstract
Recent research suggests that advanced liver fibrosis could be reversed, but the therapeutic agents needed for the prevention of liver fibrosis remain to be elucidated. The beneficial effects of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) on liver fibrosis have been reported. However, the large-scale production of MSC-EVs remains challenging. The present study investigated the therapeutic effects of mouse MSC-derived EV mimetics (MEVMs) in combination with curcumin (antifibrotic compound) using a mouse model of thioacetamide-induced liver fibrosis. MEVMs were prepared through the serial extrusion of MSCs. These MEVMs were similar in size and morphology to the EVs. The biodistribution study showed that fluorescently labeled MEVMs predominantly accumulated in the liver. The establishment of liver fibrosis was confirmed via increased collagen (histology), liver fibrosis score, α-smooth muscle actin (α-SMA), and vimentin proteins levels. Treatment with MEVMs, curcumin, or their combination decreased the amount of collagen in liver tissues, with the antifibrotic effects of MEVMs being further confirmed by the liver fibrosis score. All treatments decreased the expression of collagen 1α, α-SMA, and vimentin. MEVMs showed superior effects than curcumin. Thus, MSC-derived EVMs could be a potential alternative for the treatment of liver fibrosis.
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Affiliation(s)
- Arunnehru Gopal
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Ji Min Oh
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Ho Won Lee
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Chae Moon Hong
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Senthilkumar Kalimuthu
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Man-Hoon Han
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Pathology, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Jaetae Lee
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
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12
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Fujiwara K, Kondo T, Fujimoto K, Yumita S, Ogawa K, Ishino T, Nakagawa M, Iwanaga T, Tsuchiya S, Koroki K, Kanzaki H, Inoue M, Kobayashi K, Kiyono S, Nakamura M, Kanogawa N, Ogasawara S, Nakamoto S, Chiba T, Koizumi J, Kato J, Kato N. Clinical risk factors for portal hypertension-related complications in systemic therapy for hepatocellular carcinoma. J Gastroenterol 2024; 59:515-525. [PMID: 38583112 PMCID: PMC11128395 DOI: 10.1007/s00535-024-02097-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 03/07/2024] [Indexed: 04/08/2024]
Abstract
BACKGROUND During systemic therapy, the management of portal hypertension (PH)-related complications is vital. This study aimed to clarify factors associated with the incidence and exacerbation of PH-related complications, including the usefulness of contrast-enhanced computed tomography (CECT) in the management of PH-related complications during systemic therapy. METHODS A total of 669 patients who received systemic therapy as first-line treatment (443 patients for sorafenib, 131 for lenvatinib, and 90 for atezolizumab/bevacizumab [ATZ/BEV]) were enrolled in this retrospective study. Additionally, the lower esophageal intramural vessel diameters (EIV) on CECT and endoscopic findings in 358 patients were compared. RESULTS The cutoff values of the EIV diameter on CECT were 3.1 mm for small, 5.1 mm for medium, and 7.6 mm for large varices, demonstrating high concordance with the endoscopic findings. esophageal varices (EV) bleeding predictors include EIV ≥ 3.1 mm and portal vein tumor thrombosis (PVTT). In patients without EV before systemic therapy, factors associated with EV exacerbation after 3 months were EIV ≥ 1.9 mm and ATZ/BEV use. Predictors of hepatic encephalopathy (HE) include the ammonia level or portosystemic shunt diameter ≥ 6.8 mm. The incidence of HE within 2 weeks was significantly higher (18%) in patients with an ammonia level ≥ 73 μmol/L and a portosystemic shunt ≥ 6.8 mm. The exacerbating factors for ascites after 3 months were PVTT and low albumin levels. CONCLUSIONS Careful management is warranted for patients with risk factors for exacerbation of PH-related complications; moreover, the effective use of CECT is clinically important.
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Affiliation(s)
- Kisako Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan.
- Ultrasound Center, Chiba University Hospital, Chiba, Japan.
| | - Kentaro Fujimoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Sae Yumita
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Keita Ogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Takamasa Ishino
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Miyuki Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Terunao Iwanaga
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Satoshi Tsuchiya
- Department of Radiology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Masanori Inoue
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Jun Koizumi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
- Ultrasound Center, Chiba University Hospital, Chiba, Japan
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De Gaetano V, Pallozzi M, Cerrito L, Santopaolo F, Stella L, Gasbarrini A, Ponziani FR. Management of Portal Hypertension in Patients with Hepatocellular Carcinoma on Systemic Treatment: Current Evidence and Future Perspectives. Cancers (Basel) 2024; 16:1388. [PMID: 38611066 PMCID: PMC11011056 DOI: 10.3390/cancers16071388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
The management of CSPH in patients undergoing systemic treatment for HCC has emerged as a critical concern due to the absence of reliable diagnostic criteria and uncertainties surrounding therapeutic approaches. This review aims to underscore the primary pathophysiological aspects linking HCC and PH, while also addressing the current and emerging clinical strategies for the management of portal hypertension. A review of studies from January 2003 to June 2023 was conducted using the PubMed database and employing MeSH terms, such as "hepatocellular carcinoma", "immune checkpoint inhibitors", "systemic therapy", "portal hypertension", "variceal bleeding" and "tyrosine kinase inhibitors". Despite promising results of tyrosine kinase inhibitors in animal models for PH and fibrosis, only Sorafenib has demonstrated similar effects in human studies, whereas Lenvatinib appears to promote PH development. The impact of Atezolizumab/Bevacizumab on PH remains uncertain, with an increasing risk of bleeding related to Bevacizumab in patients with prior variceal hemorrhage. Given the absence of specific guidelines, endoscopic surveillance during treatment is advisable, and primary and secondary prophylaxis of variceal bleeding should adhere to the Baveno VII recommendations. Furthermore, in patients with advanced HCC, refinement of diagnostic criteria for CSPH and guidelines for its surveillance are warranted.
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Affiliation(s)
- Valeria De Gaetano
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Maria Pallozzi
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Lucia Cerrito
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Francesco Santopaolo
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Leonardo Stella
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Antonio Gasbarrini
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
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14
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Tan Y, Wang Z, Guo R, Zhou X, Zhang W, Wu M, Guo C, Gao H, Sun X, Zhang Z, Gong T. Dual-Targeting Macrophages and Hepatic Stellate Cells by Modified Albumin Nanoparticles for Liver Cirrhosis Treatment. ACS APPLIED MATERIALS & INTERFACES 2024; 16:11239-11250. [PMID: 38395769 DOI: 10.1021/acsami.3c17670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2024]
Abstract
Hepatic cirrhosis has become a global public health concern with high mortality and currently lacks effective clinical treatment methods. Activation of hepatic stellate cells (HSCs) and the large number of macrophages infiltrating into the liver play a critical role in the development of liver cirrhosis. This study developed a novel modified nanoparticle system (SRF-CS-PSA NPs) in which Sorafenib (SRF) was encapsulated by palmitic acid-modified albumin (PSA) and further modified with chondroitin sulfate (CS). These modifications enabled the SRF-CS-PSA NPs to effectively target hepatic stellate cells (HSCs) and macrophages. SRF-CS-PSA NPs showed uniform particle size distribution of approximately 120 nm and high loading efficiency of up to 99.5% and can be taken up by HSCs and macrophages via CD44 and SR-A receptors, respectively. In a mouse model of liver cirrhosis, SRF-CS-PSA NPs demonstrated superior targeting and inhibition of HSCs and macrophages, effectively reversing the process of liver cirrhosis. Overall, our study demonstrates the potential of SRF-CS-PSA NPs as a targeted therapy for liver cirrhosis, with promising clinical applications.
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Affiliation(s)
- Yulu Tan
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Zijun Wang
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Rui Guo
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Xueru Zhou
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Wei Zhang
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Mengying Wu
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Chenqi Guo
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Huile Gao
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Xun Sun
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Zhirong Zhang
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Tao Gong
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
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15
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Sheng JY, Meng ZF, Li Q, Yang YS. Recent advances in promising drugs for primary prevention of gastroesophageal variceal bleeding with cirrhotic portal hypertension. Hepatobiliary Pancreat Dis Int 2024; 23:4-13. [PMID: 37580228 DOI: 10.1016/j.hbpd.2023.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 08/01/2023] [Indexed: 08/16/2023]
Abstract
BACKGROUND Gastroesophageal variceal bleeding is one of the most severe complications of patients with cirrhosis. Although primary prevention drugs, including non-selective β-blockers, have effectively reduced the incidence of bleeding, their efficacy is limited due to side effects and related contraindications. With recent advances in precision medicine, precise drug treatment provides better treatment efficacy. DATA SOURCES Literature search was conducted in PubMed, MEDLINE and Web of Science for relevant articles published up to May 2022. Information on clinical trials was obtained from https://clinicaltrials.gov/ and http://www.chictr.org.cn/. RESULTS The in-depth understanding of the pathogenesis and advances of portal hypertension has enabled the discovery of multiple molecular targets for promising drugs. According to the site of action, these drugs could be classified into four classes: intrahepatic, extrahepatic, both intrahepatic and extrahepatic targets and others. All these classes of drugs offer advantages over traditional treatments in prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension. CONCLUSIONS This review classified and summarized the promising drugs, which prevent gastroesophageal variceal bleeding by targeting specific markers of pathogenesis of portal hypertension, demonstrating the significance of using the precision medicine strategy to discover and develop promising drugs for the primary prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.
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Affiliation(s)
- Ji-Yao Sheng
- Department of Hepatobiliary and Pancreatic Surgery, the Second Hospital of Jilin University, Changchun 130041, China; Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, the Second Hospital of Jilin University, Changchun 130041, China
| | - Zi-Fan Meng
- Department of Hepatobiliary and Pancreatic Surgery, the Second Hospital of Jilin University, Changchun 130041, China; Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, the Second Hospital of Jilin University, Changchun 130041, China
| | - Qiao Li
- Department of Hepatobiliary and Pancreatic Surgery, the Second Hospital of Jilin University, Changchun 130041, China
| | - Yong-Sheng Yang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Hospital of Jilin University, Changchun 130041, China; Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, the Second Hospital of Jilin University, Changchun 130041, China.
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16
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Wang C, Li T, Chen K, Niu H, Bai Y, Liu J, Wang Y, Ju S, Yao W, Zhao G, Xiong B, Zhou G. Reversion of liver cirrhosis after endovascular treatment in Chinese patients with Budd-Chiari syndrome. Hepatol Res 2023; 53:1198-1212. [PMID: 37632703 DOI: 10.1111/hepr.13960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/14/2023] [Accepted: 08/16/2023] [Indexed: 08/28/2023]
Abstract
AIMS To investigate the impact of endovascular (EV) treatment on liver cirrhosis in Chinese patients with Budd-Chiari syndrome (BCS). METHODS From September 2011 to March 2022, 97 patients from four hospitals in China who were diagnosed with primary BCS complicated with liver cirrhosis and received EV treatment were retrospectively enrolled in this study for clinical analysis. In addition, liver tissues for basic research were acquired from 25 patients between June 2022 and March 2023, including six with benign liver tumors, 11 with BCS before EV treatment, and eight with EV-treated BCS. Liver cirrhosis was assessed by clinical outcomes, histological studies, and the expression of related genes at the mRNA and protein levels. RESULTS The patients with BCS had better liver function after EV treatment, evidenced by an increased albumin level and reduced total bilirubin, ALT, and AST. The imaging findings suggested an amelioration of liver cirrhosis and portal hypertension, including increased portal vein velocity (13.52 ± 8.89 cm/s vs. 17.51 ± 6.67 cm/s, p < 0.001) and decreased liver stiffness (30.37 ± 6.39 kPa vs. 23.70 ± 7.99 kPa, p < 0.001), portal vein diameter (14.97 ± 3.42 mm vs. 13.36 ± 2.89 mm, p < 0.001), and spleen volume (870.00 ± 355.61 cm3 vs. 771.36 ± 277.45 cm3 , p < 0.001). Furthermore, histological studies revealed that EV treatment resulted in a restoration of liver architecture with reduced extracellular matrix deposition. Meanwhile, hepatic angiogenesis and inflammation, which have a close relationship with cirrhosis, were also inhibited. In addition, the state of hepatocytes switches from apoptosis to proliferation after EV treatment. CONCLUSIONS BCS-induced liver cirrhosis could be reversed by EV treatment from macroscopic to microscopic dimensions. Our study may provide further insights into understanding BCS and treating cirrhosis.
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Affiliation(s)
- Chaoyang Wang
- 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
| | - Kequan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Huanzhang Niu
- Department of Interventional Radiology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
| | - Yaowei Bai
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 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
| | - Guorui Zhao
- Department of Infectious Disease, Henan Infectious Disease Hospital, Zhengzhou, 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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Larouche V, Paré MF, Grenier PO, Wieckowska A, Gagné E, Laframboise R, Jabado N, De Bie I. A Review of the Clinical Features and Management of Systemic Congenital Mastocytosis through the Presentation of An Unusual Prenatal-Onset Case. Curr Oncol 2023; 30:8992-9003. [PMID: 37887549 PMCID: PMC10605361 DOI: 10.3390/curroncol30100649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/23/2023] [Accepted: 10/01/2023] [Indexed: 10/28/2023] Open
Abstract
Mastocytosis is a heterogeneous group of rare hematological disorders that can occur in infancy. We report a 16-year-old girl who presented with an aggressive form of systemic congenital mastocytosis, associated with a significant global developmental delay, deafness, and multiple anomalies. At 4 years of age, she developed a germinoma presenting as an invasive spinal mass. Extensive cytogenetic, metabolic, and molecular genetic studies that included whole-exome sequencing studies revealed a KIT alteration (NM_000222.3(KIT):c2447A > 7 pAsp816Val) and likely pathogenic variant in the DNA from peripheral blood and skin lesions. C-kit was also found to be overexpressed in the spinal tumor cells. We compared the features of this child to those of six previously reported pediatric patients with cutaneous mastocytosis, microcephaly, microtia, and/or hearing loss reported in OMIM as mastocytosis, conductive hearing loss, and microtia (MIM 248910), for which the etiology has not yet been determined. This report extends the currently recognized spectrum of KIT-related disorders and provides clues as to the potential etiology of a syndromic form of congenital mastocytosis. International efforts to understand the benefits of long-term targeted therapy with tyrosine kinase inhibitors for this KIT-altered rare disease should continue to be evaluated in clinical trials.
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Affiliation(s)
- Valérie Larouche
- Department of Pediatric Hemato-oncology, Centre Hospitalier Universitaire de Quebec-Université Laval, Quebec, QC G1V4G2, Canada
| | | | - Pierre-Olivier Grenier
- Department of Dermatology, Centre Hospitalier Universitaire de Quebec-Université Laval, Quebec, QC G1V4G2, Canada
| | - Anna Wieckowska
- Departement of Pediatric, Centre Hospitalier Universitaire de Quebec-Université Laval, Quebec, QC G1V4G2, Canada
| | - Eric Gagné
- Department of Pathology, Centre Hospitalier Universitaire de Quebec-Université Laval, Quebec, QC G1V4G2, Canada
| | - Rachel Laframboise
- Department of Medical Genetics, Centre Hospitalier Universitaire de Quebec-Université Laval, Quebec, QC G1V4G2, Canada
| | - Nada Jabado
- Department of Pediatric Hemato-Oncology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC G1V4G2, Canada
| | - Isabelle De Bie
- Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, QC G1V4G2, Canada
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18
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Liu W, Wu J, Cao H, Ma C, Wu Z, Tian Y, Ma C, Qiu H, Pan G. Human-Induced Hepatocytes-Derived Extracellular Vesicles Ameliorated Liver Fibrosis in Mice Via Suppression of TGF-β1/Smad Signaling and Activation of Nrf2/HO-1 Signaling. Stem Cells Dev 2023; 32:638-651. [PMID: 37345718 DOI: 10.1089/scd.2023.0110] [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] [Indexed: 06/23/2023] Open
Abstract
Liver fibrosis is a wound-healing response caused by persistent liver injury and often occurs in chronic liver diseases. Effective treatments for liver fibrosis are still pending. Recent studies have revealed that extracellular vesicles (EVs) derived from primary hepatocytes (Hep-EVs) have therapeutic potential for multiple liver diseases. However, Hep-EVs are difficult to manufacture in bulk because of the limited sources of primary hepatocytes. Human-induced hepatocytes (hiHep) are hepatocyte-like cells that can expand in vitro, and their cell culture supernatant is thus an almost unlimited resource for EVs. This study aimed to investigate the potential therapeutic effects of EVs derived from hiHeps. hiHep-EVs inhibited the expression of inflammatory genes and the secretion of inflammation-related cytokines, and suppressed the activation of hepatic stellate cells by inhibiting the transforming growth factor (TGF)-β1/Smad signaling pathway. The anti-inflammatory and antifibrotic effects of hiHep-EVs were similar to those of mesenchymal stem cell-EVs. Furthermore, the administration of hiHep-EVs ameliorated oxidative stress, inflammation, and fibrosis in a CCl4-induced liver fibrosis mouse model. The expression of α smooth muscle actin, collagen I, and collagen III was reduced, which may be attributed to the regulation of matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 by hiHep-EVs, and the protein expression of Nrf2, HO-1, and NQO1 was increased. Taken together, our results suggested that hiHep-EVs alleviated liver fibrosis by activating the Nrf2/HO-1 signaling pathway and inhibiting the TGF-β1/Smad signaling pathway. This study revealed the hepatoprotective effect of hiHep-EVs, and provided a new approach to treating liver fibrosis.
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Affiliation(s)
- Wenjing Liu
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Jiajun Wu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Huiying Cao
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Chen Ma
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhitao Wu
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Youxi Tian
- School of Pharmacy, Guang Dong Medical University, Dongguan, China
| | - Chenhui Ma
- Department of Chemical and Environmental Engineering, University of Nottingham Ningbo China, Ningbo, China
| | - Hong Qiu
- University of Chinese Academy of Sciences, Beijing, China
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Guoyu Pan
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
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19
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Panackel C, Fawaz M, Jacob M, Raja K. Pulmonary Assessment of the Liver Transplant Recipient. J Clin Exp Hepatol 2023; 13:895-911. [PMID: 37693254 PMCID: PMC10483013 DOI: 10.1016/j.jceh.2023.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 04/13/2023] [Indexed: 09/12/2023] Open
Abstract
Respiratory symptoms and hypoxemia can complicate chronic liver disease and portal hypertension. Various pulmonary disorders affecting the pleura, lung parenchyma, and pulmonary vasculature are seen in end-stage liver disease, complicating liver transplantation (LT). Approximately 8% of cirrhotic patients in an intensive care unit develop severe pulmonary problems. These disorders affect waiting list mortality and posttransplant outcomes. A thorough history, physical examination, and appropriate laboratory tests help diagnose and assess the severity to risk stratify pulmonary diseases before LT. Hepatopulmonary syndrome (HPS), portopulmonary hypertension (POPH), and hepatic hydrothorax (HH) are respiratory consequences specific to cirrhosis and portal hypertension. HPS is seen in 5-30% of cirrhosis cases and is characterized by impaired oxygenation due to intrapulmonary vascular dilatations and arteriovenous shunts. Severe HPS is an indication of LT. The majority of patients with HPS resolve their hypoxemia after LT. When pulmonary arterial hypertension occurs in patients with portal hypertension, it is called POPH. All other causes of pulmonary arterial hypertension should be ruled out before labeling as POPH. Since severe POPH (mean pulmonary artery pressure [mPAP] >50 mm Hg) is a relative contraindication for LT, it is crucial to screen for POPH before LT. Those with moderate POPH (mPAP >35 mm Hg), who improve with medical therapy, will benefit from LT. A transudative pleural effusion called hepatic hydrothorax (HH) is seen in 5-10% of people with cirrhosis. Refractory cases of HH benefit from LT. In recent years, increasing clinical expertise and advances in the medical field have resulted in better outcomes in patients with moderate to severe pulmonary disorders, who undergo LT.
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Affiliation(s)
| | - Mohammed Fawaz
- Integrated Liver Care, Aster Medcity, Kochi, Kerala, India
| | - Mathew Jacob
- Integrated Liver Care, Aster Medcity, Kochi, Kerala, India
| | - Kaiser Raja
- King's College Hospital London, Dubai Hills, Dubai, United Arab Emirates
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20
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Shaker ME, Gomaa HAM, Abdelgawad MA, El-Mesery M, Shaaban AA, Hazem SH. Emerging roles of tyrosine kinases in hepatic inflammatory diseases and therapeutic opportunities. Int Immunopharmacol 2023; 120:110373. [PMID: 37257270 DOI: 10.1016/j.intimp.2023.110373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 05/06/2023] [Accepted: 05/19/2023] [Indexed: 06/02/2023]
Abstract
Inflammation has been convicted of causing and worsening many liver diseases like acute liver failure, fibrosis, cirrhosis, fatty liver and liver cancer. Pattern recognition receptors (PRRs) like TLRs 4 and 9 localized on resident or recruited immune cells are well known cellular detectors of pathogen and damage-associated molecular patterns (PAMPs/DAMPs). Stimulation of these receptors generates the sterile and non-sterile inflammatory responses in the liver. When these responses are repeated, there will be a sustained liver injury that may progress to fibrosis and its outcomes. Crosstalk between inflammatory/fibrogenic-dependent streams and certain tyrosine kinases (TKs) has recently evolved in the context of hepatic diseases. Because of TKs increasing importance, their role should be elucidated to highlight effective approaches to manage the diverse liver disorders. This review will give a brief overview of types and functions of some TKs like BTK, JAKs, Syk, PI3K, Src and c-Abl, as well as receptors for TAM, PDGF, EGF, VEGF and HGF. It will then move to discuss the roles of these TKs in the regulation of the proinflammatory, fibrogenic and tumorigenic responses in the liver. Lastly, the therapeutic opportunities for targeting TKs in hepatic inflammatory disorders will be addressed. Overall, this review sheds light on the diverse TKs that have substantial roles in hepatic disorders and potential therapeutics modulating their activity.
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Affiliation(s)
- Mohamed E Shaker
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf, Saudi Arabia.
| | - Hesham A M Gomaa
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf, Saudi Arabia
| | - Mohamed A Abdelgawad
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf, Saudi Arabia
| | - Mohamed El-Mesery
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Germany
| | - Ahmed A Shaaban
- Department of Pharmacology & Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Sara H Hazem
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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21
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Müller L, Gairing SJ, Foerster F, Weinmann A, Mittler J, Stoehr F, Graafen D, Düber C, Galle PR, Kloeckner R, Hahn F. Portal hypertension in patients with hepatocellular carcinoma and immunotherapy: prognostic relevance of CT-morphologic estimates. Cancer Imaging 2023; 23:40. [PMID: 37098584 PMCID: PMC10127076 DOI: 10.1186/s40644-023-00558-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 04/17/2023] [Indexed: 04/27/2023] Open
Abstract
BACKGROUND Clinically significant portal hypertension (CSPH) has been identified as an important prognostic factor in patients with hepatocellular carcinoma (HCC) undergoing curative treatment. This study aimed to assess PH estimates as prognostic factors in patients with HCC treated with immunotherapy. METHODS All patients with HCC treated with an immunotherapeutic agent in first or subsequent lines at our tertiary care center between 2016 and 2021 were included (n = 50). CSPH was diagnosed using the established PH score for non-invasive PH estimation in pre-treatment CT data (cut-off ≥ 4). Influence of PH on overall survival (OS) and progression-free survival (PFS) was assessed in uni- and multivariable analyses. RESULTS Based on the PH score, 26 patients (52.0%) were considered to have CSPH. After treatment initiation, patients with CSPH had a significantly impaired median OS (4.1 vs 33.3 months, p < 0.001) and a significantly impaired median PFS (2.7 vs 5.3 months, p = 0.02). In multivariable Cox regression, CSPH remained significantly associated with survival (HR 2.9, p = 0.015) when adjusted for established risk factors. CONCLUSIONS Non-invasive assessment of CSPH using routine CT data yielded an independent prognostic factor in patients with HCC and immunotherapy. Therefore, it might function as an additional imaging biomarker to detect high-risk patients with poor survival and possibly for treatment decision making.
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Affiliation(s)
- Lukas Müller
- Department of Diagnostic and Interventional Radiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz, 55131, Germany
| | - Simon J Gairing
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Friedrich Foerster
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Arndt Weinmann
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Jens Mittler
- Department of General, Visceral and Transplant Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Fabian Stoehr
- Department of Diagnostic and Interventional Radiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz, 55131, Germany
| | - Dirk Graafen
- Department of Diagnostic and Interventional Radiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz, 55131, Germany
| | - Christoph Düber
- Department of Diagnostic and Interventional Radiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz, 55131, Germany
| | - Peter R Galle
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Roman Kloeckner
- Institute of Interventional Radiology, University Hospital Schleswig-Holstein-Campus Luebeck, Luebeck, Germany
| | - Felix Hahn
- Department of Diagnostic and Interventional Radiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
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22
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Chen B, Zhang L, Cheng J, Wu T, Lei J, Yang X, Zhang R, Safadi R, Li Y, Si T, Lu Y. Risk Factors for Hepatic Encephalopathy in Hepatocellular Carcinoma After Sorafenib or Lenvatinib Treatment: A Real-World Study. Drug Des Devel Ther 2022; 16:4429-4437. [PMID: 36597443 PMCID: PMC9805705 DOI: 10.2147/dddt.s386829] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 11/16/2022] [Indexed: 12/29/2022] Open
Abstract
Purpose This study aimed to investigate the incidence rate and risk factors for hepatic encephalopathy (HE) among unresectable hepatocellular carcinoma (uHCC) patients with liver cirrhosis who received sorafenib or lenvatinib treatment. Patients and Methods uHCC patients with cirrhosis who received first-line sorafenib or lenvatinib treatment between September 2014 and February 2021 were continually reviewed in our single-center retrospective study. The Hepatic Encephalopathy Scoring Algorithm was used to evaluate the occurrence and grade of HE during treatment, and logistic regression models were used to further explore the risk factors for HE. Results A total of 454 eligible patients were enrolled in our study, with 214 and 240 patients in the sorafenib and lenvatinib groups, respectively. At time of data cut-off (2021-12), the incidence of HE in sorafenib group (4.2%, 95% CI:2-7%) was significantly lower than that in lenvatinib group (11.3%,95% CI:7-15%) (p = 0.006), with alcoholic cirrhosis [OR: 5.857 (95% CI: 1.519-22.591)], Child-Pugh >7 [OR: 3.023 (95% CI: 1.135-8.053)], blood ammonia ≥38.65 μmol/L [OR: 4.693 (95% CI: 1.782-12.358)], total bile acid ≥29.5 μmol/L [OR: 11.047 (95% CI: 4.414-27.650)] and duration of treatment ≥5.6 months [OR: 4.350 (95% CI: 1.701-11.126)] to be risk factors for the occurrence of HE during first-line systemic therapy. Conclusion In our study, for off-label uHCC patients (Child-Pugh >7) with alcoholic cirrhosis, hyperammonemia, hypercholesterolemia, and estimated longer duration of treatment, the application of lenvatinib has to be cautious, which needs to be confirmed in future clinical trials.
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Affiliation(s)
- Bowen Chen
- Peking University 302 Clinical Medical School, Beijing, People’s Republic of China,Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China
| | - Linzhi Zhang
- Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China,Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China
| | - Jiamin Cheng
- Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China
| | - Tong Wu
- Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China
| | - Jin Lei
- Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China,Guizhou Medical University, Guiyang, People’s Republic of China
| | - Xu Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Rongling Zhang
- Department of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Rifaat Safadi
- Liver Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel
| | - Yinyin Li
- Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China
| | - Tongguo Si
- Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China,Tongguo Si, Tianjin Medical University Cancer Institute and Hospital, Tiyuan North Huanhu West Road, Hexi District, Tianjin, 300060, People’s Republic of China, Email
| | - Yinying Lu
- Peking University 302 Clinical Medical School, Beijing, People’s Republic of China,Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China,Center for Synthetic & System Biology, Tsinghua University, Beijing, People’s Republic of China,Guangdong Key Laboratory of Epigenetics, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, People’s Republic of China,Correspondence: Yinying Lu, Peking University 302 Clinical Medical School, No. 100, Middle Road of the West 4th Ring, Beijing, 100039, People’s Republic of China, Email
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23
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Zhang D, Zhang Y, Sun B. The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application. Int J Mol Sci 2022; 23:ijms232012572. [PMID: 36293428 PMCID: PMC9604031 DOI: 10.3390/ijms232012572] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 09/27/2022] [Accepted: 10/03/2022] [Indexed: 11/16/2022] Open
Abstract
Liver fibrosis results from repeated and persistent liver damage. It can start with hepatocyte injury and advance to inflammation, which recruits and activates additional liver immune cells, leading to the activation of the hepatic stellate cells (HSCs). It is the primary source of myofibroblasts (MFs), which result in collagen synthesis and extracellular matrix protein accumulation. Although there is no FDA and EMA-approved anti-fibrotic drug, antiviral therapy has made remarkable progress in preventing or even reversing the progression of liver fibrosis, but such a strategy remains elusive for patients with viral, alcoholic or nonalcoholic steatosis, genetic or autoimmune liver disease. Due to the complexity of the etiology, combination treatments affecting two or more targets are likely to be required. Here, we review the pathogenic mechanisms of liver fibrosis and signaling pathways involved, as well as various molecular targets for liver fibrosis treatment. The development of efficient drug delivery systems that target different cells in liver fibrosis therapy is also summarized. We highlight promising anti-fibrotic events in clinical trial and preclinical testing, which include small molecules and natural compounds. Last, we discuss the challenges and opportunities in developing anti-fibrotic therapies.
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Affiliation(s)
- Danyan Zhang
- School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Yaguang Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- Correspondence: (Y.Z.); (B.S.); Tel.: +86-21-5492-1375 (Y.Z.); +86-21-5492-1375 (B.S.)
| | - Bing Sun
- School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- Correspondence: (Y.Z.); (B.S.); Tel.: +86-21-5492-1375 (Y.Z.); +86-21-5492-1375 (B.S.)
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24
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Sakiani S, Heller T, Koh C. Current and investigational drugs in early clinical development for portal hypertension. Front Med (Lausanne) 2022; 9:974182. [PMID: 36300180 PMCID: PMC9589453 DOI: 10.3389/fmed.2022.974182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction The development of portal hypertension leads to a majority of complications associated with chronic liver disease. Therefore, adequate treatment of portal hypertension is crucial in the management of such patients. Current treatment options are limited and consist mainly of medications that decrease the hyperdynamic circulation, such as non-selective beta blockers, and treatment of hypervolemia with diuretics. Despite these options, mortality rates have not improved over the last two decades. Newer, more effective treatment options are necessary to help improve survival and quality of life in these patients. Areas covered Multiple preclinical models and clinical studies have demonstrated potential efficacy of a variety of new treatment modalities. We introduce treatment options including the use of vasodilation promotors, vasoconstriction inhibitors, anticoagulants, antiangiogenics, and anti-inflammatory drugs. We examine the most recent studies for treatment options within these drug classes and offer insights as to which show the most promise in this field. Methodology Published studies that identified novel medical treatment options of portal hypertension were searched using PubMed (https://pubmed.ncbi.nlm.nih.gov/). Clinical trials listed in Clinicaltrials.gov were also searched with a focus on more recent and ongoing studies, including those with completed recruitment. Searching with key terms including "portal hypertension" as well as individually searching specific treatment medications that were listed in other publications was carried out. Finally, current societal guidelines and recent review articles relevant to the management of portal hypertension were evaluated, and listed references of interest were included. Conclusion Many ongoing early phase studies demonstrate promising results and may shape the field of portal hypertension management in future. As concrete results become available, larger RCTs will be required before making definitive conclusions regarding safety and efficacy and whether or not they can be incorporated into routine clinical practice. Statins, anticoagulants, and PDE inhibitors have been among the most studied and appear to be most promising.
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Affiliation(s)
- Sasan Sakiani
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Baltimore, MD, United States
| | - Theo Heller
- Liver Diseases Branch, Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Christopher Koh
- Liver Diseases Branch, Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
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25
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Wang L, Zhang Y, Ren Y, Yang X, Ben H, Zhao F, Yang S, Wang L, Qing J. Pharmacological targeting of cGAS/STING-YAP axis suppresses pathological angiogenesis and ameliorates organ fibrosis. Eur J Pharmacol 2022; 932:175241. [PMID: 36058291 DOI: 10.1016/j.ejphar.2022.175241] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/24/2022] [Accepted: 08/26/2022] [Indexed: 11/18/2022]
Abstract
Organ fibrosis is accompanied by pathological angiogenesis. Discovering new ways to ameliorate pathological angiogenesis may bypass organ fibrosis. The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been implicated in organ injuries and its activation inhibits endothelial proliferation. Currently, a controversy exists as to whether cGAS/STING activation exacerbates inflammation and tissue injury or mitigates damage, and whether one of these effects predominates under specific context. This study unveiled a new antifibrotic cGAS/STING signaling pathway that suppresses pathological angiogenesis in liver and kidney fibrosis. We showed that cGAS expression was induced in fibrotic liver and kidney, but suppressed in endothelial cells. cGAS genetic deletion promoted liver and kidney fibrosis and pathological angiogenesis, including occurrence of endothelial-to-mesenchymal transition. Meanwhile, cGAS deletion upregulated profibrotic Yes-associated protein (YAP) signaling in endothelial cells, which was evidenced by the attenuation of organ fibrosis in mice specifically lacking endothelial YAP. Pharmacological targeting of cGAS/STING-YAP signaling by both a small-molecule STING agonist, SR-717, and a G protein-coupled receptor (GPCR)-based antagonist that blocks the profibrotic activity of endothelial YAP, attenuated liver and kidney fibrosis. Together, our data support that activation of cGAS/STING signaling mitigates organ fibrosis and suppresses pathological angiogenesis. Further, pharmacological targeting of cGAS/STING-YAP axis exhibits the potential to alleviate liver and kidney fibrosis.
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Affiliation(s)
- Lu Wang
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yuwei Zhang
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yafeng Ren
- 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, 610064, China
| | - Xue Yang
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Haijing Ben
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Fulan Zhao
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Sijin Yang
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, China
| | - Li Wang
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China.
| | - Jie Qing
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, China; MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, China.
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de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C. Reply to: 'Management of portal hypertension in patients treated with atezolizumab and bevacizumab for hepatocellular carcinoma'. J Hepatol 2022; 77:567-568. [PMID: 35526788 DOI: 10.1016/j.jhep.2022.04.029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/04/2022]
Affiliation(s)
| | - Jaume Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; Instituts d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and CIBERehd, University of Barcelona, Spain
| | | | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Cristina Ripoll
- Internal Medicine IV, Universitätsklinikum Jena, Friedrich Schiller University, Jena, Germany
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Huang HC, Hsu SJ, Chang CC, Kao YC, Chuang CL, Hou MC, Lee FY. Lycopene treatment improves intrahepatic fibrosis and attenuates pathological angiogenesis in biliary cirrhotic rats. J Chin Med Assoc 2022; 85:414-420. [PMID: 35120355 DOI: 10.1097/jcma.0000000000000699] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Liver cirrhosis is characterized by liver fibrosis and pathological angiogenesis, which results in hyperdynamic circulation, portal-systemic collateral vascular formation, and abnormal angiogenesis. Lycopene is a nutrient mostly found in tomatoes. The beneficial effects of lycopene include anti-inflammation, anti-oxidation, anti-fibrosis, and anti-angiogenesis; however, the association between liver cirrhosis and pathological angiogenesis has yet to be studied. This study aimed to investigate the effects of lycopene on biliary cirrhotic rats. METHODS The efficacy of lycopene treatment in common bile duct ligation (BDL)-induced biliary cirrhotic rats was evaluated. Sham-operated rats served as surgical controls. Lycopene (20 mg/kg/day, oral gavage) or vehicle was administered to BDL or sham-operated rats for 4 weeks, after which the hemodynamics, liver biochemistry, portal-systemic shunting, liver and mesenteric angiogenesis, and hepatic angiogenesis-related protein expressions were examined. RESULTS Lycopene alleviated hyperdynamic circulation as evidenced by decreased cardiac index and increased peripheral vascular resistance (p < 0.05), but it did not affect portal pressure or liver biochemistry in the BDL rats (p > 0.05). Lycopene significantly diminished the shunting degree of portal-systemic collaterals (p = 0.04) and mesenteric vascular density (p = 0.01), and also ameliorated intrahepatic angiogenesis and liver fibrosis. In addition, lycopene upregulated endothelial nitric oxide synthase, protein kinase B (Akt) and phosphatidylinositol 3-kinases (PI3K), and downregulated vascular endothelial growth factor receptor 2 (VEGFR-2) protein expressions (p < 0.05) in the livers of the BDL rats. CONCLUSION Lycopene ameliorated liver fibrosis, hyperdynamic circulation, and pathological angiogenesis in biliary cirrhotic rats, possibly through the modulation of intrahepatic Akt/PI3K/eNOS and VEGFR-2 pathways.
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Affiliation(s)
- Hui-Chun Huang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shao-Jung Hsu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ching-Chih Chang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yun-Chieh Kao
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chiao-Lin Chuang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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28
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Coll M, Ariño S, Mártinez-Sánchez C, Garcia-Pras E, Gallego J, Moles A, Aguilar-Bravo B, Blaya D, Vallverdú J, Rubio-Tomás T, Lozano JJ, Pose E, Graupera I, Fernández-Vidal A, Pol A, Bataller R, Geng JG, Ginès P, Fernandez M, Sancho-Bru P. Ductular reaction promotes intrahepatic angiogenesis through Slit2-Roundabout 1 signaling. Hepatology 2022; 75:353-368. [PMID: 34490644 PMCID: PMC8766889 DOI: 10.1002/hep.32140] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 07/08/2021] [Accepted: 08/06/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND AIMS Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in the wound-healing response of the liver, promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis. In the current study we investigated the potential contribution of DR cells to hepatic vascular remodeling during chronic liver disease. APPROACH AND RESULTS In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis-related genes, the expression of Slit2 and its receptor Roundabout 1 (Robo1) was localized in DR cells and neoangiogenic vessels, respectively. The angiogenic role of the Slit2-Robo1 pathway in chronic liver disease was confirmed in ROBO1/2-/+ mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which displayed reduced intrahepatic neovascular density compared to wild-type mice. However, ROBO1/2 deficiency did not affect angiogenesis in partial hepatectomy. In patients with advanced alcohol-associated disease, angiogenesis was associated with DR, and up-regulation of SLIT2-ROBO1 correlated with DR and disease severity. In vitro, human liver-derived organoids produced SLIT2 and induced tube formation of endothelial cells. CONCLUSIONS Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2-Robo1 pathway and recognize DR cells as key players in the liver wound-healing response.
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MESH Headings
- Animals
- Blood Vessels/metabolism
- Chronic Disease
- Disease Progression
- Gene Expression
- Gene Ontology
- Hepatitis, Alcoholic/pathology
- Hepatitis, Alcoholic/physiopathology
- Humans
- Intercellular Signaling Peptides and Proteins/genetics
- Intercellular Signaling Peptides and Proteins/metabolism
- Liver/metabolism
- Liver/physiopathology
- Liver Diseases, Alcoholic/genetics
- Liver Diseases, Alcoholic/metabolism
- Liver Diseases, Alcoholic/pathology
- Liver Diseases, Alcoholic/physiopathology
- Mice
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/pathology
- Neovascularization, Physiologic/genetics
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Organoids
- Patient Acuity
- Receptors, Immunologic/genetics
- Receptors, Immunologic/metabolism
- Signal Transduction/genetics
- Stem Cells
- Up-Regulation
- Vascular Remodeling
- Wound Healing
- Roundabout Proteins
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Affiliation(s)
- Mar Coll
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Silvia Ariño
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Celia Mártinez-Sánchez
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Ester Garcia-Pras
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Javier Gallego
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Anna Moles
- Cell Death and Proliferation, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Catalonia, Spain
- Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain
| | - Beatriz Aguilar-Bravo
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Delia Blaya
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Julia Vallverdú
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Teresa Rubio-Tomás
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Juan Jose Lozano
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Elisa Pose
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
- Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain
| | - Isabel Graupera
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
- Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain
| | - Andrea Fernández-Vidal
- Cell compartments and Signaling Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Albert Pol
- Cell compartments and Signaling Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Department of Biomedical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
| | - Ramón Bataller
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Jian-Guo Geng
- Department of Biologic and Material Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
| | - Pere Ginès
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
- Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain
| | - Mercedes Fernandez
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Pau Sancho-Bru
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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Aboismail A, El-Shazly M, Abdallah N, Elsayed E, Abo-Yossef R. Study of the effect of vascular endothelial growth factor (VEGF) C(+405)G (rs2010963) single nucleotide polymorphism on the development of esophageal and gastric varices and risk of variceal bleeding in cirrhotic hepatitis C virus (HCV) patients (VEGF) C(+405)G IN esophageal and gastric varices. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-021-00160-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Abstract
Background
HCV infection is a major worldwide cause of chronic liver diseases. Esophageal and gastric varices are common in cirrhotic patients due to concomitant portal hypertension. Variceal hemorrhage is a major decompensating event with high morbidity and mortality. Endothelial dysfunction, occurring in cirrhosis, facilitates the development of liver cirrhosis, portal hypertension and contributes to increased intrahepatic vascular resistance..VEGF family members are major regulators of blood vessel development and function.
Results
The study was conducted on 90 subjects admitted to Tropical Medicine Department, Alexandria Main University Hospital: 30 cirrhotic patients with endoscopically proven varices (group A), 30 cirrhotic patients without varices (group B), and 30 healthy controls (group C). All patients was subjected to detailed history taking and thorough clinical examination, laboratory investigations, ultrasound abdomen, upper gastrointestinal endoscopy, and genotyping for VEGF C(+405)G (rs2010963) by 5′ nuclease assay. The VEGF C(+405)G (rs2010963) GG genotype was associated with higher prevalence of esophageal and gastric varices and higher bleeding risk.
Conclusion
VEGF C(+405)G (rs2010963) is an important genetic determinant of esophageal varices, gastric varices, and correlates with variceal bleeding risk. Genetic testing of this SNP would be useful in prediction of esophageal and gastric varices and bleeding risk.
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Feng NN, Du XY, Zhang YS, Jiao ZK, Wu XH, Yang BM. Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma. Front Endocrinol (Lausanne) 2022; 13:1061091. [PMID: 36714595 PMCID: PMC9877416 DOI: 10.3389/fendo.2022.1061091] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 12/13/2022] [Indexed: 01/14/2023] Open
Abstract
BACKGROUNDS The pandemic of overweight and obesity (quantified by body mass index (BMI) ≥ 25) has rapidly raised the patient number of non-alcoholic fatty hepatocellular carcinoma (HCC), and several clinical trials have shown that BMI is associated with the prognosis of HCC. However, whether overweight/obesity is an independent prognostic factor is arguable, and the role of overweight/obesity-related metabolisms in the progression of HCC is scarcely known. MATERIALS AND METHODS In the present study, clinical information, mRNA expression profile, and genomic data were downloaded from The Cancer Genome Atlas (TCGA) as a training cohort (TCGA-HCC) for the identification of overweight/obesity-related transcriptome. Machine learning and the Cox regression analysis were conducted for the construction of the overweight/obesity-associated gene (OAG) signature. The Kaplan-Meier curve, receiver operating characteristic (ROC) curve, and the Cox regression analysis were performed to assess the prognostic value of the OAG signature, which was further validated in two independent retrospective cohorts from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). Subsequently, functional enrichment, genomic profiling, and tumor microenvironment (TME) evaluation were utilized to characterize biological activities associated with the OAG signature. GSE109211 and GSE104580 were retrieved to evaluate the underlying response of sorafenib and transcatheter arterial chemoembolization (TACE) treatment, respectively. The Genomics of Drug Sensitivity in Cancer (GDSC) database was employed for the evaluation of chemotherapeutic response. RESULTS Overweight/obesity-associated transcriptome was mainly involved in metabolic processes and noticeably and markedly correlated with prognosis and TME of HCC. Afterward, a novel established OAG signature (including 17 genes, namely, GAGE2D, PDE6A, GABRR1, DCAF8L1, DPYSL4, SLC6A3, MMP3, RIBC2, KCNH2, HTRA3, PDX1, ATHL1, PRTG, SHC4, C21orf29, SMIM32, and C1orf133) divided patients into high and low OAG score groups with distinct prognosis (median overall survival (OS): 24.87 vs. 83.51 months, p < 0.0001), and the values of area under ROC curve (AUC) in predicting 1-, 2-, 3-, and 4-year OS were 0.81, 0.80, 0.83, and 0.85, respectively. Moreover, the OAG score was independent of clinical features and also exhibited a good ability for prognosis prediction in the ICGC-LIHC-JP cohort and GSE54236 dataset. Expectedly, the OAG score was also highly correlated with metabolic processes, especially oxidative-related signaling pathways. Furthermore, abundant enrichment of chemokines, receptors, MHC molecules, and other immunomodulators as well as PD-L1/PD-1 expression among patients with high OAG scores indicated that they might have better responses to immunotherapy. However, probably exclusion of T cells from infiltrating tumors resulting in lower infiltration of effective T cells would restrict immunotherapeutic effects. In addition, the OAG score was significantly associated with the response of sorafenib and TACE treatment. CONCLUSIONS Overall, this study comprehensively disclosed the relationship between BMI-guided transcriptome and HCC. Moreover, the OAG signature had the potential clinical applications in the future to promote clinical management and precision medicine of HCC.
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Affiliation(s)
- Ning-Ning Feng
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xi-Yue Du
- Department of Radiotherapy, Hengshui People’s Hospital, Hengshui, Hebei, China
| | - Yue-Shan Zhang
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhi-Kai Jiao
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiao-Hui Wu
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Bao-Ming Yang
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- *Correspondence: Bao-Ming Yang, ;
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Decraecker M, Toulouse C, Blanc JF. Is There Still a Place for Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma at the Time of Immunotherapies? A Focus on Lenvatinib. Cancers (Basel) 2021; 13:6310. [PMID: 34944930 PMCID: PMC8699782 DOI: 10.3390/cancers13246310] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/12/2021] [Accepted: 12/14/2021] [Indexed: 02/08/2023] Open
Abstract
The systemic treatment of hepatocellular carcinoma is changing rapidly. Three main classes of treatment are now available. Historically, multi-targeted tyrosine kinase inhibitors (TKIs) (sorafenib and lenvatinib as first-line; regorafenib and cabozantinib as second-line) were the first to show an improvement in overall survival (OS). Anti-vascular endothelial growth factor (anti-VEGF) antibodies can be used in first-line (bevacizumab) or second-line (ramucirumab) combination therapy. More recently, immuno-oncology (IO) has profoundly changed therapeutic algorithms, and the combination of atezolizumab-bevacizumab is now the first-line standard of care. Therefore, the place of TKIs needs to be redefined. The objective of this review was to define the place of TKIs in the therapeutic algorithm at the time of IO treatment in first-line therapy, with a special focus on lenvatinib that exhibits one of the higher anti-tumoral activity among TKI in HCC. We will discuss the place of lenvatinib in first line (especially if there is a contra-indication to IO) but also after failure of atezolizumab and bevacizumab. New opportunities for lenvatinib will also be presented, including the use at an earlier stage of the disease and combination with IOs.
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Affiliation(s)
- Marie Decraecker
- Department of Oncology, Hospital Haut Leveque-CHU Bordeaux, Avenue Magellan, 33604 Pessac, France; (C.T.); (J.-F.B.)
| | - Caroline Toulouse
- Department of Oncology, Hospital Haut Leveque-CHU Bordeaux, Avenue Magellan, 33604 Pessac, France; (C.T.); (J.-F.B.)
| | - Jean-Frédéric Blanc
- Department of Oncology, Hospital Haut Leveque-CHU Bordeaux, Avenue Magellan, 33604 Pessac, France; (C.T.); (J.-F.B.)
- INSERM U1053, BaRITOn, University Victor Segalen, 146 Rue Léo Saignat, 33000 Bordeaux, France
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The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer. Cancers (Basel) 2021; 13:cancers13225719. [PMID: 34830874 PMCID: PMC8616349 DOI: 10.3390/cancers13225719] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/08/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary During the development of chronic liver disease, the hepatic sinusoid undergoes major changes that further compromise the hepatic function, inducing persistent inflammation and the formation of scar tissue, together with alterations in liver hemodynamics. This diseased background may induce the formation and development of hepatocellular carcinoma (HCC), which is the most common form of primary liver cancer and a major cause of mortality. In this review, we describe the ways in which the dysregulation of hepatic sinusoidal cells—including liver sinusoidal cells, Kupffer cells, and hepatic stellate cells—may have an important role in the development of HCC. Our review summarizes all of the known sinusoidal processes in both health and disease, and possible treatments focusing on the dysregulation of the sinusoid; finally, we discuss how some of these alterations occurring during chronic injury are shared with the pathology of HCC and may contribute to its development. Abstract The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.
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Holzner LMW, Murray AJ. Hypoxia-Inducible Factors as Key Players in the Pathogenesis of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis. Front Med (Lausanne) 2021; 8:753268. [PMID: 34692739 PMCID: PMC8526542 DOI: 10.3389/fmed.2021.753268] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/10/2021] [Indexed: 12/20/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and its more severe form non-alcoholic steatohepatitis (NASH) are a major public health concern with high and increasing global prevalence, and a significant disease burden owing to its progression to more severe forms of liver disease and the associated risk of cardiovascular disease. Treatment options, however, remain scarce, and a better understanding of the pathological and physiological processes involved could enable the development of new therapeutic strategies. One process implicated in the pathology of NAFLD and NASH is cellular oxygen sensing, coordinated largely by the hypoxia-inducible factor (HIF) family of transcription factors. Activation of HIFs has been demonstrated in patients and mouse models of NAFLD and NASH and studies of activation and inhibition of HIFs using pharmacological and genetic tools point toward important roles for these transcription factors in modulating central aspects of the disease. HIFs appear to act in several cell types in the liver to worsen steatosis, inflammation, and fibrosis, but may nevertheless improve insulin sensitivity. Moreover, in liver and other tissues, HIF activation alters mitochondrial respiratory function and metabolism, having an impact on energetic and redox homeostasis. This article aims to provide an overview of current understanding of the roles of HIFs in NAFLD, highlighting areas where further research is needed.
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Affiliation(s)
| | - Andrew J. Murray
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
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Thanapirom K, Caon E, Papatheodoridi M, Frenguelli L, Al-Akkad W, Zhenzhen Z, Vilia MG, Pinzani M, Mazza G, Rombouts K. Optimization and Validation of a Novel Three-Dimensional Co-Culture System in Decellularized Human Liver Scaffold for the Study of Liver Fibrosis and Cancer. Cancers (Basel) 2021; 13:cancers13194936. [PMID: 34638417 PMCID: PMC8508071 DOI: 10.3390/cancers13194936] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/18/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary This study aims to overcome the current methodological limitations in discovering new therapeutic targets. Therefore, we optimized and validated a co-culture system using decellularized human liver three-dimensional (3D) scaffolds obtained from healthy and cirrhotic human livers for anti-fibrotic and anti-cancer dual drug screening. Both platforms mimic the naturally healthy and physio-pathological microenvironment and are able to recapitulate the key cellular and molecular events leading to liver fibrogenesis and cancer. This study demonstrates the differences between single versus co-cultures and the usage of human-derived liver 3D ECM scaffolds from healthy and cirrhotic livers. As lead compounds, we used Sorafenib and Regorafenib, first- and second-line drugs, and identified two different drug-induced mechanisms depending on the 3D ECM microenvironment. The 3D ECM scaffolds may represent innovative platforms for disease modeling, biomarker discovery, and drug testing in fibrosis and primary cancer. Abstract The introduction of new preclinical models for in vitro drug discovery and testing based on 3D tissue-specific extracellular matrix (ECM) is very much awaited. This study was aimed at developing and validating a co-culture model using decellularized human liver 3D ECM scaffolds as a platform for anti-fibrotic and anti-cancer drug testing. Decellularized 3D scaffolds obtained from healthy and cirrhotic human livers were bioengineered with LX2 and HEPG2 as single and co-cultures for up to 13 days and validated as a new drug-testing platform. Pro-fibrogenic markers and cancer phenotypic gene/protein expression and secretion were differently affected when single and co-cultures were exposed to TGF-β1 with specific ECM-dependent effects. The anti-fibrotic efficacy of Sorafenib significantly reduced TGF-β1-induced pro-fibrogenic effects, which coincided with a downregulation of STAT3 phosphorylation. The anti-cancer efficacy of Regorafenib was significantly reduced in 3D bioengineered cells when compared to 2D cultures and dose-dependently associated with cell apoptosis by cleaved PARP-1 activation and P-STAT3 inhibition. Regorafenib reversed TGF-β1-induced P-STAT3 and SHP-1 through induction of epithelial mesenchymal marker E-cadherin and downregulation of vimentin protein expression in both co-cultures engrafting healthy and cirrhotic 3D scaffolds. In their complex, the results of the study suggest that this newly proposed 3D co-culture platform is able to reproduce the natural physio-pathological microenvironment and could be employed for anti-fibrotic and anti-HCC drug screening.
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Affiliation(s)
- Kessarin Thanapirom
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London NW3 2PF, UK; (K.T.); (E.C.); (M.P.); (L.F.); (W.A.-A.); (Z.Z.); (M.G.V.); (M.P.); (G.M.)
- Division of Gastroenterology, Department of Medicine, Liver Fibrosis and Cirrhosis Research Unit, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand
| | - Elisabetta Caon
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London NW3 2PF, UK; (K.T.); (E.C.); (M.P.); (L.F.); (W.A.-A.); (Z.Z.); (M.G.V.); (M.P.); (G.M.)
| | - Margarita Papatheodoridi
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London NW3 2PF, UK; (K.T.); (E.C.); (M.P.); (L.F.); (W.A.-A.); (Z.Z.); (M.G.V.); (M.P.); (G.M.)
| | - Luca Frenguelli
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London NW3 2PF, UK; (K.T.); (E.C.); (M.P.); (L.F.); (W.A.-A.); (Z.Z.); (M.G.V.); (M.P.); (G.M.)
| | - Walid Al-Akkad
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London NW3 2PF, UK; (K.T.); (E.C.); (M.P.); (L.F.); (W.A.-A.); (Z.Z.); (M.G.V.); (M.P.); (G.M.)
| | - Zhang Zhenzhen
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London NW3 2PF, UK; (K.T.); (E.C.); (M.P.); (L.F.); (W.A.-A.); (Z.Z.); (M.G.V.); (M.P.); (G.M.)
| | - Maria Giovanna Vilia
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London NW3 2PF, UK; (K.T.); (E.C.); (M.P.); (L.F.); (W.A.-A.); (Z.Z.); (M.G.V.); (M.P.); (G.M.)
| | - Massimo Pinzani
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London NW3 2PF, UK; (K.T.); (E.C.); (M.P.); (L.F.); (W.A.-A.); (Z.Z.); (M.G.V.); (M.P.); (G.M.)
- Sheila Sherlock Liver Centre, Royal Free Hospital, London NW3 2QG, UK
| | - Giuseppe Mazza
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London NW3 2PF, UK; (K.T.); (E.C.); (M.P.); (L.F.); (W.A.-A.); (Z.Z.); (M.G.V.); (M.P.); (G.M.)
| | - Krista Rombouts
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London NW3 2PF, UK; (K.T.); (E.C.); (M.P.); (L.F.); (W.A.-A.); (Z.Z.); (M.G.V.); (M.P.); (G.M.)
- Correspondence:
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Orlandi P, Solini A, Banchi M, Brunetto MR, Cioni D, Ghiadoni L, Bocci G. Antiangiogenic Drugs in NASH: Evidence of a Possible New Therapeutic Approach. Pharmaceuticals (Basel) 2021; 14:ph14100995. [PMID: 34681219 PMCID: PMC8539163 DOI: 10.3390/ph14100995] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/22/2021] [Accepted: 09/27/2021] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease is the most common liver disorder worldwide, and its progressive form non-alcoholic steatohepatitis (NASH) is a growing cause of liver cirrhosis and hepatocellular carcinoma (HCC). Lifestyle changes, which are capable of improving the prognosis, are hard to achieve, whereas a pharmacologic therapy able to combine efficacy and safety is still lacking. Looking at the pathophysiology of various liver diseases, such as NASH, fibrosis, cirrhosis, and HCC, the process of angiogenesis is a key mechanism influencing the disease progression. The relationship between the worsening of chronic liver disease and angiogenesis may suggest a possible use of drugs with antiangiogenic activity as a tool to stop or slow the progression of the disorder. In this review, we highlight the available preclinical data supporting a role of known antiangiogenic drugs (e.g., sorafenib), or phytotherapeutic compounds with multiple mechanism of actions, including also antiangiogenic activities (e.g., berberine), in the treatment of NASH.
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Affiliation(s)
- Paola Orlandi
- Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Via Roma 55, 56126 Pisa, Italy; (P.O.); (M.B.); (M.R.B.); (L.G.)
| | - Anna Solini
- Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell’Area Critica, Università di Pisa, 56126 Pisa, Italy; (A.S.); (D.C.)
| | - Marta Banchi
- Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Via Roma 55, 56126 Pisa, Italy; (P.O.); (M.B.); (M.R.B.); (L.G.)
| | - Maurizia Rossana Brunetto
- Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Via Roma 55, 56126 Pisa, Italy; (P.O.); (M.B.); (M.R.B.); (L.G.)
| | - Dania Cioni
- Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell’Area Critica, Università di Pisa, 56126 Pisa, Italy; (A.S.); (D.C.)
| | - Lorenzo Ghiadoni
- Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Via Roma 55, 56126 Pisa, Italy; (P.O.); (M.B.); (M.R.B.); (L.G.)
| | - Guido Bocci
- Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Via Roma 55, 56126 Pisa, Italy; (P.O.); (M.B.); (M.R.B.); (L.G.)
- Correspondence: ; Tel.: +39-0502218756
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Iwakiri Y, Trebicka J. Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy. JHEP Rep 2021; 3:100316. [PMID: 34337369 PMCID: PMC8318926 DOI: 10.1016/j.jhepr.2021.100316] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 04/19/2021] [Accepted: 05/12/2021] [Indexed: 12/14/2022] Open
Abstract
Portal hypertension, defined as increased pressure in the portal vein, develops as a consequence of increased intrahepatic vascular resistance due to the dysregulation of liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), frequently arising from chronic liver diseases. Extrahepatic haemodynamic changes contribute to the aggravation of portal hypertension. The pathogenic complexity of portal hypertension and the unsuccessful translation of preclinical studies have impeded the development of effective therapeutics for patients with cirrhosis, while counteracting hepatic and extrahepatic mechanisms also pose a major obstacle to effective treatment. In this review article, we will discuss the following topics: i) cellular and molecular mechanisms of portal hypertension, focusing on dysregulation of LSECs, HSCs and hepatic microvascular thrombosis, as well as changes in the extrahepatic vasculature, since these are the major contributors to portal hypertension; ii) translational/clinical advances in our knowledge of portal hypertension; and iii) future directions.
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Key Words
- ACE2, angiogenesis-converting enzyme 2
- ACLF, acute-on-chronic liver failure
- AT1R, angiotensin II type I receptor
- CCL2, chemokine (C-C motif) ligand 2
- CCl4, carbon tetrachloride
- CLD, chronic liver disease
- CSPH, clinically significant portal hypertension
- Dll4, delta like canonical Notch ligand 4
- ECM, extracellular matrix
- EUS, endoscopic ultrasound
- FXR
- FXR, farnesoid X receptor
- HCC, hepatocellular carcinoma
- HRS, hepatorenal syndrome
- HSC
- HSCs, hepatic stellate cells
- HVPG, hepatic venous pressure gradient
- Hsp90, heat shock protein 90
- JAK2, Janus kinase 2
- KO, knockout
- LSEC
- LSEC, liver sinusoidal endothelial cells
- MLCP, myosin light-chain phosphatase
- NET, neutrophil extracellular trap
- NO
- NO, nitric oxide
- NSBB
- NSBBs, non-selective beta blockers
- PDE, phosphodiesterase
- PDGF, platelet-derived growth factor
- PIGF, placental growth factor
- PKG, cGMP-dependent protein kinase
- Rho-kinase
- TIPS
- TIPS, transjugular intrahepatic portosystemic shunt
- VCAM1, vascular cell adhesion molecule 1
- VEGF
- VEGF, vascular endothelial growth factor
- angiogenesis
- eNOS, endothelial nitric oxide synthase
- fibrosis
- liver stiffness
- statins
- β-Arr2, β-arrestin 2
- β1-AR, β1-adrenergic receptor
- β2-AR, β2-adrenergic receptor
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Affiliation(s)
- Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, University Clinic Frankfurt, Frankfurt, Germany
- European Foundation for the Study of Chronic Liver Failure-EF Clif, Barcelona, Spain
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Glycyrrhizin Attenuates Portal Hypertension and Collateral Shunting via Inhibition of Extrahepatic Angiogenesis in Cirrhotic Rats. Int J Mol Sci 2021; 22:ijms22147662. [PMID: 34299285 PMCID: PMC8304322 DOI: 10.3390/ijms22147662] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 01/14/2023] Open
Abstract
Portal hypertension develops along with liver cirrhosis then induces the formation of portal-systemic collaterals and lethal complications. Extrahepatic angiogenesis plays an important role. Glycyrrhizin has been found to exhibit anti-angiogenic features, which leads to its extensive use. However, the relevant effects of glycyrrhizin on liver cirrhosis and portal hypertension have not been evaluated. This study thus aimed to investigate the impact of glycyrrhizin on portal hypertension-related derangements in cirrhotic rats. Male Sprague-Dawley rats received bile duct ligation (BDL) to induce cirrhosis or sham operation as control. The rats were subdivided to receive glycyrrhizin (150 mg/kg/day, oral gavage) or vehicle beginning on the 15th day post operation, when BDL-induced liver fibrosis developed. The effects of glycyrrhizin were determined on the 28th day, the typical timing of BDL-induced cirrhosis. Glycyrrhizin significantly reduced portal pressure (p = 0.004). The splanchnic inflow as measured by superior mesenteric arterial flow decreased by 22% (p = 0.029). The portal-systemic collateral shunting degree reduced by 30% (p = 0.024). The mesenteric angiogenesis and phospho-VEGFR2 protein expression were also downregulated (p = 0.038 and 0.031, respectively). Glycyrrhizin did not significantly influence the liver biochemistry data. Although glycyrrhizin tended to reverse liver fibrosis, statistical significance was not reached (p = 0.069). Consistently, hepatic inflow from portal side, hepatic vascular resistance, and liver fibrosis-related protein expressions were not affected. Glycyrrhizin treatment at the stage of hepatic fibrosis still effectively attenuated portal hypertension and portosystemic collateral shunting. These beneficial effects were attributed to, at least in part, the suppression of mesenteric angiogenesis by VEGF signaling pathway downregulation.
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Huang X, Khoong Y, Han C, Su D, Ma H, Gu S, Li Q, Zan T. Targeting Dermal Fibroblast Subtypes in Antifibrotic Therapy: Surface Marker as a Cellular Identity or a Functional Entity? Front Physiol 2021; 12:694605. [PMID: 34335301 PMCID: PMC8319956 DOI: 10.3389/fphys.2021.694605] [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: 04/14/2021] [Accepted: 06/16/2021] [Indexed: 02/01/2023] Open
Abstract
Fibroblasts are the chief effector cells in fibrotic diseases and have been discovered to be highly heterogeneous. Recently, fibroblast heterogeneity in human skin has been studied extensively and several surface markers for dermal fibroblast subtypes have been identified, holding promise for future antifibrotic therapies. However, it has yet to be confirmed whether surface markers should be looked upon as merely lineage landmarks or as functional entities of fibroblast subtypes, which may further complicate the interpretation of cellular function of these fibroblast subtypes. This review aims to provide an update on current evidence on fibroblast surface markers in fibrotic disorders of skin as well as of other organ systems. Specifically, studies where surface markers were treated as lineage markers and manipulated as functional membrane proteins are both evaluated in parallel, hoping to reveal the underlying mechanism behind the pathogenesis of tissue fibrosis contributed by various fibroblast subtypes from multiple angles, shedding lights on future translational researches.
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Affiliation(s)
- Xin Huang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yimin Khoong
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chengyao Han
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Dai Su
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Ma
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shuchen Gu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qingfeng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Tao Zan
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Zhu J, Qiu J, Chen K, Wang W, Zheng S. Tea polyphenols and Levofloxacin alleviate the lung injury of hepatopulmonary syndrome in common bile duct ligation rats through Endotoxin -TNF signaling. Biomed Pharmacother 2021; 137:111263. [PMID: 33516071 DOI: 10.1016/j.biopha.2021.111263] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 01/06/2021] [Accepted: 01/07/2021] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND & AIMS Hepatopulmonary syndrome (HPS) is characterized by pulmonary vasodilation and arterial blood oxygen desaturation in patients with chronic liver disease. Generally, common bile duct ligation (CBDL) rats are a suitable experimental model for studying hepatopulmonary syndrome. Our previous study demonstrated that endotoxin surges markedly, followed by bacterial translocation and the loss of liver immune function in all the stages of CBDL, thereby contributing to the pathogenesis of HPS. However, the mechanisms behind the increase of the endotoxin and how to alleviate it have not yet been elucidated. Pulmonary injury induced by increased bilirubin, endotoxin, and inflammatory mediators occurs in the early and later stages of CBDL. This study assessed the effects of Tea polyphenols (TP) and Levofloxacin on endotoxin reduction and suppression of lung injury in HPS rats in the long and short term, respectively. METHODS Morphological change of pulmonary injury, HPS relative index, endotoxin concentration, and the activation extent of Malondialdehyde (MDA) and Myeloperoxidase (MPO) were evaluated in CBDL rats with or without TP and Levofloxacin for three weeks or six weeks. The inflammation factors of serum, lung tissue, and BALF were then compared at the same condition for the two time periods. This was followed by adoption of the network pharmacology approach, which was mainly composed of active component gathering, target prediction, HPS gene collection, network analysis, and gene enrichment analysis. Finally, the mRNA and protein levels of the inflammatory factors were studied and relative signaling expression was assessed using RT-PCR and Western blot analysis. RESULTS The obtained results indicated that the pulmonary injury manifestation was perceived and endotoxin, MDA, and MPO activation were markedly increased in the early and later stages of CBDL. TP and Levofloxacin treatment alleviated endotoxin infection and inflammation factor expression three weeks and six weeks after CBDL. In addition, Levofloxacin displayed a short time anti-bacterial effect, while TP exerted a long period function. TP and Levofloxacin also reduced TNF-α, TGF-β, IL-1β, PDGF-BB, NO, ICAM-1, and ET-1 expression on the mRNA or protein expression. With regard to the pharmacological mechanism, the network analysis indicated that 12 targets might be the therapeutic targets of TP and Levofloxacin on HPS, namely ET-1, NOs3, VEGFa, CCl2, TNF, Ptgs2, Hmox1, Alb, Ace, Cav1, and Mmp9. The gene enrichment analysis implied that TP and Levofloxacin probably benefited patients with HPS by modulating pathways associated with the AGE-RAGE signaling pathway, the TNF signaling pathway, the HIF-1 signaling pathway, the VEGF signaling pathway, and the IL-17 signaling pathway, Rheumatoid arthritis, Fluid shear stress, and atherosclerosis. Finally, the TNF-α level was mainly diminished on the protein level following CBDL. CONCLUSIONS TP and Levofloxacin could alleviate pulmonary injury for short and long period, respectively, while at the same time preventing endotoxin and the development of HPS in CBDL rats. These effects are possibly associated with the regulation of the Endotoxin -TNF-α pathways.
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Affiliation(s)
- Jiyun Zhu
- Hepatobiliary Surgery Department, Ningbo First Hospital, Ningbo, People's Republic of China
| | - Jiangfeng Qiu
- Department of Gastrointestinal Surgery, Shanghai Renji Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, People's Republic of China
| | - Kaibo Chen
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, People's Republic of China
| | - Wenbo Wang
- Hepatobiliary Surgery Department, Ningbo First Hospital, Ningbo, People's Republic of China.
| | - Siming Zheng
- Hepatobiliary Surgery Department, Ningbo First Hospital, Ningbo, People's Republic of China
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Cai J, Hu M, Chen Z, Ling Z. The roles and mechanisms of hypoxia in liver fibrosis. J Transl Med 2021; 19:186. [PMID: 33933107 PMCID: PMC8088569 DOI: 10.1186/s12967-021-02854-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis occurs in response to any etiology of chronic liver injury. Lack of appropriate clinical intervention will lead to liver cirrhosis or hepatocellular carcinoma (HCC), seriously affecting the quality of life of patients, but the current clinical treatments of liver fibrosis have not been developed yet. Recent studies have shown that hypoxia is a key factor promoting the progression of liver fibrosis. Hypoxia can cause liver fibrosis. Liver fibrosis can, in turn, profoundly further deepen the degree of hypoxia. Therefore, exploring the role of hypoxia in liver fibrosis will help to further understand the process of liver fibrosis, and provide the theoretical basis for its diagnosis and treatment, which is of great significance to avoid further deterioration of liver diseases and protect the life and health of patients. This review highlights the recent advances in cellular and molecular mechanisms of hypoxia in developments of liver fibrosis.
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Affiliation(s)
- Jingyao Cai
- Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
| | - Min Hu
- Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China.
| | - Zhiyang Chen
- Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
| | - Zeng Ling
- Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
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Role of Angiogenesis in the Pathogenesis of NAFLD. J Clin Med 2021; 10:jcm10071338. [PMID: 33804956 PMCID: PMC8037441 DOI: 10.3390/jcm10071338] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/15/2021] [Accepted: 03/17/2021] [Indexed: 12/19/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, exposing to the risk of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Angio-genesis is a complex process leading to the development of new vessels from pre-existing vessels. Angiogenesis is triggered by hypoxia and inflammation and is driven by the action of proangiogenic cytokines, mainly vascular endothelial growth factor (VEGF). In this review, we focus on liver angiogenesis associated with NAFLD and analyze the evidence of liver angiogenesis in animal models of NAFLD and in NAFLD patients. We also report the data explaining the role of angiogenesis in the progression of NAFLD and discuss the potential of targeting angiogenesis, notably VEGF, to treat NAFLD.
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Li H. Angiogenesis in the progression from liver fibrosis to cirrhosis and hepatocelluar carcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:217-233. [PMID: 33131349 DOI: 10.1080/17474124.2021.1842732] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Persistent inflammation and hypoxia are strong stimulus for pathological angiogenesis and vascular remodeling, and are also the most important elements resulting in liver fibrosis. Sustained inflammatory process stimulates fibrosis to the end-point of cirrhosis and sinusoidal portal hypertension is an important feature of cirrhosis. Neovascularization plays a pivotal role in collateral circulation formation of portal vein, mesenteric congestion, and high perfusion. Imbalance of hepatic artery and portal vein blood flow leads to the increase of hepatic artery inflow, which is beneficial to the formation of nodules. Angiogenesis contributes to progression from liver fibrosis to cirrhosis and hepatocellular carcinoma (HCC) and anti-angiogenesis therapy can improve liver fibrosis, reduce portal pressure, and prolong overall survival of patients with HCC. Areas covers: This paper will try to address the difference of the morphological characteristics and mechanisms of neovascularization in the process from liver fibrosis to cirrhosis and HCC and further compare the different efficacy of anti-angiogenesis therapy in these three stages. Expert opinion: More in-depth understanding of the role of angiogenesis factors and the relationship between angiogenesis and other aspects of the pathogenesis and transformation may be the key to enabling future progress in the treatment of patients with liver fibrosis, cirrhosis, and HCC.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine , Chengdu, Sichuan Province, P. R. China
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Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol 2021; 18:151-166. [PMID: 33128017 DOI: 10.1038/s41575-020-00372-7] [Citation(s) in RCA: 1091] [Impact Index Per Article: 272.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2020] [Indexed: 01/18/2023]
Abstract
Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. The primary source of these myofibroblasts are the resident hepatic stellate cells. Clinical and experimental liver fibrosis regresses when the causative agent is removed, which is associated with the elimination of these activated myofibroblasts and resorption of the fibrous scar. Understanding the mechanisms of liver fibrosis regression could identify new therapeutic targets to treat liver fibrosis. This Review summarizes studies of the molecular mechanisms underlying the reversibility of liver fibrosis, including apoptosis and the inactivation of hepatic stellate cells, the crosstalk between the liver and the systems that orchestrate the recruitment of bone marrow-derived macrophages (and other inflammatory cells) driving fibrosis resolution, and the interactions between various cell types that lead to the intracellular signalling that induces fibrosis or its regression. We also discuss strategies to target hepatic myofibroblasts (for example, via apoptosis or inactivation) and the myeloid cells that degrade the matrix (for example, via their recruitment to fibrotic liver) to facilitate fibrosis resolution and liver regeneration.
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Affiliation(s)
- Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA.
| | - David Brenner
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
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Mariotti V, Fiorotto R, Cadamuro M, Fabris L, Strazzabosco M. New insights on the role of vascular endothelial growth factor in biliary pathophysiology. JHEP Rep 2021; 3:100251. [PMID: 34151244 PMCID: PMC8189933 DOI: 10.1016/j.jhepr.2021.100251] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/06/2021] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
The family of vascular endothelial growth factors (VEGFs) includes 5 members (VEGF-A to -D, and placenta growth factor), which regulate several critical biological processes. VEGF-A exerts a variety of biological effects through high-affinity binding to tyrosine kinase receptors (VEGFR-1, -2 and -3), co-receptors and accessory proteins. In addition to its fundamental function in angiogenesis and endothelial cell biology, VEGF/VEGFR signalling also plays a role in other cell types including epithelial cells. This review provides an overview of VEGF signalling in biliary epithelial cell biology in both normal and pathologic conditions. VEGF/VEGFR-2 signalling stimulates bile duct proliferation in an autocrine and paracrine fashion. VEGF/VEGFR-1/VEGFR-2 and angiopoietins are involved at different stages of biliary development. In certain conditions, cholangiocytes maintain the ability to secrete VEGF-A, and to express a functional VEGFR-2 receptor. For example, in polycystic liver disease, VEGF secreted by cystic cells stimulates cyst growth and vascular remodelling through a PKA/RAS/ERK/HIF1α-dependent mechanism, unveiling a new level of complexity in VEFG/VEGFR-2 regulation in epithelial cells. VEGF/VEGFR-2 signalling is also reactivated during the liver repair process. In this context, pro-angiogenic factors mediate the interactions between epithelial, mesenchymal and inflammatory cells. This process takes place during the wound healing response, however, in chronic biliary diseases, it may lead to pathological neo-angiogenesis, a condition strictly linked with fibrosis progression, the development of cirrhosis and related complications, and cholangiocarcinoma. Novel observations indicate that in cholangiocarcinoma, VEGF is a determinant of lymphangiogenesis and of the immune response to the tumour. Better insights into the role of VEGF signalling in biliary pathophysiology might help in the search for effective therapeutic strategies.
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Key Words
- ADPKD, adult dominant polycystic kidney disease
- Anti-Angiogenic therapy
- BA, biliary atresia
- BDL, bile duct ligation
- CCA, cholangiocarcinoma
- CCl4, carbon tetrachloride
- CLDs, chronic liver diseases
- Cholangiocytes
- Cholangiopathies
- DP, ductal plate
- DPM, ductal plate malformation
- DRCs, ductular reactive cells
- Development
- HIF-1α, hypoxia-inducible factor type 1α
- HSCs, hepatic stellate cells
- IHBD, intrahepatic bile ducts
- IL-, interleukin-
- LECs, lymphatic endothelial cells
- LSECs, liver sinusoidal endothelial cells
- Liver repair
- MMPs, matrix metalloproteinases
- PBP, peribiliary plexus
- PC, polycystin
- PDGF, platelet-derived growth factor
- PIGF, placental growth factor
- PLD, polycystic liver diseases
- Polycystic liver diseases
- SASP, senescence-associated secretory phenotype
- TGF, transforming growth factor
- VEGF, vascular endothelial growth factors
- VEGF-A
- VEGF/VEGFR-2 signalling
- VEGFR-1/2, vascular endothelial growth factor receptor 1/2
- mTOR, mammalian target of rapamycin
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Affiliation(s)
- Valeria Mariotti
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA
| | - Romina Fiorotto
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA
| | - Massimiliano Cadamuro
- Department of Molecular Medicine, University of Padua, School of Medicine, Padua, Italy
| | - Luca Fabris
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA.,Department of Molecular Medicine, University of Padua, School of Medicine, Padua, Italy
| | - Mario Strazzabosco
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA
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Lim J, Kim HI, Kim E, Kim J, An J, Chang S, Kim SO, Lee HC, Lee YS, Shim JH. Variceal bleeding is aggravated by portal venous invasion of hepatocellular carcinoma: a matched nested case-control study. BMC Cancer 2021; 21:11. [PMID: 33402105 PMCID: PMC7786454 DOI: 10.1186/s12885-020-07708-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 12/03/2020] [Indexed: 02/07/2023] Open
Abstract
Background We hypothesized that portal vein tumor thrombosis (PVTT) in hepatocellular carcinoma (HCC) increases portal pressure and causes esophageal varices and variceal bleedings. We examined the incidence of high-risk varices and variceal bleeding and determined the indications for variceal screening and prophylaxis. Methods This study included 1709 asymptomatic patients without any prior history of variceal hemorrhage or endoscopic prophylaxis who underwent upper endoscopy within 30 days before or after initial anti-HCC treatment. Of these patients, 206 had PVTT, and after 1:2 individual matching, 161 of them were matched with 309 patients without PVTT. High-risk varices were defined as large/medium varices or small varices with red-color signs and variceal bleeding. Bleeding rates from the varices were compared between matched pairs. Risk factors for variceal bleeding in the entire set of patients with PVTT were also explored. Results In the matched-pair analysis, the proportion of high-risk varices at screening (23.0% vs. 13.3%; P = 0.003) and the cumulative rate of variceal bleeding (4.5% vs. 0.4% at 1 year; P = 0.009) were significantly greater in the PVTT group. Prolonged prothrombin time, lower platelet count, presence of extrahepatic metastasis, and Vp4 PVTT were independent risk factors related to high-risk varices in the total set of 206 patients with PVTT (Adjusted odds ratios [95% CIs], 1.662 [1.151–2.401]; 0.985 [0.978–0.993]; 4.240 [1.783–10.084]; and 3.345 [1.457–7.680], respectively; Ps < 0.05). During a median follow-up of 43.2 months, 10 patients with PVTT experienced variceal bleeding episodes, 9 of whom (90%) had high-risk varices. Presence of high-risk varices and sorafenib use for HCC treatment were significant predictors of variceal bleeding in the complete set of patients with PVTT (Adjusted hazard ratios [95% CIs], 26.432 [3.230–216.289]; and 5.676 [1.273–25.300], respectively; Ps < 0.05). Conclusions PVTT in HCC appears to increase the likelihood of high-risk varices and variceal bleeding. In HCC patients with PVTT, endoscopic prevention could be considered, at least in high-risk variceal carriers taking sorafenib.
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Affiliation(s)
- Jihye Lim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Ha Il Kim
- Gastroenterology, Kyung Hee University Hospital, Seoul, Republic of Korea
| | - Eunju Kim
- Gastroenterology, Department of Internal Medicine, Haeundae Paik Hospital, College of Medicine, Inje University, Busan, Republic of Korea
| | - Jiyoon Kim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Jihyun An
- Gastroenterology, Hanyang University College of Medicine, Guri, Gyeonggi-do, Republic of Korea
| | - Seheon Chang
- Internal Medicine, Myongji St. Mary's Hospital, Seoul, Republic of Korea
| | - Seon-Ok Kim
- Biostatistics and Clinical Epidemiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.,Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yung Sang Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.,Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea. .,Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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Gunarathne LS, Rajapaksha H, Shackel N, Angus PW, Herath CB. Cirrhotic portal hypertension: From pathophysiology to novel therapeutics. World J Gastroenterol 2020; 26:6111-6140. [PMID: 33177789 PMCID: PMC7596642 DOI: 10.3748/wjg.v26.i40.6111] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/28/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin II type receptor 1 blockers, which target the components of the classical renin angiotensin system (RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant off-target effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective -blockers (NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs. Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.
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Affiliation(s)
- Lakmie S Gunarathne
- Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia
| | - Harinda Rajapaksha
- School of Molecular Science, College of Science, Health and Engineering, La Trobe University, Bundoora, VIC 3086, Australia
| | | | - Peter W Angus
- Department of Gastroenterology, Austin Health, Heidelberg, VIC 3084, Australia
| | - Chandana B Herath
- Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia
- South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Ingham Institute for Applied Medical Research, 1 Campbell Street, Liverpool, NSW 2170, Australia
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Hidaka H, Uojima H, Nakazawa T, Shao X, Hara Y, Iwasaki S, Wada N, Kubota K, Tanaka Y, Shibuya A, Kanoh Y, Kokubu S, Koizumi W. Portal hemodynamic effects of lenvatinib in patients with advanced hepatocellular carcinoma: A prospective cohort study. Hepatol Res 2020; 50:1083-1090. [PMID: 32515895 DOI: 10.1111/hepr.13531] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/16/2020] [Accepted: 05/31/2020] [Indexed: 02/08/2023]
Abstract
AIM Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor, which suppress tumor angiogenesis and tumor progression. It was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma (HCC). Sorafenib had a beneficial effect on portocollateral circulation with portal hypertension in translating and clinical studies. However, the hemodynamic effects of lenvatinib appear to be different from those of sorafenib because the efficacy of lenvatinib for vascular endothelial growth factor receptors and fibroblast growth factor receptors is different from that of sorafenib. This study was prospectively performed to evaluate the portal hemodynamic effect of lenvatinib in patients with advanced HCC using duplex Doppler ultrasonography. METHODS In total, 28 Child-Pugh class A or B patients with advanced HCC received lenvatinib depending on body weight daily for 2 weeks. Primary outcomes were changes in the hemodynamics of the portal venous system using duplex Doppler ultrasonography before and after the 2-week administration of lenvatinib. RESULTS The portal venous flow velocity (cm/s) significantly reduced (27 ± 12.1 vs. 22.6 ± 8.0, P = 0.019), while portal venous area (cm2 ) did not change after the 2-week administration (0.80 ± 0.36 vs. 0.82 ± 0.27, P = 0.665). Therefore, the congestion index (portal venous area/portal venous flow velocity), which reflects the pathophysiological hemodynamics of the portal venous system significantly worsened (0.037 ± 0.025 vs. 0.043 ± 0.024, P = 0.045). CONCLUSIONS Considering that this was a short-term study, because lenvatinib could be an agent that aggravates portal hypertension, it will be necessary to verify its clinical effects for portal hypertension in future studies.
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Affiliation(s)
- Hisashi Hidaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takahide Nakazawa
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Xue Shao
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.,Department of Hepatopancreatobiliary Medicine, Second Hospital, Jilin University, Changchun, China
| | - Yusuke Hara
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Shuichiro Iwasaki
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Naohisa Wada
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kosuke Kubota
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoshiaki Tanaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Akitaka Shibuya
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yuhsaku Kanoh
- Department of Laboratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Shigehiro Kokubu
- Institute for Liver Disease Minimal Invasive Treatment, Shin Yurigaoka General Hospital, Kawasaki, Kanagawa, Japan
| | - Wasaburo Koizumi
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
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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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Bevacizumab Does Not Influence the Efficacy of Partial Splenic Embolization in the Management of Chemotherapy-Induced Hypersplenism. Clin Colorectal Cancer 2020; 19:e189-e199. [PMID: 32680816 DOI: 10.1016/j.clcc.2020.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 04/27/2020] [Accepted: 04/30/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND Antiangiogenics attenuate chemotherapy-related hepatotoxicity and portal hypertension. The potential impact of bevacizumab on the efficacy and safety of partial splenic embolization (PSE) in the management of chemotherapy-induced hypersplenism (CIH) has never been investigated. PATIENTS AND METHODS We conducted a retrospective study with gastrointestinal cancer patients who have undergone PSE for the treatment of thrombocytopenia resulting from hypersplenism. Pre- and post-PSE platelet count (PC), the percentage of patients who resumed systemic therapy, and complication rates were compared between patients exposed and not exposed to bevacizumab. RESULTS A total of 110 patients were eligible. Colorectal cancer was the predominant neoplasm (60%), and 5-fluorouracil, oxaliplatin, and bevacizumab were the most commonly provided drugs (70%, 65%, and 65% of patients, respectively). After PSE, 80% of patients recovered PC ≥ 100 × 109/L (100K). Systemic therapy was resumed in 81% of patients. Seventy-one patients exposed to bevacizumab had a median PC before PSE of 77.5K and after PSE of 167.0K, with a mean difference of 108K (P < .0001). Thirty-nine patients not exposed to bevacizumab had a median PC of pre-PSE of 73.0K and post-PSE of 187.0K, with a mean difference of 117.7K (P < .0001). Both groups had similar values of percentages of patients with PC post-PSE ≥ 100K (83% vs. 74%; P = .463), resumption of systemic therapy (85% vs. 74%; P = .213), and complication rates. A linear association between splenic infarction rate and increment in PC was found (P < .0001). CONCLUSION PSE is a safe and effective procedure in the management of CIH, regardless of the provision of bevacizumab. Splenic infarction rate should be optimized to enhance patient outcomes.
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50
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Iswandana R, Pham BT, Suriguga S, Luangmonkong T, van Wijk LA, Jansen YJM, Oosterhuis D, Mutsaers HAM, Olinga P. Murine Precision-cut Intestinal Slices as a Potential Screening Tool for Antifibrotic Drugs. Inflamm Bowel Dis 2020; 26:678-686. [PMID: 31943022 PMCID: PMC7150673 DOI: 10.1093/ibd/izz329] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Intestinal fibrosis is a hallmark of Crohn's disease. Here, we investigated the impact of several putative antifibrotic compounds on the expression of fibrosis markers using murine precision-cut intestinal slices. METHODS Murine precision-cut intestinal slices were cultured for 48 hours in the presence of profibrotic and/or antifibrotic compounds. The fibrotic process was studied on gene and protein level using procollagen 1a1 (Col1α1), heat shock protein 47 (Hsp47), fibronectin (Fn2), and plasminogen activator inhibitor-1 (Pai-1). The effects of potential antifibrotic drugs mainly inhibiting the transforming growth factor β (TGF-β) pathway (eg, valproic acid, tetrandrine, pirfenidone, SB203580, and LY2109761) and compounds mainly acting on the platelet-derived growth factor (PDGF) pathway (eg, imatinib, sorafenib, and sunitinib) were assessed in the model at nontoxic concentrations. RESULTS Murine precision-cut intestinal slices remained viable for 48 hours, and an increased expression of fibrosis markers was observed during culture, including Hsp47, Fn2, and Pai-1. Furthermore, TGF-β1 stimulated fibrogenesis, whereas PDGF did not have an effect. Regarding the tested antifibrotics, pirfenidone, LY2109761, and sunitinib had the most pronounced impact on the expression of fibrosis markers, both in the absence and presence of profibrotic factors, as illustrated by reduced levels of Col1α1, Hsp47, Fn2, and Pai-1 after treatment. Moreover, sunitinib significantly reduced Hsp47 and Fn2 protein expression and the excretion of procollagen 1. CONCLUSIONS Precision-cut intestinal slices can successfully be used as a potential preclinical screening tool for antifibrotic drugs. We demonstrated that sunitinib reduced the expression of several fibrosis markers, warranting further evaluation of this compound for the treatment of intestinal fibrosis.
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Affiliation(s)
- Raditya Iswandana
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands,Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia
| | - Bao Tung Pham
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands,Department of Pharmaceutics, Hanoi University of Pharmacy, Hanoi, Vietnam
| | - Su Suriguga
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Theerut Luangmonkong
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands,Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Louise A van Wijk
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Yvette J M Jansen
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Dorenda Oosterhuis
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Henricus Antonius Maria Mutsaers
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Peter Olinga
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands,Address correspondence to: Professor Peter Olinga, Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands. E-mail:
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