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Nirwan A, Saini D, Kaur J, Swain A, Sarkar A, Yadav PP, Mishra DP. Coagulin-L alleviates hepatic stellate cells activation and angiogenesis through modulation of the PI3K/AKT pathway during liver fibrosis. Biochem Pharmacol 2025; 238:116979. [PMID: 40345560 DOI: 10.1016/j.bcp.2025.116979] [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: 03/04/2025] [Revised: 04/08/2025] [Accepted: 05/06/2025] [Indexed: 05/11/2025]
Abstract
Fibrosis, a wound healing response in chronic liver diseases, is a potential therapeutic target during the disease progression. The activation of hepatic stellate cells (HSCs) plays a central role in liver fibrosis and depicts phenotypic change during fibrosis progression. Coagulin-L, a withanolide from Withania coagulans, has shown diverse biological activities, including anti-hyperglycemic and anti-dyslipidemic effects. However, its therapeutic efficacy against HSC activation, pathological angiogenesis and liver fibrosis is unknown. This study investigates the effects of Coagulin-L on HSC activation, pathological angiogenesis and validates these findings in vivo using a methionine and choline-deficient (MCD) diet-induced liver fibrosis model in C57BL/6 mice. Therapeutic efficacy of Coagulin-L was studied using transforming growth factor beta (TGF-β) activated HSC cell line LX-2 in vitro. Network pharmacology was used for target prediction, followed by Human umbilical vein endothelial cells (HUVEC) cell based angiogenic assays. The validation studies were carried out in a mice model of MCD diet induced liver fibrosis using serum biochemistry, histopathological assessment and immunohistochemistry methods. We found that Coagulin-L mitigated TGF-β induced activation of stellate cells and exhibited anti-angiogenic effects by downregulation of vascular endothelial growth factor (VEGF) expression and secretion from stellate cells with inhibition of the PI3K/AKT signaling pathway. In the MCD diet-induced liver fibrosis model, Coagulin-L alleviated liver injury, improved liver function, and reduced collagen deposition. Collectively, our results underscored the anti-fibrotic and anti-angiogenic effects of Coagulin-L in vitro and in vivo liver fibrosis models, thereby indicating its therapeutic potential in chronic liver diseases including metabolic dysfunctional-associated steatohepatitis (MASH).
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Affiliation(s)
- Abhishek Nirwan
- Cell Death Research Laboratory, Endocrinology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension Lucknow, Uttar Pradesh 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Deepika Saini
- Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension Lucknow, Uttar Pradesh 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Jaspreet Kaur
- Cell Death Research Laboratory, Endocrinology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension Lucknow, Uttar Pradesh 226031, India
| | - Abinash Swain
- Cell Death Research Laboratory, Endocrinology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension Lucknow, Uttar Pradesh 226031, India
| | - Abhisek Sarkar
- Cell Death Research Laboratory, Endocrinology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension Lucknow, Uttar Pradesh 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Prem Prakash Yadav
- Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension Lucknow, Uttar Pradesh 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Durga Prasad Mishra
- Cell Death Research Laboratory, Endocrinology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension Lucknow, Uttar Pradesh 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Harding-Fox SL, Cellek S. The role of cyclic adenosine monophosphate (cAMP) in pathophysiology of fibrosis. Drug Discov Today 2025; 30:104368. [PMID: 40318753 DOI: 10.1016/j.drudis.2025.104368] [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: 02/05/2025] [Revised: 04/11/2025] [Accepted: 04/28/2025] [Indexed: 05/07/2025]
Abstract
Fibrosis, the excessive production and disorganised deposition of extracellular matrix proteins, can occur in any organ system, disrupting functionality and causing fatality. The number, efficacy and safety of antifibrotic drugs are incredibly limited. Therapeutics which elevate intracellular cyclic adenosine monophosphate (cAMP) offer a potential solution. In this review, we present the signalling mechanisms involved in fibrosis pathophysiology, how cAMP and its effectors might interact with these pathways, and the current preclinical and clinical efforts in this field. cAMP elevating agents have the potential to be future antifibrotic drug candidates, but further studies are required, particularly to develop tissue specific therapeutics.
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Affiliation(s)
- Sophie L Harding-Fox
- Fibrosis Research Group, Medical Technology Research Centre, School of Allied Health and Social Care, Faculty of Health, Medicine and Social Care, Anglia Ruskin University, Chelmsford, Essex CM1 1SQ, UK.
| | - Selim Cellek
- Fibrosis Research Group, Medical Technology Research Centre, School of Allied Health and Social Care, Faculty of Health, Medicine and Social Care, Anglia Ruskin University, Chelmsford, Essex CM1 1SQ, UK
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Liu C, Li S, Zhang C, Jin CH. Recent Advances in Research on Active Compounds Against Hepatic Fibrosis. Curr Med Chem 2024; 31:2571-2628. [PMID: 37497688 DOI: 10.2174/0929867331666230727102016] [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: 12/16/2022] [Revised: 05/14/2023] [Accepted: 06/26/2023] [Indexed: 07/28/2023]
Abstract
BACKGROUND Almost all chronic liver diseases cause fibrosis, which can lead to cirrhosis and eventually liver cancer. Liver fibrosis is now considered to be a reversible pathophysiological process and suppression of fibrosis is necessary to prevent liver cancer. At present, no specific drugs have been found that have hepatic anti-fibrotic activity. OBJECTIVE The research progress of anti-hepatic fibrosis compounds in recent ten years was reviewed to provide a reference for the design and development of anti-hepatic fibrosis drugs. METHODS According to the structure of the compounds, they are divided into monocyclic compounds, fused-heterocyclic compounds, and acyclic compounds. RESULTS In this article, the natural products and synthetic compounds with anti-fibrotic activity in recent ten years were reviewed, with emphasis on their pharmacological activity and structure-activity relationship (SAR). CONCLUSION Most of these compounds are natural active products and their derivatives, and there are few researches on synthetic compounds and SAR studies on natural product.
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Affiliation(s)
- Chuang Liu
- Key Laboratory of Natural Resources of Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China
| | - Siqi Li
- Key Laboratory of Natural Resources of Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China
| | - Changhao Zhang
- Key Laboratory of Natural Resources of Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China
| | - Cheng-Hua Jin
- Key Laboratory of Natural Resources of Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China
- Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin, 133002, China
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Chang J, Huang C, Li S, Jiang X, Chang H, Li M. Research Progress Regarding the Effect and Mechanism of Dietary Polyphenols in Liver Fibrosis. Molecules 2023; 29:127. [PMID: 38202710 PMCID: PMC10779665 DOI: 10.3390/molecules29010127] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/02/2023] [Accepted: 12/18/2023] [Indexed: 01/12/2024] Open
Abstract
The development of liver fibrosis is a result of chronic liver injuries may progress to liver cirrhosis and liver cancer. In recent years, liver fibrosis has become a major global problem, and the incidence rate and mortality are increasing year by year. However, there are currently no approved treatments. Research on anti-liver-fibrosis drugs is a top priority. Dietary polyphenols, such as plant secondary metabolites, have remarkable abilities to reduce lipid metabolism, insulin resistance and inflammation, and are attracting more and more attention as potential drugs for the treatment of liver diseases. Gradually, dietary polyphenols are becoming the focus for providing an improvement in the treatment of liver fibrosis. The impact of dietary polyphenols on the composition of intestinal microbiota and the subsequent production of intestinal microbial metabolites has been observed to indirectly modulate signaling pathways in the liver, thereby exerting regulatory effects on liver disease. In conclusion, there is evidence that dietary polyphenols can be therapeutically useful in preventing and treating liver fibrosis, and we highlight new perspectives and key questions for future drug development.
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Affiliation(s)
- Jiayin Chang
- Department of Pharmacy, Baotou Medical College, Baotou 014040, China; (J.C.); (C.H.); (S.L.); (X.J.)
| | - Congying Huang
- Department of Pharmacy, Baotou Medical College, Baotou 014040, China; (J.C.); (C.H.); (S.L.); (X.J.)
| | - Siqi Li
- Department of Pharmacy, Baotou Medical College, Baotou 014040, China; (J.C.); (C.H.); (S.L.); (X.J.)
| | - Xiaolei Jiang
- Department of Pharmacy, Baotou Medical College, Baotou 014040, China; (J.C.); (C.H.); (S.L.); (X.J.)
| | - Hong Chang
- Department of Pharmacy, Baotou Medical College, Baotou 014040, China; (J.C.); (C.H.); (S.L.); (X.J.)
| | - Minhui Li
- Department of Pharmacy, Baotou Medical College, Baotou 014040, China; (J.C.); (C.H.); (S.L.); (X.J.)
- Inner Mongolia Autonomous Region Hospital of Traditional Chinese Medicine, Hohhot 010020, China
- Inner Mongolia Key Laboratory of Characteristic Geoherbs Resources Protection and Utilization, Baotou 014040, China
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Yang L, Liu YN, Gu Y, Guo Q. Deltonin enhances gastric carcinoma cell apoptosis and chemosensitivity to cisplatin via inhibiting PI3K/AKT/mTOR and MAPK signaling. World J Gastrointest Oncol 2023; 15:1739-1755. [PMID: 37969408 PMCID: PMC10631430 DOI: 10.4251/wjgo.v15.i10.1739] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/23/2023] [Accepted: 07/19/2023] [Indexed: 10/10/2023] Open
Abstract
BACKGROUND As an active ingredient derived from Dioscorea zingiberensis C.H. Wright, deltonin has been reported to show anti-cancer effects in a variety of malignancies. AIM To investigate the role and mechanism of action of deltonin in promoting gastric carcinoma (GC) cell apoptosis and chemosensitivity to cisplatin. METHODS The GC cell lines AGS, HGC-27, and MKN-45 were treated with deltonin and then subjected to flow cytometry and 3-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltetrazolium bromide assays for cell apoptosis and viability determination. Western blot analysis was conducted to examine alterations in the expression of apoptosis-related proteins (Bax, Bid, Bad, and Fas), DNA repair-associated proteins (Rad51 and MDM2), and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/AKT/mTOR) and p38-mitogen-activated protein kinase (MAPK) axis proteins. Additionally, the influence of deltonin on GC cell chemosensitivity to cisplatin was evaluated both in vitro and in vivo. RESULTS Deltonin treatment weakened viability, enhanced apoptosis, and dampened DNA repair in GC cell lines in a dose-dependent pattern. Furthermore, deltonin mitigated PI3K, AKT, mTOR, and p38-MAPK phosphorylation. HS-173, an inhibitor of PI3K, attenuated GC cell viability and abolished deltonin inhibition of GC cell viability and PI3K/AKT/mTOR and p38-MAPK pathway activation. Deltonin also promoted the chemosensitivity of GC cells to cisplatin via repressing GC cell proliferation and growth and accelerating apoptosis. CONCLUSION Deltonin can boost the chemosensitivity of GC cells to cisplatin via inactivating p38-MAPK and PI3K/AKT/mTOR signaling.
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Affiliation(s)
- Lin Yang
- Intensive Care Unit, Second Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Ya-Nan Liu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Yi Gu
- Nursing Department of Obstetrics and Gynecology, Second Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Qi Guo
- Department of Radiotherapy, Second Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
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Liao YJ, Lee CY, Twu YC, Suk FM, Lai TC, Chang YC, Lai YC, Yuan JW, Jhuang HM, Jian HR, Huang LC, Chen KP, Hsu MH. Isolation and Biological Evaluation of Alfa-Mangostin as Potential Therapeutic Agents against Liver Fibrosis. Bioengineering (Basel) 2023; 10:1075. [PMID: 37760177 PMCID: PMC10526009 DOI: 10.3390/bioengineering10091075] [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: 07/27/2023] [Revised: 08/18/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023] Open
Abstract
The increased proliferation and activation of hepatic stellate cells (HSCs) are associated with liver fibrosis development. To date, there are no FDA-approved drugs for the treatment of liver cirrhosis. Augmentation of HSCs apoptosis is one of the resolutions for liver fibrosis. In this study, we extracted α-mangostin (1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methyl-2-butenyl)-9H-xanthen-9-one) from the fruit waste components of mangosteen pericarp. The isolated α-mangostin structure was determined and characterized with nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) and compared with those known compounds. The intracellular signaling pathway activities of α-mangostin on Transforming growth factors-beta 1 (TGF-β1) or Platelet-derived growth factor subunit B (PDGF-BB) induced HSCs activation and were analyzed via Western blot and Real-time Quantitative Polymerase Chain Reaction (Q-PCR). α-Mangostin-induced mitochondrial dysfunction and apoptosis in HSCs were measured by seahorse assay and caspase-dependent cleavage. The in vivo anti-fibrotic effect of α-mangostin was assessed by carbon tetrachloride (CCl4) treatment mouse model. The data showed that α-mangostin treatment inhibited TGF-β1-induced Smad2/3 phosphorylation and alpha-smooth muscle actin (α-SMA) expression in HSCs in a dose-dependent manner. Regarding the PDGF-BB-induced HSCs proliferation signaling pathways, α-mangostin pretreatment suppressed the phosphorylation of extracellular-signal-regulated kinase (ERK) and p38. The activation of caspase-dependent apoptosis and dysfunction of mitochondrial respiration (such as oxygen consumption rate, ATP production, and maximal respiratory capacity) were observed in α-mangostin-treated HSCs. The CCl4-induced liver fibrosis mouse model showed that the administration of α-mangostin significantly decreased the expression of the fibrosis markers (α-SMA, collagen-a2 (col1a2), desmin and matrix metalloproteinase-2 (MMP-2)) as well as attenuated hepatic collagen deposition and liver damage. In conclusion, this study demonstrates that α-mangostin attenuates the progression of liver fibrosis through inhibiting the proliferation of HSCs and triggering apoptosis signals. Thus, α-mangostin may be used as a potential novel therapeutic agent against liver fibrosis.
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Affiliation(s)
- Yi-Jen Liao
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; (Y.-J.L.)
| | - Chun-Ya Lee
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; (Y.-J.L.)
| | - Yuh-Ching Twu
- Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Fat-Moon Suk
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Tzu-Chieh Lai
- Department of Chemistry, National Changhua University of Education, Changhua 500, Taiwan
| | - Ya-Ching Chang
- Department of Chemistry, National Changhua University of Education, Changhua 500, Taiwan
| | - Yi-Cheng Lai
- Department of Chemistry, National Changhua University of Education, Changhua 500, Taiwan
| | - Jing-Wei Yuan
- Department of Chemistry, National Changhua University of Education, Changhua 500, Taiwan
| | - Hong-Ming Jhuang
- Department of Chemistry, National Changhua University of Education, Changhua 500, Taiwan
| | - Huei-Ruei Jian
- Department of Chemistry, National Changhua University of Education, Changhua 500, Taiwan
| | - Li-Chia Huang
- Department of Chemistry, National Changhua University of Education, Changhua 500, Taiwan
| | - Kuang-Po Chen
- Department of Chemistry, Chinese Culture University, Taipei 111, Taiwan
| | - Ming-Hua Hsu
- Department of Chemistry, National Changhua University of Education, Changhua 500, Taiwan
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Liu Y, Lyu Y, Zhu L, Wang H. Role of TRP Channels in Liver-Related Diseases. Int J Mol Sci 2023; 24:12509. [PMID: 37569884 PMCID: PMC10420300 DOI: 10.3390/ijms241512509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/31/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
The liver plays a crucial role in preserving the homeostasis of an entire organism by metabolizing both endogenous and exogenous substances, a process that relies on the harmonious interactions of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells (KCs), and vascular endothelial cells (ECs). The disruption of the liver's normal structure and function by diverse pathogenic factors imposes a significant healthcare burden. At present, most of the treatments for liver disease are palliative in nature, rather than curative or restorative. Transient receptor potential (TRP) channels, which are extensively expressed in the liver, play a crucial role in regulating intracellular cation concentration and serve as the origin or intermediary stage of certain signaling pathways that contribute to liver diseases. This review provides an overview of recent developments in liver disease research, as well as an examination of the expression and function of TRP channels in various liver cell types. Furthermore, we elucidate the molecular mechanism by which TRP channels mediate liver injury, liver fibrosis, and hepatocellular carcinoma (HCC). Ultimately, the present discourse delves into the current state of research and extant issues pertaining to the targeting of TRP channels in the treatment of liver diseases and other ailments. Despite the numerous obstacles encountered, TRP channels persist as an extremely important target for forthcoming clinical interventions aimed at treating liver diseases.
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Affiliation(s)
- Yusheng Liu
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China; (Y.L.); (Y.L.)
| | - Yihan Lyu
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China; (Y.L.); (Y.L.)
| | - Lijuan Zhu
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing 210009, China;
| | - Hongmei Wang
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China; (Y.L.); (Y.L.)
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Pei Q, Yi Q, Tang L. Liver Fibrosis Resolution: From Molecular Mechanisms to Therapeutic Opportunities. Int J Mol Sci 2023; 24:ijms24119671. [PMID: 37298621 DOI: 10.3390/ijms24119671] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 05/25/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
The liver is a critical system for metabolism in human beings, which plays an essential role in an abundance of physiological processes and is vulnerable to endogenous or exogenous injuries. After the damage to the liver, a type of aberrant wound healing response known as liver fibrosis may happen, which can result in an excessive accumulation of extracellular matrix (ECM) and then cause cirrhosis or hepatocellular carcinoma (HCC), seriously endangering human health and causing a great economic burden. However, few effective anti-fibrotic medications are clinically available to treat liver fibrosis. The most efficient approach to liver fibrosis prevention and treatment currently is to eliminate its causes, but this approach's efficiency is too slow, or some causes cannot be fully eliminated, which causes liver fibrosis to worsen. In cases of advanced fibrosis, the only available treatment is liver transplantation. Therefore, new treatments or therapeutic agents need to be explored to stop the further development of early liver fibrosis or to reverse the fibrosis process to achieve liver fibrosis resolution. Understanding the mechanisms that lead to the development of liver fibrosis is necessary to find new therapeutic targets and drugs. The complex process of liver fibrosis is regulated by a variety of cells and cytokines, among which hepatic stellate cells (HSCs) are the essential cells, and their continued activation will lead to further progression of liver fibrosis. It has been found that inhibiting HSC activation, or inducing apoptosis, and inactivating activated hepatic stellate cells (aHSCs) can reverse fibrosis and thus achieve liver fibrosis regression. Hence, this review will concentrate on how HSCs become activated during liver fibrosis, including intercellular interactions and related signaling pathways, as well as targeting HSCs or liver fibrosis signaling pathways to achieve the resolution of liver fibrosis. Finally, new therapeutic compounds targeting liver fibrosis are summarized to provide more options for the therapy of liver fibrosis.
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Affiliation(s)
- Qiying Pei
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Qian Yi
- Department of Physiology, School of Basic Medical Science, Southwest Medical University, Luzhou 646000, China
| | - Liling Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
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Wu CP, Hung CY, Hsieh YJ, Murakami M, Huang YH, Su TY, Hung TH, Yu JS, Wu YS, Ambudkar SV. ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines. Cells 2023; 12:cells12071056. [PMID: 37048130 PMCID: PMC10093605 DOI: 10.3390/cells12071056] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/27/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023] Open
Abstract
Constitutive activation of the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is crucial for tumor growth and progression. As such, this pathway has been an enticing target for drug discovery. Although HS-173 is a potent PI3K inhibitor that halts cancer cell proliferation via G2/M cell cycle arrest, the resistance mechanisms to HS-173 have not been investigated. In this study, we investigated the susceptibility of HS-173 to efflux mediated by the multidrug efflux transporters ABCB1 and ABCG2, which are two of the most well-known ATP-binding cassette (ABC) transporters associated with the development of cancer multidrug resistance (MDR). We found that the overexpression of ABCB1 or ABCG2 significantly reduced the efficacy of HS-173 in human cancer cells. Our data show that the intracellular accumulation of HS-173 was substantially reduced by ABCB1 and ABCG2, affecting G2/M arrest and apoptosis induced by HS-173. More importantly, the efficacy of HS-173 in multidrug-resistant cancer cells could be recovered by inhibiting the drug-efflux function of ABCB1 and ABCG2. Taken together, our study has demonstrated that HS-173 is a substrate for both ABCB1 and ABCG2, resulting in decreased intracellular concentration of this drug, which may have implications for its clinical use.
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Affiliation(s)
- Chung-Pu Wu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan
| | - Cheng-Yu Hung
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Ya-Ju Hsieh
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Megumi Murakami
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Yang-Hui Huang
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan
| | - Tsung-Yao Su
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Tai-Ho Hung
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Jau-Song Yu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 33302, Taiwan
| | - Yu-Shan Wu
- Department of Chemistry, Tunghai University, Taichung 40704, Taiwan
| | - Suresh V. Ambudkar
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
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10
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Cho YA, Ko IG, Jin JJ, Hwang L, Kim SH, Jeon JW, Yang MJ, Kim CJ. Polydeoxyribonucleotide ameliorates alcoholic liver injury though suppressing phosphatidylinositol 3-kinase/protein kinase B signaling pathway in mice. J Exerc Rehabil 2022; 18:350-355. [PMID: 36684531 PMCID: PMC9816614 DOI: 10.12965/jer.2244504.252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 11/03/2022] [Indexed: 12/29/2022] Open
Abstract
Polydeoxyribonucleotide (PDRN), which is adenosine A2A receptor agonist, facilitates healing and inhibits inflammation and apoptosis. The effect of PDRN on alcoholic liver injury (ALI) was evaluated focusing on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. The mice were given daily oral administration of 50% ethanol at a dose of 4 g/kg during 8 weeks. After 4 weeks of alcohol intake, 200 μL of normal saline containing 8-mg/kg PDRN was intraperitoneally administered 3 times a week for 4 weeks. To determine whether the action of PDRN occurs through the adenosine A2A receptor, 8-mg/kg 3,7-dimethyl-1-propargylxanthine (DMPX) with PDRN was treated. The concentration of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was detected. For liver histopathological score, hematoxylin and eosin staining was conducted. Enzyme-linked immunoassay was used to measure cyclic adenosine-3',5'-monophosphate (cAMP) concentration. PI3K and Akt expression was determined using Western blot analysis. In the results, PDRN treatment suppressed AST and ALT level in serum and liver tissue, and improved damaged liver tissue and decreased histological score. PDRN application inhibited the expression of phosphorylated PI3K/Akt signaling pathway. The increasing effect of PDRN on cAMP level ats as a mechanism for ALI treatment. Co-treatment of DMPX with PDRN did not reduce apoptosis, causing no improvement in liver function. As a result of this experiment, PDRN has the potential to be selected as a therapeutic agent for ALI.
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Affiliation(s)
- Young-A Cho
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul,
Korea
| | - Il-Gyu Ko
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul,
Korea
| | - Jun-Jang Jin
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul,
Korea
| | - Lakkyong Hwang
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul,
Korea
| | - Sang-Hoon Kim
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul,
Korea,Department of Sport and Health Sciences, College of Art and Culture, Sangmyung University, Seoul,
Korea
| | - Jung Won Jeon
- Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul,
Korea
| | - Myoung Joo Yang
- Department of Sports Science, Hongik University, Sejong,
Korea
| | - Chang-Ju Kim
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul,
Korea,Corresponding author: Chang-Ju Kim, Department of Physiology, College of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea,
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11
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Rampa DR, Feng H, Allur-Subramaniyan S, Shim K, Pekcec A, Lee D, Doods H, Wu D. Kinin B1 receptor blockade attenuates hepatic fibrosis and portal hypertension in chronic liver diseases in mice. J Transl Med 2022; 20:590. [PMID: 36514072 PMCID: PMC9746183 DOI: 10.1186/s12967-022-03808-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 12/03/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND AIMS Kinin B1 receptors (B1Rs) are implicated in the pathogenesis of fibrosis. This study examined the anti-fibrotic effects of B1R blockade with BI 113823 in two established mouse models of hepatic fibrosis induced by intraperitoneal carbon tetrachloride (CCl4) injection or bile duct ligation (BDL). The mechanisms underlying the protection afforded by B1R inhibition were examined using human peripheral blood cells and LX2 human hepatic stellate cells (HSCs). METHODS Fibrotic liver diseases were induced in mice by intraperitoneal carbon tetrachloride (CCl4) injection for 6 weeks, and by bile duct ligation (BDL) for 3 weeks, respectively. Mice received daily treatment of vehicle or BI 113823 (B1R antagonist) from onset of the experiment until the end of the study. RESULTS B1Rs were strongly induced in fibrotic mouse liver. BI 113823 significantly attenuated liver fibrosis and portal hypertension (PH), and improved survival in both CCl4 and BDL mice. BI 113823 significantly reduced the expression of fibrotic proteins α-SMA, collagens 1, 3, 4, and profibrotic growth factors PDGF, TGFβ, CTGF, VEGF, proliferating cell nuclear antigen; and reduced hepatic Akt phosphorylation in CCl4- and BDL-induced liver fibrosis. BI 113823 also reduced expression of Cytokines IL-1, IL-6; chemokines MCP-1, MCP-3 and infiltration of inflammatory cells; and inhibited human monocyte and neutrophil activation, transmigration, TNF-α & MPO production in vitro. BI 113823 inhibited TGF-β and B1R agonist-stimulated human-HSC activation, contraction, proliferation, migration and fibrosis protein expression, and inhibited activation of PI3K/Akt signalling pathway. CONCLUSIONS B1Rs merits consideration as a novel therapeutic target for chronic liver fibrosis and PH.
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Affiliation(s)
- Dileep Reddy Rampa
- grid.411545.00000 0004 0470 4320Department of Bio-Nanotechnology and Bio-Convergence Engineering, Jeonbuk National University, Jeonju, South Korea
| | - Huiying Feng
- grid.411545.00000 0004 0470 4320Department of Bio-Nanotechnology and Bio-Convergence Engineering, Jeonbuk National University, Jeonju, South Korea
| | - Sivakumar Allur-Subramaniyan
- grid.411545.00000 0004 0470 4320Department of Animal Biotechnology & Agricultural Convergence Technology, Jeonbuk National University, Jeonju, South Korea
| | - Kwanseob Shim
- grid.411545.00000 0004 0470 4320Department of Animal Biotechnology & Agricultural Convergence Technology, Jeonbuk National University, Jeonju, South Korea
| | - Anton Pekcec
- grid.420061.10000 0001 2171 7500Research Beyond Borders, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Dongwon Lee
- grid.411545.00000 0004 0470 4320Department of Bio-Nanotechnology and Bio-Convergence Engineering, Jeonbuk National University, Jeonju, South Korea
| | - Henri Doods
- grid.420061.10000 0001 2171 7500Research Beyond Borders, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Dongmei Wu
- grid.411545.00000 0004 0470 4320Department of Bio-Nanotechnology and Bio-Convergence Engineering, Jeonbuk National University, Jeonju, South Korea ,grid.410396.90000 0004 0430 4458Department of Research, Mount Sinai Medical Center, Miami Beach, FL USA
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12
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Basta MD, Menko AS, Walker JL. PI3K Isoform-Specific Regulation of Leader and Follower Cell Function for Collective Migration and Proliferation in Response to Injury. Cells 2022; 11:3515. [PMID: 36359913 PMCID: PMC9658457 DOI: 10.3390/cells11213515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/02/2022] [Accepted: 11/04/2022] [Indexed: 07/29/2023] Open
Abstract
To ensure proper wound healing it is important to elucidate the signaling cues that coordinate leader and follower cell behavior to promote collective migration and proliferation for wound healing in response to injury. Using an ex vivo post-cataract surgery wound healing model we investigated the role of class I phosphatidylinositol-3-kinase (PI3K) isoforms in this process. Our findings revealed a specific role for p110α signaling independent of Akt for promoting the collective migration and proliferation of the epithelium for wound closure. In addition, we found an important role for p110α signaling in orchestrating proper polarized cytoskeletal organization within both leader and wounded epithelial follower cells to coordinate their function for wound healing. p110α was necessary to signal the formation and persistence of vimentin rich-lamellipodia extensions by leader cells and the reorganization of actomyosin into stress fibers along the basal domains of the wounded lens epithelial follower cells for movement. Together, our study reveals a critical role for p110α in the collective migration of an epithelium in response to wounding.
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Affiliation(s)
- Morgan D. Basta
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - A. Sue Menko
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Department of Ophthalmology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Janice L. Walker
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Department of Ophthalmology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
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13
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Wei C, Qiu J, Wu Y, Chen Z, Yu Z, Huang Z, Yang K, Hu H, Liu F. Promising traditional Chinese medicine for the treatment of cholestatic liver disease process (cholestasis, hepatitis, liver fibrosis, liver cirrhosis). JOURNAL OF ETHNOPHARMACOLOGY 2022; 297:115550. [PMID: 35863612 DOI: 10.1016/j.jep.2022.115550] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/04/2022] [Accepted: 07/13/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cholestatic liver disease (CLD) is mainly characterized by cholestasis. If not treated, it will deteriorate to cholestatic hepatitis, liver fibrosis, liver cirrhosis, and even liver failure. CLD has a high clinical incidence, and limited treatment with single therapy. In the long-term clinical exploration, traditional Chinese medicine (TCM) has been corroborated with unique therapeutic effects on the CLD process. AIM OF THIS REVIEW This paper summarizes the effective single and compound TCMs for the treatment of CLD. According to 4 important clinical stages of CLD: cholestasis, hepatitis, liver fibrosis, liver cirrhosis, pharmacological effects and mechanisms of 5 typical TCM examples are reviewed, aims to provide basis for clinical drug selection in different processes of CLD. MATERIALS AND METHODS Relevant scientific articles regarding therapeutic effects of TCM for the CLD were collected from different databases. We collated three single herbs including Artemisia scoparia Waldst. et Kit. or Artemisia capillaris Thunb. (Artemisiae Scopariae Herba, Yin Chen in Chinese), Paeonia lactiflora Pall. or Paeonia veitchii Lynch. (Paeoniae radix rubra, Chi Shao in Chinese), Poria cocos (Schw.) Wolf (Poria, Fu Ling in Chinese), and two compound herbs of Huang Qi Decoction (HQD) and Yin Chen Hao Decoction (YCHD) to studied and analyzed. RESULTS We proposed five promising TCMs treatments for the important developmental stages of CLD. Among them, Yin Chen is an essential medicine for protecting liver and gallbladder, and its TCM prescription is also a promising strategy for cholestasis. Based on clinical evidence, high-dose application of Chi Shao is a clinical special treatment of cholestasis hepatitis. Fu Ling can regulate immune cells and increase antibody levels in serum, which is expected to be an emerging therapy to prevent cholestatic liver fibrosis to cirrhosis. HQD can be used as routine clinical medicine for liver fibrosis. In addition, YCHD can exert better comprehensive advantages with multiple components, can treat the whole course of CLD and prevent it from developing to the end-stage. CONCLUSION Yin Chen, Chi Shao, Fu Ling, HQD and YCHD have shown good clinical efficacy in controlling the development of CLD. Clinically, it is easier to curb the development of CLD by adopting graded diagnosis and treatment measures. We suggest that CLD should be risk stratified in clinical treatment to ensure personalized treatment for patients, so as to slow down the development of the disease.
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Affiliation(s)
- Chunlei Wei
- Key Laboratory of Standardization of Chinese Herbal Medicine, Ministry of Education, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan, Chengdu, 611137, China.
| | - Jing Qiu
- Key Laboratory of Standardization of Chinese Herbal Medicine, Ministry of Education, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan, Chengdu, 611137, China.
| | - Yuyi Wu
- Key Laboratory of Standardization of Chinese Herbal Medicine, Ministry of Education, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan, Chengdu, 611137, China.
| | - Ziqiang Chen
- Key Laboratory of Standardization of Chinese Herbal Medicine, Ministry of Education, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan, Chengdu, 611137, China.
| | - Ziwei Yu
- Key Laboratory of Standardization of Chinese Herbal Medicine, Ministry of Education, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan, Chengdu, 611137, China.
| | - Zecheng Huang
- Key Laboratory of Standardization of Chinese Herbal Medicine, Ministry of Education, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan, Chengdu, 611137, China.
| | - Ke Yang
- Key Laboratory of Standardization of Chinese Herbal Medicine, Ministry of Education, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan, Chengdu, 611137, China.
| | - Huiling Hu
- Key Laboratory of Standardization of Chinese Herbal Medicine, Ministry of Education, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan, Chengdu, 611137, China.
| | - Fang Liu
- Key Laboratory of Standardization of Chinese Herbal Medicine, Ministry of Education, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan, Chengdu, 611137, China.
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14
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Booijink R, Salgado‐Polo F, Jamieson C, Perrakis A, Bansal R. A type IV Autotaxin inhibitor ameliorates acute liver injury and nonalcoholic steatohepatitis. EMBO Mol Med 2022; 14:e16333. [PMID: 35833384 PMCID: PMC9449594 DOI: 10.15252/emmm.202216333] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 11/09/2022] Open
Abstract
The lysophosphatidic acid (LPA) signaling axis is an important but rather underexplored pathway in liver disease. LPA is predominantly produced by Autotaxin (ATX) that has gained significant attention with an impressive number of ATX inhibitors (type I-IV) reported. Here, we evaluated the therapeutic potential of a (yet unexplored) type IV inhibitor, Cpd17, in liver injury. We first confirmed the involvement of the ATX-LPA signaling axis in human and murine diseased livers. Then, we evaluated the effects of Cpd17, in comparison with the classic type I inhibitor PF8380, in vitro, where Cpd17 showed higher efficacy. Thereafter, we characterized the mechanism-of-action of both inhibitors and found that Cpd17 was more potent in inhibiting RhoA-mediated cytoskeletal remodeling, and phosphorylation of MAPK/ERK and AKT/PKB. Finally, the therapeutic potential of Cpd17 was investigated in CCl4 -induced acute liver injury and diet-induced nonalcoholic steatohepatitis, demonstrating an excellent potential of Cpd17 in reducing liver injury in both disease models in vivo. We conclude that ATX inhibition, by type IV inhibitor in particular, has an excellent potential for clinical application in liver diseases.
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Affiliation(s)
- Richell Booijink
- Translational Liver Research, Department of Medical Cell BioPhysics, Faculty of Science and TechnologyUniversity of TwenteEnschedeThe Netherlands
- Oncode Institute, Division of BiochemistryNetherlands Cancer InstituteAmsterdamThe Netherlands
| | - Fernando Salgado‐Polo
- Oncode Institute, Division of BiochemistryNetherlands Cancer InstituteAmsterdamThe Netherlands
| | - Craig Jamieson
- Department of Pure and Applied ChemistryUniversity of StrathclydeGlasgowUK
| | - Anastassis Perrakis
- Oncode Institute, Division of BiochemistryNetherlands Cancer InstituteAmsterdamThe Netherlands
| | - Ruchi Bansal
- Translational Liver Research, Department of Medical Cell BioPhysics, Faculty of Science and TechnologyUniversity of TwenteEnschedeThe Netherlands
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15
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Menko AS, Walker JL. The Pro-Fibrotic Response to Lens Injury Is Signaled in a PI3K Isoform-Specific Manner. Biomolecules 2022; 12:1181. [PMID: 36139020 PMCID: PMC9496593 DOI: 10.3390/biom12091181] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 08/18/2022] [Accepted: 08/23/2022] [Indexed: 12/11/2022] Open
Abstract
The signaling inputs that function to integrate biochemical and mechanical cues from the extracellular environment to alter the wound-repair outcome to a fibrotic response remain poorly understood. Here, using a clinically relevant post-cataract surgery wound healing/fibrosis model, we investigated the role of Phosphoinositide-3-kinase (PI3K) class I isoforms as potential signaling integrators to promote the proliferation, emergence and persistence of collagen I-producing alpha smooth muscle actin (αSMA+) myofibroblasts that cause organ fibrosis. Using PI3K isoform specific small molecule inhibitors, our studies revealed a requisite role for PI3K p110α in signaling the CD44+ mesenchymal leader cell population that we previously identified as resident immune cells to produce and organize a fibronectin-EDA rich provisional matrix and transition to collagen I-producing αSMA+ myofibroblasts. While the PI3K effector Akt was alone insufficient to regulate myofibroblast differentiation, our studies revealed a role for Rac, another potential PI3K effector, in this process. Our studies further uncovered a critical role for PI3K p110α in signaling the proliferation of CD44+ leader cells, which is important to the emergence and expansion of myofibroblasts. Thus, these studies identify activation of PI3K p110α as a critical signaling input following wounding to the development and progression of fibrotic disease.
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Affiliation(s)
- A. Sue Menko
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Department of Ophthalmology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Janice L. Walker
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Department of Ophthalmology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
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16
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Kitsugi K, Noritake H, Matsumoto M, Hanaoka T, Umemura M, Yamashita M, Takatori S, Ito J, Ohta K, Chida T, Ulmasov B, Neuschwander-Tetri BA, Suda T, Kawata K. Arg-Gly-Asp-binding integrins activate hepatic stellate cells via the hippo signaling pathway. Cell Signal 2022; 99:110437. [PMID: 35970425 DOI: 10.1016/j.cellsig.2022.110437] [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: 05/22/2022] [Revised: 07/27/2022] [Accepted: 08/09/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND & AIMS Liver fibrosis characterizes advanced chronic liver disease, and persistent activation of hepatic stellate cells (HSCs) is the primary cause of excessive hepatic fibrogenesis. CWHM12, an analog of the arginine-glycine-aspartic acid (RGD) amino acid sequence found in specific integrins, improves liver fibrosis; however, the detailed mechanisms remain unclear. This study aimed to clarify the cell signaling mechanisms of CWHM12 in activated HSCs. METHODS Immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on intracellular signaling via the disruption of RGD-binding integrins. RESULTS CWHM12 strongly promoted phosphorylation and inhibited the nuclear accumulation of Yes-associated protein (YAP), which is a critical effector of the Hippo signaling pathway, leading to the inhibition of proliferation, suppression of viability, promotion of apoptosis, and induction of cell cycle arrest at the G1 phase in activated HSCs. Further investigations revealed that inhibition of TGF-β was involved in the consequences of CWHM12. Moreover, CWHM12 suppressed focal adhesion kinase (FAK) phosphorylation; consequently, Src, phosphatidylinositol 3-kinase, pyruvate dehydrogenase kinase 1, and serine-threonine kinase phosphorylation led to the translocation of YAP. These favorable effects of CWHM12 on activated HSCs were reversed by inhibiting FAK. CONCLUSIONS These results indicate that pharmacological inhibition of RGD-binding integrins suppresses activated HSCs by blocking the Hippo signaling pathway, a cellular response which may be valuable in the treatment of hepatic fibrosis.
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Affiliation(s)
- Kensuke Kitsugi
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Hidenao Noritake
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
| | - Moe Matsumoto
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Tomohiko Hanaoka
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Masahiro Umemura
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Maho Yamashita
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Shingo Takatori
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Jun Ito
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kazuyoshi Ohta
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Takeshi Chida
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Barbara Ulmasov
- Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO, United States of America
| | - Brent A Neuschwander-Tetri
- Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO, United States of America
| | - Takafumi Suda
- Division of Respiratory Medicine, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kazuhito Kawata
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
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17
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Hydrophobic Bile Salts Induce Pro-Fibrogenic Proliferation of Hepatic Stellate Cells through PI3K p110 Alpha Signaling. Cells 2022; 11:cells11152344. [PMID: 35954188 PMCID: PMC9367387 DOI: 10.3390/cells11152344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/08/2022] [Accepted: 07/26/2022] [Indexed: 11/17/2022] Open
Abstract
Bile salts accumulating during cholestatic liver disease are believed to promote liver fibrosis. We have recently shown that chenodeoxycholate (CDC) induces expansion of hepatic stellate cells (HSCs) in vivo, thereby promoting liver fibrosis. Mechanisms underlying bile salt-induced fibrogenesis remain elusive. We aimed to characterize the effects of different bile salts on HSC biology and investigated underlying signaling pathways. Murine HSCs (mHSCs) were stimulated with hydrophilic and hydrophobic bile salts. Proliferation, cell mass, collagen deposition, and activation of signaling pathways were determined. Activation of the human HSC cell line LX 2 was assessed by quantification of α-smooth muscle actin (αSMA) expression. Phosphatidyl-inositol-3-kinase (PI3K)-dependent signaling was inhibited both pharmacologically and by siRNA. CDC, the most abundant bile salt accumulating in human cholestasis, but no other bile salt tested, induced Protein kinase B (PKB) phosphorylation and promoted HSC proliferation and subsequent collagen deposition. Pharmacological inhibition of the upstream target PI3K-inhibited activation of PKB and pro-fibrogenic proliferation of HSCs. The PI3K p110α-specific inhibitor Alpelisib and siRNA-mediated knockdown of p110α ameliorated pro-fibrogenic activation of mHSC and LX 2 cells, respectively. In summary, pro-fibrogenic signaling in mHSCs is selectively induced by CDC. PI3K p110α may be a potential therapeutic target for the inhibition of bile salt-induced fibrogenesis in cholestasis.
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18
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Forsythiaside A Regulates Activation of Hepatic Stellate Cells by Inhibiting NOX4-Dependent ROS. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9938392. [PMID: 35035671 PMCID: PMC8754607 DOI: 10.1155/2022/9938392] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 07/27/2021] [Accepted: 12/03/2021] [Indexed: 11/30/2022]
Abstract
Hepatic stellate cells (HSCs) activation is an important step in the process of hepatic fibrosis. NOX4 and reactive oxygen species expressed in HSCs play an important role in liver fibrosis. Forsythiaside A (FA), a phenylethanoid glycoside extracted and isolated from Forsythiae Fructus, has significant antioxidant activities. However, it is not clear whether FA can play a role in inhibiting the HSCs activation through regulating NOX4/ROS pathway. Therefore, our purpose is to explore the effect and mechanism of FA on HSCs activation to alleviate liver fibrosis. LX2 cells were activated by TGF-β1 in vitro. MTT assay and Wound Healing assay were used to investigate the effect of FA on TGF-β1-induced LX2 cell proliferation and migration. Elisa kit was used to measure the expression of MMP-1 and TIMP-1. Western blot and RT-qPCR were used to investigate the expression of fibrosis-related COLI, α-SMA, MMP-1 and TIMP-1, and inflammation-related TNF-α, IL-6 and IL-1β. The hydroxyproline content was characterized using a biochemical kit. The mechanism of FA to inhibit HSCs activation and apoptosis was detected by DCF-DA probe, RT-qPCR, western blot and flow cytometry. NOX4 siRNA was used to futher verify the effect of FA on NOX4/ROS pathway. The results showed that FA inhibited the proliferation and migration of LX2 cells and adjusted the expression of MMP-1, TIMP-1, COLI, α-SMA, TNF-α, IL-6 and IL-1β as well as promoted collagen metabolism to show potential in anti-hepatic fibrosis. Mechanically, FA down-regulated NOX4/ROS signaling pathway to improve oxidation imbalances, and subsequently inhibited PI3K/Akt pathway to suppress proliferation. FA also promoted the apoptosis of LX2 cells by Bax/Bcl2 pathway. Furthermore, the effects of FA on TGF-β1-induced increased ROS levels and α-SMA and COLI expression were weaken by silencing NOX4. In conclusion, FA had potential in anti-hepatic fibrosis at least in part by remolding of extracellular matrix and improving oxidation imbalances to inhibit the activation of HSCs and promote HSCs apoptosis.
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19
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Chen Z, Lin Z, Yu J, Zhong H, Zhuo X, Jia C, Wan Y. Mitofusin-2 Restrains Hepatic Stellate Cells' Proliferation via PI3K/Akt Signaling Pathway and Inhibits Liver Fibrosis in Rats. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:6731335. [PMID: 35083025 PMCID: PMC8786480 DOI: 10.1155/2022/6731335] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/20/2021] [Accepted: 12/24/2021] [Indexed: 12/20/2022]
Abstract
The mitochondrial GTPase mitofusin-2 (MFN2) gene can suppress the cell cycle and regulate cell proliferation in a number of cell types. However, its function in hepatic fibrosis remains largely unexplored. We attempted to understand the mechanism of MFN2 in hepatic stellate cell (HSC) proliferation and the development of hepatic fibrosis. Rat HSC-T6 HSC were cultured and transfected by adenovirus- (Ad-) Mfn2 or its negative control (NC) vector (Ad-green fluorescent protein (GFP)); a rat liver cirrhosis model was established via subcutaneous injection with carbon tetrachloride (CCl4). Seventy-two rats were randomly divided into four groups: CCl4, Mfn2, GFP, and NC. Ad-Mfn2 or Ad-GFP was transfected into the circulation via intravenous injection at day 1, 14, 28, 42, or 56 after the first injection of CCl4 in the Mfn2/GFP groups. Biomarkers related to HSC proliferation and the development of hepatic fibrosis were detected using western blotting, hematoxylin-eosin and Masson staining, and immunohistochemistry. In vitro, Mfn2 interfered specifically with platelet-derived growth factor- (PDGF-) induced signaling pathway (phosphatidylinositol 3-kinase- (PI3K-) AKT), inhibiting HSC-T6 cell activation and proliferation. During the process of hepatic fibrosis in vivo, extracellular collagen deposition and the expression of fibrosis-related proteins increased progressively, while Mfn2 expression decreased gradually. Upregulating Mfn2 expression at the early stage of fibrosis impeded the process, triggered the downregulation of type I collagen, and antagonized the formation of factors associated with liver fibrosis. Mfn2 suppresses HSC proliferation and activation and exhibits antifibrotic potential in early-stage hepatic fibrosis. Therefore, it may represent a significant therapeutic target for eradicating hepatic fibrosis.
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Affiliation(s)
- Zhiping Chen
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
| | - Zeyu Lin
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
| | - Jiandong Yu
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
| | - Haifeng Zhong
- Department of Hepatobiliary Surgery, Meizhou People's Hospital, Meizhou Hospital Affiliate to Sun Yat-Sen University, Meizhou 514021, Guangdong Province, China
| | - Xianhua Zhuo
- Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
| | - Changku Jia
- Department of Hepatobiliary Surgery, The Affiliated Hangzhou First People's Hospital,School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Yunle Wan
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
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Mohammed RA, Shawky HM, Rashed LA, Elhanbuli HM, Abdelhafez DN, Said ES, Shamardan RM, Mahmoud RH. Combined effect of hydrogen sulfide and mesenchymal stem cells on mitigating liver fibrosis induced by bile duct ligation: Role of anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-fibrotic biomarkers. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:1753-1762. [PMID: 35432809 PMCID: PMC8976911 DOI: 10.22038/ijbms.2021.56477.12604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 10/30/2021] [Indexed: 12/04/2022]
Abstract
OBJECTIVES Liver fibrosis eventually develops into cirrhosis and hepatic failure, which can only be treated with liver transplantation. We aimed to assess the potential role of hydrogen sulfide (H2S) alone and combined with bone marrow-derived mesenchymal stem cells (BM-MSCs) on hepatic fibrosis induced by bile-duct ligation (BDL) and to compare their effects to silymarin. MATERIALS AND METHODS Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), and alkaline phosphatase (ALP) were investigated in serum. Gene expression levels of CBS (cystathionine β-synthase), CSE (cystathionine γ-lyase), and alpha-smooth muscle actin (α- SMA) were measured in liver tissues using RT-PCR. Hepatic protein kinase (Akt) was assessed by Western blot assay. Liver oxidative stress markers, malondialdehyde (MDA), and reduced glutathione (GSH) were analyzed by the colorimetric method. Lipocalin-2 (LCN2) and transforming growth factor-β (TGF-β) were measured using ELIZA. Liver tissues were examined by H&E and Masson trichome staining for detection of liver necrosis or fibrosis. Caspase 3 expression was evaluated by immunohistochemistry. RESULTS H2S and BM-MSCs ameliorated liver function and inhibited inflammation and oxidative stress detected by significantly decreased serum ALT, AST, ALP, TB, and hepatic MDA, Akt, TGF-β, LCN2, and α-SMA expression and significantly increased CBS and CSE gene expression levels. They attenuated hepatic apoptosis evidenced by decreased hepatic caspase expression. CONCLUSION Combined treatment with H2S and BM-MSCs could attenuate liver fibrosis induced by BDL through mechanisms such as anti-inflammation, anti-oxidation, anti-apoptosis, anti-fibrosis, and regenerative properties indicating that using H2S and MSCs may represent a promising approach for management of cholestatic liver fibrosis.
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Affiliation(s)
| | | | - Laila Ahmed Rashed
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Egypt
| | | | | | - Eman Sayed Said
- Departments of Pharmacology, Faculty of Medicine, Fayoum University, Egypt,Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 52571, Saudi Arabia
| | | | - Rania Hosny Mahmoud
- Departments of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Egypt,Corresponding author: Rania Hosny Mahmoud. Saad Zaghloul Street, Fayoum, Egypt. Postal code: 63511.Email address: ;
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21
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Kim HY, Ahn SB, Hong JM, Oh JH, Saeed WK, Kim GS, Kim H, Kang JK, Kang S, Jun DW. BTT-105 ameliorates hepatic fibrosis in non-alcoholic fatty liver animal model. FASEB J 2021; 35:e21979. [PMID: 34694029 DOI: 10.1096/fj.202002656rrr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 09/08/2021] [Accepted: 09/22/2021] [Indexed: 12/29/2022]
Abstract
BTT-105 (1-O-hexyl-2,3,5-trimethylhydroquinone), a hydroquinone derivative, is a potent anti-oxidant that was safe and tolerable in phase I clinical trial. This study examined the anti-fibrotic effect of BTT-105 in a mouse model of non-alcoholic fatty liver disease (NAFLD) along with the underlying mechanisms. In vivo, efficacy of BTT-105 evaluated from three kinds of NAFLD models (methionine/choline deficient diet (MCD), high fat diet (HF) and western diet (WD)). Metabolomics and transcriptomics profiling analysis in liver tissues were conducted. In vitro, anti-fibrotic effect of BTT-105 assessed in human hepatic stellated cells (HSCs) and primary mouse HSCs. BTT-105 improved NAFLD activity score in three kinds of NAFLD animal models (MCD, HF, and WD). BTT-105 also decreased levels of hepatic pro-collagen and collagen fibers deposition in liver tissue. Metabolome and transcriptome analysis revealed that BTT-105 decreased lipid metabolites and increased antioxidants in NAFLD mice. In HepG2 cells, BTT-105 enhanced Nrf2-ARE reporter activity in a dose-dependent manner and increased the levels of antioxidant gene expression. BTT-105 showed inhibition of HSCs activation and migration. Gene expression profiling and protein expression showed that BTT-105 increased Nrf2 activation as well as decreased PI3K-Akt pathway in activated HSCs. BTT-105 attenuated ameliorates steatohepatitis and hepatic fibrosis.
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Affiliation(s)
- Hye Young Kim
- Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul, Republic of Korea
| | - Sang Bong Ahn
- Department of Internal Medicine, Eulji University School of Medicine, Seoul, Republic of Korea
| | | | - Ju Hee Oh
- Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul, Republic of Korea
| | - Waqar Khalid Saeed
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Republic of Korea
| | - Gyu Sik Kim
- Biotoxtech Co., Ltd., Cheongju, Republic of Korea
| | - Hyun Kim
- Biotoxtech Co., Ltd., Cheongju, Republic of Korea
| | | | - Sukmo Kang
- Biotoxtech Co., Ltd., Cheongju, Republic of Korea
| | - Dae Won Jun
- Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul, Republic of Korea.,Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Republic of Korea
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22
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Zillikens H, Kasprick A, Osterloh C, Gross N, Radziewitz M, Hass C, Hartmann V, Behnen-Härer M, Ernst N, Boch K, Vidarsson G, Visser R, Laskay T, Yu X, Petersen F, Ludwig RJ, Bieber K. Topical Application of the PI3Kβ-Selective Small Molecule Inhibitor TGX-221 Is an Effective Treatment Option for Experimental Epidermolysis Bullosa Acquisita. Front Med (Lausanne) 2021; 8:713312. [PMID: 34557502 PMCID: PMC8452940 DOI: 10.3389/fmed.2021.713312] [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: 05/22/2021] [Accepted: 08/17/2021] [Indexed: 11/23/2022] Open
Abstract
Class I phosphoinositide 3-kinases (PI3K) have been implemented in pathogenesis of experimental epidermolysis bullosa acquisita (EBA), an autoimmune skin disease caused by type VII collagen (COL7) autoantibodies. Mechanistically, inhibition of specific PI3K isoforms, namely PI3Kβ or PI3Kδ, impaired immune complex (IC)-induced neutrophil activation, a key prerequisite for EBA pathogenesis. Data unrelated to EBA showed that neutrophil activation is also modulated by PI3Kα and γ, but their impact on the EBA has, so far, remained elusive. To address this and to identify potential therapeutic targets, we evaluated the impact of a panel of PI3K isoform-selective inhibitors (PI3Ki) on neutrophil function in vitro, and in pre-clinical EBA mouse models. We document that distinctive, and EBA pathogenesis-related activation-induced neutrophil in vitro functions depend on distinctive PI3K isoforms. When mice were treated with the different PI3Ki, selective blockade of PI3Kα (alpelisib), PI3Kγ (AS-604850), or PI3Kβ (TGX-221) impaired clinical disease manifestation. When applied topically, only TGX-221 impaired induction of experimental EBA. Ultimately, multiplex kinase activity profiling in the presence of disease-modifying PI3Ki identified unique signatures of different PI3K isoform-selective inhibitors on the kinome of IC-activated human neutrophils. Collectively, we here identify topical PI3Kβ inhibition as a potential therapeutic target for the treatment of EBA.
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Affiliation(s)
- Hannah Zillikens
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Anika Kasprick
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Colin Osterloh
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Natalie Gross
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Michael Radziewitz
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Cindy Hass
- Priority Area Asthma and Allergy, Research Center Borstel, Airway Research Center North, German Center for Lung Research, Borstel, Germany
| | - Veronika Hartmann
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Martina Behnen-Härer
- Department for Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany
| | - Nancy Ernst
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Katharina Boch
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Gestur Vidarsson
- Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands
| | - Remco Visser
- Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands
| | - Tamás Laskay
- Department for Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany
| | - Xinhua Yu
- Priority Area Asthma and Allergy, Research Center Borstel, Airway Research Center North, German Center for Lung Research, Borstel, Germany
| | - Frank Petersen
- Priority Area Asthma and Allergy, Research Center Borstel, Airway Research Center North, German Center for Lung Research, Borstel, Germany
| | - Ralf J Ludwig
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Katja Bieber
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
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23
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Yu L, Wei J, Liu P. Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer. Semin Cancer Biol 2021; 85:69-94. [PMID: 34175443 DOI: 10.1016/j.semcancer.2021.06.019] [Citation(s) in RCA: 313] [Impact Index Per Article: 78.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 06/10/2021] [Accepted: 06/22/2021] [Indexed: 02/08/2023]
Abstract
Cancer is the second leading cause of human death globally. PI3K/Akt/mTOR signaling is one of the most frequently dysregulated signaling pathways observed in cancer patients that plays crucial roles in promoting tumor initiation, progression and therapy responses. This is largely due to that PI3K/Akt/mTOR signaling is indispensable for many cellular biological processes, including cell growth, metastasis, survival, metabolism, and others. As such, small molecule inhibitors targeting major kinase components of the PI3K/Akt/mTOR signaling pathway have drawn extensive attention and been developed and evaluated in preclinical models and clinical trials. Targeting a single kinase component within this signaling usually causes growth arrest rather than apoptosis associated with toxicity-induced adverse effects in patients. Combination therapies including PI3K/Akt/mTOR inhibitors show improved patient response and clinical outcome, albeit developed resistance has been reported. In this review, we focus on revealing the mechanisms leading to the hyperactivation of PI3K/Akt/mTOR signaling in cancer and summarizing efforts for developing PI3K/Akt/mTOR inhibitors as either mono-therapy or combination therapy in different cancer settings. We hope that this review will facilitate further understanding of the regulatory mechanisms governing dysregulation of PI3K/Akt/mTOR oncogenic signaling in cancer and provide insights into possible future directions for targeted therapeutic regimen for cancer treatment, by developing new agents, drug delivery systems, or combination regimen to target the PI3K/Akt/mTOR signaling pathway. This information will also provide effective patient stratification strategy to improve the patient response and clinical outcome for cancer patients with deregulated PI3K/Akt/mTOR signaling.
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Affiliation(s)
- Le Yu
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | | | - Pengda Liu
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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24
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Mroweh M, Roth G, Decaens T, Marche PN, Lerat H, Macek Jílková Z. Targeting Akt in Hepatocellular Carcinoma and Its Tumor Microenvironment. Int J Mol Sci 2021; 22:1794. [PMID: 33670268 PMCID: PMC7917860 DOI: 10.3390/ijms22041794] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 02/07/2021] [Accepted: 02/09/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide, and its incidence is rising. HCC develops almost exclusively on the background of chronic liver inflammation, which can be caused by chronic alcohol consumption, viral hepatitis, or an unhealthy diet. The key role of chronic inflammation in the process of hepatocarcinogenesis, including in the deregulation of innate and adaptive immune responses, has been demonstrated. The inhibition of Akt (also known as Protein Kinase B) directly affects cancer cells, but this therapeutic strategy also exhibits indirect anti-tumor activity mediated by the modulation of the tumor microenvironment, as demonstrated by using Akt inhibitors AZD5363, MK-2206, or ARQ 092. Moreover, the isoforms of Akt converge and diverge in their designated roles, but the currently available Akt inhibitors fail to display an isoform specificity. Thus, selective Akt inhibition needs to be better explored in the context of HCC and its possible combination with immunotherapy. This review presents a compact overview of the current knowledge concerning the role of Akt in HCC and the effect of Akt inhibition on the HCC and liver tumor microenvironment.
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Affiliation(s)
- Mariam Mroweh
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (G.R.); (T.D.); (P.N.M.); (H.L.)
- Université Grenoble-Alpes, 38000 Grenoble, France
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath Beirut 6573-14, Lebanon
| | - Gaël Roth
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (G.R.); (T.D.); (P.N.M.); (H.L.)
- Université Grenoble-Alpes, 38000 Grenoble, France
- Service D’hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
| | - Thomas Decaens
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (G.R.); (T.D.); (P.N.M.); (H.L.)
- Université Grenoble-Alpes, 38000 Grenoble, France
- Service D’hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
| | - Patrice N. Marche
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (G.R.); (T.D.); (P.N.M.); (H.L.)
- Université Grenoble-Alpes, 38000 Grenoble, France
| | - Hervé Lerat
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (G.R.); (T.D.); (P.N.M.); (H.L.)
- Université Grenoble-Alpes, 38000 Grenoble, France
| | - Zuzana Macek Jílková
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (G.R.); (T.D.); (P.N.M.); (H.L.)
- Université Grenoble-Alpes, 38000 Grenoble, France
- Service D’hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
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Dolivo D, Weathers P, Dominko T. Artemisinin and artemisinin derivatives as anti-fibrotic therapeutics. Acta Pharm Sin B 2021; 11:322-339. [PMID: 33643815 PMCID: PMC7893118 DOI: 10.1016/j.apsb.2020.09.001] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 08/18/2020] [Accepted: 08/21/2020] [Indexed: 12/18/2022] Open
Abstract
Fibrosis is a pathological reparative process that can occur in most organs and is responsible for nearly half of deaths in the developed world. Despite considerable research, few therapies have proven effective and been approved clinically for treatment of fibrosis. Artemisinin compounds are best known as antimalarial therapeutics, but they also demonstrate antiparasitic, antibacterial, anticancer, and anti-fibrotic effects. Here we summarize literature describing anti-fibrotic effects of artemisinin compounds in in vivo and in vitro models of tissue fibrosis, and we describe the likely mechanisms by which artemisinin compounds appear to inhibit cellular and tissue processes that lead to fibrosis. To consider alternative routes of administration of artemisinin for treatment of internal organ fibrosis, we also discuss the potential for more direct oral delivery of Artemisia plant material to enhance bioavailability and efficacy of artemisinin compared to administration of purified artemisinin drugs at comparable doses. It is our hope that greater understanding of the broad anti-fibrotic effects of artemisinin drugs will enable and promote their use as therapeutics for treatment of fibrotic diseases.
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Key Words
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AMPK, AMP-activated protein kinase
- ASP, aspartate aminotransferase
- Artemisia
- Artemisinin
- Artesunate
- BAD, BCL-2-associated agonist of cell death
- BDL, bile duct ligation
- BSA, bovine serum albumin
- BUN, blood urea nitrogen
- CCl4, carbon tetrachloride
- CTGF, connective tissue growth factor
- Col I, type I collagen
- DHA, dihydroartemisinin
- DLA, dried leaf Artemisia
- ECM, extracellular matrix
- EMT, epithelial-to-mesenchymal transition
- FLS, fibroblast-like synoviocyte
- Fibroblast
- Fibrosis
- HA, hyaluronic acid
- HSC, hepatic stellate cell
- HUVEC, human umbilical vein endothelial cell
- LAP, latency-associated peptide
- LDH, lactate dehydrogenase
- MAPK, mitogen-activated protein kinase
- MI, myocardial infarction
- MMP, matrix metalloproteinase
- Myofibroblast
- NAG, N-acetyl-β-d-glucosaminidase
- NICD, Notch intracellular domain
- PCNA, proliferating cell nuclear antigen
- PHN, passive heymann nephritis
- ROS, reactive oxygen species
- STZ, streptozotocin
- Scar
- TGF, β-transforming growth factor-β
- TGF-β
- TIMP, tissue inhibitor of metalloproteinase
- UUO, unilateral ureteral obstruction
- i.p., intraperitoneal
- mTOR, mechanistic target of rapamycin
- sCr, serum creatinine
- α-SMA, smooth muscle α-actin
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Affiliation(s)
- David Dolivo
- Department of Surgery, Northwestern University-Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Pamela Weathers
- Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, MA 01609, USA
| | - Tanja Dominko
- Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, MA 01609, USA
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26
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Kurniawan DW, Booijink R, Pater L, Wols I, Vrynas A, Storm G, Prakash J, Bansal R. Fibroblast growth factor 2 conjugated superparamagnetic iron oxide nanoparticles (FGF2-SPIONs) ameliorate hepatic stellate cells activation in vitro and acute liver injury in vivo. J Control Release 2020; 328:640-652. [PMID: 32979454 DOI: 10.1016/j.jconrel.2020.09.041] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 09/01/2020] [Accepted: 09/20/2020] [Indexed: 12/17/2022]
Abstract
Liver diseases are the growing health problem with no clinically approved therapy available. Activated hepatic stellate cells (HSCs) are the key driver cells responsible for extracellular matrix deposition, the hallmark of liver fibrosis. Fibroblast growth factor 2 (FGF2) has shown to possess anti-fibrotic effects in fibrotic diseases including liver fibosis, and promote tissue regeneration. Among the fibroblast growth factor receptors (FGFRs), FGF2 interact primarily with FGFR1, highly overexpressed on activated HSCs, and inhibit HSCs activation. However, FGF2 poses several limitations including poor systemic half-life and stability owing to enzymatic degradation. The aim of this study is to improve the stability and half-life of FGF2 thereby improving the therapuetic efficacy of FGF2 for the treatment of liver fibrosis. We found that FGFR1-3 mRNA levels were overexpressed in cirrhotic human livers, while FGFR1c, 2c, 3c, 4 and FGF2 mRNA levels were overexpressed in TGFβ-activated HSCs (LX2 cells) and FGFR1 protein expression was highly increased in TGFβ-activated HSCs. Treatment with FGF2 inhibited TGFβ-induced HSCs activation, migration and contraction in vitro. FGF2 was conjugated to superparamagnetic iron-oxide nanoparticles (SPIONs) using carbodiimide chemistry, and the resulting FGF2-SPIONs were confirmed by dynamic light scattering (DLS), zeta potential, dot-blot analysis and Prussian Blue iron-staining. In vitro, treatment with FGF2-SPIONs evidenced increased therapeutic effects (attenuated TGFβ-induced HSCs activation, migration and contraction) of FGF2 in TGFβ-activated HSCs and ameliorated early liver fibrogenesis in vivo in acute carbon tetrachloride (CCl4)-induced liver injury mouse model. In contrast, free FGF2 showed no significant effects in vivo. Altogether, this study presents a promising therapeutic approach using FGF2-SPIONs for the treatment of liver fibrosis.
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Affiliation(s)
- Dhadhang Wahyu Kurniawan
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands; Department of Pharmacy, Universitas Jenderal Soedirman, Purwokerto, Indonesia
| | - Richell Booijink
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Lena Pater
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Irene Wols
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Aggelos Vrynas
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Gert Storm
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands; Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands
| | - Jai Prakash
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Ruchi Bansal
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands.
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BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells. Biomedicines 2020; 8:biomedicines8090330. [PMID: 32899801 DOI: 10.3390/biomedicines8090330] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 12/12/2022] Open
Abstract
Activation of hepatic stellate cells (HSCs) is a critical pathogenic feature of liver fibrosis and cirrhosis. BAY 41-2272 is a canonical non-nitric oxide (NO)-based soluble guanylyl cyclase (sGC) stimulator that triggers cyclic guanosine monophosphate (cGMP) signaling for attenuation of fibrotic disorders; however, the impact of BAY 41-2272 on HSC activation remains ill-defined. Transforming growth factor (TGF)β and its downstream connective tissue growth factor (CTGF or cellular communication network factor 2, CCN2) are critical fibrogenic cytokines for accelerating HSC activation. Here, we identified that BAY 41-2272 significantly inhibited the TGFβ1-induced mRNA and protein expression of CTGF in mouse primary HSCs. Indeed, BAY 41-2272 increased the sGC activity and cGMP levels that were potentiated by two NO donors and inhibited by a specific sGC inhibitor, ODQ. Surprisingly, the inhibitory effects of BAY 41-2272 on CTGF expression were independent of the sGC/cGMP pathway in TGFβ1-activated primary HSCs. BAY 41-2272 selectively restricted the TGFβ1-induced phosphorylation of Akt but not canonical Smad2/3 in primary HSCs. Together, we illustrate a unique framework of BAY 41-2272 for inhibiting TGFβ1-induced CTGF upregulation and HSC activation via a noncanonical Akt-dependent but sGC/cGMP-independent pathway.
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Lin X, Li Y, Zhang X, Wei Y, Wen S, Lu Z, Huang Q, Wei J. Tormentic acid inhibits hepatic stellate cells activation via blocking PI3K/Akt/mTOR and NF-κB signalling pathways. Cell Biochem Funct 2020; 39:77-87. [PMID: 32564421 DOI: 10.1002/cbf.3564] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/06/2020] [Accepted: 05/17/2020] [Indexed: 01/06/2023]
Abstract
The present study was to investigate the inhibitory effect and underlying mechanism of Tormentic acid (TA) on hepatic stellate cells (HSCs). HSC-T6 cells were stimulated with Platelet-derived growth factor-BB (PDGF-BB) and TA, and then cell proliferation, apoptosis, inflammatory factor, and collagen-related indicators were detected. In order to elucidate the potential mechanism, the PI3K/Akt/mTOR and NF-κB signalling pathways were also detected. The results showed that TA treatment markedly inhibited PDGF-BB-stimulated HSC-T6 cell activation, as evidenced by the inhibition of cell proliferation, migration and colony formation, as well as the decreased expression of TGF-β and α-SMA. TA treatment caused a significant increase in the activity of lactate dehydrogenase and significantly promoted cell apoptosis. TA treatment significantly reduced aspartate aminotransferase, alanine aminotransferase and total bilirubin activity. Importantly, TA inhibited the expression of collagen type I and III, alleviating the excessive deposition of extracellular matrix (ECM). Further experiments showed that TA administration significantly inhibited the phosphorylation of PI3K, Akt, FAK and mTOR and the protein expression of P70S6K, indicating the inhibition of the PI3K/Akt/mTOR pathway. Moreover, treatment with TA markedly decreased the phosphorylation of IκBα, NF-κB p65 and IKKα/β, thereby blocking the NF-κB signal transduction. In summary, this study demonstrates that TA significantly inhibits HSC activation and promotes cell apoptosis via the inhibition of the PI3K/Akt/mTOR and NF-κB signalling pathways. SIGNIFICANCE OF THE STUDY: Tormentic acid (TA) could inhibit HSC activation and alleviate collagen-based ECM deposition, suggesting that TA exerted anti-hepatic fibrosis. Further mechanism research revealed that the inhibition of TA on HSC activation might be through blocking the PI3K/Akt/mTOR and NF-κB signalling pathways. These findings provided a new cue to understand the protective effect of TA against liver fibrosis, which may provide a potential nature medicine for the treatment of liver fibrosis.
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Affiliation(s)
- Xing Lin
- Guangxi Medical University, Nanning, China
| | - Yan Li
- Guangxi Medical University, Nanning, China
| | | | | | | | - Zhongpeng Lu
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA
| | - Quanfang Huang
- The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Jinbin Wei
- Guangxi Medical University, Nanning, China
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Bheemanaboina RR. Isoform-Selective PI3K Inhibitors for Various Diseases. Curr Top Med Chem 2020; 20:1074-1092. [DOI: 10.2174/1568026620666200106141717] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 11/29/2019] [Accepted: 12/05/2019] [Indexed: 12/13/2022]
Abstract
Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that
control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive
target for the development of novel pharmaceuticals to treat cancer and various other diseases.
In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib
were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors
are currently under active clinical development. So far clinical candidates are non-selective kinase
inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery
of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development
of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding
therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective
inhibition will ultimately be determined, with the development of drug resistance and the demand
for next-generation inhibitors, it will continue to be of great significance to understand the potential
mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in
various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable
efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective
PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.
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Affiliation(s)
- Rammohan R.Y. Bheemanaboina
- Department of Chemistry and Biochemistry, Sokol Institute for Pharmaceutical Life Sciences, Montclair State University, Montclair, NJ 07043, United States
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Exogenous Therapeutics of Microrna-29a Attenuates Development of Hepatic Fibrosis in Cholestatic Animal Model through Regulation of Phosphoinositide 3-Kinase p85 Alpha. Int J Mol Sci 2020; 21:ijms21103636. [PMID: 32455716 PMCID: PMC7279217 DOI: 10.3390/ijms21103636] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 05/14/2020] [Accepted: 05/19/2020] [Indexed: 12/12/2022] Open
Abstract
Recent studies have found that microRNA-29a (miR-29a) levels are significantly lower in fibrotic livers, as shown with human liver cirrhosis. Such downregulation influences the activation of hepatic stellate cells (HSC). Phosphoinositide 3-kinase p85 alpha (PI3KP85α) is implicated in the regulation of proteostasis mitochondrial integrity and unfolded protein response (UPR) and apoptosis in hepatocytes. This study aimed to investigate the potential therapeutic role of miR-29a in a murine bile duct ligation (BDL)-cholestatic injury and liver fibrosis model. Mice were assigned to four groups: sham, BDL, BDL + scramble miRs, and BDL + miR-29a-mimic. Liver fibrosis and inflammation were assessed by histological staining and mRNA/protein expression of representative markers. Exogenous therapeutics of miR-29a in BDL-stressed mice significantly attenuated glutamic oxaloacetic transaminase (GOT)/glutamic-pyruvic transaminase (GPT) and liver fibrosis, and caused a significant downregulation in markers related to inflammation (IL-1β), fibrogenesis (TGF-β1, α-SMA, and COL1α1), autophagy (p62 and LC3B II), mitochondrial unfolded protein response (UPRmt; C/EBP homologous protein (CHOP), heat shock protein 60 (HSP60), and Lon protease-1 (LONP1, a mitochondrial protease), and PI3KP85α within the liver tissue. An in vitro luciferase reporter assay further confirmed that miR-29a mimic directly targets mRNA 3′ untranslated region (UTR) of PI3KP85α to suppress its expression in HepG2 cell line. Our data provide new insights that therapeutic miR-29a improves cholestasis-induced hepatic inflammation and fibrosis and proteotstasis via blocking PI3KP85α, highlighting the potential of miR-29a targeted therapy for liver injury.
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Gore E, Bigaeva E, Oldenburger A, Kim YO, Rippmann JF, Schuppan D, Boersema M, Olinga P. PI3K inhibition reduces murine and human liver fibrogenesis in precision-cut liver slices. Biochem Pharmacol 2019; 169:113633. [PMID: 31494146 DOI: 10.1016/j.bcp.2019.113633] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 09/03/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Liver fibrosis results from continuous inflammation and injury. Despite its high prevalence worldwide, no approved antifibrotic therapies exist. Omipalisib is a selective inhibitor of the PI3K/mTOR pathway that controls nutrient metabolism, growth and proliferation. It has shown antifibrotic properties in vitro. While clinical trials for idiopathic pulmonary fibrosis have been initiated, an in-depth preclinical evaluation is lacking. We evaluated omipalisib's effects on fibrogenesis using the ex vivo model of murine and human precision-cut tissue slices (PCTS). METHODS Murine and human liver and jejunum PCTS were incubated with omipalisib up to 10 μM for 48 h. PI3K pathway activation was assessed through protein kinase B (Akt) phosphorylation and antifibrotic efficacy was determined via a spectrum of fibrosis markers at the transcriptional and translational level. RESULTS During incubation of PCTS the PI3K pathway was activated and incubation with omipalisib prevented Akt phosphorylation (IC50 = 20 and 1.5 nM for mouse and human, respectively). Viability of mouse and human liver PCTS was compromised only at the high concentration of 10 and 1-5 μM, respectively. However, viability of jejunum PCTS decreased with 0.1 (mouse) and 0.01 μM (human). Spontaneously increased fibrosis related genes and proteins were significantly and similarly suppressed in mouse and in human liver PCTS. CONCLUSIONS Omipalisib has antifibrotic properties in ex vivo mouse and human liver PCTS, but higher concentrations showed toxicity in jejunum PCTS. While the PI3K/mTOR pathway appears to be a promising target for the treatment of liver fibrosis, PCTS revealed likely side effects in the intestine at higher doses.
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Affiliation(s)
- Emilia Gore
- Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713AV, The Netherlands
| | - Emilia Bigaeva
- Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713AV, The Netherlands
| | - Anouk Oldenburger
- Cardiometabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss 88397, Germany
| | - Yong Ook Kim
- Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Obere Zahlbacherstraße 63, Mainz 55131, Germany
| | - Jörg F Rippmann
- Cardiometabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss 88397, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Obere Zahlbacherstraße 63, Mainz 55131, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 330 Brookline Avenue, MA 02215, USA
| | - Miriam Boersema
- Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713AV, The Netherlands
| | - Peter Olinga
- Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713AV, The Netherlands.
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Elias MDB, Oliveira FL, Guma FCR, Martucci RB, Borojevic R, Teodoro AJ. Lycopene inhibits hepatic stellate cell activation and modulates cellular lipid storage and signaling. Food Funct 2019; 10:1974-1984. [PMID: 30889234 DOI: 10.1039/c8fo02369g] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hepatic stellate cells are liver-specific perivascular cells, identified as the major source of collagen in liver fibrosis, following their activation and conversion to myofibroblast-like cells. Lycopene is a carotenoid with biological activities and protective effects described in different pathologies, but little is known about its role in liver protection. We evaluated the influence of lycopene on the cell cycle and lipid metabolism and monitored the possible pathways involved in lycopene inhibition of stellate cell activation. Lycopene induced expression of the lipocyte phenotype, with an accumulation of fat droplets in cytoplasm, with high synthesis and turnover of phospholipids and triglycerides. Cell proliferation analysis showed that lycopene reduced the growth of GRX cells. Lycopene induced an arrest in the G0/G1 phase, followed by a decrease of cells in the G2/M phase, regardless of the concentration of lycopene used. Lycopene modulated relevant signaling pathways related to cholesterol metabolism, cellular proliferation, and lipid metabolism. Also, lycopene treatment increased the expression of RXR-α, RXR-β, and PPARγ, important biomarkers of liver regeneration. These results show that lycopene was able to negatively modulate events related to the activation of hepatic stellate cells through mechanisms that involve changes in expression of cellular lipid metabolism factors, and suggest that this compound might provide a novel pharmacological approach for the prevention and treatment of fibrotic liver diseases.
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Affiliation(s)
- Monique de Barros Elias
- Laboratory of Functional Foods, Universidade Federal do Estado do Rio de Janeiro, Av. Pastuer 296, Brazil.
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Zhang Z, Wen H, Weng J, Feng L, Liu H, Hu X, Zeng F. Silencing of EPCAM suppresses hepatic fibrosis and hepatic stellate cell proliferation in mice with alcoholic hepatitis via the PI3K/Akt/mTOR signaling pathway. Cell Cycle 2019; 18:2239-2254. [PMID: 31378124 PMCID: PMC6738525 DOI: 10.1080/15384101.2019.1642067] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Alcoholic hepatitis (AH) is a severe condition developed in patients with underlying alcoholic liver disease. Epithelial cell adhesion molecule (EPCAM) plays a role in hepatitis. Therefore, the current study aimed to explore the effect of EPCAM and its potential mechanism in AH. Bioinformatic analysis was performed to screen differentially expressed genes associated with AH. AH mouse models were established through a Lieber-DeCarli liquid diet containing 4% ethanol, which were co-treated with siRNA against EPCAM or the PI3K/Akt/mTOR signaling pathway inhibitor in order to investigate the effects of EPCAM and the PI3K/Akt/mTOR signaling pathway on hepatic fibrosis, hepatic stellate cell (HSC) proliferation and apoptosis. The relationship between EPCAM and the PI3K/Akt/mTOR signaling pathway was investigated for the purposes of elucidating the potential mechanism of EPCAM in AH. EPCAM was predicted to regulate AH progression through the PI3K/Akt/mTOR signaling pathway. Silencing EPCAM or inhibition of the PI3K/Akt/mTOR signaling pathway inhibited the hepatic fibrosis and HSC proliferation yet induced HSC apoptosis. Moreover, silencing EPCAM was found to repress the PI3K/Akt/mTOR signaling pathway as evidenced by decreased levels of Bcl2 yet increased levels of caspase-3. Collectively, silencing EPCAM could hinder AH progression by inhibiting the PI3K/Akt/mTOR signaling pathway, which might serve as a potential therapeutic target for AH treatment.
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Affiliation(s)
- Zhi Zhang
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, P. R. China,CONTACT Zhi Zhang
| | - Huiqing Wen
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Jun Weng
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Lei Feng
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Hongya Liu
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Xiaojun Hu
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Fanhong Zeng
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, P. R. China
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Wu SM, Li TH, Yun H, Ai HW, Zhang KH. miR-140-3p Knockdown Suppresses Cell Proliferation and Fibrogenesis in Hepatic Stellate Cells via PTEN-Mediated AKT/mTOR Signaling. Yonsei Med J 2019; 60:561-569. [PMID: 31124340 PMCID: PMC6536388 DOI: 10.3349/ymj.2019.60.6.561] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 01/07/2019] [Accepted: 02/14/2019] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Liver fibrosis is a major cause of morbidity and mortality and the outcome of various chronic liver diseases. Activation of hepatic stellate cells (HSCs) is the key event in liver fibrosis. Studies have confirmed that miR-140-3p plays a potential regulatory effect on HSC activation. However, whether miR-140-3p mediates the liver fibrosis remains unknown. MATERIALS AND METHODS Expression of miR-140-3p was detected by real-time quantitative PCR (qPCR). Cell proliferation was measured by MTT, while cell apoptosis rate was determined via flow cytometry. Western blot assay was used to detect the expression of cleaved PARP. The fibrogenic effect was evaluated by expression of α-smooth muscle actin and desmin. Functional experiments were performed in transforming growth factor β1 (TGF-β1)-induced HSC-T6 cells with transfection of anti-miR-140-3p and/or siPTEN. Target binding between miR-140-3p and PTEN was predicted by the TargetScan database and identified using luciferase reporter assay and RNA immunoprecipitation. RESULTS TGF-β1 induced the activation of HSC-T6 cells, and miR-140-3p expression varied according to HSC-T6 cell activation status. Knockdown of miR-140-3p reduced cell proliferation and the expressions of α-SMA and desmin, as well as increased apoptosis, in TGF-β1-induced HSC-T6 cells, which could be blocked by PTEN silencing. Additionally, inactivation of the AKT/mTOR signaling pathway stimulated by miR-140-3p knockdown was abolished when silencing PTEN expression. PTEN was negatively regulated by miR-140-3p via direct binding in HSC-T6 cells. CONCLUSION miR-140-3p is an important mediator in HSC-T6 cell activation, and miR-140-3p knockdown suppresses cell proliferation and fibrogenesis in TGF-β1-induced HSC-T6 cells, indicating that miR-140-3p may be a potential novel molecular target for liver fibrosis.
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Affiliation(s)
- Shi Min Wu
- Wuhan Center for Clinical Laboratory, Wuhan Forth Hospital; Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tian Hong Li
- Department of Ophthalmology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Yun
- Wuhan Center for Clinical Laboratory, Wuhan Forth Hospital; Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Wu Ai
- Department of Clinical Laboratory, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ke Hui Zhang
- Wuhan Center for Clinical Laboratory, Wuhan Forth Hospital; Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Kobayashi H. Somatic driver mutations in endometriosis as possible regulators of fibrogenesis (Review). ACTA ACUST UNITED AC 2019. [DOI: 10.3892/wasj.2019.12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Hiroshi Kobayashi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan
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Screening of PI3K-Akt-targeting Drugs for Silkworm against Bombyx mori Nucleopolyhedrovirus. Molecules 2019; 24:molecules24071260. [PMID: 30939726 PMCID: PMC6480691 DOI: 10.3390/molecules24071260] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 03/08/2019] [Accepted: 03/09/2019] [Indexed: 11/17/2022] Open
Abstract
Bombyx mori nucleopolyhedrovirus (BmNPV) is the most prevalent threat to silkworms. Hence, there is a need for antiviral agents in sericulture. The PI3K-Akt pathway is essential for the efficient replication of the baculovirus. In an attempt to screen antiviral drugs against BmNPV, we summarized the commercial compounds targeting PI3K-Akt and selected the following seven oral drugs for further analyses: afuresertib, AZD8835, AMG319, HS173, AS605240, GDC0941, and BEZ235. Cell viability assay revealed that the cytotoxicity of these drugs at 10 µM concentration was not strong. Viral fluorescence observation and qPCR analysis showed that these candidate drugs significantly inhibited BmNPV in BmE cells. Only AMG319 and AZD8835 inhibited viral proliferation in silkworm larvae. The mortality of AZD8835-treated silkworms was lower than that of the control silkworms. Western blotting showed that AMG319 and AZD8835 decreased p-Akt expression after BmNPV infection. These results suggest that AZD8835 has application potential in sericulture.
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Park JH, Jung KH, Kim SJ, Yoon YC, Yan HH, Fang Z, Lee JE, Lim JH, Mah S, Hong S, Kim YS, Hong SS. HS-173 as a novel inducer of RIP3-dependent necroptosis in lung cancer. Cancer Lett 2019; 444:94-104. [DOI: 10.1016/j.canlet.2018.12.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 12/06/2018] [Accepted: 12/11/2018] [Indexed: 12/22/2022]
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Mi XJ, Hou JG, Jiang S, Liu Z, Tang S, Liu XX, Wang YP, Chen C, Wang Z, Li W. Maltol Mitigates Thioacetamide-induced Liver Fibrosis through TGF-β1-mediated Activation of PI3K/Akt Signaling Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:1392-1401. [PMID: 30644744 DOI: 10.1021/acs.jafc.8b05943] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Our previous study has confirmed that maltol can attenuate alcohol-induced acute hepatic damage and prevent oxidative stress in mice. Therefore, maltol might have the capacity to improve thioacetamide (TAA)-induced liver fibrosis. The purpose of this work was to explore the antifibrotic efficacy and underlying mechanisms of maltol for TAA-treated mice. Progressive liver fibrosis was established with a dose-escalating protocol in which the mice received TAA intraperitoneal three times a week for a total duration of 9 weeks. The injection doses of TAA were 50 mg/kg for the first week, 100 mg/kg for the second and third weeks, and 150 mg/kg for the rest of the injections. Maltol with doses of 50 and 100 mg/kg was given by gavage after 4 weeks of intraperitoneal injection of TAA, respectively, once daily for 5 weeks. Results indicated that TAA intraperitoneal injection significantly increased serum activities of alanine aminotransferase (ALT) (52.93 ± 13.21 U/L vs 10.22 ± 3.36 U/L) and aspartate aminotransferase (AST) (67.58 ± 25.84 U/L vs 39.34 ± 3.89 U/L); these elevations were significantly diminished by pretreatment with maltol. Additionally, maltol ameliorated TAA-induced oxidative stress with attenuation in MDA ( p < 0.05 or p < 0.01) content; evident elevation in the GSH levels, GSH/GSSG ratio ( p < 0.05 or p < 0.01), and superoxide dismutase (SOD) ( p < 0.01); and restored liver histology accompanied by a decrease of α-smooth muscle actin (α-SMA) expression. Furthermore, maltol significantly suppressed the transforming growth factor-β1 (TGF-β1) expression and the PI3K/Akt pathway. This study suggested that maltol alleviated experimental liver fibrosis by suppressing the activation of HSCs and inducing apoptosis of activated HSCs through TGF-β1-mediated PI3K/Akt signaling pathway. These findings further clearly suggested that maltol is a potent therapeutic candidate for the alleviation of liver fibrosis.
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Affiliation(s)
- Xiao-Jie Mi
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
| | - Jin-Gang Hou
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
- Intelligent Synthetic Biology Center , Daejeon 34141 , Republic of Korea
| | - Shuang Jiang
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
| | - Zhi Liu
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
| | - Shan Tang
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
| | - Xiang-Xiang Liu
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
| | - Ying-Ping Wang
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
- National & Local Joint Engineering Research Center for Ginseng Breeding and Development , Changchun 130118 , China
| | - Chen Chen
- School of Biomedical Sciences, Queensland Brain Institute , The University of Queensland , Brisbane , Queensland 4072 , Australia
| | - Zi Wang
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
| | - Wei Li
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
- National & Local Joint Engineering Research Center for Ginseng Breeding and Development , Changchun 130118 , China
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Zhang Q, Chen K, Wu T, Song H. Swertiamarin ameliorates carbon tetrachloride-induced hepatic apoptosis via blocking the PI3K/Akt pathway in rats. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2018; 23:21-28. [PMID: 30627006 PMCID: PMC6315090 DOI: 10.4196/kjpp.2019.23.1.21] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 04/04/2018] [Accepted: 06/01/2018] [Indexed: 01/07/2023]
Abstract
Swertiamarin (STM) is an iridoid compound that is present in the Gentianaceae swertia genus. Here we investigated antiapoptotic effects of STM on carbon tetrachloride (CCl4)-induced liver injury and its possible mechanisms. Adult male Sprague Dawley rats were randomly divided into a control group, an STM 200 mg/kg group, a CCl4 group, a CCl4+STM 100 mg/kg group, and a CCl4+STM 200 mg/kg group. Rats in experimental groups were subcutaneously injected with 40% CCl4 twice weekly for 8 weeks. STM (100 and 200 mg/kg per day) was orally given to experimental rats by gavage for 8 consecutive weeks. Hepatocyte apoptosis was determined by TUNEL assay and the expression levels of Bcl-2, Bax, and cleaved caspase-3 proteins were evaluated by western blot analysis. The expression of TGF-β1, collagen I, collagen III, CTGF and fibronectin mRNA were estimated by qRT-PCR. The results showed that STM significantly reduced the number of TUNEL-positive cells compared with the CCl4 group. The levels of Bax and cleaved caspase-3 proteins, and TGF-β1, collagen I, collagen III, CTGF, and fibronectin mRNA were significantly reduced by STM compared with the CCl4 group. In addition, STM markedly abrogated the repression of Bcl-2 by CCl4. STM also attenuated the activation of the PI3K/Akt pathway in the liver. These results suggested that STM ameliorated CCl4-induced hepatocyte apoptosis in rats.
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Affiliation(s)
- Qianrui Zhang
- Department of Pharmacy, General Hospital of the Yangtze River Shipping, Wuhan 430022, China
| | - Kang Chen
- Department of Pharmacy, Huanggang Central Hospital, Huanggang 438000, China
| | - Tao Wu
- Department of Pharmacy, Wuhan NO.4 Hospital, Wuhan Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hongping Song
- Department of Pharmacy, Wuhan NO.4 Hospital, Wuhan Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Wang A, Zhou F, Li D, Lu JJ, Wang Y, Lin L. γ-Mangostin alleviates liver fibrosis through Sirtuin 3-superoxide-high mobility group box 1 signaling axis. Toxicol Appl Pharmacol 2018; 363:142-153. [PMID: 30502394 DOI: 10.1016/j.taap.2018.11.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 11/21/2018] [Accepted: 11/26/2018] [Indexed: 12/29/2022]
Abstract
The activation of hepatic stellate cells (HSCs) plays a critical role in liver fibrosis. In the current study, γ-mangostin (γ-man), one of the major xanthones from mangosteen (Garcinia mangostana), was found to alleviate fibrogenesis in human immortalized HSCs (LX-2 cells) and in liver from chronic carbon tetrachloride (CCl4) injured mice. γ-Man suppressed the expression levels of collagen I and α-smooth muscle actin (α-SMA) in LX-2 cells in both dose and time dependent manners. Furthermore, γ-man inhibited NAD(P)H oxidase activity through induction of sirtuin 3 (SIRT3), resulting in reduced intracellular oxidative stress in LX-2 cells. Moreover, γ-man stimulated the expression of histone deacetylase 1, which in turn decreased the acetylation and cytoplasmic shuttling of high mobility group box 1 (HMGB1), to impair autocrine HMGB1-induced HSC activation. In CCl4-injured mice, γ-man enhanced the expression of SIRT3 and decreased the expression of HMGB1, resulting in decreased accumulation of collagen I and α-SMA in liver. Consequently, γ-man might be a potent candidate to treat oxidative stress induced liver fibrosis.
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Affiliation(s)
- Anqi Wang
- Guangdong-Macau Traditional Chinese Medicine Technology Industrial Park Development Co., Ltd, Hengqin New Area, Zhuhai, Guangdong 519031, China; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
| | - Fayang Zhou
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
| | - Dan Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
| | - Jin-Jian Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
| | - Yitao Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
| | - Ligen Lin
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
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Eissa LA, Kenawy HI, El-Karef A, Elsherbiny NM, El-Mihi KA. Antioxidant and anti-inflammatory activities of berberine attenuate hepatic fibrosis induced by thioacetamide injection in rats. Chem Biol Interact 2018; 294:91-100. [PMID: 30138605 DOI: 10.1016/j.cbi.2018.08.016] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 07/26/2018] [Accepted: 08/17/2018] [Indexed: 12/14/2022]
Abstract
Berberine (BBR) is an isoquinoline alkaloid extracted from the roots, rhizomes and stems of coptis. Liver fibrosis is a worldwide health problem with no established therapy until now. The aim of our study is to investigate the efficacy of BBR on hepatic fibrosis induced in rats and to uncover other mechanisms. Rats were injected with thioacetamide (TAA) (200 mg/kg, i.p) twice per week for 6 weeks to induce fibrosis. Treated groups were gavaged with BBR (50 mg/kg/day, p.o) simultaneously with TAA injection. Hepatic antioxidant enzymes (catalase, SOD, GPx) were assessed in hepatic homogenate. Their activities were attenuated by TAA injection and elevated by BBR administration. Additionally, serum IL-6 and mRNA levels of IL-1β, IL-6, IL-10 and IFN-γ were evaluated as inflammatory markers. Our results showed that BBR suppressed the inflammation induced by TAA injection. Tissue expression of α-SMA (marker of activated HSCs), TGF-β1 and fibronectin were measured by immunohistochemistry as well as mRNA expressions of TGF-β1 and fibronectin were quantified as fibrotic markers. The collagen deposition in hepatic tissues was assessed by Masson's trichome staining. BBR significantly alleviated TGF-β1 production, decreased collagen and fibronectin deposition and consequently attenuated hepatic fibrogenesis. Akt pathway controls cell survival, proliferation, migration and adhesion. The relative phosphorylation of Akt was determined in hepatic homogenates that was increased with TAA injection and decreased by BBR treatment. Inhibition of Akt pathway has been linked to the intrinsic pathway of apoptosis. Caspase-3, caspase-9, Bcl-2 and Bax were quantified as apoptotic markers using qPCR and also caspase-3 by immunohistochemistry. BBR-treated rats showed an increase in the expression of apoptotic markers. Moreover, BBR-treated rats showed restoration of normal liver lobular architecture as shown by H&E staining. In conclusion, BBR is a potential therapeutic candidate for liver fibrosis owing to its antioxidant and anti-inflammatory activities.
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Affiliation(s)
- Laila Ahmed Eissa
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Hany Ibrahim Kenawy
- Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Amro El-Karef
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Nehal Mohsen Elsherbiny
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Kholoud Alaa El-Mihi
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
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Emerging role and therapeutic implication of Wnt signaling pathways in liver fibrosis. Gene 2018; 674:57-69. [PMID: 29944952 DOI: 10.1016/j.gene.2018.06.053] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 06/14/2018] [Accepted: 06/16/2018] [Indexed: 02/08/2023]
Abstract
Activation of hepatic stellate cells (HSCs) is a pivotal cellular event in liver fibrosis. Therefore, improving our understanding of the molecular pathways that are involved in these processes is essential to generate new therapies for liver fibrosis. Greater knowledge of the role of the Wnt signaling pathway in liver fibrosis could improve understanding of the liver fibrosis pathogenesis. The aim of this review is to describe the present knowledge about the Wnt signaling pathway, which significantly participates in liver fibrosis and HSC activation, and look ahead on new perspectives of Wnt signaling pathway research. Moreover, we will discuss the different interactions with Wnt signaling pathway-regulated liver fibrosis. The Wnt signaling pathway modulates several important aspects of function, including cell proliferation, activation and differentiation. Targeting the Wnt signaling pathway can be a promising direction in liver fibrosis treatment. We discuss new perspectives of Wnt signaling pathway activation in liver fibrosis. For example, antagonist to Wnt and Wnt ligands could inhibit liver fibrosis by regulating Wnt/β-catenin signaling pathway. These findings identify the Wnt signaling pathway as a potentially important for therapeutic targets in liver fibrosis. Future studies are needed in order to find safer and more effective Wnt-based drugs.
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Zhou F, Wang A, Li D, Wang Y, Lin L. Pinocembrin from Penthorum chinense Pursh suppresses hepatic stellate cells activation through a unified SIRT3-TGF-β-Smad signaling pathway. Toxicol Appl Pharmacol 2018; 341:38-50. [DOI: 10.1016/j.taap.2018.01.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 01/03/2018] [Accepted: 01/13/2018] [Indexed: 01/18/2023]
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Steiner CA, Higgins PDR. Anti-Fibrotic Therapies from Other Organs: What the Gut Can Learn from the Liver, Skin, Lung and Heart. FIBROSTENOTIC INFLAMMATORY BOWEL DISEASE 2018:347-385. [DOI: 10.1007/978-3-319-90578-5_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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45
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Hedgehog signaling inhibitor GANT61 induces endoplasmic reticulum stress-mediated protective autophagy in hepatic stellate cells. Biochem Biophys Res Commun 2017; 493:487-493. [DOI: 10.1016/j.bbrc.2017.08.164] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Accepted: 08/31/2017] [Indexed: 02/07/2023]
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Milette S, Sicklick JK, Lowy AM, Brodt P. Molecular Pathways: Targeting the Microenvironment of Liver Metastases. Clin Cancer Res 2017; 23:6390-6399. [PMID: 28615370 PMCID: PMC5668192 DOI: 10.1158/1078-0432.ccr-15-1636] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 04/27/2017] [Accepted: 06/09/2017] [Indexed: 12/31/2022]
Abstract
Curative treatment for metastatic solid cancers remains elusive. The liver, which is nourished by a rich blood supply from both the arterial and portal venous systems, is the most common site of visceral metastases, particularly from cancers arising in the gastrointestinal tract, with colorectal cancer being the predominant primary site in Western countries. A mounting body of evidence suggests that the liver microenvironment (LME) provides autocrine and paracrine signals originating from both parenchymal and nonparenchymal cells that collectively create both pre- and prometastatic niches for the development of hepatic metastases. These resident cells and their molecular mediators represent potential therapeutic targets for the prevention and/or treatment of liver metastases (LM). This review summarizes: (i) the current therapeutic options for treating LM, with a particular focus on colorectal cancer LM; (ii) the role of the LME in LM at each of its phases; (iii) potential targets in the LME identified through preclinical and clinical investigations; and (iv) potential therapeutic approaches for targeting elements of the LME before and/or after the onset of LM as the basis for future clinical trials. Clin Cancer Res; 23(21); 6390-9. ©2017 AACR.
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Affiliation(s)
- Simon Milette
- Departments of Surgery, Medicine, and Oncology McGill University and the McGill University Health Centre, Montreal, Quebec, Canada
| | - Jason K. Sicklick
- Division of Surgical Oncology, Department of Surgery, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Andrew M. Lowy
- Division of Surgical Oncology, Department of Surgery, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Pnina Brodt
- Departments of Surgery, Medicine, and Oncology McGill University and the McGill University Health Centre, Montreal, Quebec, Canada
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He J, Bai K, Hong B, Zhang F, Zheng S. Docosahexaenoic acid attenuates carbon tetrachloride-induced hepatic fibrosis in rats. Int Immunopharmacol 2017; 53:56-62. [PMID: 29035816 DOI: 10.1016/j.intimp.2017.09.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2017] [Revised: 09/15/2017] [Accepted: 09/15/2017] [Indexed: 02/07/2023]
Abstract
Fish oil containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) has been reported to exert beneficial health effects, including hepatoprotection. However, the effect of DHA alone has not been well studied, and the mechanism is not fully understood. In the present study, we reported the protective effect of DHA on carbon tetrachloride (CCl4) induced hepatic fibrosis. Compared with the control group, the CCl4 group showed hepatic damage as evidenced by histological changes and elevation in serum transaminase activity, fibrosis, inflammation and oxidative stress levels. These pathophysiological changes were attenuated by chronic DHA supplementation. The anti-fibrotic effect of DHA was accompanied by reductions in gene and protein expression of α-smooth muscle actin (α-SMA), fibronectin, and collagen in the liver tissue. DHA also attenuated CCl4-induced elevation of lipid peroxidation (LPO) and decrease of glutathione (GSH)/oxidized GSH (GSSG) ratio. The upregulated inflammatory cytokines tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-6 by CCl4 were also ameliorated by DHA. Peroxisome proliferator-activated receptor (PPAR)-γ upregulation and type I and II receptors for transforming growth factor (TGF)-β (Tβ-RI and Tβ-RII) and platelet-derived growth factor (PDGF)-β receptor (PDGF-βR) downregulation on both mRNA and protein levels were observed by DHA treatment compared to CCl4 group. Moreover, in vitro study showed that DHA inhibited HSC activation, being associated with elevating PPARγ level and reducing the phosphorylation levels of Smad2/3 and ERKs, which are downstream intermediates of TGFβ and PDGF receptors, respectively. Taken together, the hepatoprotective, anti-inflammatory and anti-fibrotic effects of DHA appeared to be multifactorial. Further, one of the mechanisms of the anti-fibrotic effect of chronic DHA supplementation is probably through PPARγ signaling to interrupt TGFβ/Smad and PDGF/ERK pathways in HSCs.
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Affiliation(s)
- Jianlin He
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, PR China; Third Institute of Oceanography, State Oceanic Administration, Xiamen 361005, PR China
| | - Kaikai Bai
- Third Institute of Oceanography, State Oceanic Administration, Xiamen 361005, PR China
| | - Bihong Hong
- Third Institute of Oceanography, State Oceanic Administration, Xiamen 361005, PR China
| | - Feng Zhang
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, PR China
| | - Shizhong Zheng
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, PR China.
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El-Mihi KA, Kenawy HI, El-Karef A, Elsherbiny NM, Eissa LA. Naringin attenuates thioacetamide-induced liver fibrosis in rats through modulation of the PI3K/Akt pathway. Life Sci 2017; 187:50-57. [PMID: 28830755 DOI: 10.1016/j.lfs.2017.08.019] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Revised: 08/10/2017] [Accepted: 08/18/2017] [Indexed: 12/12/2022]
Abstract
AIMS Naringin (NR) is a flavanone glycoside extracted from grapefruits and citrus fruits. The aim of this study is to investigate the antifibrotic efficacy of NR in thioacetamide (TAA)-induced hepatic fibrosis in rats through evaluating NR effect on the PI3K/Akt pathway. MAIN METHODS Hepatic fibrosis was induced in rats by intraperitoneal injection of TAA (200mg/kg) twice per week for 6weeks. Simultaneously, NR (40mg/kg/day, p.o.) was given along with TAA injection. The ratio of P-Akt/Akt was assessed in hepatic homogenate as well as antioxidant enzymes (catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx)) and lipid peroxidation marker, malondialdehyde (MDA). Serum level of interleukin (IL)-6 were measured using ELISA. Hepatic tissues were examined histopathologically using hematoxylin and eosin (H&E) and Masson trichome staining. Tissue expression of alpha smooth muscle actin (α-SMA), transforming growth factor β1 (TGF-β1), caspase-3 and fibronectin were scored immunohistochemically. Finally, the mRNA level of cytokine genes (IL-1β, IL-6, IL-10, interferon gamma (IFN-γ)), caspase-3, TGF-β1 and fibronectin were quantified using qPCR. KEY FINDINGS NR significantly suppressed Akt phosphorylation associated with increased number of caspase-3 positive cells especially in the fibrotic areas. Liver tissues of treated rats showed restoration of normal liver histology and decrease in collagen and fibronectin deposition. Furthermore, NR treatment ameliorated oxidative stress and inflammatory cytokine production. SIGNIFICANCE NR alleviated experimental liver fibrosis through inhibition of PI3K/Akt pathway beside its anti-inflammatory and antioxidant effects. Therefore, NR is a promising therapeutic candidate for hepatic fibrosis.
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Affiliation(s)
- Kholoud Alaa El-Mihi
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Hany Ibrahim Kenawy
- Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Amro El-Karef
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | | | - Laila Ahmed Eissa
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
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Kikuchi A, Pradhan-Sundd T, Singh S, Nagarajan S, Loizos N, Monga SP. Platelet-Derived Growth Factor Receptor α Contributes to Human Hepatic Stellate Cell Proliferation and Migration. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:2273-2287. [PMID: 28734947 DOI: 10.1016/j.ajpath.2017.06.009] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 05/19/2017] [Accepted: 06/08/2017] [Indexed: 02/06/2023]
Abstract
Platelet-derived growth factor receptor α (PDGFRα), a tyrosine kinase receptor, is up-regulated in hepatic stellate cells (HSCs) during chronic liver injury. HSCs mediate hepatic fibrosis through their activation from a quiescent state partially in response to profibrotic growth factors. HSC activation entails enhanced expression of profibrotic genes, increase in proliferation, and increase in motility, which facilitates migration within the hepatic lobule. We show colocalization of PDGFRα in murine carbon tetrachloride, bile duct ligation, and 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine models of chronic liver injury, and investigate the role of PDGFRα on proliferation, profibrotic gene expression, and migration in primary human HSCs (HHSteCs) using the PDGFRα-specific inhibitory monoclonal antibody olaratumab. Although lacking any effects on HHSteC transdifferentiation assessed by gene expression of ACTA2, TGFB1, COL1A1, SYP1, and FN1, olaratumab specifically reduced HHSteC proliferation (AlamarBlue assay) and cell migration (transwell migration assays). Using phospho-specific antibodies, we show that olaratumab attenuates PDGFRα activation in response to PDGF-BB, and reduced phosphorylation of extracellular signal-regulated kinase 1 and 2, Elk-1, p38, Akt, focal adhesion kinase, mechanistic target of rapamycin, C10 regulator of kinase II, and C10 regulator of kinase-like, suggesting that PDGFRα contributes to mitogenesis and actin reorganization through diverse downstream effectors. Our findings support a distinct contribution of PDGFRα signaling to HSC proliferation and migration and provide evidence that inhibition of PDGFRα signaling could alter the pathogenesis of hepatic fibrosis.
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Affiliation(s)
- Alexander Kikuchi
- Department of Pathology and Medicine and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Tirthadipa Pradhan-Sundd
- Department of Pathology and Medicine and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Sucha Singh
- Department of Pathology and Medicine and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Shanmugam Nagarajan
- Department of Pathology and Medicine and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Nick Loizos
- Department of Immunology, Eli Lilly and Company, New York, New York
| | - Satdarshan P Monga
- Department of Pathology and Medicine and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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50
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de Oliveira da Silva B, Ramos LF, Moraes KCM. Molecular interplays in hepatic stellate cells: apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis. Cell Biol Int 2017; 41:946-959. [PMID: 28498509 DOI: 10.1002/cbin.10790] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 05/08/2017] [Indexed: 12/18/2022]
Abstract
Liver fibrosis is a pathophysiological process correlated with intense repair and cicatrization mechanisms in injured liver, and over the past few years, the characterization of the fine-tuning of molecular interconnections that support the development of liver fibrosis has been investigated. In this cellular process, the hepatic stellate cells (HSCs) support the organ fibrogenesis. The HSCs are found in two distinct morpho-physiological states: quiescent and activated. In normal liver, most HSCs are found in quiescent state, presenting a considerable amount of lipid droplets in the cytoplasm, while in injured liver, the activated phenotype of HSCs is a myofibroblast, that secrete extracellular matrix elements and contribute to the establishment of the fibrotic process. Studies on the molecular mechanisms by which HSCs try to restore their quiescent state have been performed; however, no effective treatment to reverse fibrosis has been so far prescribed. Therefore, the elucidation of the cellular and molecular mechanisms of apoptosis, senescence, and the cell reversion phenotype process from activate to quiescent state will certainly contribute to the development of effective therapies to treat hepatic fibrosis. In this context, this review aimed to address central elements of apoptosis, senescence, and reversal of HSC phenotype in the control of hepatic fibrogenesis, as a guide to future development of therapeutic strategies.
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Affiliation(s)
- Brenda de Oliveira da Silva
- Universidade Federal de Ouro Preto, Núcleo de Pesquisa em Ciências Biológicas, Programa de Pós-Graduação em Biotecnologia, Ouro Preto, Minas Gerais, Brazil.,Molecular Biology Laboratory, Departamento de Biologia, Instituto de Biociências, Universidade Estadual Paulista "Júlio de Mesquita Filho"-Campus Rio Claro, Rio Claro, São Paulo, Brazil
| | - Letícia Ferrreira Ramos
- Molecular Biology Laboratory, Departamento de Biologia, Instituto de Biociências, Universidade Estadual Paulista "Júlio de Mesquita Filho"-Campus Rio Claro, Rio Claro, São Paulo, Brazil
| | - Karen C M Moraes
- Molecular Biology Laboratory, Departamento de Biologia, Instituto de Biociências, Universidade Estadual Paulista "Júlio de Mesquita Filho"-Campus Rio Claro, Rio Claro, São Paulo, Brazil
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