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Liang K, Ma S, Luo K, Wang R, Xiao C, Zhang X, Gao Y, Li M. Salidroside: An Overview of Its Promising Potential and Diverse Applications. Pharmaceuticals (Basel) 2024; 17:1703. [PMID: 39770545 PMCID: PMC11678419 DOI: 10.3390/ph17121703] [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: 11/04/2024] [Revised: 12/05/2024] [Accepted: 12/12/2024] [Indexed: 01/11/2025] Open
Abstract
Salidroside, a phenolic compound isolated from various Rhodiola plants, is the principal active constituent of Traditional Chinese Medicine known for its adaptogenic properties. Due to the challenging environment of Rhodiola species, such as high altitude, high radiation, drought, and hypoxia, the source of salidroside is scarce. However, numerous studies have shown that salidroside has a range of biological activities, including cardiovascular and central nervous system activity, and anti-hypoxia, anti-inflammatory, and anti-aging activities. Although previous studies have partially summarized the pharmacological effects of salidroside, the overall pharmacological effects have not been analyzed. Hence, this review will systematically summarize the isolation, purification, synthesis, derivatization, pharmacological activity, pharmacokinetics, clinical application, and safety of salidroside. It is expected to provide new insights for the further research and pharmaceutical development of salidroside.
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Affiliation(s)
- Keke Liang
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China; (K.L.); (S.M.); (K.L.); (R.W.)
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (C.X.); (X.Z.)
| | - Shuhe Ma
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China; (K.L.); (S.M.); (K.L.); (R.W.)
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (C.X.); (X.Z.)
| | - Kai Luo
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China; (K.L.); (S.M.); (K.L.); (R.W.)
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (C.X.); (X.Z.)
| | - Renjie Wang
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China; (K.L.); (S.M.); (K.L.); (R.W.)
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (C.X.); (X.Z.)
| | - Chenrong Xiao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (C.X.); (X.Z.)
| | - Xianxie Zhang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (C.X.); (X.Z.)
| | - Yue Gao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (C.X.); (X.Z.)
- National Key Laboratory of Kidney Diseases, Beijing 100850, China
| | - Maoxing Li
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China; (K.L.); (S.M.); (K.L.); (R.W.)
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (C.X.); (X.Z.)
- National Key Laboratory of Kidney Diseases, Beijing 100850, China
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Sun L, Zheng M, Gao Y, Brigstock DR, Gao R. Retinoic acid signaling pathway in pancreatic stellate cells: Insight into the anti-fibrotic effect and mechanism. Eur J Pharmacol 2024; 967:176374. [PMID: 38309676 DOI: 10.1016/j.ejphar.2024.176374] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 01/15/2024] [Accepted: 01/30/2024] [Indexed: 02/05/2024]
Abstract
Pancreatic stellate cells (PSCs) are activated following loss of cytoplasmic vitamin A (retinol)-containing lipid droplets, which is a key event in the process of fibrogenesis of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDCA). PSCs are the major source of cancer-associated fibroblasts (CAFs) that produce stroma to induce PDAC cancer cell growth, invasion, and metastasis. As an active metabolite of retinol, retinoic acid (RA) can regulate target gene expression in PSCs through its nuclear receptor complex (RAR/RXR or RXR/RXR) or transcriptional intermediary factor. Additionally, RA also has extranuclear and non-transcriptional effects. In vitro studies have shown that RA induces PSC deactivation which reduces extracellular matrix production through multiple modes of action, such as inhibiting TβRⅡ, PDGFRβ, β-catenin and Wnt production, downregulating ERK1/2 and JNK phosphorylation and suppressing active TGF-β1 release. RA alone or in combination with other reagents have been demonstrated to have an effective anti-fibrotic effect on cerulein-induced mouse CP models in vivo studies. Clinical trial data have shown that repurposing all-trans retinoic acid (ATRA) as a stromal-targeting agent for human pancreatic cancer is safe and tolerable, suggesting the possibility of using RA for the treatment of CP and PDCA in humans. This review focuses on RA signaling pathways in PSCs and the effects and mechanisms of RA in PSC-mediated fibrogenesis as well as the anti-fibrotic and anti-tumor effects of RA targeting PSCs or CAFs in vitro and in vivo, highlighting the potential therapies of RA against CP and PDAC.
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Affiliation(s)
- Li Sun
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Department of Pathology, First Hospital of Jilin University, Changchun, China
| | - Meifang Zheng
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Yanhang Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Department of Infectious Diseases, First Hospital of Jilin University, Changchun, China.
| | - David R Brigstock
- The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States
| | - Runping Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Department of Infectious Diseases, First Hospital of Jilin University, Changchun, China.
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Chen G, Weiskirchen S, Weiskirchen R. Vitamin A: too good to be bad? Front Pharmacol 2023; 14:1186336. [PMID: 37284305 PMCID: PMC10239981 DOI: 10.3389/fphar.2023.1186336] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/09/2023] [Indexed: 06/08/2023] Open
Abstract
Vitamin A is a micronutrient important for vision, cell growth, reproduction and immunity. Both deficiency and excess consuming of vitamin A cause severe health consequences. Although discovered as the first lipophilic vitamin already more than a century ago and the definition of precise biological roles of vitamin A in the setting of health and disease, there are still many unresolved issues related to that vitamin. Prototypically, the liver that plays a key role in the storage, metabolism and homeostasis of vitamin A critically responds to the vitamin A status. Acute and chronic excess vitamin A is associated with liver damage and fibrosis, while also hypovitaminosis A is associated with alterations in liver morphology and function. Hepatic stellate cells are the main storage site of vitamin A. These cells have multiple physiological roles from balancing retinol content of the body to mediating inflammatory responses in the liver. Strikingly, different animal disease models also respond to vitamin A statuses differently or even opposing. In this review, we discuss some of these controversial issues in understanding vitamin A biology. More studies of the interactions of vitamin A with animal genomes and epigenetic settings are anticipated in the future.
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Affiliation(s)
- Guoxun Chen
- College of Food Science and Technology, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, China
| | - Sabine Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
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Chen L, Xia S, Wang S, Zhou Y, Wang F, Li Z, Li Y, Kong D, Zhang Z, Shao J, Xu X, Zhang F, Zheng S. Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway. J Clin Transl Hepatol 2023; 11:26-37. [PMID: 36406329 PMCID: PMC9647116 DOI: 10.14218/jcth.2022.00120] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/01/2022] [Accepted: 04/07/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease. The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin. METHODS The relationship between the cGAS-stimulator of interferon genes (STING) pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database. Histopathology, immunohistochemistry, fluorescence staining, Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers. Molecular docking was performed to evaluate the relationship between naringenin and cGAS, and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro. RESULTS Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease. Naringenin ameliorated liver injury and liver fibrosis, decreased collagen deposition and cGAS expression, and inhibited inflammation in carbon tetrachloride (CCl4)-treated mice. Molecular docking found that cGAS may be a direct target of naringenin. Consistent with the in vivo results, we verified the inhibitory effect of naringenin on activated hepatic stellate cells (HSCs). By using the cGAS-specific agonist double-stranded (ds)DNA, we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA. We verified that naringenin inhibited the cGAS-STING pathway, thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis. CONCLUSIONS Interrupting the cGAS-STING pathway helped reverse the fibrosis process. Naringenin has potential as an antihepatic fibrosis drug.
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Affiliation(s)
- Li Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Siwei Xia
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Shuqi Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yuanyuan Zhou
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Feixia Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Zhanghao Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yang Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Desong Kong
- Chinese Medicine Modernization and Big Data Research Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jiangjuan Shao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xuefen Xu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Correspondence to: Shizhong Zheng and Feng Zhang, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China. ORCID: https://orcid.org/0000-0003-4925-9390 (SZ). Tel/Fax: +86-25-85811246, E-mail: (SZ) and (FZ)
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Correspondence to: Shizhong Zheng and Feng Zhang, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China. ORCID: https://orcid.org/0000-0003-4925-9390 (SZ). Tel/Fax: +86-25-85811246, E-mail: (SZ) and (FZ)
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Garbuzenko DV. Pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. World J Clin Cases 2022; 10:3662-3676. [PMID: 35647163 PMCID: PMC9100727 DOI: 10.12998/wjcc.v10.i12.3662] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/17/2021] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a complex pathological process controlled by a variety of cells, mediators and signaling pathways. Hepatic stellate cells play a central role in the development of liver fibrosis. In chronic liver disease, hepatic stellate cells undergo dramatic phenotypic activation and acquire fibrogenic properties. This review focuses on the pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. They enter the cell cycle under the influence of various triggers. The "Initiation" phase of hepatic stellate cells activation overlaps and continues with the "Perpetuation" phase, which is characterized by a pronounced inflammatory and fibrogenic reaction. This is followed by a resolution phase if the injury subsides. Knowledge of these pathophysiological mechanisms paved the way for drugs aimed at preventing the development and progression of liver fibrosis. In this respect, impairments in intracellular signaling, epigenetic changes and cellular stress response can be the targets of therapy where the goal is to deactivate hepatic stellate cells. Potential antifibrotic therapy may focus on inducing hepatic stellate cells to return to an inactive state through cellular aging, apoptosis, and/or clearance by immune cells, and serve as potential antifibrotic therapy. It is especially important to prevent the formation of liver cirrhosis since the only radical approach to its treatment is liver transplantation which can be performed in only a limited number of countries.
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Wang S, Yu J, Kane MA, Moise AR. Modulation of retinoid signaling: therapeutic opportunities in organ fibrosis and repair. Pharmacol Ther 2019; 205:107415. [PMID: 31629008 DOI: 10.1016/j.pharmthera.2019.107415] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 09/17/2019] [Indexed: 02/08/2023]
Abstract
The vitamin A metabolite, retinoic acid, is an important signaling molecule during embryonic development serving critical roles in morphogenesis, organ patterning and skeletal and neural development. Retinoic acid is also important in postnatal life in the maintenance of tissue homeostasis, while retinoid-based therapies have long been used in the treatment of a variety of cancers and skin disorders. As the number of people living with chronic disorders continues to increase, there is great interest in extending the use of retinoid therapies in promoting the maintenance and repair of adult tissues. However, there are still many conflicting results as we struggle to understand the role of retinoic acid in the multitude of processes that contribute to tissue injury and repair. This review will assess our current knowledge of the role retinoic acid signaling in the development of fibroblasts, and their transformation to myofibroblasts, and of the potential use of retinoid therapies in the treatment of organ fibrosis.
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Affiliation(s)
- Suya Wang
- Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Jianshi Yu
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, 21201, USA
| | - Maureen A Kane
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, 21201, USA.
| | - Alexander R Moise
- Medical Sciences Division, Northern Ontario School of Medicine, Sudbury, ON P3E 2C6, Canada; Departments of Chemistry and Biochemistry, and Biology and Biomolecular Sciences Program, Laurentian University, Sudbury, ON, P3E 2C6, Canada.
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Nagpal I, Wei LN. All- trans Retinoic Acid as a Versatile Cytosolic Signal Modulator Mediated by CRABP1. Int J Mol Sci 2019; 20:ijms20153610. [PMID: 31344789 PMCID: PMC6696438 DOI: 10.3390/ijms20153610] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 07/18/2019] [Accepted: 07/20/2019] [Indexed: 12/12/2022] Open
Abstract
All-trans retinoic acid (AtRA), an active metabolite of vitamin A, is recognized for its classical action as an endocrine hormone that triggers genomic effects mediated through nuclear receptors RA receptors (RARs). New evidence shows that atRA-mediated cellular responses are biphasic with rapid and delayed responses. Most of these rapid atRA responses are the outcome of its binding to cellular retinoic acid binding protein 1 (CRABP1) that is predominantly localized in cytoplasm and binds to atRA with a high affinity. This review summarizes the most recent studies of such non-genomic outcomes of atRA and the role of CRABP1 in mediating such rapid effects in different cell types. In embryonic stem cells (ESCs), atRA-CRABP1 dampens growth factor sensitivity and stemness. In a hippocampal neural stem cell (NSC) population, atRA-CRABP1 negatively modulates NSC proliferation and affects learning and memory. In cardiomyocytes, atRA-CRABP1 prevents over-activation of calcium-calmodulin-dependent protein kinase II (CaMKII), protecting heart function. These are supported by the fact that CRABP1 gene knockout (KO) mice exhibit multiple phenotypes including hippocampal NSC expansion and spontaneous cardiac hypertrophy. This indicates that more potential processes/signaling pathways involving atRA-CRABP1 may exist, which remain to be identified.
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Affiliation(s)
- Isha Nagpal
- Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Li-Na Wei
- Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
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