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Sadr S, Ahmadi Simab P, Niazi M, Yousefsani Z, Lotfalizadeh N, Hajjafari A, Borji H. Anti-inflammatory and immunomodulatory effects of mesenchymal stem cell therapy on parasitic drug resistance. Expert Rev Anti Infect Ther 2024; 22:435-451. [PMID: 38804866 DOI: 10.1080/14787210.2024.2360684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 05/23/2024] [Indexed: 05/29/2024]
Abstract
INTRODUCTION The emergence of antiparasitic drug resistance poses a concerning threat to animals and humans. Mesenchymal Stem Cells (MSCs) have been widely used to treat infections in humans, pets, and livestock. Although this is an emerging field of study, the current review outlines possible mechanisms and examines potential synergism in combination therapies and the possible harmful effects of such an approach. AREAS COVERED The present study delved into the latest pre-clinical research on utilizing MSCs to treat parasitic infections. As per investigations, the introduction of MSCs to patients grappling with parasitic diseases like schistosomiasis, malaria, cystic echinococcosis, toxoplasmosis, leishmaniasis, and trypanosomiasis has shown a reduction in parasite prevalence. This intervention also alters the levels of both pro- and anti-inflammatory cytokines. Furthermore, the combined administration of MSCs and antiparasitic drugs has demonstrated enhanced efficacy in combating parasites and modulating the immune response. EXPERT OPINION Mesenchymal stem cells are a potential solution for addressing parasitic drug resistance. This is mainly because of their remarkable immunomodulatory abilities, which can potentially help combat parasites' resistance to drugs.
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Affiliation(s)
- Soheil Sadr
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Pouria Ahmadi Simab
- Department of Pathobiology, Faculty of Veterinary Medicine, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran
| | - Mahta Niazi
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Zahra Yousefsani
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Narges Lotfalizadeh
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Ashkan Hajjafari
- Department of Pathobiology, Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Hassan Borji
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
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Liu Z, Xiang H, Xiang D, Xiao S, Xiang H, Xiao J, Ren H, Hu P, Liu H, Peng M. Revealing potential anti-fibrotic mechanism of Ganxianfang formula based on RNA sequence. Chin Med 2022; 17:23. [PMID: 35180857 PMCID: PMC8855591 DOI: 10.1186/s13020-022-00579-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 02/01/2022] [Indexed: 11/18/2022] Open
Abstract
Background Ganxianfang (GXF) formula as a traditional Chinese medicine (TCM) is used for liver fibrosis in clinical practice while its mechanism is unclear. The aim of this study is to explore the molecular mechanism of GXF against CCl4-induced liver fibrosis rats. Methods Detected the main compounds of GXF by UPLC-MS/MS. Evaluated the efficacy of GXF (1.58, 3.15, 4.73 g/kg/day) and Fuzheng Huayu (FZHY, positive control, 0.47 g/kg/day) through serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels and histopathological changes. Explored the underlying mechanisms by integrating our total liver RNA sequencing (RNA-seq) data with recent liver single-cell sequencing (scRNA-seq) studies. Verified potential pharmacodynamic substances of GXF by hepatic stellate cell (HSC)-T6 line. Results Main compounds were identified in GXF by UPLC-MS/MS, including baicalin, wogonoside and matrine etc. With GXF-high dose treatment, the elevation of ALT and AST induced by CCl4 were significantly reduced, and the protective effect of GXF-high dose treatment was better than FZHY. Liver histopathological changes were alleviated by GXF-high dose treatment, the ISHAK scoring showed the incidence of liver cirrhosis (F5/F6) decreased from 76.5 to 55.6%. The results of liver hydroxyproline content were consistent with the histopathological changes. RNA-seq analysis revealed the differential genes (DEGs) were mainly enriched in ECM-receptor interaction and chemokine signaling pathway. GXF effectively inhibited collagen deposition and significantly downregulated CCL2 to inhibit the recruitment of macrophages in liver tissue. Integrating scRNA-seq data revealed that GXF effectively inhibited the expansion of scar-associated Trem2+CD9+ macrophages subpopulation and PDGFRα+PDGFRβ+ scar-producing myofibroblasts in the damaged liver, and remodeled the fibrotic niche via regulation of ligand-receptor interactions including TGFβ/EGFR, PDGFB/PDGFRα, and TNFSF12/TNFRSF12a signaling. In vitro experiments demonstrated that baicalin, matrine and hesperidin in GXF inhibited the activation of hepatic stellate cells. Conclusions This study clarified the potential anti-fibrotic effects and molecular mechanism of GXF in CCl4-induced liver fibrosis rats, which deserves further promotion and application. Supplementary Information The online version contains supplementary material available at 10.1186/s13020-022-00579-7.
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Affiliation(s)
- Zongyi Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Huanyu Xiang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Dejuan Xiang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Shuang Xiao
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Hongyan Xiang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Jing Xiao
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Peng Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Huabao Liu
- Department of Liver Diseases, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China.
| | - Mingli Peng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
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Effect of Shenfu Injection on Differentiation of Bone Marrow Mesenchymal Stem Cells into Pacemaker-Like Cells and Improvement of Pacing Function of Sinoatrial Node. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4299892. [PMID: 35186186 PMCID: PMC8853776 DOI: 10.1155/2022/4299892] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 01/16/2022] [Accepted: 01/26/2022] [Indexed: 11/17/2022]
Abstract
Sick sinus syndrome (SSS), a complex type of cardiac arrhythmia, is a major health threat to humans. Shenfu injection (SFI), a formula of traditional Chinese medicine (TCM), is effective in improving bradyarrhythmia. However, the underlying mechanism of SFI’s therapeutic effect is subject to few systematic investigations. The purpose of the present research is to examine whether SFI can boost the differentiation effectiveness of bone marrow mesenchymal stem cells (BMSCs) into pacemaker-like cells and whether the transplantation of these cells can improve the pacing function of the sinoatrial node (SAN) in a rabbit model of SSS. BMSCs from New Zealand rabbits were extracted, followed by incubation in vitro. The flow cytometry was utilized to identify the expression of CD29, CD44, CD90, and CD105 surface markers. The isolated BMSCs were treated with SFI, and the whole-cell patch-clamp method was performed to detect hyperpolarization-the activated cyclic nucleotide-gated potassium channel 4 (HCN4) channel current activation curve. The SSS rabbit model was established using the formaldehyde wet dressing method, and BMSCs treated with SFI were transplanted into the SAN of the SSS rabbit model. We detected changes in the body-surface electrocardiogram and recorded dynamic heart rate measurements. Furthermore, transplanted SFI-treated BMSCs were subjected to HE staining, TUNEL staining, qPCR, western blotting, immunofluorescence, immunohistochemistry, and enzyme-linked immunosorbent assay to study their characteristics. Our results indicate that the transplantation of SFI-treated BMSCs into the SAN of SSS rabbits improved the pacing function of the SAN. In vitro data showed that SFI induced the proliferation of BMSCs, promoted their differentiation capacity into pacemaker-like cells, and increased the HCN4 expression in BMSCs. In vivo, the transplantation of SFI treated-BMSCs preserved the function of SAN in SSS rabbits, improved the expression of the HCN4 gene and gap junction proteins (Cx43 and Cx45), and significantly upregulated the expression of cAMP in the SAN, compared to the SSS model group. In summary, the present research demonstrated that SFI might enhance the differentiation capacity of BMSCs into pacemaker-like cells, hence offering a novel approach for the development of biological pacemakers. Additionally, we confirmed the effectiveness and safety of pacemaker-like cells differentiated from BMSCs in improving the pacing function of the SAN.
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Xiong Y, Hu J, Xuan C, Tian J, Tan K, Chen Z, Luo Y, Du X, Cheng J, Zhang L, Cao W. Transcriptome analysis reveals the molecular mechanism of Yiqi Rougan decoction in reducing CCl 4-induced liver fibrosis in rats. Chin Med 2021; 16:142. [PMID: 34952623 PMCID: PMC8709947 DOI: 10.1186/s13020-021-00552-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022] Open
Abstract
Background Liver fibrosis develops from various chronic liver diseases, and there is currently a lack of specific treatment strategies. Yiqi Rougan decoction (YQRG) is a traditional Chinese medicine that has shown durative effects in the treatment of liver fibrosis; however, the mechanism associated with YQRG-related improvements in liver fibrosis remains to be experimentally determined. This study evaluated the therapeutic effect of YQRG on carbon tetrachloride (CCl4)-induced liver fibrosis in rats and its molecular mechanism. Methods We used low-, medium-, and high-dose YQRG to treat CCl4-induced liver fibrosis in rats, followed by assessment of liver injury and fibrosis according to liver appearance, body weight, liver mass index, histopathologic examination, and serum testing. Additionally, we performed transcriptome analysis using RNA-sequencing (RNA-seq) technology, including cluster, Gene Ontology (GO), and pathway analyses, to identify differentially expressed genes (DEGs), and protein and gene expression were detected by immunofluorescence (IFC), western blot and real-time quantitative PCR. Results The results showed that YQRG effectively alleviated CCl4-induced liver injury and fibrosis in rats, including observations of improved liver function, decreased activity of hepatic stellate cells (HSCs), and decreased extracellular matrix (ECM) deposition. Moreover, we identified downregulated and upregulated DEGs in the model group relative to the control and YQRG-treated groups, with GO analysis revealing their enrichment in biological processes, such as endoplasmic reticulum stress (ERS), apoptosis, and autophagy. Furthermore, pathway analysis showed that YQRG treatment downregulated the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/Akt (PI3K/AKT) signalling pathways and upregulated other signalling pathways, including those related to peroxisome proliferator-activated receptors(PPAR) and AMP-activated protein kinase(AMPK), with these findings subsequently verified experimentally. Conclusion These findings showed that YQRG improved CCl4-induced liver fibrosis through multiple mechanisms and pathways, offering critical insight into the YQRG-related therapeutic mechanism and promoting further research into its potential application. Supplementary Information The online version contains supplementary material available at 10.1186/s13020-021-00552-w.
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Affiliation(s)
- Yu Xiong
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Jinyuan Hu
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Chen Xuan
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Jiayu Tian
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Kaiyue Tan
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Zhiwei Chen
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Yan Luo
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China.,Department of Kidney Disease, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China
| | - Xuqin Du
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Junxiong Cheng
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Lanyue Zhang
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Wenfu Cao
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China. .,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China. .,Department of Combination of Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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Liu Q, Chen L, Yin W, Nie Y, Zeng P, Yang X. Anti-tumor effect of ginkgetin on human hepatocellular carcinoma cell lines by inducing cell cycle arrest and promoting cell apoptosis. Cell Cycle 2021; 21:74-85. [PMID: 34878966 DOI: 10.1080/15384101.2021.1995684] [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] [Indexed: 10/19/2022] Open
Abstract
This study explored the anti-tumor effect of ginkgetin, an extract from ginkgo biloba, on human hepatocellular carcinoma cell lines and the underlying mechanisms. Cell viability was measured by MTT assay. Apoptotic cell morphology was observed under an inverted microscope after Hoechst 33,258 staining, and the ratio of apoptotic and necrotic cells was examined by flow cytometry after FITC/PI staining. Cell cycle changes were analyzed using flow cytometry. Cytochrome c release and caspase 3 and 8 activities were monitored using the relevant reagent kits. The levels of cell cycle-related proteins were detected by Western blot. MTT results indicated that ginkgetin significantly reduced HepG2 cell viability in a dose-dependent manner. Cellular morphology observation revealed that ginkgetin induced typical apoptotic morphological features of HepG2 cells, such as increased apoptotic bodies and cell shrinkage. Cell cycle analysis showed that ginkgetin increased the proportion of cells in the S phase. S-phase cell accumulation could be attributed to the decreased expression of cell cycle regulatory factors. Similarly, ginkgetin also induced the apoptosis and S phase cell accumulation of another human HCC cell line SK-HEP-1. Furthermore, ginkgetin treatment increased caspase-3 activity and cytochrome c release but not caspase-8 activity, implying that ginkgetin might mediate cell apoptosis through the mitochondrial pathway. In addition, the tumor formation experiment in nude mice showed that ginkgetin administration inhibited tumor growth. These results suggest that ginkgetin could be a cell apoptosis stimulator by affecting the balance between cell proliferation and apoptosis, suggesting that ginkgetin might be suitable for human HCC treatment.
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Affiliation(s)
- Qiong Liu
- The First Affiliated Hospital, Department of Infectious Diseases, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Lingying Chen
- The First Affiliated Hospital, Department of blood transfusion, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Wenjun Yin
- The First Affiliated Hospital, Department of Clinical Laboratory, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yuehua Nie
- The First Affiliated Hospital, Department of Radiation Oncology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Penghui Zeng
- The First Affiliated Hospital, Department of Clinical Laboratory, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xin Yang
- The First Affiliated Hospital, Department of Infectious Diseases, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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Zhou Y, Wu R, Cai FF, Zhou WJ, Lu YY, Zhang H, Chen QL, Sun MY, Su SB. Development of a novel anti-liver fibrosis formula with luteolin, licochalcone A, aloe-emodin and acacetin by network pharmacology and transcriptomics analysis. PHARMACEUTICAL BIOLOGY 2021; 59:1594-1606. [PMID: 34808067 PMCID: PMC8635660 DOI: 10.1080/13880209.2021.1999275] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
CONTEXT Xiaoyaosan decoction (XYS), a classical Traditional Chinese Medicine (TCM) formula is used to treat liver fibrosis in clinics. OBJECTIVE This study explores defined compound combinations from XYS decoction to treat liver fibrosis. MATERIALS AND METHODS Network pharmacology combined with transcriptomics analysis was used to analyze the XYS decoction and liver depression and spleen deficiency syndrome liver fibrosis. From the constructed XYS-Syndrome-liver fibrosis network, the top 10 active formulas were developed by topological analysis according to network stability. The most active formula was determined by in vitro study. The anti-fibrosis effect was evaluated by in vitro and in vivo studies. RESULTS According to the network XYS-Syndrome-liver fibrosis network, 8 key compounds and 255 combinations were predicted from in XYS. Luteolin, licochalcone A, aloe-emodin and acacetin formula (LLAAF) had a synergistic effect on the proliferation inhibition of hepatic stellate cells compared to individual compounds alone. The treatment of XYS and LLAAF showed a similar anti-liver fibrotic effect that reduced histopathological changes of liver fibrosis, Hyp content and levels of α-SMA and collagen I in CCl4-induced liver fibrosis in rats. Transcriptomics analysis revealed LLAAF regulated PI3K-Akt, AMPK, FoxO, Jak-STAT3, P53, cell cycle, focal adhesion, and PPAR signalling. Furthermore, LLAAF was confirmed to regulate Jak-STAT and PI3K-Akt-FoxO signalling in vitro and in vivo. CONCLUSIONS This study developed a novel anti-liver formula LLAAF from XYS, and demonstrated its anti-liver fibrotic activity which may be involved in the regulation of Jak-STAT and PI3K-Akt-FoxO signalling.
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Affiliation(s)
- Yuan Zhou
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rong Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fei-fei Cai
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wen-Jun Zhou
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yi-Yu Lu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hui Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qi-Long Chen
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ming-Yu Sun
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Mingyu Sun
| | - Shi-Bing Su
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- CONTACT Shi-Bing Su
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Zhou Y, Wu R, Cai FF, Zhou WJ, Lu YY, Zhang H, Chen QL, Su SB. Xiaoyaosan decoction alleviated rat liver fibrosis via the TGFβ/Smad and Akt/FoxO3 signaling pathways based on network pharmacology analysis. JOURNAL OF ETHNOPHARMACOLOGY 2021; 264:113021. [PMID: 32479885 DOI: 10.1016/j.jep.2020.113021] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 05/12/2020] [Accepted: 05/24/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Liver fibrosis is an outcome of many chronic liver diseases and often results in cirrhosis, liver failure, and even hepatocarcinoma. Xiaoyaosan decoction (XYS) as a classical Traditional Chinese Medicine (TCM) formula is used to liver fibrosis in clinical practice while its mechanism is unclear. AIM OF THE STUDY The aim of this study was to investigate the anti-fibrosis effect of XYS and to explore the molecular mechanisms by combining network pharmacology and transcriptomic technologies. MATERIALS AND METHODS The carbon tetrachloride (CCl4)-induced liver fibrosis rat were treated with three doses of XYS. The liver fibrosis and function were evaluated by histopathological examination and serum biochemical detection. The fibrosis related protein a-SMA and collagen I were assessed by Western blot. Different expressed genes (DEGs) between XYS-treated group and model group were analyzed. The herb-component-target network was constructed combined the network pharmacology. The predict targets and pathways were validated by in vitro and in vivo experiments. RESULTS With XYS treatment, the liver function was significantly improved, and fibrotic changes were alleviated. The a-SMA and collagen I expression levels in the liver were also decreased in XYS-treated rats compared with CCl4 model rats. 108 active components and 42 targets from 8 herbs constituted herb-compound-target network by transcriptomics and network pharmacology analysis. The KEGG pathway and GO enrichment analyses showed that the FoxO, TGFβ, AMPK, MAPK, PPAR, and hepatitis B and C pathways were involved in the anti-fibrosis effects of XYS. In the liver tissues, p-FoxO3a and p-Akt expression levels were significantly increased in the CCl4 model group but decreased in the XYS-treated group. The TGFβ1/Smad pathway and Akt/FoxO3 pathway were verified in LX2 cells by inhibiting phosphorylation of Smad3 and Akt activity, respectively. CONCLUSIONS Our findings suggested that XYS markedly alleviated CCl4-induced liver fibrosis in histopathological and serum liver function analyses, and this effect may occur via the TGFβ1/Smad and Akt/FoxO signaling pathways.
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Affiliation(s)
- Yuan Zhou
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Rong Wu
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Fei-Fei Cai
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Wen-Jun Zhou
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yi-Yu Lu
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Hui Zhang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Qi-Long Chen
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Xie Z, Qiang J, Pi X, Wang J, Chen Y, Yu Q, Zhang Q. Favorable outcome of adjunctive traditional Chinese medicine therapy in liver cirrhosis: A large cohort study in Southwest China. Complement Ther Med 2020; 51:102446. [DOI: 10.1016/j.ctim.2020.102446] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 02/05/2020] [Accepted: 05/13/2020] [Indexed: 02/07/2023] Open
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Qiao M, Yang J, Zhu Y, Zhao Y, Hu J. Transcriptomics and proteomics analysis of system-level mechanisms in the liver of apigenin-treated fibrotic rats. Life Sci 2020; 248:117475. [PMID: 32119963 DOI: 10.1016/j.lfs.2020.117475] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 02/18/2020] [Accepted: 02/26/2020] [Indexed: 02/06/2023]
Abstract
AIMS Liver fibrosis is a crucial pathological feature which could result in cirrhosis and hepatocarcinoma. But until now, there is no favourable treatment for it. Apigenin (APG) is a flavonoid, which exhibits efficient anti-liver fibrosis activity, but its underlying mechanisms were rarely studied. So this work aims to estimate the potential therapeutic action of APG on liver fibrosis rats and to gain insight into its system-level mechanisms. MAIN METHODS Hepatic fibrosis was induced by CCl4 in Wistar rats, and APG was given in the light of the regimen. Biochemical indexes, histopathological change and immunohistochemistry of liver were evaluated. The optimal effect group of APG was selected for further transcriptomic and proteomic analysis. KEY FINDINGS APG ameliorated liver fibrosis via reducing the levels of AST, ALT, ALP, LDH, Hyp, TP, TB, DB, HA, LN, PCIII and IV-C, mitigating fibrosis and inflammation of liver in H&E and Masson staining. Mechanistically, APG elevated the activity of ALB, SOD and GSH-PX with reducing the level of MDA. The results of microarray and TMT revealed that 4919 genes and 4876 proteins were differentially expressed in the APG and model groups. Besides, transcriptomics and proteomics analyses unfolded 120 overlapped proteins, enriched in 111 GO terms containing apoptotic process, angiogenesis, cell migration and proliferation, etc. Meanwhile, KEGG pathway analysis showed that 26 pathways containing HIF-1/MAPK/eNOS/VEGF/PI3K/Akt signaling pathway, regulation of actin cytoskeleton and focal adhesion mostly. SIGNIFICANCE APG can ameliorate CCl4-induced liver fibrosis via VEGF-mediated FAK phosphorylation through the MAPKs, PI3K/Akt, HIF-1, ROS, and eNOS pathways, which may hopefully become the anti-liver fibrosis activity of natural product.
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Affiliation(s)
- Ming Qiao
- College of Pharmacy, Xinjiang Medical University, Urumqi 830011, China
| | - Jianhua Yang
- Department of Pharmacy, The First Affiliated Hospital, Xinjiang Medical University, Urumqi 830011, China
| | - Yi Zhu
- Department of Pharmacy, The First Affiliated Hospital, Xinjiang Medical University, Urumqi 830011, China
| | - Yao Zhao
- College of Pharmacy, Xinjiang Medical University, Urumqi 830011, China
| | - Junping Hu
- College of Pharmacy, Xinjiang Medical University, Urumqi 830011, China.
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Hao J, Ni X, Giunta S, Wu J, Shuang X, Xu K, Li R, Zhang W, Xia S. Pyrroloquinoline quinone delays inflammaging induced by TNF-α through the p16/p21 and Jagged1 signalling pathways. Clin Exp Pharmacol Physiol 2019; 47:102-110. [PMID: 31520547 DOI: 10.1111/1440-1681.13176] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 09/05/2019] [Accepted: 09/06/2019] [Indexed: 12/15/2022]
Abstract
Previous studies on the longevity effect of pyrroloquinoline quinine (PQQ) on nematode worms have revealed that PQQ can enhance the antioxidant capacity of nematode worms, thus extending the lifespan of the worms. The induction and development of cellular senescence are closely connected with inflammatory reactions. The aim of this study was to determine the effect of PQQ and ageing factors on senescent cells. To this end, we cultivated human embryonic lung fibroblasts in nutrient solution with or without tumour necrosis factor-alpha (TNF-α) to establish an inflammaging model in vitro. The cells were preincubated with or without PQQ to determine if PQQ had any anti-inflammaging effect. More senescent cells were detected with the addition of TNF-α than without (P < .01). The ratio of senescent cells to non-senescent cells in the TNF-α group was greater than that in the control group (P < .01). When cells were preincubated with PQQ prior to TNF-α treatment, there were fewer senescent cells than those in the control group, which was not pretreated with PQQ (P < .05). The same tendency was noted with regard to p21, p16, and Jagged1. In summary, we used TNF-α, a well-known pro-inflammatory cytokine associated with inflammaging, to establish an in vitro inflammaging model and provided evidence that PQQ delays TNF-α -induced cellular senescence and has anti-inflammaging properties.
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Affiliation(s)
- Jingjing Hao
- Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai, China
| | - Xiushi Ni
- Department of Geriatrics, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Sergio Giunta
- Casa di Cura Prof. Nobili-GHC Garofalo Health Care, - Castiglione dei Pepoli, Bologna, Italy
| | - Junzhen Wu
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaoping Shuang
- Department of Cardiovascular Diseases, Xiangyang Hospital of Traditional Chinese Medicine, Xiangyang, Hubei Province, China
| | - Kangqiao Xu
- Department of Geriatrics, Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University, Shanghai, China
| | - Rui Li
- Department of Traditional Chinese Medicine, Guizhou Provincial People's Hospital, Guiyang, Guizhou Province, China
| | - Wei Zhang
- Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai, China
| | - Shijin Xia
- Department of Geriatrics, Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University, Shanghai, China
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Cai FF, Bian YQ, Wu R, Sun Y, Chen XL, Yang MD, Zhang QR, Hu Y, Sun MY, Su SB. Yinchenhao decoction suppresses rat liver fibrosis involved in an apoptosis regulation mechanism based on network pharmacology and transcriptomic analysis. Biomed Pharmacother 2019; 114:108863. [PMID: 30991286 DOI: 10.1016/j.biopha.2019.108863] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 03/25/2019] [Accepted: 04/04/2019] [Indexed: 01/25/2023] Open
Abstract
Yinchenhao decoction (YCHD) is a classical Traditional Chinese Medicine (TCM) formula that has been widely used in the treatment of liver fibrosis caused by chronic hepatitis B and jaundice for more than 1800 years. The purpose of this study was to investigate the apoptosis regulation mechanisms of YCHD and its active components suppresses liver fibrosis. The active components and putative targets of YCHD were predicted by network pharmacology approach. Functional and pathway enrichment analysis were presented in the present study by using clusterProfiler. Further, experimental validation was done by using terminal deoxynucleotidyl transferase (TDT) dUTP nick end labelling (TUNEL) assay and western blotting in dimethylnitrosamine (DMN)-induced liver fibrosis rats, and cell proliferation assay, apoptosis assay, and western blotting in human hepatic L02 cells and LX2 cells. 45 active compounds in YCHD formula, 592 potential target proteins and 1191 liver fibrosis-related human genes were identified. Functional and pathway enrichment analysis indicated that YCHD obviously influenced TNF, PI3K-Akt signaling pathways. Further, In vivo experiment indicated that YCHD treatment not only attenuated the symptoms of liver fibrosis, but also decrease the apoptosis of hepatic parenchyma cells. Moreover, in vitro experiments showed that rhein, kaempferol and quercetin treatments remarkably decreased the protein levels of cleaved caspase-3 and increased p-ERK1/2, PI3K and Bcl-XL protein expression in TNF-α-stimulated L02 cells. On the contrary, rhein, kaempferol, aloe-emodin and quercetin inhibited the proliferation of LX2 cells and up-regulated the protein levels of Bax and cleaved caspase-8. In conclusion, 45 active components and 296 potential targets of YCHD against liver fibrosis were identified by the analysis of network pharmacology and transcriptomics combination. The mechanisms of YCHD against liver fibrosis were involved in the regulation of multiple targets, especially affecting the apoptosis-related signaling pathways.
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Affiliation(s)
- Fei-Fei Cai
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Yan-Qin Bian
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200233, China; Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200052, China.
| | - Rong Wu
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Yang Sun
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Xiao-Le Chen
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Meng-Die Yang
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Qian-Ru Zhang
- School of Pharmacy, Zunyi Medical University, Guizhou 563000, China.
| | - Yuanjia Hu
- State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China.
| | - Ming-Yu Sun
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200233, China.
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Wu R, Dong S, Cai FF, Chen XL, Yang MD, Liu P, Su SB. Active Compounds Derived from Fuzheng Huayu Formula Protect Hepatic Parenchymal Cells from Apoptosis Based on Network Pharmacology and Transcriptomic Analysis. Molecules 2019; 24:molecules24020338. [PMID: 30669350 PMCID: PMC6358846 DOI: 10.3390/molecules24020338] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 01/16/2019] [Accepted: 01/17/2019] [Indexed: 12/15/2022] Open
Abstract
Fuzheng huayu formula (FZHY), an antifibrotic traditional Chinese medicine, is frequently used for the treatment of liver fibrosis. In this study, network analysis, transcriptomic analysis, assays of cell apoptosis, viability and protein expression were used for investigating the effects and mechanisms of compounds derived from FZHY on hepatic parenchymal cell (HPC) protection and hepatic stellate cell activation. Network pharmacology analysis found that 6 major compounds and 39 potential targets were important network nodes. Our analysis predicted that the active compounds of FZHY, including hederagenin, luteolin and tanshinone IIA inhibited cell apoptosis (p < 0.05), increased PI3K expression and reduced cleaved caspase 3 expression and the Bax/Bcl-w ratio (p < 0.05) in L02 cells that had apoptosis induced by TNF-α. Few significant changes caused by FZHY, hederagenin, luteolin and tanshinone IIA were observed in hepatic stellate Lx2 cells upon TGF-β1 induction. These data suggest that FZHY is active against liver fibrosis, protects hepatic parenchymal cells from apoptosis, and recovers liver function, possibly through the effects of its active compounds hederagenin, luteolin and tanshinone IIA and is involved in the inhibition of apoptosis in HPCs, possibly through regulating the PI3K, ERK, cleaved caspase 3 and Bax/Bcl-w levels.
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Affiliation(s)
- Rong Wu
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Shu Dong
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Fei-Fei Cai
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Xiao-Le Chen
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Meng-Die Yang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Ping Liu
- E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Chinese herbal formula Fuzheng Huayu alleviates CCl 4-induced liver fibrosis in rats: a transcriptomic and proteomic analysis. Acta Pharmacol Sin 2018; 39:930-941. [PMID: 29094729 DOI: 10.1038/aps.2017.150] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 08/13/2017] [Indexed: 12/11/2022]
Abstract
Liver fibrosis is a consequence of chronic liver disease that can progress to liver cirrhosis or even hepatocarcinoma. Fuzheng Huayu (FZHY), a Chinese herbal formula, has been shown to exert anti-fibrotic effects. To better understand the molecular mechanisms underlying the anti-fibrotic effects of FZHY, we analyzed transcriptomic and proteomic combination profiles in CCl4-induced liver fibrosis in rats, which were treated with extracted FZHY powder (0.35 g·kg-1·d-1, ig) for 3 weeks. We showed that FZHY administration significantly improved liver function, alleviated hepatic inflammatory and fibrotic changes, and decreased the hydroxyproline content in the livers of CCl4-treated rats. When their liver tissues were examined using microarray and iTRAQ, we found 255 differentially expressed genes (fold change ≥1.5, P<0.05) and 499 differentially expressed proteins (fold change ≥1.2, P<0.05) in the FZHY and model groups. Functional annotation with DAVID (The Database for Annotation, Visualization and Integrated Discovery) showed that 15 enriched gene ontology terms, including drug metabolic process, response to extracellular stimulus, response to vitamins, arachidonic acid metabolic process, response to wounding, and oxidation reduction might be involved in the anti-fibrotic effects of FZHY; whereas KEGG pathway analysis revealed that eight enriched pathways, including arachidonic acid metabolism, retinol metabolism, metabolism of xenobiotics by cytochrome P450, and drug metabolism might also be involved. Moreover, the protein-protein interaction network demonstrated that 10 core genes/proteins overlapped, with Ugt2a3, Cyp2b1 and Cyp3a18 in retinol metabolism pathway overlapped to a higher degree. Compared to the model rats, the livers of FZHY-treated rats had significantly higher mRNA and protein expression levels of Ugt2a3, Cyp2b1 and Cyp3a18. Furthermore, the concentration of retinoic acid was significantly higher in the FZHY-treated rats compared with the model rats. The results suggest that the anti-fibrotic effects of FZHY emerge through multiple targets, multiple functions, and multiple pathways, including FZHY-regulated retinol metabolism, xenobiotic metabolism by cytochrome P450, and drug metabolism through up-regulated Ugt2a3, Cyp2b1, and Cyp3a18. These genes may play important anti-fibrotic roles in FZHY-treated rats.
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Ma ZG, Lv XD, Zhan LL, Chen L, Zou QY, Xiang JQ, Qin JL, Zhang WW, Zeng ZJ, Jin H, Jiang HX, Lv XP. Human urokinase-type plasminogen activator gene-modified bone marrow-derived mesenchymal stem cells attenuate liver fibrosis in rats by down-regulating the Wnt signaling pathway. World J Gastroenterol 2016; 22:2092-2103. [PMID: 26877613 PMCID: PMC4726681 DOI: 10.3748/wjg.v22.i6.2092] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Revised: 09/27/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the therapeutic effects of bone marrow-derived mesenchymal stem cells (BMSCs) with human urokinase-type plasminogen activator (uPA) on liver fibrosis, and to investigate the mechanism of gene therapy.
METHODS: BMSCs transfected with adenovirus-mediated human urokinase plasminogen activator (Ad-uPA) were transplanted into rats with CCl4-induced liver fibrosis. All rats were sacrificed after 8 wk, and their serum and liver tissue were collected for biochemical, histopathologic, and molecular analyzes. The degree of liver fibrosis was assessed by hematoxylin and eosin or Masson’s staining. Western blot and quantitative reverse transcription-polymerase chain reaction were used to determine protein and mRNA expression levels.
RESULTS: Serum levels of alanine aminotransferase, aminotransferase, total bilirubin, hyaluronic acid, laminin, and procollagen type III were markedly decreased, whereas the levels of serum albumin were increased by uPA gene modified BMSCs treatment. Histopathology revealed that chronic CCl4-treatment resulted in significant fibrosis while uPA gene modified BMSCs treatment significantly reversed fibrosis. By quantitatively analysing the fibrosis area of liver tissue using Masson staining in different groups of animals, we found that model animals with CCl4-induced liver fibrosis had the largest fibrotic area (16.69% ± 1.30%), while fibrotic area was significantly decreased by BMSCs treatment (12.38% ± 2.27%) and was further reduced by uPA-BMSCs treatment (8.31% ± 1.21%). Both protein and mRNA expression of β-catenin, Wnt4 and Wnt5a was down-regulated in liver tissues following uPA gene modified BMSCs treatment when compared with the model animals.
CONCLUSION: Transplantation of uPA gene modified BMSCs suppressed liver fibrosis and ameliorated liver function and may be a new approach to treating liver fibrosis. Furthermore, treatment with uPA gene modified BMSCs also resulted in a decrease in expression of molecules of the Wnt signaling pathway.
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Liver stiffness measurement, better than APRI, Fibroindex, Fib-4, and NBI gastroscopy, predicts portal hypertension in patients with cirrhosis. Cell Biochem Biophys 2015; 71:865-73. [PMID: 25417057 DOI: 10.1007/s12013-014-0275-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver stiffness measurement (LSM) is frequently used as non-invasive alternative for liver fibrosis including cirrhosis, which can lead to portal hypertension. This study was conducted to evaluate the predictive value of LSM in cirrhosis-induced portal hypertension patients. Between July 2011 and December 2013, 153 participants were enrolled into a single-center, prospective, cross-sectional study. Each subject received both gastroscopy and LSM. Baseline biochemical, APRI, Fibroindex, and Fib-4 were also performed. LSM of cirrhosis patients with portal hypertension was significantly higher compared to those without portal hypertension (P < 0.05). A LSM ≥ 13.6 kPa had a sensitivity of 83.87 % and a specificity of 72.53 % with an accuracy of 77.1 for the prediction of portal hypertension, which are higher than those of APRI, Fib-4, and Fibroscan separately. A combination of Fibroscan combined with Fib-4 achieved a maximum AUC of 0.833 and accuracy of 77.8. Discriminant and internal validation analysis showed that Fibroscan plus APRI obtained a lower false negative rate compared to Fibroscan plus Fib-4 and Fibroscan plus Fibroindex (9.68, 17.74, and 11.29 %, respectively). A good relationship was found between LSM and NBI mean optical density both by linear and polynomial correlation analysis (r = 0.5533 and r = 0.7349, both P < 0.001). There was a trend toward a better performance of LSM for assessing portal hypertension compared with NBI gastroscopy mean optical density (P = 0.028 and P = 0.05, respectively). Better than APRI, Fibroindex, Fib-4, and NBI gastroscopy, LSM can predict portal hypertension in cirrhosis patients. A LSM of 13.6 kPa can be considered to be the predictive value for portal hypertension.
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Ling C, Wang Y, Zhang Y, Ejjigani A, Yin Z, Lu Y, Wang L, Wang M, Li J, Hu Z, Aslanidi GV, Zhong L, Gao G, Srivastava A, Ling C. Selective in vivo targeting of human liver tumors by optimized AAV3 vectors in a murine xenograft model. Hum Gene Ther 2015; 25:1023-34. [PMID: 25296041 DOI: 10.1089/hum.2014.099] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Current challenges for recombinant adeno-associated virus (rAAV) vector-based cancer treatment include the low efficiency and the lack of specificity in vivo. rAAV serotype 3 (rAAV3) vectors have previously been shown to be ineffective in normal mouse tissues following systemic administration. In the present study, we report that rAAV3 vectors can efficiently target and transduce various human liver cancer cells in vivo. Elimination of specific surface-exposed serine and threonine residues on rAAV3 capsids results in further augmentation in the transduction efficiency of these vectors, without any change in the viral tropism and cellular receptor interactions. In addition, we have identified a potential chemotherapy drug, shikonin, as a multifunctional compound to inhibit liver tumor growth as well as to significantly enhance the efficacy of rAAV vector-based gene therapy in vivo. Furthermore, we also document that suppression of tumorigenesis in a human liver cancer xenograft model can be achieved through systemic administration of the optimized rAAV3 vectors carrying a therapeutic gene, and shikonin at a dose that does not lead to liver damage. Our research provides a novel means to achieve not only targeted delivery but also the potential for gene therapy of human liver cancer.
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Affiliation(s)
- Chen Ling
- 1 Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine , Gainesville, FL 32611
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Dong S, Chen QL, Su SB. Curative Effects of Fuzheng Huayu on Liver Fibrosis and Cirrhosis: A Meta-Analysis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2015; 2015:125659. [PMID: 26221168 PMCID: PMC4499386 DOI: 10.1155/2015/125659] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 04/07/2015] [Accepted: 04/16/2015] [Indexed: 02/06/2023]
Abstract
The Fuzheng Huayu (FZHY) formula is being used in antiliver fibrosis treatment in China. For systemic evaluation of the curative effects of FZHY on liver fibrosis and cirrhosis progress, a total of 1392 subjects (714 cases and 678 controls) were found to be eligible for meta-analysis in this study. Standard mean differences (SMDs) with 95% confidence interval (CI) were calculated for changes between FZHY groups and controls by employing fixed effects or random effects model. In the overall analysis, alanine transaminase (ALT) (P = 0.003, SMD = -0.87, 95% CI: -1.46 to -0.29), total bilirubin (TBil) (P = 0.001, SMD = -1.30, 95% CI: -2.10 to -0.50), hyaluronic acid (HA) (P = 0.000, SMD = -0.94, 95% CI: -1.30 to -0.58), laminin (LN) (P = 0.000, SMD = -0.80, 95% CI: -1.20 to -0.41), type III procollagen (PC-III) (P = 0.000, SMD = -1.27, 95% CI: -1.93 to -0.60), and type IV procollagen (IV-C) (P = 0.000, SMD = -0.78, 95% CI: -1.05 to -0.51) were decreased after FZHY treatment; however, albumin (ALB) was increased (P = 0.037, SMD = 1.10, 95% CI: 0.07 to 2.12) significantly. Furthermore, the Child-Pugh score was reduced significantly and the life quality was improved after FZHY treatment in cirrhosis patients. The results of this meta-analysis indicated that FZHY effectively improves the liver function, alleviates hepatic fibrosis, decreases Child-Pugh score, and relieves TCM symptoms caused by liver dysfunction, indicating that FZHY may contribute to the alleviation of liver fibrosis and cirrhosis.
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Affiliation(s)
- Shu Dong
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qi-Long Chen
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Zhang YH, Wang Y, Yusufali AH, Ashby F, Zhang D, Yin ZF, Aslanidi GV, Srivastava A, Ling CQ, Ling C. Cytotoxic genes from traditional Chinese medicine inhibit tumor growth both in vitro and in vivo. JOURNAL OF INTEGRATIVE MEDICINE-JIM 2015; 12:483-94. [PMID: 25412666 DOI: 10.1016/s2095-4964(14)60057-1] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Little effort has been made to study the protein-encoding genes isolated from traditional Chinese medicine (TCM) drugs, and the delivery of these genes into malignant cells through recombinant adeno-associated virus (rAAV) vectors has not been attempted. METHODS We synthesized the cDNAs of five known cytotoxic proteins isolated from TCM drugs and the FLAG epitope-tagged cDNAs were subcloned into a rAAV plasmid vector. The protein expression was confirmed by Western blot assay. Various cancer cell lines were transfected with the above plasmids and cell growth was monitored both in vitro and in vivo. The best cytotoxic gene was further packaged into rAAV vectors, under the control of a liver cancer-specific promoter. The liver tumor growth was then monitored following intratumor administration of the rAAV vectors. RESULTS The expression plasmids, encoding individual potential cytotoxic genes tagged with FLAG epitope, were successfully generated and sequenced. Among these genes, trichosanthin (TCS) gene yielded the most promising results for the inhibition of cancer cell growth in vitro. The over-expressed TCS functioned as a type I ribosome-inactivating protein, followed by inducing apoptosis that is associated with the Bcl-PARP signaling pathway. Furthermore, intratumor injection of rAAV vectors containing the TCS gene significantly inhibited the growth of human hepatocellular carcinoma tumors in a murine xenograft model. CONCLUSION Our studies suggest that the use of TCM cytotoxic genes is a useful therapeutic strategy for treating human cancers in general, and liver tumors in particular.
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Affiliation(s)
- Yuan-hui Zhang
- Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai 200433, China
| | - Yuan Wang
- Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai 200433, China
| | - Ali Hussein Yusufali
- Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida 32611, USA
| | - Frederick Ashby
- Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida 32611, USA
| | - Daniel Zhang
- Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida 32611, USA
| | - Zi-fei Yin
- Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai 200433, China
| | - George V Aslanidi
- Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida 32611, USA
| | - Arun Srivastava
- Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida 32611, USA
| | - Chang-quan Ling
- Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai 200433, China; E-mail:
| | - Chen Ling
- Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida 32611, USA; E-mail:
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Effect of Rat Medicated Serum Containing Zuo Gui Wan and/or You Gui Wan on the Differentiation of Stem Cells Derived from Human First Trimester Umbilical Cord into Oocyte-Like Cells In Vitro. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:825805. [PMID: 25688279 PMCID: PMC4320897 DOI: 10.1155/2015/825805] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Revised: 09/16/2014] [Accepted: 10/27/2014] [Indexed: 02/06/2023]
Abstract
Zuo Gui Wan (ZGW) and You Gui Wan (YGW) are two classic formulas used in clinical treatment of infertility in traditional Chinese medicine (TCM). However, the actions of the formulas remain to be proven at the cellular and molecular levels. In this study, we investigate whether the two formulas have any effect on germ cell formation and differentiation by culturing rat medicated serums containing YGW or ZGW with stem cells derived from human first trimester umbilical cord. Our results showed that while the normal rat serums had no significant effects, the rat medicated serums had significant effects on the differentiation of the stem cells into oocyte-like cells (OLCs) based on (1) cell morphological changes that resembled purative cumulus-oocyte complexes (COCs); (2) expressions of specific markers that were indicative of germ cell formation and oocyte development; and (3) estradiol production by the COC-like cells. Furthermore, ZGW medicated serums exhibited more obvious effects on specific gene expressions of germ cells, whereas YGW medicated serums showed stronger effects on estradiol production. Accordingly, our study provides evidence demonstrating for the first time that one of molecular and cellular actions of YGW or ZGW in treating human reproductive dysfunctions may be through an enhancement of neooogenesis.
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The Effects of Uygur Herb Hyssopus officinalis L. on the Process of Airway Remodeling in Asthmatic Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:710870. [PMID: 25383084 PMCID: PMC4212596 DOI: 10.1155/2014/710870] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 08/27/2014] [Accepted: 09/02/2014] [Indexed: 11/23/2022]
Abstract
It has been proved that Uygur herb Hyssopus offcinalis L. could affect the levels of some cytokines (such as IL-4, IL-6, IL-17, and IFN-γ) in asthmatic mice. By detection of the expressions of MMP-9 and TIMP-1 and the morphological changes, the aim of this research is to reveal the mechanism of Uygur herb Hyssopus offcinalis L. in the process of airway remodeling. It was observed that the expressions of MMP-9 and TIMP-1 increased, but the ratio of MMP-9/TIMP-1 decreased in airway remodeling group. However, the expression of both MMP-9 and TIMP-1 decreased after being treated with dexamethasone and Hyssopus offcinalis L., accompanied by the relieved pathological changes, including collagen deposition, mucus secretion, and smooth muscle proliferation. It is suggested that Uygur herb Hyssopus offcinalis L. could inhibit airway remodeling by correcting imbalance of MMP-9/TIMP-1 ratio.
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