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Gao Y, Li Y, Zhou JS, Zhao P, Wu PQ, Mu Q, Yue JM, Zhou B. Harnessing Functional Food Sources: Deriving Anti-Inflammatory and Antibacterial Naphthalene Derivatives from the Edible Bulbs of Eleutherine bulbosa. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:4126-4136. [PMID: 39930623 DOI: 10.1021/acs.jafc.4c12108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
The red bulbs of Eleutherine bulbosa, commonly used as a daily dietary ingredient in cooking, are well-known for their rich nutritional profile and potential medicinal properties. This study focused on identifying bioactive components from E. bulbosa by a bioactivity-guided approach combined with global natural products' social molecular networking, which led to the characterization of 12 new naphthalene derivatives, eleuthalenes A-L (1-12), and 22 known analogues. The structures of these compounds were determined through spectroscopic data, X-ray crystallography, and quantum chemical calculations. The anti-inflammatory and antibacterial activities of these compounds were evaluated, with some demonstrating significant anti-inflammatory and moderate antibacterial activities. Further studies revealed that the most potent compound 5 displayed an anti-inflammatory effect in LPS-induced RAW 264.7 cells by suppressing the NF-κB/MAPK and activating Nrf2/Keap1 signaling pathways. The results suggested that bioactive naphthalene derivatives are the major pharmacodynamic substances of E. bulbosa.
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Affiliation(s)
- Yuan Gao
- School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
| | - Ying Li
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, 198 East Binhai Road, Yantai, Shandong 264117, People's Republic of China
| | - Jun-Su Zhou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
| | - Peng Zhao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
| | - Pei-Qian Wu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
| | - Qing Mu
- School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China
| | - Jian-Min Yue
- School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, 198 East Binhai Road, Yantai, Shandong 264117, People's Republic of China
| | - Bin Zhou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, 198 East Binhai Road, Yantai, Shandong 264117, People's Republic of China
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Wang YC, Zhu Y, Meng WT, Zheng Y, Guan XQ, Shao CL, Li XY, Hu D, Wang MZ, Guo HD. Dihydrotanshinone I improves cardiac function by promoting lymphangiogenesis after myocardial ischemia-reperfusion injury. Eur J Pharmacol 2025; 989:177245. [PMID: 39753160 DOI: 10.1016/j.ejphar.2024.177245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 12/26/2024] [Accepted: 12/30/2024] [Indexed: 01/11/2025]
Abstract
Dihydrotanshinone I (DHT) is an active ingredient derived from Salvia miltiorrhiza. Previous studies have demonstrated that DHT can improve cardiac function in rats with myocardial ischemia-reperfusion injury (IR). However, the mechanism by which DHT improves myocardial injury in rats still requires further research. Lymphangiogenesis can reduce myocardial edema, inflammation, and fibrosis after myocardial infarction in rats, and improve cardiac function. In this study, the changes in cardiac functions, collagen fiber deposition in the infarcted area and the level of relevant indicators of lymphangiogenesis were examined by echocardiography, Masson's trichrome staining, immunohistochemistry and Western blot, respectively. Human lymphatic endothelial cells (HLECs) were transfected with siVE-cadherin and siVEGFR-3, and the effects of DHT on HLEC cell viability, migration and tube formation were detected through CCK8, TUNEL, transwell, wound healing and tube formation assay. We found that in myocardial IR rats treated with DHT, the levels of LYVE-1, PROX1, VEGF-C, VEGFR-3, IGF-1, podoplanin and IGF-1R, which are associated with lymphangiogenesis, were increased, as well as the level of VE-cadherin, which maintains endothelial cell function. DHT reduced the levels of inflammatory factors and myocardial cell apoptosis, thereby improving cardiac function after I/R. To explore the mechanism of DHT promoting lymphangiogenesis, H2O2 and OGD/R injury models of HLECs were constructed to simulate the microenvironment of myocardial IR in vitro. The results proved that DHT could reduce the damage and apoptosis of HLECs. On the other hand, DHT enhanced the expression of VEGFR-3 and VE-cadherin in HLECs, promoted cell migration and tube formation. The effects of DHT on the tube formation and migration of HLECs were significantly decreased after knocking down VEGFR-3 or VE-cadherin. Our research proposed that DHT could improve the heart function after IR through the enhancement of lymphangiogenesis and contributed to the development of the treatment methods for myocardial IR.
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Affiliation(s)
- Ya-Chao Wang
- Academy of Integrated Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Zhu
- Department of Neurological Rehabilitation, The Second Rehabilitation Hospital of Shanghai, Shanghai, China
| | - Wan-Ting Meng
- Academy of Integrated Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Zheng
- Jiading Hospital of Traditional Chinese Medicine, Shanghai, China
| | - Xiao-Qi Guan
- Academy of Integrated Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chang-le Shao
- Academy of Integrated Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiu-Ya Li
- Academy of Integrated Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dan Hu
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China.
| | - Ming-Zhu Wang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
| | - Hai-Dong Guo
- Academy of Integrated Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Xiang Y, Kuang G, Gong X, Xie H, Lin Y, Zhang X, Chen Z, Wan J, Li Z. Dihydrotanshinone I Attenuates Diet-Induced Nonalcoholic Fatty Liver Disease via Up-Regulation of IRG1. Phytother Res 2025. [PMID: 39853881 DOI: 10.1002/ptr.8443] [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: 09/12/2024] [Revised: 01/01/2025] [Accepted: 01/15/2025] [Indexed: 01/26/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, but effective therapeutic drugs are still lacking. Dihydrotanshinone I (DHTS), a natural product isolated from Salvia miltiorrhiza, has been shown to have ameliorative effects on NAFLD. The aim of this study was to investigate the hepatoprotective effect of DHTS on NAFLD and its mechanism. A model of NAFLD and DHTS treatment was established using a Western diet to observe the effect of DHTS on NAFLD, which were detected by immunohistochemical, immunofluorescence, and other experiments. The mechanism was further explored by constructing immune responsive gene 1 (IRG1) knockout mice, RNA sequence, and molecular docking. The results revealed that DHTS significantly improved diet-induced metabolic disorders in mice, notably alleviating liver inflammation, oxidative stress, and fibrosis. Further analysis revealed that the intervention of DHTS was associated with the activation of IRG1. Subsequent experiments confirmed that IRG1 gene deletion reversed the above protective effects of DHTS in NAFLD. Mechanistically, DHTS enhanced the antioxidant nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway through IRG1/itaconate and blocked the oxidative stress response in the liver. In addition, DHTS also inhibited the activation of NACHT-, leucine-rich repeat (LRR)-, and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome via IRG1/itaconate, blocking the inflammatory amplification effect in the liver. The study suggests that DHTS may be a potential drug for the treatment of NAFLD, which exerts protective regulatory effects mainly through the IRG1/itaconate molecular pathway.
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Affiliation(s)
- Yang Xiang
- Department of Endocrinology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Ge Kuang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Xia Gong
- Department of Anatomy, Chongqing Medical University, Chongqing, China
| | - Huang Xie
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Yan Lin
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Xijian Zhang
- Department of Endocrinology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Zhongpei Chen
- Department of Endocrinology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Jingyuan Wan
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Zhenhan Li
- Department of Endocrinology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
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Pan S, Peng L, Yi Q, Qi W, Yang H, Wang H, Wang L. Ginsenoside Rh 2 Alleviates LPS-Induced Inflammatory Responses by Binding to TLR 4/MD-2 and Blocking TLR 4 Dimerization. Int J Mol Sci 2024; 25:9546. [PMID: 39273493 PMCID: PMC11395244 DOI: 10.3390/ijms25179546] [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: 08/02/2024] [Revised: 08/26/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Lipopolysaccharide (LPS) triggers a severe systemic inflammatory reaction in mammals, with the dimerization of TLR4/MD-2 upon LPS stimulation serving as the pivotal mechanism in the transmission of inflammatory signals. Ginsenoside Rh2 (G-Rh2), one of the active constituents of red ginseng, exerts potent anti-inflammatory activity. However, whether G-Rh2 can block the TLR4 dimerization to exert anti-inflammatory effects remains unclear. Here, we first investigated the non-cytotoxic concentration of G-Rh2 on RAW 264.7 cells, and detected the releases of pro-inflammatory cytokines in LPS-treated RAW 264.7 cells, and then uncovered the mechanisms involved in the anti-inflammatory activity of G-Rh2 through flow cytometry, fluorescent membrane localization, Western blotting, co-immunoprecipitation (Co-IP), molecular docking and surface plasmon resonance (SPR) analysis in LPS-stimulated macrophages. Our results show that G-Rh2 stimulation markedly inhibited the secretion of LPS-induced interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Additionally, G-Rh2 blocked the binding of LPS with the membrane of RAW 264.7 cells through direct interaction with TLR4 and MD-2 proteins, leading to the disruption of the dimerization of TLR4 and MD-2, followed by suppression of the TLR4/NF-κB signaling pathway. Our results suggest that G-Rh2 acts as a new inhibitor of TLR4 dimerization and may serve as a promising therapeutic agent against inflammation.
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Affiliation(s)
- Shujuan Pan
- School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China; (S.P.); (H.W.)
- Engineering Research Center of the Utilization for Characteristic Bio-Pharma Ceutical Resources in Southwest, Ministry of Education, Guizhou University, Guiyang 550025, China; (Q.Y.); (W.Q.); (H.Y.)
| | - Luyuan Peng
- College of Veterinary Medicine, Jilin University, Changchun 130062, China;
| | - Qion Yi
- Engineering Research Center of the Utilization for Characteristic Bio-Pharma Ceutical Resources in Southwest, Ministry of Education, Guizhou University, Guiyang 550025, China; (Q.Y.); (W.Q.); (H.Y.)
| | - Weijin Qi
- Engineering Research Center of the Utilization for Characteristic Bio-Pharma Ceutical Resources in Southwest, Ministry of Education, Guizhou University, Guiyang 550025, China; (Q.Y.); (W.Q.); (H.Y.)
| | - Hui Yang
- Engineering Research Center of the Utilization for Characteristic Bio-Pharma Ceutical Resources in Southwest, Ministry of Education, Guizhou University, Guiyang 550025, China; (Q.Y.); (W.Q.); (H.Y.)
| | - Hongying Wang
- School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China; (S.P.); (H.W.)
- Engineering Research Center of the Utilization for Characteristic Bio-Pharma Ceutical Resources in Southwest, Ministry of Education, Guizhou University, Guiyang 550025, China; (Q.Y.); (W.Q.); (H.Y.)
| | - Lu Wang
- School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China; (S.P.); (H.W.)
- Engineering Research Center of the Utilization for Characteristic Bio-Pharma Ceutical Resources in Southwest, Ministry of Education, Guizhou University, Guiyang 550025, China; (Q.Y.); (W.Q.); (H.Y.)
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Yu Z, Yue B, Gao R, Zhang B, Geng X, Lv C, Wang H, Wang Z, Wang Z, Dou W. Gastrodin Attenuates Colitis and Prevents Tumorigenesis in Mice by Interrupting TLR4/MD2/NF-κB Signaling Transduction. Anticancer Agents Med Chem 2024; 24:853-866. [PMID: 38584532 DOI: 10.2174/0118715206286233240328045215] [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: 11/10/2023] [Revised: 03/01/2024] [Accepted: 03/06/2024] [Indexed: 04/09/2024]
Abstract
INTRODUCTION Chronic inflammation is one of the causative factors for tumorigenesis. Gastrodin is a main active ingredient isolated from Gastrodia elata Blume, a famous medicinal herb with a long edible history. AIM This study aimed to explore the effects of gastrodin on colitis-associated carcinogenesis (CRC) in mice and to elucidate its potential molecular mechanisms. METHODS Balb/c mice were induced with azoxymethane (AOM) and dextran sulfate sodium (DSS) for 12 weeks. Gastrodin (50 mg/kg) was administered via oral gavage three times per week until the end of the experiment. Disease indexes, including body weight, bloody diarrhea, colon length, histopathological score, and tumor size, were measured. Tumor cell proliferation was evaluated by BrdU incorporation assay and tumor cell cytotoxicity was assessed by cell counting kit (CCK-8). The expression levels of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling molecules, NF-κB luciferase, and pro-inflammatory cytokines were determined by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), immunoblotting, immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), or reporter gene assays. The binding affinity between gastrodin and myeloid differentiation protein-2 (MD2) was analyzed by molecular docking and cellular thermal shift assay (CETSA). RESULTS Gastrodin administration was demonstrated to mitigate various CRC-related symptoms in mice, including weight loss, diarrhea, and tissue abnormalities. Notably, gastrodin suppressed tumor cell growth during colitis- associated tumorigenesis, resulting in fewer and smaller adenomas in the colon. Unlike irinotecan, a broadspectrum antitumor drug, gastrodin did not exhibit apparent cytotoxicity in various colorectal adenocarcinoma cell lines. Additionally, gastrodin downregulated TLR4/NF-κB signaling molecules and pro-inflammatory mediators in mice and macrophages. Molecular docking and CETSA experiments suggested that gastrodin binds to the MD2 protein, potentially interfering with the recognition of lipopolysaccharide (LPS) by TLR4, leading to NF-κB pathway inhibition. CONCLUSION This study provides evidence for the first time that gastrodin attenuated colitis and prevented colitisrelated carcinogenesis in mice, at least partially, by diminishing tumor-promoting cytokines through the interruption of TLR4/MD2/NF-κB signaling transduction.
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Affiliation(s)
- Zhilun Yu
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, 201203, China
| | - Bei Yue
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, 201203, China
| | - Ruiyang Gao
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, 201203, China
| | - Beibei Zhang
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, 201203, China
| | - Xiaolong Geng
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, 201203, China
| | - Cheng Lv
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, 201203, China
| | - Hao Wang
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, 201203, China
| | - Ziyi Wang
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, 201203, China
| | - Zhengtao Wang
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, 201203, China
| | - Wei Dou
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, 201203, China
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Zhang YZ, Wei ZJ, Yu SN, Wang XY, Wang Y, Wu CA, Jiang X. Dihydrotanshinone I protects human chondrocytes and alleviates damage from spontaneous osteoarthritis in a guinea pig model. Sci Rep 2023; 13:21355. [PMID: 38049518 PMCID: PMC10696037 DOI: 10.1038/s41598-023-48902-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/30/2023] [Indexed: 12/06/2023] Open
Abstract
Osteoarthritis (OA) is the most common degenerative joint disease. Currently, no satisfactory pharmacological treatment exists for OA. The potential anti-inflammatory properties of Dihydrotanshinone I (DHT) have been reported, but its effects on OA are unclear. In this study, we assess the impact of DHT on the viability of human chondrocytes in vitro. We then use a guinea pig model to investigate the effects of DHT on knee osteoarthritis progression. Twelve-week-old Dunkin Hartley guinea pigs spontaneously developing OA were intraperitoneally injected with different doses of DHT for eight weeks. Micro-CT analysis was performed on the subchondral bone in the knee, and histological assessment of the knee joint was done using stained sections, the ratio of hyaline to calcified cartilage, and Mankin scores. DHT successfully restored IL-1β-induced decreases in cell viability in human primary chondrocytes. In the guinea pig model, intraperitoneal injections of DHT ameliorated age-induced OA, effectively reduced the expression level of two cartilage metabolism-related genes (ADAMTS4 and MMP13) and decreased the inflammatory biomarker IL-6 in the serum of guinea pigs developing spontaneous osteoarthritis. These findings demonstrate DHT's protective effects on chondrocytes and suggest that it alleviates cartilage degradation and proteoglycan loss in OA.
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Affiliation(s)
- Yan-Zhuo Zhang
- National Center for Orthopaedics, Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, People's Republic of China
| | - Zhen-Jie Wei
- National Center for Orthopaedics, Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, People's Republic of China
| | - Shu-Nan Yu
- National Center for Orthopaedics, Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, People's Republic of China
| | - Xin-Yu Wang
- National Center for Orthopaedics, Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, People's Republic of China
| | - Ying Wang
- National Center for Orthopaedics, Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, People's Republic of China
| | - Cheng-Ai Wu
- National Center for Orthopaedics, Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, People's Republic of China
| | - Xu Jiang
- National Center for OrthopaedicsDepartment of Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, People's Republic of China.
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Rizq AT, Sirwi A, El-Agamy DS, Abdallah HM, Ibrahim SRM, Mohamed GA. Cepabiflas B and C as Novel Anti-Inflammatory and Anti-Apoptotic Agents against Endotoxin-Induced Acute Kidney and Hepatic Injury in Mice: Impact on Bax/Bcl2 and Nrf2/NF-κB Signalling Pathways. BIOLOGY 2023; 12:938. [PMID: 37508369 PMCID: PMC10376508 DOI: 10.3390/biology12070938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/25/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023]
Abstract
Cepabiflas B and C (CBs) are flavonoid dimers separated from Allium cepa. They demonstrated antioxidant and α-glucosidase and protein tyrosine phosphatase 1B inhibition capacities. However, their anti-inflammatory activities and their effects on endotoxemia are unknown. The current study aimed at exploring the protective activities of CBs on lipopolysaccharide (LPS)-induced kidney and liver damage in mice and investigating the possible molecular mechanisms. Mice were orally treated with a low (40 mg/kg) or high (60 mg/kg) dose of CBs for five days prior to a single intraperitoneal injection of LPS (10 mg/kg). Samples of serum and hepatic and kidney tissues were collected 24 h after the LPS challenge. Changes in serum indices of hepatic and renal injury, pathological changes, molecular biological parameters, and proteins/genes related to inflammation and apoptosis of these organs were estimated. LPS injection resulted in deleterious injury to both organs as indicated by elevation of serum ALT, AST, creatinine, and BUN. The deteriorated histopathology of hepatic and renal tissues confirmed the biochemical indices. CBs treated groups showed a reduction in these parameters and improved histopathological injurious effects of LPS. LPS-induced hepatorenal injury was linked to elevated oxidative stress as indicated by high levels of MDA, 4-HNE, as well as repressed antioxidants (TAC, SOD, and GSH) in hepatic and kidney tissues. This was accompanied with suppressed Nrf2/HO-1 activity. Additionally, there was a remarkable inflammatory response in both organs as NF-κB signalling was activated and high levels of downstream cytokines were produced following the LPS challenge. Apoptotic changes were observed as the level and gene expression of Bax and caspase-3 were elevated along with declined level and gene expression of Bcl2. Interestingly, CBs reversed all these molecular and genetic changes and restricted oxidative inflammatory and apoptotic parameters after LPS-injection. Collectedly, our findings suggested the marked anti-inflammatory and anti-apoptotic activity of CBs which encouraged its use as a new candidate for septic patients.
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Affiliation(s)
- Akaber T Rizq
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Alaa Sirwi
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Dina S El-Agamy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Hossam M Abdallah
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Sabrin R M Ibrahim
- Department of Chemistry, Preparatory Year Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia
- Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
| | - Gamal A Mohamed
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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8
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Duan S, Zhang M, Zeng H, Song J, Zhang M, Gao S, Yang H, Ding M, Li P. Integrated proteomics and phosphoproteomics profiling reveals the cardioprotective mechanism of bioactive compounds derived from Salvia miltiorrhiza Burge. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 117:154897. [PMID: 37307738 DOI: 10.1016/j.phymed.2023.154897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/29/2023] [Accepted: 05/21/2023] [Indexed: 06/14/2023]
Abstract
BACKGROUND Natural products are an important source for discovering novel drugs due to their various pharmacological activities. Salvia miltiorrhiza Burge (Danshen) has been shown to have promising therapeutic potential in the management of heart diseases, making it a candidate for cardiovascular drug discovery. Currently, there is limited quantitative analysis of the phosphorylation levels of Danshen-derived natural products on a proteome-wide, which may bias the study of their mechanisms of action. PURPOSE This study aimed to evaluate the global signaling perturbation induced by Danshen-derived bioactive compounds and their potential relationship with myocardial ischemia/reperfusion (IR) injury therapy. STUDY DESIGN We employed quantitative proteome and phosphoproteome analysis to identify dysregulated signaling in IR injury hearts from mice. We compared changes induced by Danshen-derived compounds based on IR-associated phospho-events, using an integrative approach that maps relative abundance of proteins and phosphorylation sites. METHODS Isobaric chemical tandem mass tags (TMT) labeled multiplexing strategy was used to generate unbiased quantitative proteomics and phosphoproteomics data. Highly accurate and precise TMT quantitation was performed using the Orbitrap Fusion Tribrid Mass Spectrometer with synchronous precursor selection MS3 detection mode. Mass spectrometric raw files were analyzed with MaxQuant (2.0.1.0) and statistical and bioinformatics analysis was conducted with Perseus (1.6.15). RESULTS We quantified 3661 proteins and over 11,000 phosphosites in impaired heart tissue of the IR mice model, expanding our knowledge of signaling pathways and other biological processes disrupted in IR injury. Next, 1548 and 5545 differently expressed proteins and phosphosites were identified by quantifying the proteome and phosphoproteome of H9c2 cells treated by five Danshen bioactive compounds respectively. Results revealed the vast differences in abilities of five Danshen-derived bioactive compounds to regulate phosphorylation modifications in cardiomyocytes, with dihydrotanshinone I (DHT) showing potential for protecting against IR injury by modulating the AMPK/mTOR signaling pathway. CONCLUSIONS This study provides a new strategy for analyzing drug/natural product-regulated phosphorylation modification levels on a proteome-wide scale, leading to a better understanding of cell signaling pathways and downstream phenotypic responses.
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Affiliation(s)
- Shengnan Duan
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Meiting Zhang
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Hao Zeng
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tongjia Lane, Nanjing 210009, China
| | - Jinyi Song
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Min Zhang
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Song Gao
- Department of Pharmaceutical and Environmental Health Sciences, Texas Southern University, 3100 Cleburne Street, Houston, TX 77004, USA
| | - Hua Yang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tongjia Lane, Nanjing 210009, China
| | - Ming Ding
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
| | - Ping Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tongjia Lane, Nanjing 210009, China.
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Li X, Qiu H, Gan J, Liu Z, Yang S, Yuan R, Gao H. Total tanshinones protect against acute lung injury through the PLCγ2/NLRP3 inflammasome signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2023; 314:116478. [PMID: 37121449 DOI: 10.1016/j.jep.2023.116478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/04/2023] [Accepted: 04/07/2023] [Indexed: 05/22/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Salvia miltiorrhiza Bunge is a widely used traditional Chinese medicine with anticholinesterase, antitumor, and anti-inflammatory. Total Tanshinones (TTN), the most significant active ingredient of Salvia miltiorrhiza Bunge, exerts anti-inflammatory activity. However, the protective mechanism of total Tanshinones on acute lung injury (ALI) still needs to be explored. AIM OF THIS STUDY In this study, the underlying mechanisms of TTN to treat with ALI were investigated in vitro and in vivo. MATERIALS AND METHODS Cell experiments established an in vitro model of LPS-induced J774A.1 and MH-S macrophages to verify the mechanism. The levels of inflammatory cytokines (TNF-α, IL-6 and IL-1β) were estimated by ELISA. The changes of ROS, Ca2+ and NO were detected by flow cytometry. The expression levels of proteins related to the NLRP3 inflammasome were determined by Western blotting. The effect of TTN on NLRP3 inflammasome activation was examined by immunofluorescence analysis of caspase-1 p20. Male BALB/c mice were selected to establish the ALI model. The experiment was randomly divided into six groups: control, LPS, LPS + si-NC, LPA + si-Nek7, LPS + TTN, and DEX. Pathological alterations were explored by H&E staining. The expression levels of proteins related to the NLRP3 inflammasome were analyzed by Western blotting. RESULTS TTN decreased pro-inflammatory cytokines levels like TNF-α, IL-6, IL-1β, NO, and ROS in alveolar macrophages. TTN bound to NIMA-related kinase 7 (NEK7), a new therapeutic protein to modulate NLRP3 inflammasome and PLCγ2-PIP2 signaling pathway. In ALI mice, LPS enhanced IL-1β levels in the serum, lung tissues, and bronchoalveolar lavage fluid (BALF),which were reversed by TTN. TTN decreased cleaved-caspase-1 and NLRP3 expressions in lung tissues. When Nek7 was knocked down in mice by siRNA, the syndrome of ALI in mice was significantly suppressed, of which the effect was similar to that of TTN. CONCLUSIONS This research demonstrates that TTN alleviated ALI by binding to NEK7 in vitro and in vivo to modulate NLRP3 inflammasome activation and PLCγ2-PIP2 signaling pathways.
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Affiliation(s)
- Xinxing Li
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530200, China; Department of Natural Medicine, School of Pharmacy, Fudan University, Shanghai, 201203, China.
| | - Haixin Qiu
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530200, China.
| | - Jinyue Gan
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530200, China.
| | - Zhenjie Liu
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530200, China.
| | - Shilin Yang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530200, China.
| | - Renyikun Yuan
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530200, China.
| | - Hongwei Gao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530200, China.
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10
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Chen S, Wang Y, Liu Y, Bai L, Li F, Wu Y, Xie X, Zhang N, Zeng C, Zhang L, Wang X. Investigating the effect of dehydromiltirone on septic AKI using a network pharmacology method, molecular docking, and experimental validation. Front Pharmacol 2023; 14:1145675. [PMID: 37007048 PMCID: PMC10050741 DOI: 10.3389/fphar.2023.1145675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 02/27/2023] [Indexed: 03/17/2023] Open
Abstract
Acute kidney injury (AKI) is a severe and frequent complication of sepsis that occurs in intensive care units with inflammation and rapid decline in renal function as the main pathological features. Systemic inflammation, microvascular dysfunction, and tubule injury are the main causes of sepsis-induced AKI (SI-AKI). The high prevalence and death rate from SI-AKI is a great challenge for clinical treatment worldwide. However, in addition to hemodialysis, there is no effective drug to improve renal tissue damage and alleviate the decline in kidney function. We conducted a network pharmacological analysis of Salvia miltiorrhiza (SM), a traditional Chinese medicine, which is widely used for the treatment of kidney disease. Then, we combined molecular docking and a dynamics simulation to screen for the active monomer dehydromiltirone (DHT) that has therapeutic effects on SI-AKI and investigated its potential mechanism of action through experimental validation. The components and targets of SM were obtained by searching the database, and 32 overlapping genes were screened by intersection analysis with AKI targets. GO and KEGG data showed that the functions of a common gene were closely related to oxidative stress, mitochondrial function, and apoptosis. The molecular docking results combined with molecular dynamics simulations provide evidence for a binding model between DHT and cyclooxygenase-2 (COX2), both of which are mainly driven by van der Waals interactions and a hydrophobic effect. In vivo, we found that mice pretreated with an intraperitoneal injection of DHT (20 mg/kg/d) for 3 days ameliorated CLP surgery-induced renal function loss and renal tissue damage and inhibited inflammatory mediators IL-6, IL-1β, TNF-α, and MCP-1 production. In vitro, the DHT pretreatment decreased LPS-induced expression of COX2, inhibited cell death and oxidative stress, alleviated mitochondrial dysfunction, and restrained apoptosis in HK-2 cells. Our research indicates that the renal preventive effect of DHT is related to maintaining mitochondrial dynamic balance, restoring mitochondrial oxidative phosphorylation, and inhibiting cell apoptosis. The findings in this study provide a theoretical basis and a novel method for the clinical therapy of SI-AKI.
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Affiliation(s)
- Sijia Chen
- Department of Nephrology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanzhe Wang
- Department of Nephrology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuyuan Liu
- Department of Nephrology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Linnan Bai
- Department of Nephrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fengqin Li
- Department of Nephrology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Wu
- Department of Nephrology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinmiao Xie
- Department of Nephrology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Nan Zhang
- Department of Nephrology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuchu Zeng
- Department of Nephrology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Zhang
- Department of Obstetrics and Gynecology, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- *Correspondence: Xiaoxia Wang, , Ling Zhang,
| | - Xiaoxia Wang
- Department of Nephrology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Xiaoxia Wang, , Ling Zhang,
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11
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Wang L, Xu X, Chen D, Li C. Dihydrotanshinone I inhibits hepatocellular carcinoma cells proliferation through DNA damage and EGFR pathway. PeerJ 2023; 11:e15022. [PMID: 36935927 PMCID: PMC10019332 DOI: 10.7717/peerj.15022] [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: 09/19/2022] [Accepted: 02/17/2023] [Indexed: 03/16/2023] Open
Abstract
Background The incidence and mortality of hepatocellular carcinoma (HCC) are globally on the rise. Dihydrotanshinone I, a natural product isolated from Salvia miltiorrhiza Bunge, has attracted extensive attention in recent years for its anti-tumour proliferation efficiency. Methods Cell proliferations in hepatoma cells (Huh-7 and HepG2) were evaluated by MTT and colony formation assays. Immunofluorescence (IF) of 53BP1 and flow cytometry analysis were performed to detect DNA damage and cell apoptosis. Furthermore, network pharmacological analysis was applied to explore the potential therapeutic targets and pathway of dihydrotanshinone I. Results The results showed that dihydrotanshinone I effectively inhibited the proliferation of Huh-7 and HepG2 cells. Moreover, dihydrotanshinone I dose-dependently induced DNA-damage and apoptosis in vitro. Network pharmacological analysis and molecular simulation results indicated that EGFR might be a potential therapeutic target of dihydrotanshinone I in HCC. Collectively, our findings suggested that dihydrotanshinone I is a novel candidate therapeutic agent for HCC treatment.
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Affiliation(s)
- Linjun Wang
- Department of Hepatopancreatobiliary Surgery, The First People’s Hospital of Yongkang, Yongkang, Zhejiang, China
| | - Xiangwei Xu
- Department of Pharmacy, The First People’s Hosipital of Yongkang, Yongkang, Zhejiang, China
| | - Dexing Chen
- Department of Hepatopancreatobiliary Surgery, The First People’s Hospital of Yongkang, Yongkang, Zhejiang, China
| | - Chenghang Li
- Department of Infectious Liver Disease, The First People’s Hospital of Yongkang, Yongkang, Zhejiang, China
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12
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Nie C, Zou Y, Liao S, Gao Q, Li Q. Molecular Targets and Mechanisms of 6,7-Dihydroxy-2,4-dimethoxyphenanthrene from Chinese Yam Modulating NF-κB/COX-2 Signaling Pathway: The Application of Molecular Docking and Gene Silencing. Nutrients 2023; 15:nu15040883. [PMID: 36839242 PMCID: PMC9963849 DOI: 10.3390/nu15040883] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 02/03/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Chinese yam (Dioscorea opposita) tuber has a significant effect of invigorating the intestine and improving the symptoms of long-term diarrhea according to the records of the Chinese Pharmacopoeia. Phenanthrene polyphenols from Chinese yam, with higher inhibition of cyclooxygenase-2 (COX-2) than anti-inflammatory drugs, are an important material basis in alleviating ulcerative colitis via nuclear factor kappa-B (NF-κB)/COX-2 pathway, based on our previous research. The present study further explored the target and molecular mechanisms of phenanthrenes' modulation of the NF-κB/COX-2 signaling pathway by means of molecular docking and gene silencing. Firstly, interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) expression of 6-hydroxy-2,4,7-trimethoxyphenanthrene (PC2)/6,7-dihydroxy-2,4-dimethoxyphe-nanthrene (PC4) were compared on TNF-α induced human colon adenocarcinoma (Caco-2) cells. Secondly, molecular docking and dynamics simulation were implemented for PC2/PC4 and COX-2. Finally, COX-2 silencing was performed on TNF-α induced Caco-2 cells to confirm the target of PC4 on NF-κB/COX-2 pathway. Lower expression of IL-8 and TNF-α in PC4 treated Caco-2 cells indicated that PC4 had stronger anti-inflammatory activity than PC2. The binding of PC4 and COX-2 was stronger due to the hydrogen bond between hydroxyl group and Tyr385. No significant differences were found in phosphorylation nuclear factor kappa-B inhibitor alpha (pIkBα), phosphorylation NF-κB (pNF-κB) and phosphorylation extracellular signal-regulated kinase 1/2 (pERK1/2) expression between control and PC4 group after silencing, while these protein expressions significantly decreased in PC4 group without silencing, which confirmed that COX-2 was the important target for PC4 in alleviating ulcerative colitis. These findings indicate that PC4 was supposed to have inhibited NF-κB pathway mediated inflammation via suppression of positive feedback targeting COX-2.
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Affiliation(s)
- Congyi Nie
- Guangdong Academy of Agricultural Sciences, Sericultural & Agri-Food Research Institute/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
| | - Yuxiao Zou
- Guangdong Academy of Agricultural Sciences, Sericultural & Agri-Food Research Institute/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China
| | - Sentai Liao
- Guangdong Academy of Agricultural Sciences, Sericultural & Agri-Food Research Institute/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China
| | - Qunyu Gao
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
| | - Qian Li
- Guangdong Academy of Agricultural Sciences, Sericultural & Agri-Food Research Institute/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China
- Correspondence: ; Tel.: +86-13430362787
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13
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Liu C, Han M, Lv F, Gao Y, Wang X, Zhang X, Guo Y, Cheng Y, Qian H. Study on the Cellular Anti-Inflammatory Effect of Torularhodin Produced by Sporidiobolus pararoseus ZQHL Isolated from Vinegar Fungus. Molecules 2023; 28:molecules28031436. [PMID: 36771110 PMCID: PMC9920945 DOI: 10.3390/molecules28031436] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 01/30/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
The red stretcher bacterium Sporidiobolus pararoseus is a high producer of carotenoids such as torularhodin, but its presence in vinegar has not been detected. Moreover, torularhodin has several biological activities, but its effect on the LPS-induced RAW 264.7 inflammatory cell model has also yet to be elucidated. In this study, S. pararoseus was identified in different vinegar samples from China by ITS sequencing. Meanwhile, one of the strains was deeply resolved by whole genome sequencing and functional annotation and named S. pararoseus ZQHL. Subsequently, the antioxidant effect of the fungal carotenoid torularhodin was investigated using in vitro DPPH, ABTS, and cellular models. Finally, LPS-induced RAW 264.7 cells were used as an inflammation model to assess torularhodin's protective effect on inflammatory cells and to determine whether the TLR4 pathway is associated with this process. The results indicate that torularhodin has good free radical scavenging ability in vitro and can contribute to cell viability. More importantly, torularhodin alleviated LPS-induced cellular inflammatory damage and reduced the expression of inflammatory factors such as TLR4, MyD88, and TNF-a. The mechanism may attenuate the cellular inflammatory response by inhibiting the TLR4 inflammatory pathway. In conclusion, torularhodin produced by S. pararoseus fungi in vinegar samples significantly scavenged free radicals in vitro and alleviated RAW 264.7 cellular inflammation by modulating the TLR4 pathway.
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Affiliation(s)
- Chang Liu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, No. 1800 Lihu Avenue, Wuxi 214122, China
| | - Mei Han
- Department of Food Science, Shanghai Business School, Shanghai 200235, China
| | - Fuqiang Lv
- Jiangsu Hengshun Vinegar-Industry Co., Ltd., No. 66 Hengshun Road, Zhenjiang 212143, China
| | - Yaobin Gao
- Shanxi Mature Vinegar Group Co., Ltd., No. 26 Madaopo, Xinghua District, Taiyuan 030013, China
| | - Xiaoyun Wang
- Shanxi Mature Vinegar Group Co., Ltd., No. 26 Madaopo, Xinghua District, Taiyuan 030013, China
| | - Xujiao Zhang
- Shanxi Zilin Vinegar Industry Co., Ltd., No. 550 Gaohua Duan, Taimao Road, Taiyuan 030100, China
| | - Yahui Guo
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, No. 1800 Lihu Avenue, Wuxi 214122, China
| | - Yuliang Cheng
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, No. 1800 Lihu Avenue, Wuxi 214122, China
- Correspondence: (Y.C.); (H.Q.)
| | - He Qian
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, No. 1800 Lihu Avenue, Wuxi 214122, China
- Correspondence: (Y.C.); (H.Q.)
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14
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Xu Q, Shen Y, Zhao J, Shen J. Salvianolate injection for hypertensive nephropathy patients who were using valsartan: A systematic review and meta-analysis. Front Pharmacol 2023; 14:1119150. [PMID: 36794275 PMCID: PMC9922779 DOI: 10.3389/fphar.2023.1119150] [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: 12/08/2022] [Accepted: 01/18/2023] [Indexed: 02/01/2023] Open
Abstract
Background: The treatment of hypertensive nephropathy has remained unchanged for many years. Salvianolate is the main active component extracted from Salvia Miltiorrhiza. The current studies seem to suggest that salvianolate has a certain therapeutic effect on hypertensive nephropathy. Objective: The purpose of this meta-analysis is to evaluate the effect and safety of salvianolate on hypertensive nephropathy under the condition of standardized use of valsartan. Methods: We conducted a systematic search (unlimited initial date to 22 October 2022) in PubMed, Web of Science, the Cochrane Library, Embase, China National Knowledge Infrastructure, Wanfang Data knowledge service platform, China Science and Technology Journal Database, China Biomedical Literature Service System. Searching for the study of salvianolate on hypertensive nephropathy. Two reviewers independently included the study that met the inclusion criteria, and extracted data, evaluated the quality of the study. We use RevMan5.4 and stata15 software for this meta-analysis. We use GRADEprofiler 3.2.2 software for evidence quality assessment. Results: This meta-analysis included seven studies (525 patients). Compared with the use of valsartan combined with conventional treatment, salvianolate combined with valsartan and conventional treatment can further improve the efficacy (RR = 1.28, 95%CI:1.17 to 1.39), reduce blood pressure [systolic blood pressure (MD = 8.98, 95%CI:-12.38 to -5.59); diastolic blood pressure (MD = 5.74, 95%CI:-7.20 to -4.29)], serum creatinine (MD = -17.32, 95%CI:-20.55 to -14.10), blood urea nitrogen (MD = -1.89, 95%CI:-3.76 to -0.01), urine microalbumin (MD = -23.90, 95%CI:-26.54 to -21.26), and urinary protein to creatinine ratio (MD = -1.92, 95%CI:-2.15 to -1.69), cystatin C (MD = -1.04, 95%CI: -1.63 to -0.45) and increase calcitonin gene-related peptide (MD = 18.68, 95%CI:12.89 to 24.46) without increasing adverse reactions (RR = 2.20, 95%CI:0.52 to 9.40). But it has no additional effect on endothelin-1 and malondialdehyde. The quality of evidence ranged from moderate to very low. Conclusion: This meta-analysis shows that the salvianolate can further improve renal function of hypertensive nephropathy patients based on valsartan was used. Therefore, salvianolate can be used as a clinical supplement for hypertensive nephropathy. However, the quality of the evidence is not high due to the uneven quality of the included studies and the insufficient sample size, we still need a lot of large sample size studies with more perfect design to confirm these results. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022373256, identifier CRD42022373256.
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Affiliation(s)
- Qiyao Xu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China,Graduate School, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuehong Shen
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jianqiao Zhao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China,Graduate School, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jianping Shen
- Graduate School, Nanjing University of Chinese Medicine, Nanjing, China,*Correspondence: Jianping Shen,
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15
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Liu X, Zhan XQ, Wang MJ, Cui WB, Chen XH, Qi FM, Yu JN, Dai JY, Fei DQ, Zhang ZX. Bioactive diterpenoids and sesquiterpenoids with different skeletons from Salvia digitaloides Diels. PHYTOCHEMISTRY 2023; 205:113501. [PMID: 36343681 DOI: 10.1016/j.phytochem.2022.113501] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 10/14/2022] [Accepted: 11/01/2022] [Indexed: 06/16/2023]
Abstract
Salvia has been regarded as a beneficial healing herb in ancient Egypt, Rome and Greece, and is listed as an official medicine in the pharmacopoeias of many countries worldwide. Currently, Salvia is widely used to flavor and preserve food. Here, two undescribed norabietane-type diterpenoids, sadigitaloides A and B, two undescribed germacrane-type sesquiterpenoids, sadigitaloides C and D, five undescribed guaiane-type sesquiterpenoid lactones, sadigitaloides E-I, two undescribed noreudesmane-type sesquiterpenoids, sadigitaloides J and K, one known diterpenoid, three known sesquiterpenoids, and three other types of known compounds were isolated from the 95% ethanol extract of the whole plants of Salvia digitaloides. Their structures and absolute configurations were characterized using 1D and 2D NMR spectroscopic techniques, electronic circular dichroism (ECD) calculations, HRESIMS experiments, and single-crystal X-ray diffraction analysis. Some compounds were evaluated for their anti-inflammatory activities against lipopolysaccharide (LPS)-induced TNF-α production in rat macrophage NR8383 cells. Sadigitaloide A showed noticeable anti-inflammatory activity at a concentration of 100.0 μM. At a concentration of 60 μM, sadigitaloide B exhibited better protection of dopaminergic neurons than the positive control n-butylidenephthalide in the Caenorhabditis elegans model injured by 6-OHDA. The phytotoxic activities of some compounds were attributed to considerable inhibitory effects on the growth of the roots and hypocotyls of Raphanus sativus L seedlings, especially cis, trans-abscisic acid, whose inhibition rates were much higher than those of glyphosate at concentrations ranging from 50 to 400 ppm. These results indicated that abietane-type diterpenoids possessed excellent anti-inflammatory and neuroprotective activities and further suggested that the low-molecular-weight compounds exhibited outstanding phytotoxic activities.
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Affiliation(s)
- Xu Liu
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, PR China
| | - Xiao-Qing Zhan
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, PR China
| | - Mei-Jie Wang
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, PR China
| | - Wen-Bo Cui
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, PR China
| | - Xiao-Han Chen
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, PR China
| | - Feng-Ming Qi
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, PR China
| | - Jian-Ning Yu
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, PR China
| | - Jian-Ye Dai
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, PR China
| | - Dong-Qing Fei
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, PR China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin, 541004, PR China.
| | - Zhan-Xin Zhang
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, PR China.
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16
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Zhan H, Pu Q, Long X, Lu W, Wang G, Meng F, Liao Z, Lan X, Chen M. Oxybaphus himalaicus Mitigates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting TLR4/MD2 Complex Formation. Antioxidants (Basel) 2022; 11:antiox11122307. [PMID: 36552516 PMCID: PMC9774781 DOI: 10.3390/antiox11122307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 11/14/2022] [Accepted: 11/18/2022] [Indexed: 11/24/2022] Open
Abstract
Acute kidney injury (AKI) is described as the abrupt decrease in kidney function always accompanied by inflammation. The roots of Oxybaphus himalaicus Edgew. have long been used in Tibetan folk medicine for the treatment of nephritis. Nevertheless, modern pharmacological studies, especially about the underlying mechanism of O. himalaicus medications, are still lacking. Here, in lipopolysaccharide (LPS)-induced RAW264.7 macrophages, the O. himalaicus extract (OE) showed significant anti-inflammatory activity with the dose dependently reducing the LPS-stimulated release of nitric oxide and the mRNA level and protein expression of inflammatory cytokines and reversed the activation of nuclear factor kappa B (NF-κB). Co-immunoprecipitation assay indicated that OE inhibited Toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD2) complex formation and further suppressed both myeloid differentiation factor 88 (MyD88)-dependent and TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent cascades activation. In addition, OE could restrain NADPH oxidase 2 (NOX2) endocytosis by blocking TLR4/MD2 complex formation to prevent reactive oxygen species production. In LPS-induced AKI mice, OE treatment mitigated renal injury and inflammatory infiltration by inhibiting TLR4/MD2 complex formation. UPLC-MS/MS analysis tentatively identified 41 components in OE. Our results indicated that OE presented significant anti-inflammatory activity by inhibiting TLR4/MD2 complex formation, which alleviated LPS-induced AKI in mice.
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Affiliation(s)
- Honghong Zhan
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education; College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Qingxiu Pu
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education; College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Xiaoliang Long
- School of Life Sciences, Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City and Southwest University, The Provincial and Ministerial Co-Founded Collaborative Innovation Center for R&D in Tibet Characteristic Agricultural and Animal Husbandry Resources, TAAHC-SWU Medicinal Plant Joint R&D Centre, Southwest University, Chongqing 400715, China
| | - Wei Lu
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education; College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Guowei Wang
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education; College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Fancheng Meng
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education; College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Zhihua Liao
- School of Life Sciences, Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City and Southwest University, The Provincial and Ministerial Co-Founded Collaborative Innovation Center for R&D in Tibet Characteristic Agricultural and Animal Husbandry Resources, TAAHC-SWU Medicinal Plant Joint R&D Centre, Southwest University, Chongqing 400715, China
| | - Xiaozhong Lan
- TAAHC-SWU Medicinal Plant R&D Center, Tibet Agricultural and Animal Husbandry University, Nyingchi 860000, China
| | - Min Chen
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education; College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
- Correspondence:
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Liu C, Liu Y, Wang C, Guo Y, Cheng Y, Qian H, Zhao Y. Lycopene-Loaded Bilosomes Ameliorate High-Fat Diet-Induced Chronic Nephritis in Mice through the TLR4/MyD88 Inflammatory Pathway. Foods 2022; 11:foods11193042. [PMID: 36230117 PMCID: PMC9564075 DOI: 10.3390/foods11193042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/06/2022] [Accepted: 09/16/2022] [Indexed: 11/27/2022] Open
Abstract
Chronic kidney disease caused by a high-fat diet (HFD)-induced metabolic syndrome has received widespread attention. Lycopene has a wide range of biological activities and can improve a variety of chronic diseases through anti-inflammatory effects. In this study, HFD-fed mice were used as a metabolic syndrome model to evaluate the protective effect of lycopene in a sustained-release vehicle (bilosomes) in the small intestine against renal injury and to determine whether the TLR4/MyD88 pathway and related metabolic pathways are involved in this process. The results showed that lycopene bilosomes alleviated HFD-induced kidney damage, as evidenced by lower serum urea nitrogen, creatinine, and uric acid levels. Histopathology studies showed that lycopene bilosomes attenuated HFD-induced tubular cell and glomerular injury. In addition, Elisa, RT-PCR, and Western blotting results showed that lycopene bilosomes also reduced the expression of inflammatory factors such as TLR4, MyD88, NF-kB, TNF-a, and IL-6 in mouse kidneys. The mechanism was to attenuate renal inflammatory response by inhibiting the TLR4/MyD88 inflammatory pathway. These findings suggested that lycopene can alleviate nephritis and metabolic disorders caused by HFD, inhibiting the TLR4/MyD88 inflammatory pathway and its downstream pro-inflammatory cytokines and further regulating the vitamin K metabolism, beta-alanine metabolism, and glutathione metabolism pathways to relieve chronic nephritis.
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Affiliation(s)
- Chang Liu
- State Key Laboratory of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi 214122, China
| | - Yu Liu
- Wuxi 9th People’s Hospital Affiliated to Soochow University, Wuxi 214122, China
| | - Ciwan Wang
- State Key Laboratory of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi 214122, China
| | - Yahui Guo
- State Key Laboratory of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi 214122, China
| | - Yuliang Cheng
- State Key Laboratory of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi 214122, China
| | - He Qian
- State Key Laboratory of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi 214122, China
| | - Yong Zhao
- Thoracic and Cardiac Surgery, Affiliated Hospital of Jiangnan University, No.1000, He Feng Road, Wuxi 214122, China
- Correspondence:
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Anti-Inflammatory Effects of Phlebia sp. Extract in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages. BIOMED RESEARCH INTERNATIONAL 2022; 2022:2717196. [PMID: 35872858 PMCID: PMC9303134 DOI: 10.1155/2022/2717196] [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: 01/14/2022] [Revised: 05/26/2022] [Accepted: 06/14/2022] [Indexed: 11/17/2022]
Abstract
Lichens are a life form in which algae and fungi have a symbiotic relationship and have various biological activities, including anti-inflammatory and antiproliferative activities. This is the first study to investigate the anti-inflammatory activity of a Phlebia sp. fungal extract (PSE) isolated from Peltigera neopolydactyla in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophage. PSE reduced the production of the proinflammatory cytokine (tumor necrosis factor-α, interleukin-6, and interleukin-1β), chemokine (granulocyte-macrophage colony-stimulating factor), nitric oxide, and prostaglandin E2 in the LPS-stimulated RAW264.7 macrophages. Especially, PSE inhibits the phosphorylation of activator protein-1 (AP-1) signaling (c-Fos and c-Jun) and their upstream mitogen-activated protein kinase kinases/mitogen-activated protein kinases (MKK/MAPKs: MKK4, MKK7, and JNK) and finally reduced the production of the inflammatory cytokines. The inhibitory effects mainly act via suppressing JNK-mediated AP-1 rather than the NF-κB pathway. Furthermore, PSE inhibited the production of final inflammatory effector molecules involved in AP-1 signaling, including nitric oxide (NO) and prostaglandin E2 (PGE2). Here, we report that PSE has the potential to be developed as an anti-inflammatory agent.
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Weidong Wang, Zhang J, Liu Z, Zhu Y, Mei L, Tao Y, Jiang L. Xanthotoxol from Saussurea obvallata Attenuates LPS-Induced RAW 264.7 Cells Inflammatory Responses through NF-κB Pathway. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2022. [DOI: 10.1134/s1068162022020248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Kuang QX, Lei LR, Li QZ, Peng W, Wang YM, Dai YF, Wang D, Gu YC, Deng Y, Guo DL. Investigation of the Anti-Inflammatory Activity of Fusaproliferin Analogues Guided by Transcriptome Analysis. Front Pharmacol 2022; 13:881182. [PMID: 37124719 PMCID: PMC10136769 DOI: 10.3389/fphar.2022.881182] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/21/2022] [Indexed: 12/21/2022] Open
Abstract
Background: Excessive inflammation results in severe tissue damage as well as serious acute or chronic disorders, and extensive research has focused on finding new anti-inflammatory hit compounds with safety and efficacy profiles from natural products. As promising therapeutic entities for the treatment of inflammation-related diseases, fusaproliferin and its analogs have attracted great interest. However, the underlying anti-inflammatory mechanism is still poorly understood and deserves to be further investigated.Methods: For the estimation of the anti-inflammatory activity of fusaproliferin (1) and its analogs (2-4)in vitro and in vivo, lipopolysaccharide (LPS)-induced RAW264.7 macrophages and zebrafish embryos were employed. Then, transcriptome analysis was applied to guide subsequent western blot analysis of critical proteins in related signaling pathways. Surface plasmon resonance assays (SPR) combined with molecular docking analyses were finally applied to evaluate the affinity interactions between 1-4 and TLR4 and provide a possible interpretation of the downregulation of related signaling pathways.Results: 1-4 significantly attenuated the production of inflammatory messengers, including nitric oxide (NO), reactive oxygen species (ROS), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), as well as nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in LPS-induced RAW264.7 macrophages. Transcriptome analyses based on RNA-seq indicated the ability of compound 1 to reverse LPS stimulation and the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPKs) signaling pathways contribute to the anti-inflammatory process. Experimental verification at the protein level revealed that 1 can inhibit the activation of inhibitor of NF-κB kinase (IKK), degradation of inhibitor of NF-κB (IκB), and phosphorylation of NF-κB and reduce nuclear translocation of NF-κB. 1 also decreased the phosphorylation of MAPKs, including p38, extracellular regulated protein kinases (ERK), and c-Jun N-terminal kinase (JNK). SPR assays and molecular docking results indicated that 1-4 exhibited affinity for the TLR4 protein with KD values of 23.5–29.3 μM.Conclusion: Fusaproliferin and its analogs can be hit compounds for the treatment of inflammation-associated diseases.
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Affiliation(s)
- Qi-Xuan Kuang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li-Rong Lei
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qing-Zhou Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wan Peng
- Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Yu-Mei Wang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yi-Fei Dai
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Dong Wang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yu-Cheng Gu
- Syngenta Jealott’s Hill International Research Centre, Berkshire, United Kingdom
| | - Yun Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Yun Deng, ; Da-Le Guo,
| | - Da-Le Guo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Yun Deng, ; Da-Le Guo,
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Salvia miltiorrhiza Bunge as a Potential Natural Compound against COVID-19. Cells 2022; 11:cells11081311. [PMID: 35455990 PMCID: PMC9028742 DOI: 10.3390/cells11081311] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/01/2022] [Accepted: 04/06/2022] [Indexed: 02/06/2023] Open
Abstract
Salvia miltiorrhiza Bunge, commonly called danshen, is widely used in traditional Chinese medicine for its cardiovascular and neuroprotective effects, which include antioxidative, anti-inflammatory, and antifibrotic properties. The purpose of this study was to evaluate the preclinical potential of S. miltiorrhiza extracts for the treatment of COVID-19. First, the impact of the extract on the binding between SARS-CoV-2 and the cellular ACE2 receptors was assessed using atomic force microscopy (AFM), showing a significant reduction in binding by the extract at concentrations in the µg/mL range. Second, the interference of this extract with the inflammatory response of blood mononuclear cells (PBMCs) was determined, demonstrating potent inhibitory properties in the same concentration range on pro-inflammatory cytokine release and interference with the activation of NFκB signaling. Together, these in vitro data demonstrate the potential of S. miltiorrhiza against COVID-19, consisting first of the blockade of the binding of SARS-CoV-2 to the ACE2 receptor and the mitigation of the inflammatory response from leukocytes by interfering with NFκB signaling. This dataset prompts the launch of a clinical trial to address in vivo the clinical benefits of this promising agent.
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22
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Kuang QX, Li QZ, Lei LR, Wang YM, Huang LJ, Dai YF, Peng W, Zhang MZ, Wang D, Gu YC, Deng Y, Guo DL. Proliferatins Suppress Lipopolysaccharide-induced Inflammation via Inhibition of the NF-κB and MAPK Signaling Pathways. Bioorg Chem 2022; 124:105810. [DOI: 10.1016/j.bioorg.2022.105810] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 02/08/2023]
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Han S, Yuan R, Cui Y, He J, Wang QQ, Zhuo Y, Yang S, Gao H. Hederasaponin C Alleviates Lipopolysaccharide-Induced Acute Lung Injury In Vivo and In Vitro Through the PIP2/NF-κB/NLRP3 Signaling Pathway. Front Immunol 2022; 13:846384. [PMID: 35281058 PMCID: PMC8913935 DOI: 10.3389/fimmu.2022.846384] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 02/09/2022] [Indexed: 12/04/2022] Open
Abstract
Gene transcription is governed by epigenetic regulation that is essential for the pro-inflammatory mediators surge following pathological triggers. Acute lung injury (ALI) is driven by pro-inflammatory cytokines produced by the innate immune system, which involves the nod-like receptor 3 (NLRP3) inflammasome and nuclear factor-κB (NF-κB) pathways. These two pathways are interconnected and share a common inducer the phosphatidylinositol 4,5-bisphosphate (PIP2), an epigenetic regulator of (Ribosomal ribonucleic acid (rRNA) gene transcription, to regulate inflammation by the direct inhibition of NF-κB phosphorylation and NLRP3 inflammasome activation. Herein, we report that hederasaponin C (HSC) exerted a therapeutic effect against ALI through the regulation of the PIP2/NF-κB/NLRP3 signaling pathway. In lipopolysaccharide (LPS)/lipopolysaccharide + adenosine triphosphate (LPS+ATP)-stimulated macrophages, our results showed that HSC remarkably inhibited the secretion of interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α). Moreover, HSC inhibited NF-κB/p65 nuclear translocation and the binding of PIP2 to transforming growth factor-β activated kinase 1 (TAK1). The intracellular calcium (Ca2+) level was decreased by HSC via the PIP2 signaling pathway, which subsequently inhibited the activation of NLRP3 inflammasome. HSC markedly alleviated LPS-induced ALI, restored lung function of mice, and rescued ALI-induced mice death. In addition, HSC significantly reduced the level of white blood cells (WBC), neutrophils, and lymphocytes, as well as pro-inflammatory mediators like IL-6, IL-1β, and TNF-α. Hematoxylin and eosin (H&E) staining results suggested HSC has a significant therapeutic effect on lung injury of mice. Interestingly, the PIP2/NF-κB/NLRP3 signaling pathway was further confirmed by the treatment of HSC with ALI, which is consistent with the treatment of HSC with LPS/LPS+ATP-stimulated macrophages. Overall, our findings revealed that HSC demonstrated significant anti-inflammatory activity through modulating the PIP2/NF-κB/NLRP3 axis in vitro and in vivo, suggesting that HSC is a potential therapeutic agent for the clinical treatment of ALI.
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Affiliation(s)
- Shan Han
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
- State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Renyikun Yuan
- State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Yushun Cui
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
| | - Jia He
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
- State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Qin-Qin Wang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
| | - Youqiong Zhuo
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
| | - Shilin Yang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Guangxi University of Chinese Medicine, Nanning, China
| | - Hongwei Gao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Guangxi University of Chinese Medicine, Nanning, China
- *Correspondence: Hongwei Gao,
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Wang W, Jiang L, Zhu Y, Mei L, Tao Y, Liu Z. Bioactivity-guided isolation of cyclooxygenase-2 inhibitors from Saussurea obvallata (DC.) Edgew. Using affinity solid phase extraction assay. JOURNAL OF ETHNOPHARMACOLOGY 2022; 284:114785. [PMID: 34718104 DOI: 10.1016/j.jep.2021.114785] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 10/23/2021] [Accepted: 10/25/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Saussurea obvallata (DC.) Edgew. is a traditional Tibetan medicine used for the treatment of inflammation-related diseases, but the scientific validation was very limited. AIM OF THE STUDY This study aimed to rapid screen and targeted isolate cyclooxygenase-2 (COX-2) inhibitors from S. obvallata extract. MATERIALS AND METHODS An efficient ligand-fishing method based on affinity solid phase extraction (A-SPE) combining with HPLC was developed. The identified COX-2 inhibitors were separated using preparative liquid chromatography. In vitro COX-2 inhibition assays were employed to confirm the inhibitory activities of the isolated compounds. In addition, the effect of the isolated compounds on the production of prostaglandin E2 (PGE2) and the expression of COX-2 in LPS-induced RAW 264.7 were evaluated. RESULTS A total of four phenylpropanoids, isolariciresinol, syringaresinol, pinoresinol and balanophonin were targeted isolated as COX-2 inhibitors with IC50 values of 36.4 ± 2.6 μM, 23.1 ± 1.8 μM, 3.6 ± 0.3 μM and 12.1 ± 0.9 μM, respectively. The isolated compounds significantly inhibited LPS-induced NO production in a dose-dependent manner. And, the results of the inhibitory effect on the release of PGE2 and the expression of COX-2 in LPS-induced macrophages were consistent with A-SPE analysis. CONCLUSION The present work demonstrated that the developed A-SPE-HPLC method could successfully targeted isolated COX-2 inhibitors from S. obvallata extract. And, the isolation results indicated that the therapeutic effect of S. obvallata on inflammation-related diseases was partly based on the COX-2 active ingredients.
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Affiliation(s)
- Weidong Wang
- Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China; Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Xining, Qinghai, China; University of Chinese Academy of Science, Beijing, China
| | - Lei Jiang
- Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China; Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Xining, Qinghai, China
| | - Yunhe Zhu
- Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China; Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Xining, Qinghai, China; University of Chinese Academy of Science, Beijing, China
| | - Lijuan Mei
- Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China; Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Xining, Qinghai, China
| | - Yanduo Tao
- Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China; Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Xining, Qinghai, China.
| | - Zenggen Liu
- Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China; Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Xining, Qinghai, China.
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In vivo and in vitro studies of Danzhi Jiangtang capsules against diabetic cardiomyopathy via TLR4/MyD88/NF-κB signaling pathway. Saudi Pharm J 2022; 29:1432-1440. [PMID: 35002381 PMCID: PMC8720806 DOI: 10.1016/j.jsps.2021.11.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 11/05/2021] [Indexed: 12/18/2022] Open
Abstract
Objectives Danzhi Jiangtang capsule (DJC) is widely used for preventing and treating diabetic cardiomyopathy (DCM). However, the underlying mechanisms of the anti-inflammatory and antiapoptotic activities are unclear. Methods In the in vivo diabetic cardiomyopathy rat model, cardiac function was measured through echocardiography, histological changes in the myocardium were visualized using HE staining, and cardiomyocyte apoptosis was detected using TUNEL. The serum levels of anti-inflammatory cytokines were detected using ELISA. Finally, TLR4, MyD88, and NF-κB mRNA expressions were analyzed using RT-qPCR. In the in vitro experiments, the apoptosis rate of the H9c2 cells was detected using FCM; moreover, TLR4, MyD88 and NF-κB mRNA expressions were measured using RT-qPCR and related protein levels were investigated using Western blotting. Results In vivo, DJC effectively improved cardiac function, alleviated the pathological changes, and reduced the apoptosis rate. Moreover, DJC reduced TNF-α, IL-1β, and IL-6 activities, with significant inhibition of the TLR4, MyD88 and NF-κB p65 mRNA expression. Moreover, in vitro, DJC effectively inhibited high-glucose-induced H9c2 apoptosis-an effect similar to that for TAK242. Finally, both the DJC and TAK242 considerably reduced TLR4, MyD88, NF-κB, Bax, and caspase-3 protein expression but increased that of BCL-2. Conclusions DJC prevented the overactivation of the TLR4/MyD88/NF-κB signaling pathway and regulate cardiomyocyte apoptosis against DCM.
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Wu Q, Yin CH, Li Y, Cai JQ, Yang HY, Huang YY, Zheng YX, Xiong K, Yu HL, Lu AP, Wang KX, Guan DG, Chen YP. Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis. Front Pharmacol 2021; 12:769190. [PMID: 34938184 PMCID: PMC8687625 DOI: 10.3389/fphar.2021.769190] [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: 09/01/2021] [Accepted: 11/04/2021] [Indexed: 11/13/2022] Open
Abstract
Sepsis is a systemic inflammatory reaction caused by various infectious or noninfectious factors, which can lead to shock, multiple organ dysfunction syndrome, and death. It is one of the common complications and a main cause of death in critically ill patients. At present, the treatments of sepsis are mainly focused on the controlling of inflammatory response and reduction of various organ function damage, including anti-infection, hormones, mechanical ventilation, nutritional support, and traditional Chinese medicine (TCM). Among them, Xuebijing injection (XBJI) is an important derivative of TCM, which is widely used in clinical research. However, the molecular mechanism of XBJI on sepsis is still not clear. The mechanism of treatment of "bacteria, poison and inflammation" and the effects of multi-ingredient, multi-target, and multi-pathway have still not been clarified. For solving this issue, we designed a new systems pharmacology strategy which combines target genes of XBJI and the pathogenetic genes of sepsis to construct functional response space (FRS). The key response proteins in the FRS were determined by using a novel node importance calculation method and were condensed by a dynamic programming strategy to conduct the critical functional ingredients group (CFIG). The results showed that enriched pathways of key response proteins selected from FRS could cover 95.83% of the enriched pathways of reference targets, which were defined as the intersections of ingredient targets and pathogenetic genes. The targets of the optimized CFIG with 60 ingredients could be enriched into 182 pathways which covered 81.58% of 152 pathways of 1,606 pathogenetic genes. The prediction of CFIG targets showed that the CFIG of XBJI could affect sepsis synergistically through genes such as TAK1, TNF-α, IL-1β, and MEK1 in the pathways of MAPK, NF-κB, PI3K-AKT, Toll-like receptor, and tumor necrosis factor signaling. Finally, the effects of apigenin, baicalein, and luteolin were evaluated by in vitro experiments and were proved to be effective in reducing the production of intracellular reactive oxygen species in lipopolysaccharide-stimulated RAW264.7 cells, significantly. These results indicate that the novel integrative model can promote reliability and accuracy on depicting the CFIGs in XBJI and figure out a methodological coordinate for simplicity, mechanism analysis, and secondary development of formulas in TCM.
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Affiliation(s)
- Qi- Wu
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chuan-Hui Yin
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China
| | - Yi Li
- Department of Radiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jie-Qi Cai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China
| | - Han-Yun Yang
- The First Clinical Medical College of Southern Medical University, Guangzhou, China
| | - Ying-Ying Huang
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yi-Xu Zheng
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ke Xiong
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hai-Lang Yu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China
| | - Ai-Ping Lu
- Institute of Integrated Bioinformedicine and Translational Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong China
| | - Ke-Xin Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,National Key Clinical Specialty/Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Neurosurgery Institute, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Dao-Gang Guan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China
| | - Yu-Peng Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China
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Li M, Ge Q, Du H, Lin S. Tricholoma matsutake-Derived Peptides Ameliorate Inflammation and Mitochondrial Dysfunction in RAW264.7 Macrophages by Modulating the NF-κB/COX-2 Pathway. Foods 2021; 10:2680. [PMID: 34828964 PMCID: PMC8621704 DOI: 10.3390/foods10112680] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 12/28/2022] Open
Abstract
Tricholoma matsutake is an edible fungus that contains various bioactive substances, some of them with immunostimulatory properties. Presently, there is limited knowledge about the functional components of T. matsutake. Our aim was to evaluate the protective effects and molecular mechanisms of two T. matsutake-derived peptides, SDLKHFPF and SDIKHFPF, on lipopolysaccharide (LPS)-induced mitochondrial dysfunction and inflammation in RAW264.7 macrophages. Tricholoma matsutake peptides significantly ameliorated the production of inflammatory cytokines and inhibited the expression of COX-2, iNOS, IKKβ, p-IκB-α, and p-NF-κB. Immunofluorescence assays confirmed the inhibitory effect of T. matsutake peptides on NF-κB/p65 nuclear translocation. Furthermore, the treatment with T. matsutake peptides prevented the accumulation of reactive oxygen species, increased the Bcl-2/Bax ratio, reversed the loss of mitochondrial membrane potential, and rescued abnormalities in cellular energy metabolism. These findings indicate that T. matsutake peptides can effectively inhibit the activation of NF-κB/COX-2 and may confer an overall protective effect against LPS-induced cell damage.
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Affiliation(s)
| | | | | | - Songyi Lin
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China; (M.L.); (Q.G.); (H.D.)
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28
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Abulizi A, Hu L, Ma A, Shao FY, Zhu HZ, Lin SM, Shao GY, Xu Y, Ran JH, Li J, Zhou H, Lin DM, Wang LF, Li M, Yang BX. Ganoderic acid alleviates chemotherapy-induced fatigue in mice bearing colon tumor. Acta Pharmacol Sin 2021; 42:1703-1713. [PMID: 33927358 PMCID: PMC8463583 DOI: 10.1038/s41401-021-00669-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 03/23/2021] [Indexed: 02/02/2023] Open
Abstract
Chemotherapy-related fatigue (CRF) is increasingly being recognized as one of the severe symptoms in patients undergoing chemotherapy, which not only largely reduces the quality of life in patients, but also diminishes their physical and social function. At present, there is no effective drug for preventing and treating CRF. Ganoderic acid (GA), isolated from traditional Chinese medicine Ganoderma lucidum, has shown a variety of pharmacological activities such as anti-tumor, anti-inflammation, immunoregulation, etc. In this study, we investigated whether GA possessed anti-fatigue activity against CRF. CT26 tumor-bearing mice were treated with 5-fluorouracil (5-FU, 30 mg/kg) and GA (50 mg/kg) alone or in combination for 18 days. Peripheral and central fatigue-related behaviors, energy metabolism and inflammatory factors were assessed. We demonstrated that co-administration of GA ameliorated 5-FU-induced peripheral muscle fatigue-like behavior via improving muscle quality and mitochondria function, increasing glycogen content and ATP production, reducing lactic acid content and LDH activity, and inhibiting p-AMPK, IL-6 and TNF-α expression in skeletal muscle. Co-administration of GA also retarded the 5-FU-induced central fatigue-like behavior accompanied by down-regulating the expression of IL-6, iNOS and COX2 in the hippocampus through inhibiting TLR4/Myd88/NF-κB pathway. These results suggest that GA could attenuate 5-FU-induced peripheral and central fatigue in tumor-bearing mice, which provides evidence for GA as a potential drug for treatment of CRF in clinic.
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Affiliation(s)
- Abudumijiti Abulizi
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Ling Hu
- Department of Anatomy and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing, 400016, China
| | - Ang Ma
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Fang-Yu Shao
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Hui-Ze Zhu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Si-Mei Lin
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Guang-Ying Shao
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Yue Xu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Jian-Hua Ran
- Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, China
| | - Jing Li
- Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, China
| | - Hong Zhou
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Dong-Mei Lin
- JUNCAO Technology Research Institute, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Lian-Fu Wang
- JUNCAO Technology Research Institute, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Min Li
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
| | - Bao-Xue Yang
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
- Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, 100191, China.
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Yue J, Su K, Zhang G, Yang J, Xu C, Liu X. Dihydrotanshinone Attenuates LPS-Induced Acute Lung Injury in Mice by Upregulating LXRα. Inflammation 2021; 45:212-221. [PMID: 34467464 DOI: 10.1007/s10753-021-01539-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 08/09/2021] [Indexed: 11/26/2022]
Abstract
Dihydrotanshinone (DIH) is an extract of Salvia miltiorrhiza Bunge. It has been reported that DIH could regulate NF-κB signaling pathway. The aim of this study was to investigate whether DIH could protect mice from lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. In this study, sixty mice were randomly divided into five groups, one group as blank control group, the second group as LPS control group, and the last three groups were pre-injected with different doses of DIH and then inhaled LPS for experimental comparison. After 12 h of LPS treatment, the wet-dry ratio, histopathlogical changes, and myeloperoxidase (MPO) activity of lungs were measured. In addition, ELISA kits were used to measure the levels of TNF-α and IL-1β inflammatory cytokines in bronchoalveolar lavage fluids (BALF), and western blot analysis was used to measure the activity of NF-κB signaling pathway. The results demonstrated that DIH could effectively reduce pulmonary edema, MPO activity, and improve the lung histopathlogical changes. Furthermore, DIH suppressed the levels of inflammatory cytokines in BALF, such as TNF-α and IL-1β. In addition, DIH could also downregulate the activity of NF-κB signaling pathway. We also found that DIH dose-dependently increased the expression of LXRα. In addition, DIH could inhibit LPS-induced IL-8 production and NF-κB activation in A549 cells. And the inhibitory effects were reversed by LXRα inhibitor geranylgeranyl pyrophosphate (GGPP). Therefore, we speculate that DIH regulates LPS-induced ALI in mice by increasing LXRα expression, which subsequently inhibiting NF-κB signaling pathway.
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Affiliation(s)
- Jing Yue
- Department of Anesthesiology, The Second Affiliated Hospital of Jilin University, Changchun, China
| | - Kai Su
- Department of Head and Neck Surgery, The Second Affiliated Hospital of Jilin University, Changchun, China
| | - Guangxin Zhang
- Department of Thoracic Surgery, The Second Affiliated Hospital of Jilin University, Changchun, China
| | - Jinghui Yang
- Department of Hepatobiliary Pancreatic Surgery, China-Japan Friendship Hospital of Jilin University, Changchun, China
| | - Chengbi Xu
- Department of Head and Neck Surgery, The Second Affiliated Hospital of Jilin University, Changchun, China
| | - Xueshibojie Liu
- Department of Head and Neck Surgery, The Second Affiliated Hospital of Jilin University, Changchun, China.
- Department of Head and Neck Surgery, The Second Affiliated Hospital of Jilin University, Changchun, China.
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Qi MM, He PZ, Zhang L, Dong WG. STAT3-mediated activation of mitochondrial pathway contributes to antitumor effect of dihydrotanshinone I in esophageal squamous cell carcinoma cells. World J Gastrointest Oncol 2021; 13:893-914. [PMID: 34457194 PMCID: PMC8371523 DOI: 10.4251/wjgo.v13.i8.893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/17/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies with a poor prognosis, and its treatment remains a great challenge. Dihydrotanshinone I (DHTS) has been reported to exert antitumor effect in many cancers. However, the role of DHTS in ESCC remains unclear.
AIM To investigate the antitumor effect of DHTS in ESCC and the underlying mechanisms.
METHODS CCK-8 assay and cell cycle analysis were used to detect proliferation and cell cycle in ESCC cells. Annexin V-PE/7-AAD double staining assay and Hoechst 33258 staining were used to detect apoptosis in ESCC cells. Western blot was used to detect the expression of proteins associated with the mitochondrial pathway. Immunofluorescence was used to detect the expression of phosphorylated STAT3 (pSTAT3) in DHTS-treated ESCC cells. ESCC cells with STAT3 knockdown and overexpression were constructed to verify the role of STAT3 in DHTS induced apoptosis. A xenograft tumor model in nude mice was used to evaluate the antitumor effect of DHTS in vivo.
RESULTS After treatment with DHTS, the proliferation of ESCC cells was inhibited in a dose- and time-dependent manner. Moreover, DHTS induced cell cycle arrest in the G0/1 phase. Annexin V-PE/7-AAD double staining assay and Hoechst 33258 staining revealed that DHTS induced obvious apoptosis in KYSE30 and Eca109 cells. At the molecular level, DHTS treatment reduced the expression of pSTAT3 and anti-apoptotic proteins, while increasing the expression of pro-apoptotic proteins in ESCC cells. STAT3 knockdown in ESCC cells markedly promoted the activation of the mitochondrial pathway while STAT3 overexpression blocked the activation of the mitochondrial pathway. Additionally, DHTS inhibited tumor cell proliferation and induced apoptosis in a xenograft tumor mouse model.
CONCLUSION DHTS exerts antitumor effect in ESCC via STAT3-mediated activation of the mitochondrial pathway. DHTS may be a novel therapeutic agent for ESCC.
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Affiliation(s)
- Ming-Ming Qi
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- Central Laboratory of Renmin Hospital, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Peng-Zhan He
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- Central Laboratory of Renmin Hospital, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Lan Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- Central Laboratory of Renmin Hospital, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wei-Guo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
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Zhuo Y, Yuan R, Chen X, He J, Chen Y, Zhang C, Sun K, Yang S, Liu Z, Gao H. Tanshinone I exerts cardiovascular protective effects in vivo and in vitro through inhibiting necroptosis via Akt/Nrf2 signaling pathway. Chin Med 2021; 16:48. [PMID: 34183021 PMCID: PMC8240219 DOI: 10.1186/s13020-021-00458-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 06/16/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Tanshinone I (TI) is a primary component of Salvia miltiorrhiza Bunge (Danshen), which confers a favorable role in a variety of pharmacological activities including cardiovascular protection. However, the exact mechanism of the cardiovascular protection activity of TI remains to be illustrated. In this study, the cardiovascular protective effect and its mechanism of TI were investigated. METHODS In this study, tert-butyl hydroperoxide (t-BHP)-stimulated H9c2 cells model was employed to investigate the protective effect in vitro. The cell viability was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) kit. The reactive-oxygen-species (ROS) level and mitochondrial membrane potential (MMP) were investigated by the flow cytometry and JC-1 assay, respectively. While in vivo experiment, the cardiovascular protective effect of TI was determined by using myocardial ischemia-reperfusion (MI/R) model including hematoxylin-eosin (H&E) staining assay and determination of superoxide dismutase (SOD) and malondialdehyde (MDA). Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) release were detected by Enzyme-linked immunosorbent assay (ELISA). Receptor interacting protein kinase 1 (RIP1), receptor interacting protein kinase 3 (RIP3), receptor interacting protein kinase 3 (MLKL), protein kinase B (Akt), Nuclear factor erythroid 2 related factor 2 (Nrf2), Heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO-1) were determined by western blotting. RESULTS Our data demonstrated that TI pretreatment attenuated t-BHP and MI/R injury-induced necroptosis by inhibiting the expression of p-RIP1, p-RIP3, and p-MLKL. TI activated the Akt/Nrf2 pathway to promote the expression of antioxidant-related proteins such as phosphorylation of Akt, nuclear factor erythroid 2 related factor 2 (Nrf2), quinone oxidoreductase-1 (NQO-1) and heme oxygenase-1 (HO-1) expression in t-BHP-stimulated H9c2 cells. TI relieved oxidative stress by mitigating ROS generation and reversing MMP loss. In vivo experiment, TI made electrocardiograph (ECG) recovery better and lessened the degree of myocardial tissue damage. The counts of white blood cell (WBC), neutrophil (Neu), lymphocyte (Lym), and the release of TNF-α and IL-6 were reversed by TI treatment. SOD level was increased, while MDA level was decreased by TI treatment. CONCLUSION Collectively, our findings indicated that TI exerted cardiovascular protective activities in vitro and in vivo through suppressing RIP1/RIP3/MLKL and activating Akt/Nrf2 signaling pathways, which could be developed into a cardiovascular protective agent.
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Affiliation(s)
- Youqiong Zhuo
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200, China
| | - Renyikun Yuan
- State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China
| | - Xinxin Chen
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200, China
| | - Jia He
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200, China
| | - Yangling Chen
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200, China
| | - Chenwei Zhang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200, China
| | - Kaili Sun
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200, China
| | - Shilin Yang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200, China
| | - Zhenjie Liu
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200, China
| | - Hongwei Gao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000, China.
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200, China.
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32
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Feng JH, Kim HY, Sim SM, Zuo GL, Jung JS, Hwang SH, Kwak YG, Kim MJ, Jo JH, Kim SC, Lim SS, Suh HW. The Anti-Inflammatory and the Antinociceptive Effects of Mixed Agrimonia pilosa Ledeb. and Salvia miltiorrhiza Bunge Extract. PLANTS 2021; 10:plants10061234. [PMID: 34204404 PMCID: PMC8234973 DOI: 10.3390/plants10061234] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/17/2022]
Abstract
Arthritis is a common condition that causes pain and inflammation in a joint. Previously, we reported that the mixture extract (ME) from Agrimonia pilosa Ledeb. (AP) and Salvia miltiorrhiza Bunge (SM) could ameliorate gout arthritis. In the present study, we aimed to investigate the potential anti-inflammatory and antinociceptive effects of ME and characterize the mechanism. We compared the anti-inflammatory and antinociceptive effects of a positive control, Perna canaliculus powder (PC). The results showed that one-off and one-week treatment of ME reduced the pain threshold in a dose-dependent manner (from 10 to 100 mg/kg) in the mono-iodoacetate (MIA)-induced osteoarthritis (OA) model. ME also reduced the plasma TNF-α, IL-6, and CRP levels. In LPS-stimulated RAW 264.7 cells, ME inhibited the release of NO, PGE2, LTB4, and IL-6, increased the phosphorylation of PPAR-γ protein, and downregulated TNF-α and MAPKs proteins expression in a concentration-dependent (from 1 to 100 µg/mL) manner. Furthermore, ME ameliorated the progression of ear edema in mice. In most of the experiments, ME-induced effects were almost equal to, or were higher than, PC-induced effects. Conclusions: The data presented here suggest that ME shows anti-inflammatory and antinociceptive activities, indicating ME may be a potential therapeutic for arthritis treatment.
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Affiliation(s)
- Jing-Hui Feng
- Department of Pharmacology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (J.-H.F.); (S.-M.S.)
- Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea;
| | - Hyun-Yong Kim
- Department of Food Science and Nutrition, College of Natural Science, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (H.-Y.K.); (G.-L.Z.); (S.-H.H.)
| | - Su-Min Sim
- Department of Pharmacology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (J.-H.F.); (S.-M.S.)
- Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea;
| | - Guang-Lei Zuo
- Department of Food Science and Nutrition, College of Natural Science, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (H.-Y.K.); (G.-L.Z.); (S.-H.H.)
| | - Jeon-Sub Jung
- Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea;
| | - Seung-Hwan Hwang
- Department of Food Science and Nutrition, College of Natural Science, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (H.-Y.K.); (G.-L.Z.); (S.-H.H.)
- R&D Center, Huons Co., Ltd., 55 Hanyangdaehak-ro, Ansan 15588, Gyeonggi-do, Korea
| | - Youn-Gil Kwak
- Research Institute, Huons Nature, Geumsan 32742, Choong-cheong Nam-do, Korea; (Y.-G.K.); (M.-J.K.); (J.-H.J.)
| | - Min-Jung Kim
- Research Institute, Huons Nature, Geumsan 32742, Choong-cheong Nam-do, Korea; (Y.-G.K.); (M.-J.K.); (J.-H.J.)
| | - Jeong-Hun Jo
- Research Institute, Huons Nature, Geumsan 32742, Choong-cheong Nam-do, Korea; (Y.-G.K.); (M.-J.K.); (J.-H.J.)
| | - Sung-Chan Kim
- Department of Biochemistry, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea;
| | - Soon-Sung Lim
- Department of Food Science and Nutrition, College of Natural Science, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (H.-Y.K.); (G.-L.Z.); (S.-H.H.)
- Correspondence: (S.-S.L.); (H.-W.S.); Tel.: +82-33-248-2133 (S.-S.L.); +82-33-248-2614 (H.-W.S.)
| | - Hong-Won Suh
- Department of Pharmacology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (J.-H.F.); (S.-M.S.)
- Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea;
- Correspondence: (S.-S.L.); (H.-W.S.); Tel.: +82-33-248-2133 (S.-S.L.); +82-33-248-2614 (H.-W.S.)
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Demidov MR, Osyanin VA, Osipov DV, Klimochkin YN. Three-Component Condensation of Pyridinium Ylides, β-Ketonitriles, and Aldehydes with Divergent Regioselectivity: Synthesis of 4,5-Dihydrofuran-3- and 2 H-Pyran-5-carbonitriles. J Org Chem 2021; 86:7460-7476. [PMID: 34014677 DOI: 10.1021/acs.joc.1c00423] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
A library of trans-4,5-dihydrofuran-3-carbonitriles was synthesized in a diastereoselective manner in good yields by the three-component reaction of β-ketonitriles, carbonyl- and semistabilized pyridinium ylide precursors, and aldehydes in the presence of piperidine. This one-pot transformation generates two C-C and one C-O bond and proceeds through a cascade Knoevenagel condensation, a Michael addition, and intramolecular SN2 cyclization. Formation of cyclopropanecarbonitrile derivatives, which in some cases were obtained as major products, was found to be a competing reaction. The use of arylglyoxals changes regioselectivity and leads to 2-hydroxy-2H-pyran-5-carbonitriles.
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Affiliation(s)
- Maxim R Demidov
- Samara State Technical University, 443100 Samara, Russian Federation
| | - Vitaly A Osyanin
- Samara State Technical University, 443100 Samara, Russian Federation
| | - Dmitry V Osipov
- Samara State Technical University, 443100 Samara, Russian Federation
| | - Yuri N Klimochkin
- Samara State Technical University, 443100 Samara, Russian Federation
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Li XX, Yuan R, Wang QQ, Han S, Liu Z, Xu Q, Yang S, Gao H. Rotundic acid reduces LPS-induced acute lung injury in vitro and in vivo through regulating TLR4 dimer. Phytother Res 2021; 35:4485-4498. [PMID: 33977594 DOI: 10.1002/ptr.7152] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 03/23/2021] [Accepted: 04/17/2021] [Indexed: 12/17/2022]
Abstract
Acute lung injury (ALI) is a serious clinical disease. Rotundic acid (RA), a natural ingredient isolated from Ilex rotunda Thunb, exhibits multiple pharmacological activities. However, RA's therapeutic effect and mechanism on ALI remain to be elucidated. The present study aimed to further clarify its regulating effects on inflammation in vitro and in vivo. Our results indicated that RA significantly inhibited the overproduction of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). RA decreased ROS production and calcium influx. In addition, RA inhibited the activation of PI3K, MAPK, and NF-κB pathways and enhanced the activity of nuclear factor E2-related factor 2 (Nrf2) signaling. The cellular thermal shift assay and docking results indicated that RA bind to TLR4 to block TLR4 dimerization. Furthermore, RA pretreatment effectively inhibited ear edema induced by xylene and LPS-induced endotoxin death and had a protective effect on LPS-induced ALI. Our findings collectively indicated that RA has anti-inflammatory effects, which may serve as a potential therapeutic option for pulmonary inflammation.
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Affiliation(s)
- Xin-Xing Li
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Renyikun Yuan
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Qin-Qin Wang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Shan Han
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Zhenjie Liu
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Qiongming Xu
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
| | - Shilin Yang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Hongwei Gao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
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Zhang Z, Jiang S, Tian H, Zeng Y, He K, Lin L, Yu F. Ethyl acetate fraction from Nymphaea hybrida Peck modulates inflammatory responses in LPS-stimulated RAW 264.7 cells and acute inflammation murine models. JOURNAL OF ETHNOPHARMACOLOGY 2021; 269:113698. [PMID: 33338590 DOI: 10.1016/j.jep.2020.113698] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 12/11/2020] [Accepted: 12/11/2020] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Nymphaea hybrida Peck is used as a traditional medicinal herb for treating pain and inflammatory diseases, and known for its ornamental value and as a hot drink. However, the effects of N. hybrida polar fractions on lipopolysaccharide (LPS)-induced in vitro inflammation model and acute inflammation murine models have yet to be evaluated. AIM OF THE STUDY The aim of this study was to elucidate the anti-inflammatory effects of N. hybrida ethanol extract (NHE) and its polar fractions: petroleum ether (PE), methylene chloride (MC), ethyl acetate (EA), methanol (ME), and water (WA). The underlying molecular mechanisms of active fraction in LPS-stimulated RAW 264.7 murine macrophages were further investigated. MATERIAL AND METHODS Fractions with potential anti-inflammatory effects were screened using direct nitric oxide (NO) radical scavenging and cyclooxygenase (COX)-2 inhibition assays in vitro. The anti-inflammatory properties of potential fraction were evaluated in LPS-stimulated RAW264.7 cells, xylene-induced ear edema, carrageenan-induced paw edema and xylene-induced Evans blue exudation of acute inflammation murine models. The regulation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways were investigated using western blotting and immunofluorescence. RESULTS Compared to other polar fractions, NHE-EA displayed higher phenol and flavonoid content, and exerted greater activity in direct NO radical scavenging and COX-2 inhibition assay in vitro. NHE-EA markedly decreased the levels of inflammatory mediators, NO and prostaglandin E2 (PGE2), by suppressing the over-expression of inducible nitric oxide synthase (iNOS) and COX-2 in LPS-stimulated RAW264.7 cells. The NHE-EA fraction dose-dependently alleviated over-elevation of LPS-associated intracellular calcium and decreased the abnormal secretion of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and interferon-γ (IFN-γ). The combination with NHE-EA effectively attenuated the activation and nuclear translocation of NF-κB p65, and the phosphorylation of extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), and p38 kinases of MAPK pathways. NHE-EA could significantly ameliorate the degree of swelling of the mice ear and paw, the skin exudation of Evans blue and the excessive secretion of inflammatory cytokines. CONCLUSION Our results demonstrated that NHE-EA was the most active polar fraction of N. hybrida extracts. It inhibited the LPS-associated inflammatory response by blocking the activation of NF-κB and MAPKs pathways in RAW264.7 cells. It also effectively alleviated the inflammatory response of acute inflammation. These results indicated the role of NHE-EA as adjuvants and their potential role in alternative strategy for the treatment of inflammatory diseases.
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Affiliation(s)
- Zhuangwei Zhang
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, 1 South Haida Road, Zhoushan, 316000, People's Republic of China.
| | - Shuoqi Jiang
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, 1 South Haida Road, Zhoushan, 316000, People's Republic of China.
| | - Hengqun Tian
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, 1 South Haida Road, Zhoushan, 316000, People's Republic of China.
| | - Yu Zeng
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, 1 South Haida Road, Zhoushan, 316000, People's Republic of China.
| | - Kang He
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, 1 South Haida Road, Zhoushan, 316000, People's Republic of China.
| | - Lin Lin
- ZhouShan Academy of Agriculture Sciences, Zhoushan, 316022, China
| | - Fangmiao Yu
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, 1 South Haida Road, Zhoushan, 316000, People's Republic of China.
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Cui Y, Gao H, Han S, Yuan R, He J, Zhuo Y, Feng YL, Tang M, Feng J, Yang S. Oleuropein Attenuates Lipopolysaccharide-Induced Acute Kidney Injury In Vitro and In Vivo by Regulating Toll-Like Receptor 4 Dimerization. Front Pharmacol 2021; 12:617314. [PMID: 33841147 PMCID: PMC8024564 DOI: 10.3389/fphar.2021.617314] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 02/15/2021] [Indexed: 12/11/2022] Open
Abstract
Acute kidney injury (AKI) is a common critical illness that involves multiple systems and multiple organs with a rapid decline in kidney function over short period. It has a high mortality rate and presents a great treatment challenge for physicians. Oleuropein, the main active constituent of Ilex pubescens Hook. et Arn. var. kwangsiensis Hand.-Mazz. displays significant anti-inflammatory activity, although oleuropein’s therapeutic effect and mechanism of action in AKI remain to be elucidated. The present study aimed to further clarify the mechanism by which oleuropein exerts effects on inflammation in vitro and in vivo. In vitro, the inflammatory effect and mechanism were investigated through ELISA, Western blotting, the thermal shift assay, co-immunoprecipitation, and immunofluorescence staining. Lipopolysaccharide (LPS) induced acute kidney injury was employed in an animal model to investigate oleuropein’s therapeutic effect on AKI and mechanism in vivo. The underlying mechanisms were investigated by Western blot analysis of kidney tissue. In LPS-stimulated macrophages, our data demonstrated that oleuropein significantly reduced the expression of inflammatory mediators like NO, IL-6, TNF-α, iNOS, and COX-2. Moreover, oleuropein inhibited NF-κB/p65 translocation, and had a negative regulatory effect on key proteins in the NF-κB and MAPK pathways. In addition, the thermal shift and co-immunoprecipitation assays revealed that oleuropein played an essential role in binding to the active sites of TLR4, as well as inhibiting TLR4 dimerization and suppressing the binding of TLR4 to MyD88. Oleuropein markedly alleviated LPS induced acute kidney injury, decreased serum creatinine and blood urea nitrogen (BUN) levels and proinflammatory cytokines. More importantly, the TLR4-MyD88-NF-κB/MAPK pathways were confirmed to play an important role in the oleuropein treatment of AKI. In this study, oleuropein exhibited excellent anti-inflammatory effects by regulating TLR4-MyD88-NF-κB/MAPK axis in vitro and in vivo, suggesting oleuropein as a candidate molecule for treating AKI.
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Affiliation(s)
- Yushun Cui
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Hongwei Gao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Shan Han
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Renyikun Yuan
- College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China.,State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Nanchang, China
| | - Jia He
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Youqiong Zhuo
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Yu-Lin Feng
- College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China.,State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Nanchang, China
| | - Meiwen Tang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
| | - Jianfang Feng
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Shilin Yang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.,College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
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Liu X, Liu W, Ding C, Zhao Y, Chen X, Ling D, Zheng Y, Cheng Z. Taxifolin, Extracted from Waste Larix olgensis Roots, Attenuates CCl 4-Induced Liver Fibrosis by Regulating the PI3K/AKT/mTOR and TGF-β1/Smads Signaling Pathways. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:871-887. [PMID: 33664566 PMCID: PMC7924258 DOI: 10.2147/dddt.s281369] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 12/21/2020] [Indexed: 12/13/2022]
Abstract
Purpose Taxifolin is a kind of dihydroflavone and is usually used as a food additive and health food for its antioxidant, anti-inflammatory, and anti-tumor activities. The purpose of this research is to probe into the hepatoprotective activity and the molecular mechanism of taxifolin. Materials and Methods The liver fibrosis model was established by intraperitoneal injection of 5 mL/kg body weight of CCl4 (20% CCl4 peanut oil solution), and taxifolin was dissolved with 0.9% physiological saline and administered intragastrically to mice. Results The results indicated that CCl4-induced significantly increased the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in mice. Histopathological examination showed severe hepatocyte necrosis and hepatic tissue lesion. Immunohistochemical staining and rt-PCR analysis demonstrated that the expressions of inducible nitric oxide synthetase (iNOS), cyclooxygenase-2 (COX-2), IL-1β, IL-6, and TNF-α were increased. These changes were significantly reversed when treated with taxifolin. In addition, TUNEL staining and Bcl-2/Bax pathway confirmed that taxifolin significantly inhibited hepatocyte apoptosis. Besides, the research confirmed that taxifolin also inhibited the activation of hepatic stellate cells and the production of extracellular matrix (ECM) by regulating PI3K/AKT/mTOR and TGF-β1/Smads pathways. Conclusion Taxifolin inhibited inflammation, and attenuated CCl4-induced oxidative stress and cell apoptosis by regulating PI3K/AKT/mTOR and TGF-β1/Smads pathways, which might in part contributed to taxifolin anti-hepatic fibrosis, further demonstrating that taxifolin may be an efficient hepatoprotective agent.
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Affiliation(s)
- Xinglong Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China
| | - Wencong Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China.,State Local Joint Engineering Research Center of Ginseng Breeding and Application, Changchun 130118, People's Republic of China
| | - Chuanbo Ding
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China
| | - Yingchun Zhao
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China
| | - Xueyan Chen
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China
| | - Dong Ling
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China
| | - Yinan Zheng
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China
| | - Zhiqiang Cheng
- College of Resources and Environment, Jilin Agricultural University, Changchun 130118, People's Republic of China
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Dihydrotanshinone I Is Effective against Drug-Resistant Helicobacter pylori In Vitro and In Vivo. Antimicrob Agents Chemother 2021; 65:AAC.01921-20. [PMID: 33318002 DOI: 10.1128/aac.01921-20] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 12/05/2020] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori is a major global pathogen and has been implicated in gastritis, peptic ulcer, and gastric carcinoma. The efficacy of the extensive therapy of H. pylori infection with antibiotics is compromised by the development of drug resistance and toxicity toward human gut microbiota, which urgently demands novel and selective antibacterial strategies. The present study was mainly performed to assess the in vitro and in vivo effects of a natural herbal compound, dihydrotanshinone I (DHT), against standard and clinical H. pylori strains. DHT demonstrated effective antibacterial activity against H. pylori in vitro (MIC50/90, 0.25/0.5 μg/ml), with no development of resistance during continuous serial passaging. Time-kill curves showed strong time-dependent bactericidal activity for DHT. Also, DHT eliminated preformed biofilms and killed biofilm-encased H. pylori cells more efficiently than the conventional antibiotic metronidazole. In mouse models of multidrug-resistant H. pylori infection, dual therapy with DHT and omeprazole showed in vivo killing efficacy superior to that of the standard triple-therapy approach. Moreover, DHT treatment induces negligible toxicity against normal tissues and exhibits a relatively good safety index. These results suggest that DHT could be suitable for use as an anti-H. pylori agent in combination with a proton pump inhibitor to eradicate multidrug-resistant H. pylori.
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Dolmatova EV, Wang K, Mandavilli R, Griendling KK. The effects of sepsis on endothelium and clinical implications. Cardiovasc Res 2021; 117:60-73. [PMID: 32215570 PMCID: PMC7810126 DOI: 10.1093/cvr/cvaa070] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 02/03/2020] [Accepted: 03/20/2020] [Indexed: 12/15/2022] Open
Abstract
ABSTRACT Sepsis accounts for nearly 700 000 deaths in Europe annually and is caused by an overwhelming host response to infection resulting in organ failure. The endothelium is an active contributor to sepsis and as such represents a major target for therapy. During sepsis, endothelial cells amplify the immune response and activate the coagulation system. They are both a target and source of inflammation and serve as a link between local and systemic immune responses. In response to cytokines produced by immune cells, the endothelium expresses adhesion molecules and produces vasoactive compounds, inflammatory cytokines, and chemoattractants, thus switching from an anticoagulant to procoagulant state. These responses contribute to local control of infection, but systemic activation can lead to microvascular thrombosis, capillary permeability, hypotension, tissue hypoxia, and ultimately tissue damage. This review focuses on the role of the endothelium in leucocyte adhesion and transmigration as well as production of reactive oxygen and nitrogen species, microRNAs and cytokines, formation of signalling microparticles, and disseminated intravascular coagulation. We also discuss alterations in endothelial permeability and apoptosis. Finally, we review the diagnostic potential of endothelial markers and endothelial pathways as therapeutic targets for this devastating disease.
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Affiliation(s)
- Elena V Dolmatova
- Division of Cardiology, Department of Medicine, Emory University, 101 Woodruff Circle, Atlanta, GA 30322, USA
| | - Keke Wang
- Division of Cardiology, Department of Medicine, Emory University, 101 Woodruff Circle, Atlanta, GA 30322, USA
| | - Rohan Mandavilli
- Division of Cardiology, Department of Medicine, Emory University, 101 Woodruff Circle, Atlanta, GA 30322, USA
| | - Kathy K Griendling
- Division of Cardiology, Department of Medicine, Emory University, 101 Woodruff Circle, Atlanta, GA 30322, USA
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Duan P, Huang Y, Chen K, Cheng C, Wu Z, Wu Y. 15,16-dihydrotanshinone I inhibits EOMA cells proliferation by interfering in posttranscriptional processing of hypoxia-inducible factor 1. Int J Med Sci 2021; 18:3214-3223. [PMID: 34400891 PMCID: PMC8364454 DOI: 10.7150/ijms.60774] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/21/2021] [Indexed: 02/06/2023] Open
Abstract
Infantile hemangioma (IH), which threatens the physical and mental health of patients, is the most common benign tumor in infants. Previously, we found that 15,16-dihydrotanshinone I (DHTS) was significantly more effective at inhibiting hemangioma proliferation in vitro and in vivo than the first-line treatment propranolol. To investigate the underlying mechanism of DHTS, we used EOMA cells as a model to study the effect of DHTS. We compared the transcriptomes of control and DHTS-treated EOMA cells. In total, 2462 differentially expressed genes were detected between the groups. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed downregulated activity of the hypoxia-inducible factor 1 alpha (HIF-1α) signaling pathway in EOMA cells following treatment with DHTS. Thus, we investigated HIF-1α expression at protein and mRNA levels. Our results revealed that DHTS downregulated HIF-1α expression by interfering in its posttranscriptional processing, and the RNA-binding protein HuR participated in this mechanism. Our findings provide a basis for clinical transformation of DHTS and insight into pathogenic mechanisms involved in IH.
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Affiliation(s)
- Peiwen Duan
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.,Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, China
| | - Yingying Huang
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.,Department of Reconstructive Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Kai Chen
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.,Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, China
| | - Cheng Cheng
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.,Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, China
| | - Zhixiang Wu
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.,Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, China
| | - Yeming Wu
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.,Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, China
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Wang QQ, Han S, Li XX, Yuan R, Zhuo Y, Chen X, Zhang C, Chen Y, Gao H, Zhao LC, Yang S. Nuezhenide Exerts Anti-Inflammatory Activity through the NF-κB Pathway. Curr Mol Pharmacol 2021; 14:101-111. [PMID: 32525787 PMCID: PMC8778660 DOI: 10.2174/1874467213666200611141337] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 04/04/2020] [Accepted: 04/15/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Nuezhenide (NZD), an iridoid glycoside isolated from Ilex pubescens Hook. & Arn. var. kwangsiensis Hand.-Mazz., used as a traditional Chinese medicine for clearing away heat and toxic materials, displays a variety of biological activities such as anti-tumor, antioxidant, and other life-protecting activities. However, a few studies involving anti-inflammatory activity and the mechanism of NZD have also been reported. In the present study, the anti-inflammatory and antioxidative effects of NZD are illustrated. OBJECTIVE This study aims to test the hypothesis that NZD suppresses LPS-induced inflammation by targeting the NF-κB pathway in RAW264.7 cells. METHODS LPS-stimulated RAW264.7 cells were employed to detect the effect of NZD on the release of cytokines by ELISA. Protein expression levels of related molecular markers were quantitated by western blot analysis. The levels of ROS, NO, and Ca2+ were detected by flow cytometry. The changes in mitochondrial reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were observed and verified by fluorescence microscopy. Using immunofluorescence assay, the translocation of NF-κB/p65 from the cytoplasm into the nucleus was determined by confocal microscopy. RESULTS NZD exhibited anti-inflammatory activity and reduced the release of inflammatory cytokines such as nitrite, TNF-α, and IL-6. NZD suppressed the expression of the phosphorylated proteins like IKKα/β, IκBα, and p65. Besides, the flow cytometry results indicated that NZD inhibited the levels of ROS, NO, and Ca2+ in LPS-stimulated RAW264.7 cells. JC-1 assay data showed that NZD reversed LPS-induced MMP loss. Furthermore, NZD suppressed LPS-induced NF-B/p65 translocation from the cytoplasm into the nucleus. CONCLUSION NZD exhibits anti-inflammatory effects through the NF-κB pathway on RAW264.7 cells.
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Affiliation(s)
- Qin-Qin Wang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200
| | - Shan Han
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200
| | - Xin-Xing Li
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200
| | - Renyikun Yuan
- State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China
| | - Youqiong Zhuo
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200
| | - Xinxin Chen
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200
| | - Chenwei Zhang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200
| | - Yangling Chen
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200
| | - Hongwei Gao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200
| | - Li-Chun Zhao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200
| | - Shilin Yang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530200
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Dihydrotanshinone, a Natural Diterpenoid, Preserves Blood-Retinal Barrier Integrity via P2X7 Receptor. Int J Mol Sci 2020; 21:ijms21239305. [PMID: 33291318 PMCID: PMC7730037 DOI: 10.3390/ijms21239305] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/23/2020] [Accepted: 12/04/2020] [Indexed: 02/07/2023] Open
Abstract
Activation of P2X7 signaling, due to high glucose levels, leads to blood retinal barrier (BRB) breakdown, which is a hallmark of diabetic retinopathy (DR). Furthermore, several studies report that high glucose (HG) conditions and the related activation of the P2X7 receptor (P2X7R) lead to the over-expression of pro-inflammatory markers. In order to identify novel P2X7R antagonists, we carried out virtual screening on a focused compound dataset, including indole derivatives and natural compounds such as caffeic acid phenethyl ester derivatives, flavonoids, and diterpenoids. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring and structural fingerprint clustering of docking poses from virtual screening highlighted that the diterpenoid dihydrotanshinone (DHTS) clustered with the well-known P2X7R antagonist JNJ47965567. A human-based in vitro BRB model made of retinal pericytes, astrocytes, and endothelial cells was used to assess the potential protective effect of DHTS against HG and 2′(3′)-O-(4-Benzoylbenzoyl)adenosine-5′-triphosphate (BzATP), a P2X7R agonist, insult. We found that HG/BzATP exposure generated BRB breakdown by enhancing barrier permeability (trans-endothelial electrical resistance (TEER)) and reducing the levels of ZO-1 and VE-cadherin junction proteins as well as of the Cx-43 mRNA expression levels. Furthermore, HG levels and P2X7R agonist treatment led to increased expression of pro-inflammatory mediators (TLR-4, IL-1β, IL-6, TNF-α, and IL-8) and other molecular markers (P2X7R, VEGF-A, and ICAM-1), along with enhanced production of reactive oxygen species. Treatment with DHTS preserved the BRB integrity from HG/BzATP damage. The protective effects of DHTS were also compared to the validated P2X7R antagonist, JNJ47965567. In conclusion, we provided new findings pointing out the therapeutic potential of DHTS, which is an inhibitor of P2X7R, in terms of preventing and/or counteracting the BRB dysfunctions elicited by HG conditions.
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Anemoside B4 Protects against Acute Lung Injury by Attenuating Inflammation through Blocking NLRP3 Inflammasome Activation and TLR4 Dimerization. J Immunol Res 2020; 2020:7502301. [PMID: 33344657 PMCID: PMC7732379 DOI: 10.1155/2020/7502301] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 12/25/2022] Open
Abstract
Acute lung injury (ALI) is an acute inflammatory process in the lung parenchyma. Anemoside B4 (B4) was isolated from Pulsatilla, a plant-based drug against inflammation and commonly applied in traditional Chinese medicine. However, the anti-inflammatory effect and the mechanisms of B4 are not clear. In this study, we explored the potential mechanisms and anti-inflammatory activity of B4 both in vitro and in vivo. The results indicated that B4 suppressed the expression of iNOS, COX-2, NLRP3, caspase-1, and IL-1β. The ELISA assay results showed that B4 significantly restrained the release of inflammatory cytokines like TNF-α, IL-6, and IL-1β in macrophage cells. In addition, B4 rescued mitochondrial membrane potential (MMP) loss in (lipopolysaccharide) LPS plus ATP stimulated macrophage cells. Co-IP and molecular docking results illustrated that B4 disrupted the dimerization of TLR4. For in vivo results, B4 exhibited a protective effect on LPS and bleomycin- (BLM-) induced ALI in mice through suppressing the lesions of lung tissues, the release of inflammatory cytokines, and the levels of white blood cells, neutrophils, and lymphoid cells in the blood. Collectively, B4 has a protective effect on ALI via blocking TLR4 dimerization and NLRP3 inflammasome activation, suggesting that B4 is a potential agent for the treatment of ALI.
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Yuan R, Liu Z, Zhao J, Wang QQ, Zuo A, Huang L, Gao H, Xu Q, Khan IA, Yang S. Novel compounds in fruits of coriander (Coşkuner & Karababa) with anti-inflammatory activity. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104145] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
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45
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Atraric Acid Exhibits Anti-Inflammatory Effect in Lipopolysaccharide-Stimulated RAW264.7 Cells and Mouse Models. Int J Mol Sci 2020; 21:ijms21197070. [PMID: 32992840 PMCID: PMC7582958 DOI: 10.3390/ijms21197070] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/19/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Lichens, composite organisms resulting from the symbiotic association between the fungi and algae, produce a variety of secondary metabolites that exhibit pharmacological activities. This study aimed to investigate the anti-inflammatory activities of the secondary metabolite atraric acid produced by Heterodermia hypoleuca. The results confirmed that atraric acid could regulate induced pro-inflammatory cytokine, nitric oxide, prostaglandin E2, induced nitric oxide synthase and cyclooxygenase-2 enzyme expression in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Meanwhile, atraric acid downregulated the expression of phosphorylated IκB, extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NFκB) signaling pathway to exhibit anti-inflammatory effects in LPS-stimulated RAW264.7 cells. Based on these results, the anti-inflammatory effect of atraric acid during LPS-induced endotoxin shock in a mouse model was confirmed. In the atraric acid treated-group, cytokine production was decreased in the peritoneum and serum, and each organ damaged by LPS-stimulation was recovered. These results indicate that atraric acid has an anti-inflammatory effect, which may be the underlying molecular mechanism involved in the inactivation of the ERK/NFκB signaling pathway, demonstrating its potential therapeutic value for treating inflammatory diseases.
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Uncovering the Molecular Mechanism of the Qiang-Xin 1 Formula on Sepsis-Induced Cardiac Dysfunction Based on Systems Pharmacology. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:3815185. [PMID: 32908632 PMCID: PMC7474398 DOI: 10.1155/2020/3815185] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/22/2020] [Accepted: 07/27/2020] [Indexed: 12/29/2022]
Abstract
Cardiac dysfunction is a critical manifestation of sepsis-induced multiorgan failure and results in the high mortality of sepsis. Our previous study demonstrated that a traditional Chinese medicine formula, Qiang-Xin 1 (QX1), ameliorates cardiac tissue damage in septic mice; however, the underlying pharmacology mechanism remains to be elucidated. The present study was aimed at clarifying the protective mechanism of the QX1 formula on sepsis-induced cardiac dysfunction. The moderate sepsis model of mice was established by cecal ligation and puncture surgery. Treatment with the QX1 formula improved the 7-day survival outcome, attenuated cardiac dysfunction, and ameliorated the disruption of myocardial structure in septic mice. Subsequent systems pharmacology analysis found that 63 bioactive compounds and the related 79 candidate target proteins were screened from the QX1 formula. The network analysis showed that the QX1 active components quercetin, formononetin, kaempferol, taxifolin, cryptotanshinone, and tanshinone IIA had a good binding activity with screened targets. The integrating pathway analysis indicated the calcium, PI3K/AKT, MAPK, and Toll-like receptor signaling pathways may be involved in the protective effect of the QX1 formula on sepsis-induced cardiac dysfunction. Further, experimental validation showed that the QX1 formula inhibited the activity of calcium/calmodulin-dependent protein kinase II (CaMKII), MAPK (P38, ERK1/2, and JNK), and TLR4/NF-κB signaling pathways but promoted the activation of the PI3K/AKT pathway. A cytokine array found that the QX1 formula attenuated sepsis-induced upregulated levels of serum IFN-γ, IL-1β, IL-3, IL-6, IL-17, IL-4, IL-10, and TNF-α. Our data suggested that QX1 may represent a novel therapeutic strategy for sepsis by suppressing the activity of calcium, MAPK, and TLR4/NF-κB pathways, but promoting the activation of AKT, thus controlling cytokine storm and regulating immune balance. The present study demonstrated the multicomponent, multitarget, and multipathway characteristics of the QX1 formula and provided a novel understanding of the QX1 formula in the clinical application on cardiac dysfunction-related diseases.
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Wang QQ, Gao H, Yuan R, Han S, Li XX, Tang M, Dong B, Li JX, Zhao LC, Feng J, Yang S. Procyanidin A2, a polyphenolic compound, exerts anti-inflammatory and anti-oxidative activity in lipopolysaccharide-stimulated RAW264.7 cells. PLoS One 2020; 15:e0237017. [PMID: 32756588 PMCID: PMC7406031 DOI: 10.1371/journal.pone.0237017] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 07/17/2020] [Indexed: 12/13/2022] Open
Abstract
Procyandin A2 (PCA2) is a polyphenolic compound which is isolated from grape seeds. It has been reported that PCA2 exhibits antioxidative and anti-inflammatory effects, but its molecular mechanism is still poorly understood. This study tests the hypothesis that PCA2 suppresses lipopolysaccharide (LPS)-induced inflammation and oxidative stress through targeting the nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and NF-E2-related factor 2 (Nrf2) pathways in RAW264.7 cells. PCA2 (20, 40, 80 μM) exhibited no significant cytotoxicity in RAW264.7 cells and showed an inhibitory effect on an LPS-induced nitrite level. Pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), prostaglandin E2 (PGE2), nitric oxide (NO), and reactive oxygen species (ROS) were suppressed by PCA2 with a concentration range of 0–80 μM. The mRNA levels of TNF-α and IL-6 were inhibited by PCA2 (80 μM). The hallmark-protein expression of the NF-κB (p-IKKα/β, p-IκBα, and p-p65) and MAPK (p-p38, p-JNK, and p-ERK) pathways were decreased by PCA2 in LPS-stimulated RAW264.7 cells. In addition, immunofluorescence results indicated that PCA2 (80 μM) promoted the translocation of NF-κB/p65 from the cytoplasm into the nucleus. PCA2 upregulated the expressions of Nrf2 and HO-1 and downregulated the expression of Keap-1. Simultaneously, PCA2 (80 μM) reversed LPS-induced Nrf2 translocation from the nucleus into the cytoplasm. Collectively, PCA2 protect cells against the damage from inflammation and oxidative injury, which suggest a potential therapeutic strategy for inflammatory and oxidative stress through targeting NF-κB, MAPK, and Nrf2 pathways in RAW264.7 cells.
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Affiliation(s)
- Qin-Qin Wang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Hongwei Gao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Renyikun Yuan
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
| | - Shan Han
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Xin-Xing Li
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Meiwen Tang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
| | - Baiqing Dong
- College of Public Health and Management, Guangxi University of Chinese Medicine, Nanning, China
| | - Jun-Xiu Li
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
| | - Li-Chun Zhao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
- * E-mail: (LCZ); (JF)
| | - Jianfang Feng
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
- * E-mail: (LCZ); (JF)
| | - Shilin Yang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, China
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Ding H, Lv G, Chen Y, Luo Y, Li J, Guo L, Wu Y. Synthesis of 2,3‐dihydrofurans
via
Lewis acid‐Catalyzed [4+1] Cycloaddition of Enynones with Sulfoxonium Ylides in Ionic Liquids: A Mild and Green Platform. ChemistrySelect 2020. [DOI: 10.1002/slct.202002188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Haosheng Ding
- Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal ChemistryWest China School of Pharmacy, Sichuan University Chengdu 610041 P. R. of China
| | - Guanghui Lv
- Department of Pharmacy, Taihe HospitalHubei University of Medicine No. 32 South Renmin Road Huibei, Shiyan 442000 P. R. China
| | - Yuncan Chen
- Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal ChemistryWest China School of Pharmacy, Sichuan University Chengdu 610041 P. R. of China
| | - Yi Luo
- Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal ChemistryWest China School of Pharmacy, Sichuan University Chengdu 610041 P. R. of China
| | - Jianglian Li
- Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal ChemistryWest China School of Pharmacy, Sichuan University Chengdu 610041 P. R. of China
| | - Li Guo
- Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal ChemistryWest China School of Pharmacy, Sichuan University Chengdu 610041 P. R. of China
| | - Yong Wu
- Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal ChemistryWest China School of Pharmacy, Sichuan University Chengdu 610041 P. R. of China
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He J, Yuan R, Cui X, Cui Y, Han S, Wang QQ, Chen Y, Huang L, Yang S, Xu Q, Zhao Y, Gao H. Anemoside B4 protects against Klebsiella pneumoniae- and influenza virus FM1-induced pneumonia via the TLR4/Myd88 signaling pathway in mice. Chin Med 2020; 15:68. [PMID: 32625244 PMCID: PMC7330533 DOI: 10.1186/s13020-020-00350-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 06/26/2020] [Indexed: 02/07/2023] Open
Abstract
Background Pneumonia refers to the inflammation of the terminal airway, alveoli and pulmonary interstitium, which can be caused by pathogenic microorganisms, physical and chemical factors, immune damage, and drugs. Anemoside B4, the major ingredient of Pulsatilla chinensis (Bunge) Regel, exhibited anti-inflammatory activity. However, the therapeutic effect of anemoside B4 on pneumonia has not been unraveled. This study aims to investigate that anemoside B4 attenuates the inflammatory responses in Klebsiella pneumonia (KP)- and influenza virus FM1 (FM1)-induced pneumonia mice model. Methods The network pharmacology and molecular docking assays were employed to predict the targets of anemoside B4’s treatment of pneumonia. Two models (bacterial KP-infected mice and virus FM1-infected mice) were employed in our study. BALB/c mice were divided into six groups: control, model group (KP-induced pneumonia or FM1-induced pneumonia), anemoside B4 (B4)-treated group (2.5, 5, 10 mg/kg), and positive drug group (ribavirin or ceftriaxone sodium injection). Blood samples were collected for hematology analysis. The effects of B4 on inflammation-associated mediators were investigated by Enzyme-linked immunosorbent assay (ELISA) and hematoxylin and eosin staining (HE) staining. Proteins expression was quantified by western blotting. Results The network results indicated that many pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) participated in anemoside B4’s anti-inflammatory activity. The counts of neutrophil (NEU) and white blood cell (WBC), the level of myeloperoxidase (MPO), and the release of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 increased by KP or FM1 infection, which were reversed by anemoside B4. In addition, anemoside B4 significantly suppressed the FM1-induced expression of toll-like receptor 4 (TLR4), myeloid differential protein-88 (MyD88), and myeloid differentiation protein-2 (MD-2), which were further validated by molecular docking data that anemoside B4 bound to bioactive sites of TLR4. Therefore, anemoside B4 exhibited a significant therapeutic effect on pneumonia via the TLR4/MyD88 pathway. Conclusion Our findings demonstrated that anemoside B4 attenuates pneumonia via the TLR4/Myd88 signaling pathway, suggesting that anemoside B4 is a promising therapeutic candidate for bacterial-infected or viral-infected pneumonia.
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Affiliation(s)
- Jia He
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000 China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530020 China
| | - Renyikun Yuan
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000 China.,Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004 China
| | - Xiaolan Cui
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700 China
| | - Yushun Cui
- Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004 China
| | - Shan Han
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000 China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530020 China
| | - Qin-Qin Wang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000 China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530020 China
| | - Yangling Chen
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000 China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530020 China
| | - Liting Huang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000 China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530020 China
| | - Shilin Yang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000 China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530020 China
| | - Qiongming Xu
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000 China.,College of Pharmaceutical Science, Soochow University, Suzhou, 215123 China
| | - Yonghui Zhao
- Qingdao Central Hospital, The Second Affiliated Hospital of Qingdao University, Qingdao, 266109 China
| | - Hongwei Gao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000 China.,Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning, 530020 China
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50
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Wang X, Wang Q, Li W, Zhang Q, Jiang Y, Guo D, Sun X, Lu W, Li C, Wang Y. TFEB-NF-κB inflammatory signaling axis: a novel therapeutic pathway of Dihydrotanshinone I in doxorubicin-induced cardiotoxicity. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:93. [PMID: 32448281 PMCID: PMC7245789 DOI: 10.1186/s13046-020-01595-x] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 05/11/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Doxorubicin is effective in a variety of solid and hematological malignancies. Unfortunately, clinical application of doxorubicin is limited due to a cumulative dose-dependent cardiotoxicity. Dihydrotanshinone I (DHT) is a natural product from Salvia miltiorrhiza Bunge with multiple anti-tumor activity and anti-inflammation effects. However, its anti-doxorubicin-induced cardiotoxicity (DIC) effect, either in vivo or in vitro, has not been elucidated yet. This study aims to explore the anti-inflammation effects of DHT against DIC, and to elucidate the potential regulatory mechanism. METHODS Effects of DHT on DIC were assessed in zebrafish, C57BL/6 mice and H9C2 cardiomyocytes. Echocardiography, histological examination, flow cytometry, immunochemistry and immunofluorescence were utilized to evaluate cardio-protective effects and anti-inflammation effects. mTOR agonist and lentivirus vector carrying GFP-TFEB were applied to explore the regulatory signaling pathway. RESULTS DHT improved cardiac function via inhibiting the activation of M1 macrophages and the excessive release of pro-inflammatory cytokines both in vivo and in vitro. The activation and nuclear localization of NF-κB were suppressed by DHT, and the effect was abolished by mTOR agonist with concomitant reduced expression of nuclear TFEB. Furthermore, reduced expression of nuclear TFEB is accompanied by up-regulated phosphorylation of IKKα/β and NF-κB, while TFEB overexpression reversed these changes. Intriguingly, DHT could upregulate nuclear expression of TFEB and reduce expressions of p-IKKα/β and p-NF-κB. CONCLUSIONS Our results demonstrated that DHT can be applied as a novel cardioprotective compound in the anti-inflammation management of DIC via mTOR-TFEB-NF-κB signaling pathway. The current study implicates TFEB-IKK-NF-κB signaling axis as a previously undescribed, druggable pathway for DIC.
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Affiliation(s)
- Xiaoping Wang
- grid.24695.3c0000 0001 1431 9176School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Qiyan Wang
- grid.24695.3c0000 0001 1431 9176School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Weili Li
- grid.24695.3c0000 0001 1431 9176School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Qian Zhang
- grid.24695.3c0000 0001 1431 9176School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Yanyan Jiang
- grid.24695.3c0000 0001 1431 9176School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Dongqing Guo
- grid.24695.3c0000 0001 1431 9176School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Xiaoqian Sun
- grid.24695.3c0000 0001 1431 9176School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Wenji Lu
- grid.24695.3c0000 0001 1431 9176School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Chun Li
- grid.24695.3c0000 0001 1431 9176Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Yong Wang
- grid.24695.3c0000 0001 1431 9176School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029 China ,grid.24695.3c0000 0001 1431 9176School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029 China
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