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1
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Zaki RM, Ali MAM, Said M, Chaudhary AA, Boufahja F, Afzal O, Abu-Elsaoud AM, Abdel Halim AS. Molecular mechanisms underlying the effects of statins on bone metabolism: an evolving paradigm of statins delivery modalities for bone regeneration. Pharmacol Rep 2025; 77:624-644. [PMID: 40167878 DOI: 10.1007/s43440-025-00716-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 03/12/2025] [Accepted: 03/13/2025] [Indexed: 04/02/2025]
Abstract
Statins, recognized for their lipid-lowering capabilities, have demonstrated osteoanabolic and anti-resorptive effects on bone metabolism. The effects encompass the overexpression of bone morphogenetic proteins, heightened osteoblast activity, and the control of inflammation. Nevertheless, conventional systemic administration of statins has difficulties, including restricted bone bioavailability and possible adverse effects. Recent improvements in targeted and localized drug delivery are revolutionizing the therapeutic landscape for statins in bone applications. This review consolidates existing knowledge regarding the molecular processes by which statins influence bone metabolism and describes novel drug delivery methods such as nano-carriers, biomaterial scaffolds, and controlled-release systems. It seeks to address current knowledge deficiencies and offer insights into how enhanced bioavailability and specificity can optimize the efficiency of statins in bone regeneration. The review integrates molecular insights with novel pharmacological strategies to inform future research and clinical applications, pinpointing critical areas for exploration, such as optimal dose, delivery safety, and clinical efficacy.
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Affiliation(s)
- Randa Mohammed Zaki
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt
| | - Mohamed A M Ali
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 11623, Saudi Arabia.
| | - Mayada Said
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 11623, Saudi Arabia
| | - Fehmi Boufahja
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 11623, Saudi Arabia
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | - Abdelghafar M Abu-Elsaoud
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 11623, Saudi Arabia
| | - Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, 11566, Egypt
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Ahamad S, Saquib M, Hussain MK, Bhat SA. Targeting Wnt signaling pathway with small-molecule therapeutics for treating osteoporosis. Bioorg Chem 2025; 156:108195. [PMID: 39864370 DOI: 10.1016/j.bioorg.2025.108195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 11/29/2024] [Accepted: 01/17/2025] [Indexed: 01/28/2025]
Abstract
Small molecules are emerging as potential candidates for treating osteoporosis by activating canonical Wnt signaling. These candidates work either by inhibiting DKK-1, sclerostin, SFRP-1, NOTUM, and S1P lyase or by preventing β-catenin degradation through inhibition of GSK-3β, or by targeting Dvl-CXXC5 and axin/β-catenin interactions. While many of these anti-osteoporotic small molecules are in preclinical development, the paucity of FDA-approved small molecules, or promising candidates, that have progressed to clinical trials for treating bone disorders through this mechanism poses a challenge. Despite advancements in computer-aided drug design, it is rarely employed for designing Wnt signaling activators to treat osteoporosis, and high-throughput screen (HTS) remains the primary method for discovering initial hits. Acknowledging the promising therapeutic potential of these compounds in addressing bone diseases, this review underscores the need for further mechanistic elucidation to enhance our understanding of their applications. Additionally, caution must be exercised in the design of small molecule-based Wnt activators due to their association with oncological risks.
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Affiliation(s)
- Shakir Ahamad
- Department of Chemistry, Aligarh Muslim University Aligarh 202002 India.
| | - Mohammad Saquib
- Department of Chemistry, University of Allahabad, Prayagraj (Allahabad) 211002, UP, India; Department of Chemistry, G. R. P. B. Degree College, P. R. S. University, Prayagraj (Allahabad) 211010, UP, India
| | | | - Shahnawaz Ali Bhat
- Department of Zoology, Aligarh Muslim University, Aligarh 202002, India.
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Niu YJ, Xia CJ, Ai X, Xu WM, Lin XT, Zhu YQ, Zhu HY, Zeng X, Cao ZL, Zhou W, Huang H, Shi XL. Sequential activation of ERα-AMPKα signaling by the flavonoid baicalin down-regulates viral HNF-dependent HBV replication. Acta Pharmacol Sin 2025; 46:653-661. [PMID: 39478159 PMCID: PMC11845607 DOI: 10.1038/s41401-024-01408-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 10/08/2024] [Indexed: 02/23/2025]
Abstract
Baicalin (BA), a natural component found in many traditional Chinese medicines, exerts protective effects against several viruses. Although our previous studies have revealed that the anti-hepatitis B virus (anti-HBV) activity of BA depends on hepatocyte nuclear factor (HNF) signaling, the specific mechanisms remain unclear. The present study explored the potential signaling mechanisms involved in BA-mediated HBV suppression. Transcriptomic analysis suggested that BA significantly modulates the estrogen receptor (ER) and AMPK signaling pathways in HepG2 cells. The ER alpha (ERα) binding affinity of BA and its estrogen-like agonist activity were subsequently verified through molecular docking assays, BA-ERα affinity detection experiments, ERα luciferase reporter gene assays, and qRT-PCR. ERα knockdown (shRNA) and AMPK inhibition (Compound C and doxorubicin [Dox]) experiments revealed that the sequential activation of the ERα-LKB1-AMPK-HNF signaling axis is essential for the anti-HBV effects of BA. This study indicates that BA may trigger the ERα-AMPKα-HNF pathway to inhibit HBV replication, providing insights into its potential protective mechanisms against other viruses.
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Affiliation(s)
- Yi-Jun Niu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Cheng-Jie Xia
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Xin Ai
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Wei-Ming Xu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Xiao-Tong Lin
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Ying-Qi Zhu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Hai-Yan Zhu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Xian Zeng
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Zhong-Lian Cao
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Wei Zhou
- Department of Chemistry, Fudan University, Shanghai, 201203, China
| | - Hai Huang
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Xun-Long Shi
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China.
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4
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Wu Y, Liu M, Li J, Gao R, Hu Q, Xie Y, Zhou H, Li H, He X, Li L. Kouqiangjie formula alleviates diabetic periodontitis by regulating alveolar bone homeostasis via miR-29a-3p-mediated Dkk-1/Wnt/β-catenin signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2025; 340:119270. [PMID: 39706357 DOI: 10.1016/j.jep.2024.119270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/18/2024] [Accepted: 12/17/2024] [Indexed: 12/23/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Diabetic periodontitis (DP) is a commonly co-occurring complication in diabetes patients characterized by advanced gum disease and bone resorption. Conventional treatment modalities often fail to adequately address the underlying biological disruptions caused by diabetes. The use of traditional medicinal formulas Kouqiangjie Formula (KQJF) potentially offers novel therapeutic approaches for DP, but its detailed regulatory mechanisms remain unclear. AIM OF THE STUDY This study aims to investigate the impacts of KQJF on osteoblastic activity and inflammatory responses in a rat model and in vitro pre-osteoblast cultures under conditions mimicking DP, focusing on the involvement of the miR-29a-3p-Dkk-1/Wnt/β-catenin signaling pathway. MATERIALS AND METHODS Using network pharmacological analysis, micro-CT, histological staining, and an array of molecular biology methodologies including Western blotting, RT-qPCR, and immunofluorescence, we investigated the systemic and cellular responses to KQJF treatment. Both in vivo (rat model) and in vitro (MC3T3-E1 pre-osteoblasts) models subjected to high glucose and lipopolysaccharide (HG + LPS) stress were used to simulate DP conditions. RESULTS Network pharmacological analyses, incorporating protein-protein interactions and pathway enrichment, disclosed that KQJF interacts with pathways crucial for inflammation and bone metabolism. Experimentally, KQJF significantly preserved alveolar bone architecture, reduced osteoclast activity, and dampened inflammatory cytokine production in DP rats. In pre-osteoblasts, KQJF enhanced cell viability, promoted cell cycle progression, and decreased apoptosis. At the molecular level, KQJF treatment upregulated miR-29a-3p and downregulated Dkk-1, thereby activating the Wnt/β-catenin pathway. The interventional studies with miR-29a-3p antagonists and Dkk-1 knockdown further confirmed the regulatory role of the miR-29a-3p/Dkk-1 axis in mediating the effects of KQJF. CONCLUSION KQJF mitigates the deleterious effects of DP by enhancing osteoblastic activity and reducing inflammatory responses, predominantly through the modulation of the miR-29a-3p-Dkk-1/Wnt/β-catenin signaling pathway. These discoveries underscore the therapeutic promise of KQJF in managing bone and inflammatory complications of DP, offering insights into its mechanism, and supporting its use in clinical settings.
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Affiliation(s)
- Yeke Wu
- Department of Stomatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Min Liu
- Department of Gynaecology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Jiawei Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Ranran Gao
- Department of Gynaecology, Henan Provincial People's Hospital, Zhengzhou, 450000, China.
| | - Qiongying Hu
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Yunfei Xie
- Department of Nuclear Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Hongling Zhou
- Center of Stomatology, West China Xiamen Hospital of Sichuan University, Xiamen, 361021, China.
| | - Huijing Li
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Xiang He
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Li Li
- Department of Radiology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
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Jeong JS, Noh Y, Cho SW, Hsieh CY, Cho Y, Shin JY, Kim H. Association of higher potency statin use with risk of osteoporosis and fractures in patients with stroke in a Korean nationwide cohort study. Sci Rep 2024; 14:30825. [PMID: 39730536 PMCID: PMC11680841 DOI: 10.1038/s41598-024-81628-z] [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: 09/25/2024] [Accepted: 11/27/2024] [Indexed: 12/29/2024] Open
Abstract
This population-based cohort study aimed to evaluate the risk of osteoporosis and fractures associated with higher-potency statin use compared to lower-potency statin use in patients with stroke, using data from the Health Insurance and Review Assessment database of South Korea (2010-2019). Patients who received statin within 30 days after hospitalization for a new-onset stroke (n = 276,911) were divided into higher-potency (n = 212,215, 76.6%) or lower-potency (n = 64,696, 23.4%) statin initiation groups. The primary outcome was a composite of osteoporosis and osteoporotic fractures. Secondary outcomes were individual components of the primary outcome, including osteoporosis, vertebral fracture, hip fracture, and non-hip non-vertebral fracture. Cox proportional hazard models weighted by standardized morbidity ratios were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). The risk of the composite outcome (HR 0.95, 95% CI 0.93-0.97), osteoporosis (0.93, 0.90-0.96), vertebral fracture (0.95, 0.91-0.99), and hip fracture (0.89, 0.84-0.95) were significantly lower in higher-potency statin users, while the risk for non-hip non-vertebral fracture was not significant (0.98, 0.95-1.02). The use of higher-potency statins compared to lower-potency statins was associated with a lower risk of osteoporosis, vertebral fracture, and hip fracture in patients with stroke.
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Affiliation(s)
- Jin Sook Jeong
- School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Gyeonggi-do, South Korea
| | - Yunha Noh
- School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Gyeonggi-do, South Korea
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada
| | - Sun Wook Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Cheng-Yang Hsieh
- Department of Neurology, Tainan Sin Lau Hospital, Tainan, Taiwan
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yongtai Cho
- School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Gyeonggi-do, South Korea
| | - Ju-Young Shin
- School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Gyeonggi-do, South Korea.
- Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, South Korea.
- Department of Clinical Research Design & Evaluation, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, South Korea.
| | - Hoon Kim
- School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Gyeonggi-do, South Korea.
- Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, South Korea.
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, Republic of Korea.
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Niu Q, Zhou C, Li R, Guo J, Qiao S, Chen XX, Zhang G. Proteomic analysis reveals the antiviral effects of baicalin on pseudorabies virus. Int J Biol Macromol 2024; 277:134149. [PMID: 39059539 DOI: 10.1016/j.ijbiomac.2024.134149] [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: 04/15/2024] [Revised: 06/28/2024] [Accepted: 07/23/2024] [Indexed: 07/28/2024]
Abstract
Pseudorabies virus (PRV) poses a significant threat to livestock and even humans. Baicalin, a bioactive flavonoid glycoside with medicinal potential, has been reported to have various biological activities. However, its inhibitory effect on PRV remains poorly understood. In this study, we proved that baicalin effectively inhibits PRV infection. Proteomic analysis revealed that baicalin reduces the expression of 14 viral proteins, which are associated with virus replication, release and immune evasion. Furthermore, the abundance of 116 host proteins was altered by PRV infection, but restored to normal levels after treatment with baicalin. Pathway analysis indicated that baicalin mitigates reactive oxygen species (ROS) and suppresses abnormal mitochondrion by reducing the expression of NFU1 iron‑sulfur cluster scaffold homolog (NFU1) protein induced by PRV. Notably, baicalin also activates the complete coagulation cascade by increasing the expression of coagulation factor III (F3) protein and enhances nucleoplasm by upregulating the expression of solute carrier family 3 member 2 (SLC3A2) and CCAAT enhancer binding protein beta (CEBPB) proteins, contributing to its inhibitory effects on PRV. Our findings implied that baicalin has the potential to be developed as an anti-PRV drug and provide insights into the underlying molecular basis.
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Affiliation(s)
- Qiaoge Niu
- College of Veterinary Medicine, Jilin University, Changchun, China; Institute for Animal Health, Henan Academy of Agricultural Sciences, Key Laboratory of Animal Immunology of the Ministry of Agriculture, Zhengzhou, China
| | - Chuanjie Zhou
- Institute for Animal Health, Henan Academy of Agricultural Sciences, Key Laboratory of Animal Immunology of the Ministry of Agriculture, Zhengzhou, China
| | - Rui Li
- Institute for Animal Health, Henan Academy of Agricultural Sciences, Key Laboratory of Animal Immunology of the Ministry of Agriculture, Zhengzhou, China
| | - Junqing Guo
- Institute for Animal Health, Henan Academy of Agricultural Sciences, Key Laboratory of Animal Immunology of the Ministry of Agriculture, Zhengzhou, China
| | - Songlin Qiao
- Institute for Animal Health, Henan Academy of Agricultural Sciences, Key Laboratory of Animal Immunology of the Ministry of Agriculture, Zhengzhou, China
| | - Xin-Xin Chen
- Institute for Animal Health, Henan Academy of Agricultural Sciences, Key Laboratory of Animal Immunology of the Ministry of Agriculture, Zhengzhou, China.
| | - Gaiping Zhang
- College of Veterinary Medicine, Jilin University, Changchun, China; Institute for Animal Health, Henan Academy of Agricultural Sciences, Key Laboratory of Animal Immunology of the Ministry of Agriculture, Zhengzhou, China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonose, Yangzhou University, Nanjing, China.
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7
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Li M, Wang Y, Xue J, Xu Q, Zhang Y, Liu J, Xu H, Guan Z, Bian C, Zhang G, Yu Y. Baicalin can enhance odonto/osteogenic differentiation of inflammatory dental pulp stem cells by inhibiting the NF-κB and β-catenin/Wnt signaling pathways. Mol Biol Rep 2023; 50:4435-4446. [PMID: 37009956 PMCID: PMC10068215 DOI: 10.1007/s11033-023-08398-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 03/21/2023] [Indexed: 04/04/2023]
Abstract
BACKGROUND Scutellaria baicalensis Georgi is a famous traditional Chinese medicine, which is widely used in treating fever, upper respiratory tract infection and other diseases. Pharmacology study showed it can exhibit anti-bacterial, anti-inflammation and analgesic effects. In this study, we investigated the effect of baicalin on the odonto/osteogenic differentiation of inflammatory dental pulp stem cells (iDPSCs). METHODS AND RESULTS iDPSCs were isolated from the inflamed pulps collected from pulpitis. The proliferation of iDPSCs was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2,5-tetrazolium bromide (MTT) assay and flow cytometry. Alkaline phosphatase (ALP) activity assay, alizarin red staining, Real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assay were conducted to examine the differentiation potency along with the involvement of nuclear factor kappa B(NF-κB) and β-catenin/Wnt signaling pathway. MTT assay and cell-cycle analysis demonstrated that baicalin had no influence on the proliferation of iDPSCs. ALP activity assay and alizarin red staining demonstrated that baicalin could obviously enhance ALP activity and calcified nodules formed in iDPSCs. RT-PCR and Western blot showed that the odonto/osteogenic markers were upregulated in baicalin-treated iDPSCs. Moreover, expression of cytoplastic phosphor-P65, nuclear P65, and β-catenin in iDPSCs was significantly increased compared with DPSCs, but the expression in baicalin-treated iDPSCs was inhibited. In addition, 20 µM Baicalin could accelerate odonto/osteogenic differentiation of iDPSCs via inhibition of NF-κB and β-catenin/Wnt signaling pathways. CONCLUSION Baicalin can promote odonto/osteogenic differentiation of iDPSCs through inhibition of NF-κB and β-catenin/Wnt pathways, thus providing direct evidence that baicalin may be effective in repairing pulp with early irreversible pulpitis.
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Affiliation(s)
- Mengyuan Li
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, 210029 Jiangsu China
- Department of General Dentistry, Affiliated Hospital of Stomatology, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, Jiangsu China
| | - Yumeng Wang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, 210029 Jiangsu China
- Department of General Dentistry, Affiliated Hospital of Stomatology, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, Jiangsu China
| | - Jing Xue
- Department of Critical Care, Changsha of Traditional Chinese Medicine Hospital, Changsha, Hunan China
| | - Qingqing Xu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, 210029 Jiangsu China
- Department of General Dentistry, Affiliated Hospital of Stomatology, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, Jiangsu China
| | - Yuerong Zhang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, 210029 Jiangsu China
- Department of General Dentistry, Affiliated Hospital of Stomatology, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, Jiangsu China
| | - Jie Liu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, 210029 Jiangsu China
- Department of General Dentistry, Affiliated Hospital of Stomatology, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, Jiangsu China
| | - Hai Xu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, 210029 Jiangsu China
- Department of Conservative Dentistry and Endodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, Jiangsu China
| | - Zhuo Guan
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, 210029 Jiangsu China
- Department of General Dentistry, Affiliated Hospital of Stomatology, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, Jiangsu China
| | - Chengyue Bian
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, 210029 Jiangsu China
- Department of General Dentistry, Affiliated Hospital of Stomatology, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, Jiangsu China
| | - Guangdong Zhang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, 210029 Jiangsu China
- Department of General Dentistry, Affiliated Hospital of Stomatology, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, Jiangsu China
| | - Yan Yu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, 210029 Jiangsu China
- Department of Conservative Dentistry and Endodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Shang-Hai Road 1Th, Nanjing, Jiangsu China
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8
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Hu Y, Hu H, Yin L, Wang L, Luo K, Luo N. Arachidonic acid impairs the function of the blood-testis barrier via triggering mitochondrial complex-ROS-P38 MAPK axis in hyperthermal Sertoli cells. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 252:114598. [PMID: 36774800 DOI: 10.1016/j.ecoenv.2023.114598] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 01/23/2023] [Accepted: 01/30/2023] [Indexed: 06/18/2023]
Abstract
The death of Sertoli cells (SCs) under condition of heat stress (HS) affects spermatogenesis and is associated with impaired function of the blood-testis barrier (BTB). The fatty acid arachidonic acid (AA) is essential for the maintenance of cellular function. However, excessive release of AA during HS may adversely affect the reproductive function. The molecular mechanisms through which AA modulates the BTB in SCs are unclear. In this study, we found that 100 µM AA damaged testicular morphology and accelerated SC apoptosis during HS, reducing the stability of tight junction proteins (TJPs), shown by measurement of the levels of Claudin 11, 5, Occludin, and trans-epithelial electrical resistance (TEER). It was also found that AA adversely affected TJPs by increasing the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA), activating p38 mitogen-activated protein kinases (P38 MAPK) and reducing mitochondria DNA (mtDNA) and the expression of mitochondrial complexes I and III. In contrast, pretreatment with SB203508 (a P38 MAPK inhibitor), Rotenone (an inhibitor of complex I) and Antimycin A1 (an inhibitor of complex III) reversed TJPs degradation induced by AA. Interestingly, pretreatment of cells with 10 µM Baicalein, a 12/15 lipoxygenase (12/15-LOX) -dependent inhibitor of AA production, protected against AA-induced TJPs degradation, restored mitochondrial function, and reduced apoptosis. These results suggested an intriguing link between the induction of TJPs degradation induced by AA overload and mitochondrial antioxidant function during HS, which was found to be regulated by the mitochondrial complex-ROS-P38 MAPK axis.
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Affiliation(s)
- Yu Hu
- Department of Reproductive Medicine, Affiliated Hospital of Zunyi Medical University, Department of Obstetrics and Gynecology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Han Hu
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Ling Yin
- Department of Reproductive Medicine, Affiliated Hospital of Zunyi Medical University, Department of Obstetrics and Gynecology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Li Wang
- Department of Reproductive Medicine, Affiliated Hospital of Zunyi Medical University, Department of Obstetrics and Gynecology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - KeYan Luo
- Department of Reproductive Medicine, Affiliated Hospital of Zunyi Medical University, Department of Obstetrics and Gynecology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
| | - NanJian Luo
- Department of Preclinical Medicine, Zunyi Medical University, Zunyi, China.
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Li C, Wang J, Niu Y, Zhang H, Ouyang H, Zhang G, Fu Y. Baicalin Nanocomplexes with an In Situ-Forming Biomimetic Gel Implant for Repair of Calvarial Bone Defects via Localized Sclerostin Inhibition. ACS APPLIED MATERIALS & INTERFACES 2023; 15:9044-9057. [PMID: 36753285 DOI: 10.1021/acsami.2c20946] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
In situ-forming hydrogels are highly effective in covering complex and irregular tissue defects. Herein, a biomimetic gel implant (CS-GEL) consisting of methacrylated chondroitin sulfate and gelatin is obtained via visible light irradiation, which displays rapid gelation (∼30 s), suitable mechanical properties, and biological features to support osteoblast attachment and proliferation. Sclerostin is proven to be a viable target to promote osteogenesis. Hence, baicalin, a natural flavonoid with a high affinity to sclerostin, is selected as the therapeutic compound to achieve localized neutralization of sclerostin. To overcome its poor solubility and permeability, a baicalin nanocomplex (BNP) is synthesized using Solutol HS15, which is then dispersed in the CS-GEL to afford a nanocomposite delivery system, i.e., BNP-loaded gel (BNP@CS-GEL). In vitro, BNP significantly downregulated the level of sclerostin in MLO-Y4 osteocytes. In vivo, either CS-GEL or BNP@CS-GEL is proven to effectively promote osteogenesis and angiogenesis in a calvarial critical-sized bone defect rat model, with BNP@CS-GEL showing the best pro-healing effect. Specifically, the BNP@CS-GEL-treated group significantly downregulated the sclerostin level as compared to the sham group (p < 0.05). RANKL expression was also significantly suppressed by BNP in MLO-Y4 cells and BNP@CS-GEL in vivo. Collectively, our study offers a facile and viable gel platform in combination with nanoparticulated baicalin for the localized neutralization of sclerostin to promote bone regeneration and repair.
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Affiliation(s)
- Chenrui Li
- Key Laboratory for Space Biosciences & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, Shaanxi, China
| | - Junru Wang
- Key Laboratory for Space Biosciences & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, Shaanxi, China
| | - Yining Niu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Haonan Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Hongling Ouyang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Guangwei Zhang
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Department of Public Health & College of Clinical Medicine, Xi'an Medical University, Xi'an 710021, Shaanxi, China
| | - Yao Fu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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10
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Xia YT, Wu QY, Hok-Chi Cheng E, Ting-Xia Dong T, Qin QW, Wang WX, Wah-Keung Tsim K. The inclusion of extract from aerial part of Scutellaria baicalensis in feeding of pearl gentian grouper (Epinephelus fuscoguttatus♀ × Epinephelus lanceo-latus♂) promotes growth and immunity. FISH & SHELLFISH IMMUNOLOGY 2022; 127:521-529. [PMID: 35792347 DOI: 10.1016/j.fsi.2022.06.041] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/22/2022] [Accepted: 06/23/2022] [Indexed: 06/15/2023]
Abstract
The root of Scutellaria baicalensis (Scutellaria Radix) has been used as herbal medicine for years in China; however, its stem and leaf (aerial part) are considered as waste. The water extract of aerial part of S. baicalensis, named as SBA, having anti-microbial property has been applied in fish aquaculture. To extend the usage of SBA in fish feeding, SBA was employed to feed pearl gentian grouper (a hybrid of Epinephelus fuscoguttatus♀ × Epinephelus lanceolatus♂), and subsequently the total fish output, the levels of digestive enzymes and inflammatory cytokines were determined. Feeding the fish with different doses of SBA for two months, the body length and weight were significantly increased by 5%-10%. In parallel, the expressions of alkaline phosphatase and growth-related factors in bone, liver and muscle of SBA-fed fish were doubled, which could account the growth promoting effect of SBA. Besides, the activity of digestive enzyme, lipase, and the expressions of anti-inflammatory cytokines were markedly stimulated by 2-3 times under the feeding of 3% SBA-containing diet. The results indicated the growth promoting activity of SBA in culture of pearl gentian grouper, as well as the effect of SBA in strengthening the immunity. These beneficial effects of SBA feeding can increase the total yield of pearl gentian grouper in aquaculture. Thus, the re-cycle of waste products during the farming of S. baicalensis herb in serving as fish feeding should be encouraged.
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Affiliation(s)
- Yi-Teng Xia
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Nanshan, Shenzhen, China; Division of Life Science and Centre for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong, China; Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China
| | - Qi-Yun Wu
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Nanshan, Shenzhen, China; Division of Life Science and Centre for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong, China
| | - Edwin Hok-Chi Cheng
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Nanshan, Shenzhen, China; Division of Life Science and Centre for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong, China
| | - Tina Ting-Xia Dong
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Nanshan, Shenzhen, China; Division of Life Science and Centre for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong, China; Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China
| | - Qi-Wei Qin
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China
| | - Wen-Xiong Wang
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Nanshan, Shenzhen, China; Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China; School of Energy and Environment, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Karl Wah-Keung Tsim
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Nanshan, Shenzhen, China; Division of Life Science and Centre for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong, China; Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China.
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11
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El-Ela SRA, Zaghloul RA, Eissa LA. Promising Cardioprotective Effect of Baicalin in Doxorubicin-Induced Cardiotoxicity through Targeting TLR4/NF-κB and Wnt/β-Catenin Pathways. Nutrition 2022; 102:111732. [DOI: 10.1016/j.nut.2022.111732] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 03/14/2022] [Accepted: 05/04/2022] [Indexed: 11/25/2022]
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12
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Kunimatsu R, Kimura A, Sakata S, Tsuka Y, Yoshimi Y, Abe T, Kado I, Yashima Y, Izumino J, Nakatani A, Kitagawa M, Miyauchi M, Takata T, Tanimoto K. Effects of baicalin on the proliferation and expression of OPG and RANKL in human cementoblast-lineage cells. J Dent Sci 2022; 17:162-169. [PMID: 35028034 PMCID: PMC8739232 DOI: 10.1016/j.jds.2021.05.009] [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: 04/22/2021] [Revised: 05/10/2021] [Indexed: 12/12/2022] Open
Abstract
Background/purpose Baicalin, a natural bioactive flavonoid extracted from Scutellaria baicalensis Georgi, mediates bone metabolism, and recent studies have revealed that it has cell signaling properties. However, its biological functions in cementoblasts still remain unclear. This study therefore aimed to investigate the effects of baicalin on bone resorption markers, including osteoprotegerin (OPG) and receptor activator of nuclear factor-κβ ligand (RANKL), in human cementoblast-lineage cells, as well as their proliferation ability. Materials and methods Human cementoblast cell line (HCEM) cells were cultured and treated with 0, 0.01, 0.1, or 1 μM of baicalin. The proliferative capacity of cultured HCEM cells was analyzed using bromodeoxyuridine immunoassay and cell counting. The baicalin effect on OPG and RANKL expression was determined using quantitative polymerase chain reaction (qPCR) and western blotting. Furthermore, OPG expression was measured in 1 μM baicalin-treated HCEM cells in the presence or absence of the Wnt signaling pathway inhibitor, Dickkopf (Dkk)-1, using qPCR and western blotting. Results The addition of 0.01, 0.1, and 1 μM of baicalin did not significantly change the proliferative capacity of cultured HCEM cells. Compared with the non-supplemented group, baicalin increased and suppressed OPG and RANKL gene and protein expression, respectively, in a concentration-dependent manner. OPG mRNA and protein expression levels were increased by 1 μM baicalin, which was suppressed by Dkk-1 addition. Conclusion Baicalin enhanced OPG expression in HCEM cells through the Wnt/beta-catenin signaling pathway, which could contribute to periodontal tissue regeneration.
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Affiliation(s)
- Ryo Kunimatsu
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Aya Kimura
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shuzo Sakata
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuji Tsuka
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuki Yoshimi
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takaharu Abe
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Isamu Kado
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuka Yashima
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Jin Izumino
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ayaka Nakatani
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masae Kitagawa
- Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Mutsumi Miyauchi
- Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Takata
- Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Tokuyama University, Tokuyama, Japan
| | - Kotaro Tanimoto
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
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13
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Guo B, Feng X, Wang Y, Wang X, He Y. Biomimetic and immunomodulatory baicalin-loaded graphene oxide-demineralized bone matrix scaffold for in vivo bone regeneration. J Mater Chem B 2021; 9:9720-9733. [PMID: 34787627 DOI: 10.1039/d1tb00618e] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The use of an artificial bone substitute is a potential strategy for repairing bone defects; however, the inadequate consideration of repair-immune system interactions, resulting in significant pathological changes in the microenvironment, is a major barrier to achieving effective regenerative outcomes. Here, we evaluated a biomimetic baicalin (BAI)-incorporating graphene oxide-demineralized bone matrix (GO-BAI/DBM) hybrid scaffold, which was beneficial for bone regeneration. First, by considering that bone is a kind of organic-inorganic composite, a biomimetic GO/DBM bone substitute with enhanced physiochemical and osteoinductive properties was fabricated. Furthermore, inherently therapeutic GO was also used as a drug delivery carrier to achieve the sustained and prolonged release of BAI. Notably, a series of experiments showed that the GO-BAI nanocomposites could transform inflammatory M1 macrophages into pro-healing M2 macrophages, which was beneficial for in vitro angiogenesis and osteogenesis. By using a rat subcutaneous model, it was revealed that the GO-BAI nanocomposites proactively ameliorated the inflammatory response, which was coupled with decreased fibrous encapsulation. Notably, obvious in situ calvarial bone regeneration was achieved using the GO-BAI/DBM hybrid scaffold. These findings demonstrated that the bifunctional GO-BAI/DBM scaffold, by enhancing beneficial cross-talk among bone cells and inflammatory cells, might be utilized as an effective strategy for bone regeneration.
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Affiliation(s)
- Bing Guo
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center of Stomatology, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China.
| | - Xiaodong Feng
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266000, China
| | - Yun Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
| | - Xiansong Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
| | - Yue He
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center of Stomatology, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China.
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14
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Jin S, Gao J, Yang R, Yuan C, Wang R, Zou Q, Zuo Y, Zhu M, Li Y, Man Y, Li J. A baicalin-loaded coaxial nanofiber scaffold regulated inflammation and osteoclast differentiation for vascularized bone regeneration. Bioact Mater 2021; 8:559-572. [PMID: 34541420 PMCID: PMC8436066 DOI: 10.1016/j.bioactmat.2021.06.028] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 06/01/2021] [Accepted: 06/23/2021] [Indexed: 02/05/2023] Open
Abstract
We demonstrate a simple, effective and feasible method to address the shrinkage of Poly (lactic-co-glycolic acid) (PLGA) through a core-shell structure fiber strategy. The results revealed that introducing size-stable poly-caprolactone (PCL) as the core fiber significantly improved the PLGA-based fibrous scaffold's dimensional maintenance. We further utilized fish collagen to modify the PLGA shell layer (PFC) of coaxial fibers and loaded baicalin (BA) into the PCL core layer (PCL-BA) to endow fibrous scaffold with more functional biological cues. The PFC/PCL-BA fibrous scaffold promoted the osteogenic differentiation of bone mesenchymal stem cells and stimulated the RAW264.7 cells to polarize into a pro-reparative phenotype. Importantly, the in vivo study demonstrated that the PFC/PCL-BA scaffold could regulate inflammation and osteoclast differentiation, favor neovascularization and bone formation. This work tactfully combined PLGA and PCL to establish a drug release platform based on the core-shell fibrous scaffold for vascularized bone regeneration.
A multifunctional baicalin-loaded coaxial fiber scaffold prepared by electrospinning. The coaxial nanofiber can effectively resist the shrinkage of PLGA. Baicalin endow the nanofibrous scaffold with excellent biological properties. The scaffold can alleviate the inflammation and achieve vascularized bone regeneration.
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Affiliation(s)
- Shue Jin
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, PR China
| | - Jing Gao
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, PR China
| | - Renli Yang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610065, PR China
| | - Chen Yuan
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, PR China
| | - Ruili Wang
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai, 201620, PR China
| | - Qin Zou
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, PR China
| | - Yi Zuo
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, PR China
| | - Meifang Zhu
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai, 201620, PR China
| | - Yubao Li
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, PR China
| | - Yi Man
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610065, PR China
| | - Jidong Li
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, PR China
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15
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Chen W, Wei W, Yu L, Zhang X, Huang F, Zheng Q, Wang L, Cai C. Baicalin Promotes Mammary Gland Development via Steroid-Like Activities. Front Cell Dev Biol 2021; 9:682469. [PMID: 34295892 PMCID: PMC8290356 DOI: 10.3389/fcell.2021.682469] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/07/2021] [Indexed: 12/03/2022] Open
Abstract
Baicalin, the main flavonoid component extracted from Scutellaria roots, has a variety of biological activities and is therefore used in the treatment of many kinds of diseases. However, whether baicalin affects the normal development of tissues and organs is still unclear. Here, using a mouse mammary gland model, we investigated the effects of baicalin on the expansion of mammary stem cells (MaSCs) and mammary development, as well as breast cancer progression. Interestingly, we found that baicalin administration significantly accelerates duct elongation at puberty, and promotes alveolar development and facilitates milk secretion during pregnancy. Furthermore, self-renewal of MaSCs was significantly promoted in the presence of baicalin. Moreover, in a tumor xenograft model, baicalin promoted tumor growth of the MDA-MB-231 cell line, but suppressed tumor growth of the ZR-751 cell line. Mechanistically, baicalin can induce expression of the protein C receptor, while inhibiting the expression of the estrogen receptor. Transcriptome analysis revealed that baicalin is involved in signaling pathways related to mammary gland development, immune response, and cell cycle control. Taken together, our results from comprehensive investigation of the biological activity of baicalin provide a theoretical basis for its rational clinical application.
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Affiliation(s)
- Weizhen Chen
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Medical Research Institute, Wuhan University, Wuhan, China
| | - Wei Wei
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Medical Research Institute, Wuhan University, Wuhan, China
| | - Liya Yu
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Medical Research Institute, Wuhan University, Wuhan, China
| | - Xin Zhang
- Guangzhou University of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou, China
| | - Fujing Huang
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Medical Research Institute, Wuhan University, Wuhan, China
| | - Qiping Zheng
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Hematological Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, China.,Shenzhen Academy of Peptide Targeting Technology at Pingshan, Shenzhen Tyercan Bio-pharm Co., Ltd., Shenzhen, China
| | - Lingli Wang
- Guangzhou University of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou, China
| | - Cheguo Cai
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Medical Research Institute, Wuhan University, Wuhan, China.,Dongguan and Guangzhou University of Chinese Medicine Cooperative Academy of Mathematical Engineering for Chinese Medicine, Dongguan City, China.,Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
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Chamani S, Liberale L, Mobasheri L, Montecucco F, Al-Rasadi K, Jamialahmadi T, Sahebkar A. The role of statins in the differentiation and function of bone cells. Eur J Clin Invest 2021; 51:e13534. [PMID: 33656763 DOI: 10.1111/eci.13534] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/09/2021] [Accepted: 02/27/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Statins are 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors blocking cholesterol biosynthesis in hepatic cells, thereby causing an increase in low-density lipoprotein (LDL) receptors resulting in enhanced uptake and clearance of atherogenic LDL-cholesterol (LDL-C) from the blood. Accordingly, statins decrease the risk of developing atherosclerosis and its acute complications, such as acute myocardial infarction and ischaemic stroke. Besides the LDL-C-lowering impact, statins also have other so-called pleiotropic effects. Among them, the ability to modulate differentiation and function of bone cells and exert direct effects on osteosynthesis factors. Specifically, earlier studies have shown that statins cause in vitro and in vivo osteogenic differentiation. DESIGN The most relevant papers on the bone-related 'pleiotropic' effects of statins were selected following literature search in databases and were reveiwed. RESULTS Statins increase the expression of many mediators involved in bone metabolism including bone morphogenetic protein-2 (BMP-2), glucocorticoids, transforming growth factor-beta (TGF-β), alkaline phosphatase (ALP), type I collagen and collagenase-1. As a result, they enhance bone formation and improve bone mineral density by modulating osteoblast and osteoclast differentiation. CONCLUSION This review summarizes the literature exploring bone-related 'pleiotropic' effects of statins and suggests an anabolic role in the bone tissue for this drug class. Accordingly, current knowledge encourages further clinical trials to assess the therapeutic potential of statins in the treatment of bone disorders, such as arthritis and osteoporosis.
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Affiliation(s)
- Sajad Chamani
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
- Department of Immunology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Luca Liberale
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Leila Mobasheri
- Department of Pharmacology, Faculty of medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
| | | | - Tannaz Jamialahmadi
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Bioactivity and Delivery Strategies of Phytochemical Compounds in Bone Tissue Regeneration. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11115122] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Plant-derived secondary metabolites represent a reservoir of phytochemicals for regenerative medicine application because of their varied assortment of biological properties including anti-oxidant, anti-inflammatory, antibacterial, and tissue remodeling properties. In addition, bioactive phytochemicals can be easily available, are often more cost-effective in large-scale industrialization, and can be better tolerated compared to conventional treatments mitigating the long-lasting side effects of synthetic compounds. Unfortunately, their poor bioavailability and lack of long-term stability limit their clinical impact. Nanotechnology-based delivery systems can overcome these limitations increasing bioactive molecules’ local effectiveness with reduction of the possible side effects on healthy bone. This review explores new and promising strategies in the area of delivery systems with particular emphasis on solutions that enhance bioavailability and/or health effects of plant-derived phytochemicals such as resveratrol, quercetin, epigallocatechin-3-gallate, and curcumin in bone tissue regeneration.
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18
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Li H, Wu R, Yu H, Zheng Q, Chen Y. Bioactive Herbal Extracts of Traditional Chinese Medicine Applied with the Biomaterials: For the Current Applications and Advances in the Musculoskeletal System. Front Pharmacol 2021; 12:778041. [PMID: 34776987 PMCID: PMC8581265 DOI: 10.3389/fphar.2021.778041] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 10/15/2021] [Indexed: 02/05/2023] Open
Abstract
Traditional Chinese medicine (TCM) has demonstrated superior therapeutic effect for musculoskeletal diseases for thousands of years. Recently, the herbal extracts of TCM have received rapid advances in musculoskeletal tissue engineering (MTE). A literature review collecting both English and Chinese references on bioactive herbal extracts of TCM in biomaterial-based approaches was performed. This review provides an up-to-date overview of application of TCMs in the field of MTE, involving regulation of multiple signaling pathways in osteogenesis, angiogenesis, anti-inflammation, and chondrogenesis. Meanwhile, we highlight the potential advantages of TCM, opening the possibility of its extensive application in MTE. Overall, the superiority of traditional Chinese medicine turns it into an attractive candidate for coupling with advanced additive manufacturing technology.
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Affiliation(s)
- Haotao Li
- Department of Orthopedics, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shantou University Medical College, Shantou, China
| | - Rongjie Wu
- Department of Orthopedics, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shantou University Medical College, Shantou, China
| | - Haiyang Yu
- Department of Orthopedics, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Qiujian Zheng
- Department of Orthopedics, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- *Correspondence: Qiujian Zheng, ; Yuanfeng Chen,
| | - Yuanfeng Chen
- Department of Orthopedics, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Research Department of Medical Science, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- *Correspondence: Qiujian Zheng, ; Yuanfeng Chen,
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Siddiqui S, Mahdi AA, Arshad M. Genistein contributes to cell cycle progression and regulates oxidative stress in primary culture of osteoblasts along with osteoclasts attenuation. BMC Complement Med Ther 2020; 20:277. [PMID: 32917180 PMCID: PMC7488498 DOI: 10.1186/s12906-020-03065-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 08/30/2020] [Indexed: 01/20/2023] Open
Abstract
Background The present study was designed to examine the role of isoflavone genistein (GS) on bone formation, regulating oxidative stress and cell cycle in primary osteoblasts, as well as attenuation of osteoclast formation. Methods Primary calvaria osteoblasts were isolated from 2 to 3 days old neonatal rat pups (n = 6–8) of Sprague Dawley rats. Osteoblasts were incubated with varying concentrations of GS and different assays viz. cell proliferation, differentiation, calcium deposition, cell cycle progression, antioxidant ability, and osteogenic gene expression were performed. Tartrate-resistant acid phosphatase (TRAP) staining and immunolocalization of cathepsin K protein were assessed in bone marrow-derived osteoclasts. Results Results revealed that GS markedly induced cell growth and osteoblast differentiation depending upon dose. The fluorescent dye DCFH-DA staining data proved the antioxidant ability of GS, which reduced the H2O2- induced intracellular oxidative stress in osteoblasts. Quantitative real-time PCR analysis revealed that GS treatment upregulated the expression of osteoblastic genes of Runt-related transcription factor 2 (Runx2), bone morphogenetic proteins 2 (BMP2), and osteocalcin. Immunolocalization of BMP2 also indicated the osteogenic efficacy of GS. Furthermore, TRAP staining and cathepsin K expression depicted that GS inhibited multinucleated osteoclasts formation. Conclusions In conclusion, GS isoflavone might impart protective effects against oxidative stress-induced bone loss and thus, could maintain skeletal growth.
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Affiliation(s)
- Sahabjada Siddiqui
- Department of Biotechnology, Era's Lucknow Medical College & Hospital, Era University, Lucknow, 226003, India. .,Department of Zoology, University of Lucknow, Lucknow, 226007, India.
| | - Abbas Ali Mahdi
- Department of Biochemistry, King George's Medical University, Lucknow, 226003, India
| | - Md Arshad
- Department of Zoology, University of Lucknow, Lucknow, 226007, India. .,Department of Zoology, Aligarh Muslim University, Aligarh, 202002, India.
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20
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Lin P, Guo XX, Wang YL, Wei ZL, Xin HY, Liu TB. Inhibitory effect of baicalin on orthodontically induced inflammatory root resorption in rats. J Int Med Res 2020; 48:300060520955070. [PMID: 32938271 PMCID: PMC7509374 DOI: 10.1177/0300060520955070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Objective This study investigated the inhibitory effect of baicalin on orthodontically
induced inflammatory root resorption in rats. Methods Forty-five male Wistar rats were randomly divided into three groups of 15
rats each. Fifty grams of force was used to establish an orthodontic tooth
movement model. Baicalin (40 mg/kg) was locally injected into rats in the
baicalin group at 3-day intervals; concurrently, normal saline was injected
into rats in the negative control group. On the 21st day after orthodontic
treatment, the tooth movement distance and root resorption area ratio were
measured. Histomorphology changes were observed by hematoxylin and eosin
staining and immunohistochemistry. Results There was no significant difference in tooth movement distance between
groups. The root resorption area ratio was significantly lower in the
baicalin group than in the negative control group. Runx-2 expression was
significantly higher in the baicalin group than in the negative control
group, while tumor necrosis factor (TNF)-α expression was significantly
lower in the baicalin group than in the negative control group. Conclusions Baicalin inhibits orthodontically induced inflammatory root resorption by
enhancing the expression of Runx-2 and reducing the expression of TNF-α, but
does not affect tooth movement distance.
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Affiliation(s)
- Peng Lin
- Department of Orthodontics, Jinan Stomatological Hospital, Jinan, P.R. China
| | - Xin-Xing Guo
- Department of Orthodontics, Jinan Stomatological Hospital, Jinan, P.R. China
| | - Yi-Ling Wang
- Department of Orthodontics, Jinan Stomatological Hospital, Jinan, P.R. China
| | - Zhu-Liang Wei
- Department of Orthodontics, Jinan Stomatological Hospital, Jinan, P.R. China
| | - Hai-Yan Xin
- Department of Orthodontics, Jinan Stomatological Hospital, Jinan, P.R. China
| | - Tong-Bin Liu
- Department of Prosthodontics, Binzhou Medical University Hospital, Binzhou, P.R. China
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21
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Effect of Active Ingredients of Chinese Herbal Medicine on the Rejuvenation of Healthy Aging: Focus on Stem Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:7307026. [PMID: 32724327 PMCID: PMC7366228 DOI: 10.1155/2020/7307026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 06/03/2020] [Accepted: 06/19/2020] [Indexed: 12/31/2022]
Abstract
Stem cells (SCs) are special types of cells with the ability of self-renewal and multidirectional differentiation. As the organism ages, the ability to maintain homeostasis and regeneration deteriorates and the number and activity of stem cells decline. Theoretically, the restoration of stem cells might reverse aging. However, due to their own aging, donor-derived immune rejection, and difficulties in stem cell differentiation control, a series of problems need to be solved to realize the potential for clinical application of stem cells. Chinese herbal medicine is a nature drug library which is suitable for the long-term treatment of aging-related diseases. Modern pharmacological studies have revealed that many active ingredients of Chinese herbal medicines with the effect of promoting stem cells growth and differentiation mainly belong to “reinforcing herbs.” In recent years, exploration of natural active ingredients from Chinese herbal medicines for delaying aging, improving the stem cell microenvironment, and promoting the proliferation and differentiation of endogenous stem cells has attracted substantial attention. This article will focus on active ingredients from Chinese herbs-mediated differentiation of stem cells into particular cell type, like neural cells, endothelial cells, cardiomyocytes, and osteoblasts. We will also discuss the effects of these small molecules on Wnt, Sonic Hedgehog, Notch, eNOS-cGMP, and MAP kinase signal transduction pathways, as well as reveal the role of estrogen receptor α and PPAR γ on selectively promoting or inhibiting stem cells differentiation. This review will provide new insights into the health aging strategies of active ingredients in Chinese herbal medicine in regenerative medicine.
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Chen L, Bao J, Yang Y, Wang Z, Xia M, Tan J, Zhou L, Wu Y, Sun W. Autophagy was involved in tumor necrosis factor-α-inhibited osteogenic differentiation of murine calvarial osteoblasts through Wnt/β-catenin pathway. Tissue Cell 2020; 67:101401. [PMID: 32835949 DOI: 10.1016/j.tice.2020.101401] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 06/25/2020] [Accepted: 06/26/2020] [Indexed: 02/06/2023]
Abstract
Periodontitis is an inflammatory disease with a high incidence characterized by irreversible destruction of alveolar bone. This study aimed to investigate the effect of tumor necrosis factor-α (TNF-α) on osteogenic differentiation and its molecular mechanism. TNF-α inhibited osteogenic differentiation as revealed by the lower accumulation of osteoblastic genes like runt-related transcription factor (Runx2), alkaline phosphatase (ALP), osteoprotegerin (OPG), and osteocalcin (OCN). Moreover, TNF-α down-regulated the expressions of LC3II, ATG7, and beclin 1 (BECN1); suggesting that autophagy was inhibited during the process of osteogenic differentiation. Consistently, Wnt/β-catenin signaling pathway members such as low-density lipoprotein receptor-related protein 5 (LRP5), β-catenin, and phosphorylated-β-catenin (p-β-catenin) were reduced by TNF-α. Furthermore, the inhibitory effect of TNF-α on osteogenic differentiation and the Wnt/β-catenin signaling pathway could be abated by autophagy inducers but exacerbated by autophagy inhibitors. The most intriguing finding of all was that TNF-α inhibited osteoblastic differentiation and the Wnt/β-catenin signaling pathway by down-regulating autophagy, and autophagy positively regulated the Wnt/β-catenin pathway and thus influenced osteoblastic differentiation. Our study provides a theoretical basis for autophagy-inducer therapy for the alveolar bone loss caused by periodontitis.
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Affiliation(s)
- Lili Chen
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Jiaqi Bao
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China; Cancer Institute, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou 310009, China
| | - Yuting Yang
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Zhongxiu Wang
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Mengjiao Xia
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Jingyi Tan
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Lili Zhou
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Yanmin Wu
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Weilian Sun
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China.
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Xu Y, Li D, Zhu Z, Li L, Jin Y, Ma C, Zhang W. miR‑27a‑3p negatively regulates osteogenic differentiation of MC3T3‑E1 preosteoblasts by targeting osterix. Mol Med Rep 2020; 22:1717-1726. [PMID: 32705283 PMCID: PMC7411295 DOI: 10.3892/mmr.2020.11246] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 04/04/2020] [Indexed: 12/28/2022] Open
Abstract
Osteoporosis is a complex multifactorial disorder characterized by microarchitectural deterioration, low bone mass, and increased risk of fractures or broken bones. Balanced bone remodeling is tightly regulated by the differentiation, activity and apoptosis of bone-forming osteoblasts and bone-resorbing osteoclasts. MicroRNAs (miRs) are dysregulated in osteoporosis, but whether they control osteogenic differentiation and skeletal biology, or could serve as therapeutic targets remains to be elucidated. The present study identified miR-27a-3p as a critical suppressor of osteoblastogenesis. Bioinformatics analysis and luciferase reporter assays demonstrated that miR-27a-3p directly targeted and controlled the expression of osterix (Osx), an early response gene essential for bone formation, through its 3′-untranslated region. miR-27a-3p functionally inhibited the differentiation of preosteoblasts by decreasing Osx expression, which synergistically contributed to bone formation. miR-27a-3p level was significantly decreased during osteogenic differentiation and increased in the serum of patients with osteoporosis. Together, miR-27a-3p contributed to diminished osteogenic function during osteogenic differentiation and might thus serve as a therapeutic target and diagnostic biomarker for osteoporosis.
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Affiliation(s)
- Yuexin Xu
- Research Institute of Stomatology, Nanjing Medical University, Stomatological Hospital of Jiangsu Province, Nanjing, Jiangsu 210029, P.R. China
| | - Dong Li
- Department of Orthopedics, Jiangsu Province Hospital of TCM, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Zhu Zhu
- Research Institute of Stomatology, Nanjing Medical University, Stomatological Hospital of Jiangsu Province, Nanjing, Jiangsu 210029, P.R. China
| | - Lingyun Li
- Department of Medical Genetics, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Yucui Jin
- Department of Medical Genetics, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Changyan Ma
- Department of Medical Genetics, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Wei Zhang
- Research Institute of Stomatology, Nanjing Medical University, Stomatological Hospital of Jiangsu Province, Nanjing, Jiangsu 210029, P.R. China
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Manandhar S, Kabekkodu SP, Pai KSR. Aberrant canonical Wnt signaling: Phytochemical based modulation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 76:153243. [PMID: 32535482 DOI: 10.1016/j.phymed.2020.153243] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 04/07/2020] [Accepted: 05/10/2020] [Indexed: 05/26/2023]
Abstract
BACKGROUND Wnt signaling pathway plays a major role during development like gastrulation, axis formation, organ development and organization of body plan development. Wnt signaling aberration has been linked with various disease conditions like osteoporosis, colon cancer, hair follicle tumor, Leukemia, and Alzheimer's disease. Phytochemicals like flavonoid, glycosides, polyphenols, have been reported to directly target the markers of Wnt signaling in different disease models. PURPOSE The study deals in detail about the different phytochemical targeting key players of Wnt signaling pathway in diseases like Cancer, Osteoporosis, and Alzheimer's disease. We have focused on the Pharmacological basis of disease alleviation by phytochemical specifically targeting the Wnt signaling markers in this study. METHODS The study focused on the published articles from the preclinical rodent and invitro cell line studies related to Wnt signaling and Phytochemicals related to Cancer, Alzheimer's and Osteoporosis. The electronic databases Scopus, Web of Science and Pubmed database were used for the systematic search of literatures from 2005 up to 2019 using keywords Canonical Wnt signaling pathway, Cancer, Alzheimer's disease, Osteoporosis, Phytochemicals. The focus was to identify the target specific modulation of Wnt signaling mediated by phytochemicals. RESULTS Approximately 30 phytochemicals of different class have been identified to modulate Wnt signaling pathway acting through Axin, β-catenin translocation, GSK-3β, AKT, Wif-1 in various experimental studies. The down regulation of Wnt signaling is observed in Cancer mostly colorectal cancer, breast cancer mediated through mutations in APC and Axin genes. Different class of Phytochemicals such as flavonoid, glycosides, polyphenol, alkaloids etc. have been found to target Wnt signaling markers and alleviate Cancer. Similarly, Up regulation of Wnt signaling has been reported in Osteoporosis and neurodegenerative disease like Alzheimer's disease. CONCLUSION This review highlights the possibility of the Phytochemicals to target Wnt markers and its potential to either activate or deactivate the Wnt signaling pathway. It also describes the challenges in proper targeting of Wnt signaling and the potential risk and consequences of either up regulation or down regulation of the signaling pathway. This article highlights the possibility of Wnt signaling pathway as a therapeutic option in different diseases.
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Affiliation(s)
- Suman Manandhar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, India
| | - K Sreedhara Ranganath Pai
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India.
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25
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Baicalin Represses C/EBP β via Its Antioxidative Effect in Parkinson's Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:8951907. [PMID: 32566108 PMCID: PMC7261332 DOI: 10.1155/2020/8951907] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/19/2020] [Accepted: 05/02/2020] [Indexed: 12/19/2022]
Abstract
Parkinson's disease (PD) is a neurodegenerative disease characterized by the gradual loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the formation of intracellular Lewy bodies (LB) in the brain, which aggregates α-synuclein (α-Syn) as the main component. The interest of flavonoids as potential neuroprotective agents is increasing due to its high efficiency and low side effects. Baicalin is one of the flavonoid compounds, which is a predominant flavonoid isolated from Scutellaria baicalensis Georgi. However, the key molecular mechanism by which Baicalin can prevent the PD pathogenesis remains unclear. In this study, we used bioinformatic assessment including Gene Ontology (GO) to elucidate the correlation between oxidative stress and PD pathogenesis. RNA-Seq methods were used to examine the global expression profiles of noncoding RNAs and found that C/EBPβ expression was upregulated in PD patients compared with healthy controls. Interestingly, Baicalin could protect DA neurons against reactive oxygen species (ROS) and decreased C/EBPβ and α-synuclein expression in pLVX-Tet3G-α-synuclein SH-SY5Y cells. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mouse model, the results revealed that treatment with Baicalin improved the PD model's behavioral performance and reduced dopaminergic neuron loss in the substantia nigra, associated with the inactivation of proinflammatory cytokines and oxidative stress. Hence, our study supported that Baicalin repressed C/EBPβ via redox homeostasis, which may be an effective potential treatment for PD.
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Kunimatsu R, Kimura A, Tsuka Y, Horie K, Yoshimi Y, Awada T, Gunji H, Abe T, Nakajima K, Sakata S, Nakatani A, Tanimoto K. Baicalin inhibits root resorption during tooth movement in a rodent model. Arch Oral Biol 2020; 116:104770. [PMID: 32470833 DOI: 10.1016/j.archoralbio.2020.104770] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Baicalin mediates bone metabolism and has shown protective activity against periodontal tissue damage in a rat model of periodontitis. Therefore, we hypothesized that baicalin may inhibit the root resorption that occurs during orthodontic tooth movement and examined its effect on the histological changes in periodontal tissue that occur during tooth movement. METHODS First molars of rats were subjected to traction using excessive orthodontic force to produce a root resorption model. Rats in the baicalin group received baicalin for 3 weeks during tooth movement, and the amount of first molar movement on day 21 after the initiation of traction was measured by three-dimensional micro-computed tomography analysis. After tooth movement, tissue samples from the mesial and tension sides were collected, and successive horizontal sections were prepared and examined using hematoxylin-eosin and tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemical staining for the receptor activator of NF-kB ligand (RANKL) and osteoprotegerin (OPG). The severity of root resorption was also determined by histological analysis. RESULTS There was no significant intergroup difference in tooth movement during the experimental exaggerated tooth movement. In comparison with the control group, the baicalin-treated group showed increased OPG expression, suppressed RANKL expression, and significantly fewer TRAP-positive cells in the first molars. The root resorption area was significantly smaller in the baicalin group. CONCLUSIONS Treatment with baicalin prevented root resorption without preventing tooth movement. Baicalin may be useful for the management of root resorption during orthodontic treatment.
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Affiliation(s)
- Ryo Kunimatsu
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan.
| | - Aya Kimura
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan
| | - Yuji Tsuka
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan
| | - Kayo Horie
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan
| | - Yuki Yoshimi
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan
| | - Tetsuya Awada
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan
| | - Hidemi Gunji
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan
| | - Takaharu Abe
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan
| | - Kengo Nakajima
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan
| | - Syuzou Sakata
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan
| | - Ayaka Nakatani
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan
| | - Kotaro Tanimoto
- Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan
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Zhao Y, Wang HL, Li TT, Yang F, Tzeng CM. Baicalin Ameliorates Dexamethasone-Induced Osteoporosis by Regulation of the RANK/RANKL/OPG Signaling Pathway. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:195-206. [PMID: 32021104 PMCID: PMC6970258 DOI: 10.2147/dddt.s225516] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 12/02/2019] [Indexed: 12/12/2022]
Abstract
Background Osteoporosis is a chronic bone metabolism disorder affecting millions of the world population. The RANKL/RANK/OPG signaling pathway has been confirmed to be the main regulator of osteoporosis. It is of great interest to identify appropriate therapeutic agents that can regulate the RANKL/RANK/OPG pathway. Baicalin (BA) is a well-known traditional Chinese medicine formula against various inflammatory diseases with a proven role of the RANKL/RANK/OPG pathway regulation. However, the potential effect of BA on osteoporosis and the mechanisms underlying this remain unclear. In the present study, we aimed to evaluate the efficacy of BA in the prevention of dexamethasone (DEX)-induced osteoporosis in zebrafish. Methods In this study, growth and development changes of zebrafish and calcein staining were assessed with a micrograph. The expression levels of RANKL and OPG and transcription factors in response to DEX induction and BA administration were evaluated by Western blotting and qRT-PCR. In addition, the intermolecular interactions of BA and RANKL were investigated by molecular docking. Results Results show that BA enhances the growth and development of dexamethasone (DEX)-induced osteoporosis in zebrafish larvae. Calcein staining and calcium and phosphorus determination revealed that BA ameliorates mineralization of DEX-induced osteoporosis zebrafish larvae. BA also regulates the expression of RANKL and OPG and hampers the changes in gene expression related to bone formation and resorption under the induction of DEX in zebrafish. It can be inferred by molecular docking that BA may interact directly with the extracellular domain of RANKL. Conclusion The findings, herein, reveal that BA ameliorates DEX-induced osteoporosis by regulation of the RANK/RANKL/OPG signaling pathway.
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Affiliation(s)
- Ye Zhao
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211800, People's Republic of China.,Jiangsu Synergetic Innovation Center for Advanced Bio-Manufacture, Nanjing Tech University, Nanjing 211800, People's Republic of China
| | - Hui-Ling Wang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211800, People's Republic of China
| | - Tong-Tong Li
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211800, People's Republic of China
| | - Fei Yang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211800, People's Republic of China
| | - Chi-Meng Tzeng
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211800, People's Republic of China
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Wang Q, Shi D, Geng Y, Huang Q, Xiang L. Baicalin augments the differentiation of osteoblasts via enhancement of microRNA-217. Mol Cell Biochem 2020; 463:91-100. [PMID: 31606864 DOI: 10.1007/s11010-019-03632-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 09/25/2019] [Indexed: 12/17/2022]
Abstract
Baicalin (BAI), a sort of flavonoid monomer, acquires from Scutellaria baicalensis Georgi, which was forcefully reported in diversified ailments due to the pleiotropic properties. But, the functions of BAI in osteoblast differentiation have not been addressed. The intentions of this study are to attest the influences of BAI in the differentiation of osteoblasts. MC3T3-E1 cells or rat primary osteoblasts were exposed to BAI, and then cell viability, ALP activity, mineralization process, and Runx2 and Ocn expression were appraised through implementing CCK-8, p-nitrophenyl phosphate (pNPP), Alizarin red staining, western blot, and RT-qPCR assays. The microRNA-217 (miR-217) expression was evaluated in MC3T3-E1 cells or rat primary osteoblasts after BAI disposition; meanwhile, the functions of miR-217 in BAI-administrated MC3T3-E1 cells were estimated after miR-217 inhibitor transfection. The impacts of BAI and miR-217 inhibition on Wnt/β-catenin and MEK/ERK pathways were probed to verify the involvements in BAI-regulated the differentiation of osteoblasts. BAI accelerated cell viability, osteoblast activity, and Runx2 and Ocn expression in MC3T3-E1 cells or rat primary osteoblasts, and the phenomena were mediated via activations of Wnt/β-catenin and MEK/ERK pathways. Elevation of miR-217 was observed in BAI-disposed MC3T3-E1 cells or rat primary osteoblasts, and miR-217 repression annulled the functions of BAI in MC3T3-E1 cell viability and differentiation. Additionally, the activations of Wnt/β-catenin and MEK/ERK pathways evoked by BAI were both restrained by repression of miR-217. These explorations uncovered that BAI augmented the differentiation of osteoblasts via activations of Wnt/β-catenin and MEK/ERK pathways by ascending miR-217 expression.
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Affiliation(s)
- Qi Wang
- Department of Orthopaedics, Heze Municipal Hospital, No. 2888 Caozhou Road, Heze, 274031, China
| | - Donglei Shi
- Department of Orthopaedics, Heze Municipal Hospital, No. 2888 Caozhou Road, Heze, 274031, China
| | - Yuanyuan Geng
- Department of Comprehensive Medical, Heze Infectious Disease Hospital, No. 298 Juyang Road, Heze, 274029, China
| | - Qishan Huang
- Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan West Road, Wenzhou, 325000, China
| | - Longzhan Xiang
- Department of Orthopaedics, Heze Municipal Hospital, No. 2888 Caozhou Road, Heze, 274031, China.
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29
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Cheng YH, Dong JC, Bian Q. Small molecules for mesenchymal stem cell fate determination. World J Stem Cells 2019; 11:1084-1103. [PMID: 31875870 PMCID: PMC6904864 DOI: 10.4252/wjsc.v11.i12.1084] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 09/13/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are adult stem cells harboring self-renewal and multilineage differentiation potential that are capable of differentiating into osteoblasts, adipocytes, or chondrocytes in vitro, and regulating the bone marrow microenvironment and adipose tissue remodeling in vivo. The process of fate determination is initiated by signaling molecules that drive MSCs into a specific lineage. Impairment of MSC fate determination leads to different bone and adipose tissue-related diseases, including aging, osteoporosis, and insulin resistance. Much progress has been made in recent years in discovering small molecules and their underlying mechanisms control the cell fate of MSCs both in vitro and in vivo. In this review, we summarize recent findings in applying small molecules to the trilineage commitment of MSCs, for instance, genistein, medicarpin, and icariin for the osteogenic cell fate commitment; isorhamnetin, risedronate, and arctigenin for pro-adipogenesis; and atractylenolides and dihydroartemisinin for chondrogenic fate determination. We highlight the underlying mechanisms, including direct regulation, epigenetic modification, and post-translational modification of signaling molecules in the AMPK, MAPK, Notch, PI3K/AKT, Hedgehog signaling pathways etc. and discuss the small molecules that are currently being studied in clinical trials. The target-based manipulation of lineage-specific commitment by small molecules offers substantial insights into bone marrow microenvironment regulation, adipose tissue homeostasis, and therapeutic strategies for MSC-related diseases.
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Affiliation(s)
- Yu-Hao Cheng
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Jing-Cheng Dong
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Qin Bian
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.
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Kaempferol stimulates WNT/β-catenin signaling pathway to induce differentiation of osteoblasts. J Nutr Biochem 2019; 74:108228. [DOI: 10.1016/j.jnutbio.2019.108228] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 07/31/2019] [Accepted: 08/14/2019] [Indexed: 11/23/2022]
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Li H, Yue B. Effects of various antimicrobial agents on multi-directional differentiation potential of bone marrow-derived mesenchymal stem cells. World J Stem Cells 2019; 11:322-336. [PMID: 31293715 PMCID: PMC6600849 DOI: 10.4252/wjsc.v11.i6.322] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 03/30/2019] [Accepted: 05/23/2019] [Indexed: 02/06/2023] Open
Abstract
Antimicrobial drugs of several classes play an important role in the treatment of bone and joint infections. In addition to fighting pathogenic microorganisms, the effects of drugs on local tissues and cells are also related to the course and prognosis of bone and joint infections. The multi-directional differentiation potential of bone marrow-derived mesenchymal stem cells (MSCs) is essential for tissue repair after local injury, which is directly related to the recovery of bone, cartilage, and medullary adipose tissue. Our previous studies and the literature indicate that certain antimicrobial agents can regulate the differentiation potential of bone marrow-derived MSCs. Here, in order to systematically analyze the effects of various antimicrobial drugs on local tissue regeneration, we comprehensively review the studies on the effects of these drugs on MSC differentiation, and classify them according to the three differentiation directions (osteogenesis, chondrogenesis, and adipogenesis). Our review demonstrates the specific effects of different antimicrobial agents on bone marrow-derived MSCs and the range of concentrations at which they work, and provides a basis for drug selection at different sites of infection.
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Affiliation(s)
- Hui Li
- Department of Bone and Joint Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China
| | - Bing Yue
- Department of Bone and Joint Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China.
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Yooin W, Saenjum C, Ruangsuriya J, Jiranusornkul S. Discovery of potential sclerostin inhibitors from plants with loop2 region of sclerostin inhibition by interacting with residues outside Pro-Asn-Ala-Ile-Gly motif. J Biomol Struct Dyn 2019; 38:1272-1282. [PMID: 30907243 DOI: 10.1080/07391102.2019.1599427] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Sclerostin, an antagonist of the Wnt/β-catenin signaling pathway, was discovered as a potential therapeutic target for stimulating bone formation in osteoporosis. In this study, molecular docking was employed to predict the binding of 29 herbal compounds, which were reported as bone formation stimulators, to the loop2 region of sclerostin. Then, the 50 ns molecular dynamics (MD) simulation of the complexes between sclerostin and the top 10 hits obtained from molecular docking were carried out. Root mean square deviations (RMSDs) analysis of MD trajectories pointed out that all ligands-complexes remain stable throughout the duration of MD simulations. In addition, the molecular mechanics/generalized born surface area (MM/GBSA) binding free energy and energy decomposition analyses were determined. The results here suggested that baicalin is the most promising inhibitor of sclerostin. Interestingly, baicalin binds to sclerostin via the hydrophobic interaction with the amino acid residues on loop2 region but outside the Pro-Asn-Ala-Ile-Gly (PNAIG) motif, particularly the Arg-Gly-Lys-Trp-Trp-Arg (RGKWWR) motif. This finding could be a novel strategy for developing new sclerostin inhibitors in the future.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Wipawadee Yooin
- Laboratory for Molecular Design and Simulation (LMDS), Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand
| | - Chalermpong Saenjum
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand.,Cluster of Excellence on Biodiversity based Economic and Society (B.BES-CMU), Chiang Mai University, Chiang Mai, Thailand
| | - Jetsada Ruangsuriya
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Supat Jiranusornkul
- Laboratory for Molecular Design and Simulation (LMDS), Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand
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Chen WJ, Livneh H, Hsieh MH, Yeh CC, Yeh MH, Lu MC, Chien JT, Tsai TY. Association of use of Chinese herbal medicines and the risk of fracture in patients with osteoporosis: a population-based cohort study. Osteoporos Int 2019; 30:807-815. [PMID: 30721331 DOI: 10.1007/s00198-018-4789-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 11/25/2018] [Indexed: 12/28/2022]
Abstract
UNLABELLED After utilizing a large population-based claims database and the application of propensity score match approach to reduce the confounding effects, we found that the use of Chinese herbal medicines (CHMs) was related to the lower risk of sequent osteoporotic fracture by 27% among the individuals with osteoporosis. The predominant effect was observed in those receiving CHMs for more than two years. INTRODUCTION Osteoporosis (OS) is a highly disabling condition that can lead to fragility fracture, thus posing greater burdens of functional limitations for the affected individuals. It is unclear if the use of Chinese herbal medicines (CHMs) could reduce the risk of fracture due to OS. This study aimed to investigate the association of CHMs and the subsequent osteoporotic fracture risk among OS patients. METHODS This longitudinal cohort study used the Taiwanese National Health Insurance Research Database to identify 250,699 newly diagnosed OS patients aged 20 years or older between 1998 and 2010. We recruited 103,325 CHM users following the onset of OS (CHM users) and randomly selected 103,325 subjects without CHM usage as controls (non-CHM users) by propensity score matching according to the demographic characteristics and comorbidities at enrollment. All enrollees were followed until the end of 2012 to record the incidence of osteoporotic fracture. We applied the Cox proportional hazard regression model to compute the hazard ratio (HR) of the risk of osteoporotic fracture. RESULTS During the 15-year follow-up period, 7208 CHM users and 11,453 non-CHM users sustained osteoporotic fracture, with an incidence rate of 9.26 and 12.96, respectively, per 1000 person-years. We found that CHM users had a significantly reduced risk of osteoporotic fracture compared to non-CHM users (adjusted HR 0.73; 95% confidence interval [CI] = 0.70-0.75). Those treated with CHMs for longer than 730 days had a lower fracture risk by 54%. Some commonly used CHMs, such as Yan hu suo (Rhizoma Corydalis), Huang Qin (Scutellaria Baicale), Jie Geng (Platycodon grandifloras), Xiang Fu (Cyperus rotundus), Hai Piao Xiao (Cuttlebone Sepium), Jia-Wei-Xiao-Yao-San, Ge-Gen-Tang, Shao-Yao-Gan-Cao-Tang, and Du-Huo-Ji-Sheng-Tang, are related to the lower risk of fracture. CONCLUSIONS The use of CHMs was associated with lower risk of osteoporotic fracture for OS patients, suggesting that it could be integrated into conventional therapy to prevent subsequent bone fracture.
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Affiliation(s)
- W-J Chen
- Department of Chinese Medicine, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, 2 Minsheng Road, Dalin Township, Chiayi, 62247, Taiwan
| | - H Livneh
- Rehabilitation Counseling Program, Portland State University, Portland, OR, 97207-0751, USA
| | - M-H Hsieh
- Department of Orthopedics and Center of Osteoporosis, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, 2 Minsheng Road, Dalin Township, Chiayi, 62247, Taiwan
| | - C-C Yeh
- Department of Chinese Medicine, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, 2 Minsheng Road, Dalin Township, Chiayi, 62247, Taiwan
- School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, 701 Zhongyang Road Section 3, Hualien, 97004, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan
| | - M-H Yeh
- Department of Chinese Medicine, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, 2 Minsheng Road, Dalin Township, Chiayi, 62247, Taiwan
- School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, 701 Zhongyang Road Section 3, Hualien, 97004, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan
| | - M-C Lu
- School of Medicine, Tzu Chi University, 701 Zhongyang Road Section 3, Hualien, 97004, Taiwan
- Division of Allergy, Immunology and Rheumatology, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, 2 Minsheng Road, Dalin Township, Chiayi, 62247, Taiwan
| | - J-T Chien
- Department of Orthopedics and Center of Osteoporosis, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, 2 Minsheng Road, Dalin Township, Chiayi, 62247, Taiwan.
- School of Medicine, Tzu Chi University, 701 Zhongyang Road Section 3, Hualien, 97004, Taiwan.
| | - T-Y Tsai
- Department of Medical Research, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, 2 Minsheng Road, Dalin Township, Chiayi, 62247, Taiwan.
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70428, Taiwan.
- Department of Nursing, Tzu Chi University of Science and Technology, 880 Chien-Kuo Road Section 2, Hualien, 97004, Taiwan.
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Chen DZ, Wu T, Zhao Z, Lin XQ, Yang T, Yang J. An Improved Synthesis of Scutellarin-7-O-Glucuronid. JOURNAL OF CHEMICAL RESEARCH 2019. [DOI: 10.3184/174751913x13813183192507] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Duo-Zhi Chen
- Faculty of Life Science and Technology, Kunming University of Science and Technology, (Chenggong Campus), Kunming 650500, P.R. China
| | - Ting Wu
- Faculty of Life Science and Technology, Kunming University of Science and Technology, (Chenggong Campus), Kunming 650500, P.R. China
| | - Zhao Zhao
- Faculty of Life Science and Technology, Kunming University of Science and Technology, (Chenggong Campus), Kunming 650500, P.R. China
| | - Xi-Quan Lin
- Faculty of Life Science and Technology, Kunming University of Science and Technology, (Chenggong Campus), Kunming 650500, P.R. China
| | - Tao Yang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, (Chenggong Campus), Kunming 650500, P.R. China
| | - Jian Yang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, (Chenggong Campus), Kunming 650500, P.R. China
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35
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Wang YC, Chiang JH, Hsu HC, Tsai CH. Decreased fracture incidence with traditional Chinese medicine therapy in patients with osteoporosis: a nationwide population-based cohort study. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 19:42. [PMID: 30717733 PMCID: PMC6360787 DOI: 10.1186/s12906-019-2446-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 01/21/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND There are no published studies regarding the efficacy of traditional Chinese medicine (TCM) for the prevention of osteoporotic fracture. Therefore, we conducted this nationwide, population-based cohort study to investigate the probable effect of TCM to decrease the fracture rate. METHODS We identified cases with osteoporosis and selected a comparison group that was frequency-matched according to sex, age (per 5 years), diagnosis year of osteoporosis, and index year. The difference between the two groups in the development of fracture was estimated using the Kaplan-Meier method and the log-rank test. RESULTS After inserting age, gender, urbanization level, and comorbidities into the Cox's proportional hazard model, patients who used TCM had a lower hazard ratio (HR) of fracture (adjusted HR: 0.47, 95% CI: 0.37-0.59) compared to the non-TCM user group. The Kaplan-Meier curves showed that osteoporosis patients who used TCM had a lower incidence of fracture events than those who did not (p < 0.00001). Our study also demonstrated that the longer the TCM use, the lesser the fracture rate. CONCLUSION Our study showed that TCM might have a positive impact on the prevention of osteoporotic fracture.
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Affiliation(s)
- Yu-Chi Wang
- Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jen-Huai Chiang
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
- Graduate Institute of Integrated Medicine, College of Chinese Medicine, Research Center for Chinese Medicine and Acupuncture, China Medical University, Taichung, Taiwan
| | - Hsin-Cheng Hsu
- Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan
- College of Post-baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Chun-Hao Tsai
- Department of Orthopedics, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
- School of Medicine and Department of Orthopedics, China Medical University, China Medical University Hospital, No.91 Hsueh-Shih Road, Taichung, Taiwan
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36
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Wang H, Cao Y. WIF1 enhanced dentinogenic differentiation in stem cells from apical papilla. BMC Oral Health 2019; 19:25. [PMID: 30691423 PMCID: PMC6350383 DOI: 10.1186/s12903-018-0700-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Accepted: 12/19/2018] [Indexed: 01/26/2023] Open
Abstract
Background Odontogenic mesenchymal stem cells (MSCs) isolated from tooth tissues are a reliable resource that can be utilized for dental tissue regeneration. Exploration of the mechanisms underlying the regulation of their differentiation may be helpful for investigating potential clinical applications. The stem cell niche plays an important role in maintaining cell functioning. Previous studies found that Wnt inhibitory factor 1 (WIF1) is more highly expressed in apical papilla tissues than in stem cells from apical papilla (SCAPs) using microarray analysis. However, the function of WIF1 in SCAPs remains unclear. In the present study, we investigated the function of WIF1 during dentinogenic differentiation in SCAPs. Methods A retrovirus containing HA-WIF1 was used to overexpress WIF1 in SCAPs. Using Western blot analysis, we verified the expression of HA-WIF1. Alkaline phosphatase (ALP) activity assays, Alizarin Red staining and quantitative calcium analysis were performed to investigate the in vitro potential for dentinogenic differentiation in SCAPs. The expression of dentinogenesis-associated genes DSPP, DMP1, Runx2 and OSX were assayed using real-time RT-PCR. Transplantation experiments were used to measure dentinogenesis potential in vivo. Results The real time RT-PCR results showed that WIF1 was more highly expressed in apical papilla tissues than in SCAPs, and its expression was increased during the process of dentinogenic differentiation. Overexpression of WIF1 enhanced ALP activity and mineralization in vitro, as well as the expression of DSPP, DMP1 and OSX in SCAPs. Moreover, in vivo transplantation experiments revealed that dentinogenesis in SCAPs was enhanced by WIF1 overexpression. Conclusion These results suggest that WIF1 may enhance dentinogenic differentiation potential in dental MSCs via its regulation of OSX and identified potential target genes that could be useful for improving dental tissue regeneration.
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Affiliation(s)
- Haifeng Wang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050, China.,Department of Stomatology, Beijing Bo'ai hospital, China Rehabilitation Research Center, School of Rehabilitation Capital Medical University, No.10 Jiao Men Bei Lu, Beijing, 100068, China
| | - Yu Cao
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050, China.
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Genome-Wide DNA Methylation Analysis during Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells. Stem Cells Int 2018; 2018:8238496. [PMID: 30275838 PMCID: PMC6151374 DOI: 10.1155/2018/8238496] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 08/06/2018] [Accepted: 08/13/2018] [Indexed: 12/14/2022] Open
Abstract
Bone marrow mesenchymal stem cells (BMSCs) nowadays are regarded as promising candidates in cell-based therapy for the regeneration of damaged bone tissues that are either incurable or intractable due to the insufficiency of current therapies. Recent studies suggest that BMSCs differentiate into osteoblasts, and that this differentiation is regulated by some specific patterns of epigenetic modifications, such as DNA methylation. However, the potential role of DNA methylation modification in BMSC osteogenic differentiation is unclear. In this study, we performed a genome-wide study of DNA methylation between the noninduced and induced osteogenic differentiation of BMSCs at day 7. We found that the majority of cytosines in a CpG context were methylated in induced BMSCs. Our results also revealed that, along with the induced osteogenic differentiation in BMSCs, the average genomic methylation levels and CpG methylation in transcriptional factor regions (TFs) were increased, the CpG methylation level of various genomic elements was mainly in the medium-high methylation section, and CpG methylation levels in the repeat element had highly methylated levels. The GO analysis of differentially methylated region- (DMR-) associated genes (DMGs) showed that GO terms, including cytoskeletal protein binding (included in Molecular Function GO terms), skeletal development (included in Biological Process GO terms), mesenchymal cell differentiation (included in Biological Process GO terms), and stem cell differentiation (included in Biological Process), were enriched in the hypermethylated DMGs. Then, the KEGG analysis results showed that the WNT pathway, inositol phosphate metabolism pathway, and cocaine addiction pathway were more correlative with the DMRs during the induced osteogenic differentiation in BMSCs. In conclusion, this study revealed the difference of methylated levels during the noninduced and induced osteogenic differentiation of BMSCs and provided useful information for future works to characterize the important function of epigenetic mechanisms on BMSCs' differentiation.
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Arumugam B, Balagangadharan K, Selvamurugan N. Syringic acid, a phenolic acid, promotes osteoblast differentiation by stimulation of Runx2 expression and targeting of Smad7 by miR-21 in mouse mesenchymal stem cells. J Cell Commun Signal 2018; 12:561-573. [PMID: 29350343 PMCID: PMC6039342 DOI: 10.1007/s12079-018-0449-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 01/10/2018] [Indexed: 01/10/2023] Open
Abstract
Syringic acid (SA), a phenolic acid, has been used in Chinese and Indian medicine for treating diabetes but its role in osteogenesis has not yet been investigated. In the present study, at the molecular and cellular levels, we evaluated the effects of SA on osteoblast differentiation. At the cellular level, there was increased alkaline phosphatase (ALP) activity and calcium deposition by SA treatment in mouse mesenchymal stem cells (mMSCs). At the molecular level, SA treatment of these cells stimulated expression of Runx2, a bone transcription factor, and of osteoblast differentiation marker genes such as ALP, type I collagen, and osteocalcin. It is known that Smad7 is an antagonist of TGF-β/Smad signaling and is a negative regulator of Runx2. microRNAs (miRNAs) play a key role in the regulation of osteogenesis genes at the post-transcriptional level and studies have reported that Smad7 is one of the target genes of miR-21. We found that there was down regulation of Smad7 and up regulation of miR-21 in SA-treated mMSCs. We further identified that the 3'-untranslated region (UTR) of Smad7 was directly targeted by miR-21 in these cells. Thus, our results suggested that SA promotes osteoblast differentiation via increased expression of Runx2 by miR-21-mediated down regulation of Smad7. Hence, SA may have potential in orthopedic applications.
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Affiliation(s)
- B Arumugam
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603 203, India
| | - K Balagangadharan
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603 203, India
| | - N Selvamurugan
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603 203, India.
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Shin K, Choi H, Song SK, Yu JW, Lee JY, Choi EJ, Lee DH, Do SH, Kim JW. Nanoemulsion Vehicles as Carriers for Follicular Delivery of Luteolin. ACS Biomater Sci Eng 2018; 4:1723-1729. [PMID: 33445329 DOI: 10.1021/acsbiomaterials.8b00220] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Luteolin (3',4',5,7-tetrahydroxyflavone), a type of flavonoid found in medicinal herbs and vegetables, has been of great interest due to its antioxidative, anti-inflammatory, and anticarcinogenic effects. Despite these beneficial biological properties, the ease with which luteolin forms molecular crystals in conventional aqueous formulations has hampered much wider applications. In this study, we introduce an oil-in-water (O/W) nanoemulsion vehicle system for enhanced follicular delivery of luteolin. The luteolin-loaded nanoemulsion, which had an average hydrodynamic size of approximately 290 nm, was produced by the assembly of poly(ethylene oxide)-block-poly(ε-caprolactone) and lecithin at the O/W interface. The luteolin-loaded nanoemulsion showed outstanding stability against drop coalescence and aggregation. This was confirmed from the slight drop size increase after repeated freeze-thaw cycling and long-term storage. Moreover, in vivo hair growth evaluation demonstrated that the luteolin-loaded nanoemulsions fabricated in this study possessed the hair growth-promotion activity, which is comparable with the case of using a luteolin solution in an organic solvent.
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Affiliation(s)
- Kyounghee Shin
- Department of Bionano Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 15588, Republic of Korea
| | - Hayoung Choi
- Biomaterial Research Center, Cellinbio, 88 Sinwon-ro, Yeongtong-gu, Suwon 16681, Republic of Korea
| | - Sun Kwang Song
- Biomaterial Research Center, Cellinbio, 88 Sinwon-ro, Yeongtong-gu, Suwon 16681, Republic of Korea
| | - Ji Won Yu
- Biomaterial Research Center, Cellinbio, 88 Sinwon-ro, Yeongtong-gu, Suwon 16681, Republic of Korea
| | - Jin Yong Lee
- Department of Bionano Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 15588, Republic of Korea
| | - Eun Ji Choi
- College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Dong Hee Lee
- Biomaterial Research Center, Cellinbio, 88 Sinwon-ro, Yeongtong-gu, Suwon 16681, Republic of Korea
| | - Sun Hee Do
- College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Jin Woong Kim
- Department of Bionano Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 15588, Republic of Korea.,Department of Chemical and Molecular Engineering, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 15588, Republic of Korea
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Li Z, Li AD, Xu L, Bai DW, Hou KZ, Zheng HC, Qu XJ, Liu YP. SPARC expression in gastric cancer predicts poor prognosis: Results from a clinical cohort, pooled analysis and GSEA assay. Oncotarget 2018; 7:70211-70222. [PMID: 28053291 PMCID: PMC5342547 DOI: 10.18632/oncotarget.12191] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 09/02/2016] [Indexed: 12/18/2022] Open
Abstract
Background The prognostic role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in gastric cancer (GC) remains controversial. We investigated the clinical significance, the survival relevance, and potential function of SPARC in GC with resected samples, online gene set GSE62254, and cell line SGC7901. Results High immunostaining of SPARC significantly correlated with tumor differentiation (P = 0.004), and independently predicted shorter overall survival (OS) (HR = 1.446, P = 0.022), based on the current IHC evaluation. The accuracy of the results was further validated with 1000 times bootstrapping and the time-dependent receiver-operating characteristics (ROC) curves. The meta-analysis (pooled HR = 1.60, 95% CI: 1.01−2.53) confirmed SPARC as the predictor for reduced OS in GC. Moreover, the association between enhanced SPARC expression and Adriamycin (Adr) sensitivity was revealed by GSEA, and then confirmed by comparative cellular experiments, such as the protein level analysis of SGC7901and SGC7901/Adr cell line. Materials and Methods Immunohistochemistry (IHC) method was used to detect SPARC expression in 137 GC cases. Meta-analysis was performed based on 5 studies published in English on PubMed up to March 2016. GSEA was performed using online data set GSE62254 and GC-related functional gene sets derived from molecular signatures database (MSigDB). Western Blot was carried out to compare protein-level differences between gastric carcinoma SGC7901 cell line and Adr resistant SGC7901/Adr cell line. MTT assay was done to confirm the induction of SPARC on Adr sensitivity Conclusions Increased SPARC expression in GC led to a worse clinical outcome of patients and might induce Adr sensitivity of GC cells.
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Affiliation(s)
- Zhi Li
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
| | - Ao-Di Li
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
| | - Lu Xu
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
| | - De-Wei Bai
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Department of Cell Biological Treatment Ward, Dalian Centre Hospital, Dalian, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
| | - Ke-Zuo Hou
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
| | - Hua-Chuan Zheng
- Life Science Institute of Jinzhou Medical University, Jinzhou, Liaoning Province, China
| | - Xiu-Juan Qu
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
| | - Yun-Peng Liu
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
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Xing F, Yi WJ, Miao F, Su MY, Lei TC. Baicalin increases hair follicle development by increasing canonical Wnt/β‑catenin signaling and activating dermal papillar cells in mice. Int J Mol Med 2018; 41:2079-2085. [PMID: 29336472 PMCID: PMC5810219 DOI: 10.3892/ijmm.2018.3391] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 01/10/2018] [Indexed: 11/05/2022] Open
Abstract
Baicalin is a traditional Chinese herbal medicine commonly used for hair loss, the precise molecular mechanism of which is unknown. In the present study, the mechanism of baicalin was investigated via the topical application of baicalin to reconstituted hair follicles on mice dorsa and evaluating the effect on canonical Wnt/β‑catenin signaling in the hair follicles and the activity of dermal papillar cells. The results indicate that baicalin stimulates the expression of Wnt3a, Wnt5a, frizzled 7 and disheveled 2 whilst inhibiting the Axin/casein kinase 1α/adenomatous polyposis coli/glycogen synthase kinase 3β degradation complex, leading to accumulation of β‑catenin and activation of Wnt/β‑catenin signaling. In addition, baicalin was observed to increase the alkaline phosphatase levels in dermal papillar cells, a process which was dependent on Wnt pathway activation. Given its non‑toxicity and ease of topical application, baicalin represents a promising treatment for alopecia and other forms of hair loss. Further studies of baicalin using human hair follicle transplants are warranted in preparation for future clinical use.
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Affiliation(s)
- Fei Xing
- Department of Dermatology, Wuhan University, Renmin Hospital, Wuhan, Hubei 430060, P.R. China
| | - Wen-Juan Yi
- Department of Dermatology, Wuhan University, Renmin Hospital, Wuhan, Hubei 430060, P.R. China
| | - Fang Miao
- Department of Dermatology, Wuhan University, Renmin Hospital, Wuhan, Hubei 430060, P.R. China
| | - Meng-Yun Su
- Department of Dermatology, Wuhan University, Renmin Hospital, Wuhan, Hubei 430060, P.R. China
| | - Tie-Chi Lei
- Department of Dermatology, Wuhan University, Renmin Hospital, Wuhan, Hubei 430060, P.R. China
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Wu T, Weng Z, Xu J, Wen G, Yu Y, Chai Y. Baicalin alleviates osteomyelitis by regulating TLR2 in the murine model. Pathog Dis 2017; 76:4739365. [PMID: 29253124 DOI: 10.1093/femspd/ftx123] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Accepted: 12/12/2017] [Indexed: 01/24/2023] Open
Affiliation(s)
- Tianyi Wu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200033, China
| | - Zhenjun Weng
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200033, China
| | - Jia Xu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200033, China
| | - Gen Wen
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200033, China
| | - Yaling Yu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200033, China
| | - Yimin Chai
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200033, China
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Torre E. Molecular signaling mechanisms behind polyphenol-induced bone anabolism. PHYTOCHEMISTRY REVIEWS : PROCEEDINGS OF THE PHYTOCHEMICAL SOCIETY OF EUROPE 2017; 16:1183-1226. [PMID: 29200988 PMCID: PMC5696504 DOI: 10.1007/s11101-017-9529-x] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 08/20/2017] [Indexed: 05/08/2023]
Abstract
For millennia, in the different cultures all over the world, plants have been extensively used as a source of therapeutic agents with wide-ranging medicinal applications, thus becoming part of a rational clinical and pharmacological investigation over the years. As bioactive molecules, plant-derived polyphenols have been demonstrated to exert many effects on human health by acting on different biological systems, thus their therapeutic potential would represent a novel approach on which natural product-based drug discovery and development could be based in the future. Many reports have provided evidence for the benefits derived from the dietary supplementation of polyphenols in the prevention and treatment of osteoporosis. Polyphenols are able to protect the bone, thanks to their antioxidant properties, as well as their anti-inflammatory actions by involving diverse signaling pathways, thus leading to bone anabolic effects and decreased bone resorption. This review is meant to summarize the research works performed so far, by elucidating the molecular mechanisms of action of polyphenols in a bone regeneration context, aiming at a better understanding of a possible application in the development of medical devices for bone tissue regeneration.
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Affiliation(s)
- Elisa Torre
- Nobil Bio Ricerche srl, Via Valcastellana, 26, 14037 Portacomaro, AT Italy
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44
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Jin L, Cao Y, Yu G, Wang J, Lin X, Ge L, Du J, Wang L, Diao S, Lian X, Wang S, Dong R, Shan Z. SFRP2 enhances the osteogenic differentiation of apical papilla stem cells by antagonizing the canonical WNT pathway. Cell Mol Biol Lett 2017; 22:14. [PMID: 28794794 PMCID: PMC5547503 DOI: 10.1186/s11658-017-0044-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 07/17/2017] [Indexed: 01/26/2023] Open
Abstract
Background Exploring the molecular mechanisms underlying directed differentiation is helpful in the development of clinical applications of mesenchymal stem cells (MSCs). Our previous study on dental tissue-derived MSCs demonstrated that secreted frizzled-related protein 2 (SFRP2), a Wnt inhibitor, could enhance osteogenic differentiation in stem cells from the apical papilla (SCAPs). However, how SFRP2 promotes osteogenic differentiation of dental tissue-derived MSCs remains unclear. In this study, we used SCAPs to investigate the underlying mechanisms. Methods SCAPs were isolated from the apical papilla of immature third molars. Western blot and real-time RT-PCR were applied to detect the expression of β-catenin and Wnt target genes. Alizarin Red staining, quantitative calcium analysis, transwell cultures and in vivo transplantation experiments were used to study the osteogenic differentiation potential of SCAPs. Results SFRP2 inhibited canonical Wnt signaling by enhancing phosphorylation and decreasing the expression of nuclear β-catenin in vitro and in vivo. In addition, the target genes of the Wnt signaling pathway, AXIN2 (axin-related protein 2) and MMP7 (matrix metalloproteinase-7), were downregulated by SFRP2. WNT1 inhibited the osteogenic differentiation potential of SCAPs. SFRP2 could rescue this WNT1-impaired osteogenic differentiation potential. Conclusions The results suggest that SFRP2 could bind to locally present Wnt ligands and alter the balance of intracellular Wnt signaling to antagonize the canonical Wnt pathway in SCAPs. This elucidates the molecular mechanism underlying the SFRP2-mediated directed differentiation of SCAPs and indicates potential target genes for improving dental tissue regeneration. Electronic supplementary material The online version of this article (doi:10.1186/s11658-017-0044-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Luyuan Jin
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China.,Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China
| | - Yu Cao
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China.,Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China
| | - Guoxia Yu
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China.,Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China.,Department of Stomatology, Beijing Children's Hospital, Capital Medical University, No.56 Nanlishi Road, Xicheng District, Beijing, 100045 China
| | - Jinsong Wang
- Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China.,Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medical Sciences, No. 10 Xitoutiao Youanmen, Fengtai District, Beijing, 100069 China
| | - Xiao Lin
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China.,Department of Implant Dentistry, Capital Medical University School of Stomatology, Beijing, 100050 China
| | - Lihua Ge
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China
| | - Juan Du
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China
| | - Liping Wang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China
| | - Shu Diao
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China
| | - Xiaomeng Lian
- Department of Stomatology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100045 China
| | - Songlin Wang
- Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China.,Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medical Sciences, No. 10 Xitoutiao Youanmen, Fengtai District, Beijing, 100069 China
| | - Rui Dong
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China
| | - Zhaochen Shan
- Oral and Maxillofacial Surgery Department, Capital Medical University School of Stomatology, No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China
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Wang YJ, Zhang HQ, Han HL, Zou YY, Gao QL, Yang GT. Taxifolin enhances osteogenic differentiation of human bone marrow mesenchymal stem cells partially via NF-κB pathway. Biochem Biophys Res Commun 2017; 490:36-43. [DOI: 10.1016/j.bbrc.2017.06.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 06/01/2017] [Indexed: 12/12/2022]
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Zhang G, Li C, Niu Y, Yu Q, Chen Y, Liu E. Osteoprotective Effect of Radix Scutellariae in Female Hindlimb-Suspended Sprague-Dawley Rats and the Osteogenic Differentiation Effect of Its Major Constituent. Molecules 2017; 22:1044. [PMID: 28671635 PMCID: PMC6152069 DOI: 10.3390/molecules22071044] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 05/23/2017] [Accepted: 06/15/2017] [Indexed: 12/12/2022] Open
Abstract
A number of medicinal herbs have demonstrated therapeutic effects for the prevention and treatment of disuse-induced osteoporosis. As a common ingredient in proprietary traditional Chinese medicines, the anti-osteoporosis effects of Radix Scutellariae extract (RSE, 50 mg/kg/day) were evaluated in a hindlimb suspended rat model. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry, and the micro-architecture observed by MicroCT assay with bone biomechanical properties evaluated by a three-point bending test. To elucidate potential mechanisms, the osteogenic differentiation effect of baicalin as the most abundant ingredient in RSE was investigated in rat bone marrow derived mesenchymal stem cells (rBMSC). After drug administration for 42 days, tibia-BMD was significantly increased to 0.176 ± 0.007 and 0.183 ± 0.011 g/cm² and f-BMD was enhanced to 0.200 ± 0.017 and 0.207 ± 0.021 g/cm² for RSE and ALE treatment, respectively, whereas tibia-BMD and femur-BMD of the HLS group were 0.157 ± 0.009 and 0.176 ± 0.008 g/cm². Deterioration of bone trabecula microstructure was improved by RSE and ALE with increased morphological parameters such as bone volume fraction, trabecular thickness, and trabecular number, as well as connectivity density compared to the HLS group (p < 0.01). A three-point bending test suggested that bone mechanical strength was also enhanced by RSE and ALE treatments with increased maximum stress, young's modulus, maximum load, and stiffness compared to those of the HLS group (p < 0.05). Besides, serum TRACP levels were significantly suppressed by RSE and ALE treatments. Furthermore, in vitro studies demonstrated that baicalin significantly increased ALP activities and the formation of mineralized nodules in rBMSC. Conclusively, supplementation of RSE could significantly prevent weightlessness induced osteoporosis, which might attribute to the osteogenic differentiation enhancement effect of baicalin.
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Affiliation(s)
- Guangwei Zhang
- Research Institute of Atherosclerotic Disease, College of Clinical Medicine, Xi'an Medical University, No.1Xinwang Road, Xi'an 710021, China.
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
| | - Chenrui Li
- Key Laboratory for Space Biosciences & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyixi Road, Xi'an 710072, China.
| | - Yinbo Niu
- Key Laboratory for Space Biosciences & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyixi Road, Xi'an 710072, China.
| | - Qi Yu
- Research Institute of Atherosclerotic Disease, College of Clinical Medicine, Xi'an Medical University, No.1Xinwang Road, Xi'an 710021, China.
| | - Yulong Chen
- Research Institute of Atherosclerotic Disease, College of Clinical Medicine, Xi'an Medical University, No.1Xinwang Road, Xi'an 710021, China.
| | - Enqi Liu
- Research Institute of Atherosclerotic Disease, College of Clinical Medicine, Xi'an Medical University, No.1Xinwang Road, Xi'an 710021, China.
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
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Lu L, Rao L, Jia H, Chen J, Lu X, Yang G, Li Q, Lee KKH, Yang L. Baicalin positively regulates osteoclast function by activating MAPK/Mitf signalling. J Cell Mol Med 2017; 21:1361-1372. [PMID: 28158928 PMCID: PMC5487921 DOI: 10.1111/jcmm.13066] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2016] [Accepted: 11/18/2016] [Indexed: 12/17/2022] Open
Abstract
Activation of osteoblasts in bone formation and osteoclasts in bone resorption is important during the bone fracture healing process. There has been a long interest in identifying and developing a natural therapy for bone fracture healing. In this study, we investigated the regulation of osteoclast differentiation by baicalin, which is a natural molecule extracted from Eucommiaulmoides (small tree native to China). It was determined that baicalin enhanced osteoclast maturation and bone resorption activity in a dose-dependent manner. Moreover, this involves the activation of MAPK, increased Mitf nuclear translocation and up-regulation of downstream osteoclast-related target genes expression. The baicalin-induced effect on osteoclast differentiation can be mimicked by specific inhibitors of p-ERK (U0126) and the Mitf-specific siRNA, respectively. Protein-ligand docking prediction identified that baicalin might bind to RANK, which is the upstream receptor of p-ERK/Mitf signalling in osteoclasts. This indicated that RANK might be the binding target of baicalin. In sum, our findings revealed baicalin increased osteoclast maturation and function via p-ERK/Mitf signalling. In addition, the results suggest that baicalin can potentially be used as a natural product for the treatment of bone fracture.
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Affiliation(s)
- Li Lu
- School of Life Science and BiopharmacyGuangdong Key Laboratory of Pharmaceutical Bioactive SubstancesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Li Rao
- School of Life Science and BiopharmacyGuangdong Key Laboratory of Pharmaceutical Bioactive SubstancesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Huanhuan Jia
- Guangdong Key Laboratory of Laboratory AnimalsGuangdong Laboratory Animals Monitoring InstituteGuangzhouChina
| | - Jun Chen
- School of Life Science and BiopharmacyGuangdong Key Laboratory of Pharmaceutical Bioactive SubstancesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Xingyan Lu
- School of Life Science and BiopharmacyGuangdong Key Laboratory of Pharmaceutical Bioactive SubstancesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Guozhu Yang
- School of Life Science and BiopharmacyGuangdong Key Laboratory of Pharmaceutical Bioactive SubstancesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Qingnan Li
- School of Life Science and BiopharmacyGuangdong Key Laboratory of Pharmaceutical Bioactive SubstancesGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong Key Laboratory of Laboratory AnimalsGuangdong Laboratory Animals Monitoring InstituteGuangzhouChina
| | - Kenneth Ka Ho Lee
- Stem Cell and Regeneration Thematic Research ProgramSchool of Biomedical SciencesThe Chinese University of Hong KongShatinHong Kong SARChina
| | - Li Yang
- Zhujiang Hospital of Southern Medical UniversityGuangzhouChina
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Tang X, Lin J, Wang G, Lu J. MicroRNA-433-3p promotes osteoblast differentiation through targeting DKK1 expression. PLoS One 2017. [PMID: 28628652 PMCID: PMC5476290 DOI: 10.1371/journal.pone.0179860] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Dickkopf-1 (DKK1) is a powerful antagonist of canonical WNT signaling pathway, and is regarded as a biomarker for osteoporosis. Its expression is highly correlated with bone mass and osteoblasts maturation. In this study, mouse primary bone marrow cells and osteoblast cell lines were used. Luciferase reporter assay and western blotting methods were employed to validate if miRNA-433-3p epigenetically regulated DKK1 translation. Rat bone marrow derived osteoblasts were infected with lentivirus vector in which miR-433-3p was constructed. The authors constructed lentivirus mediated miRNA-433-3p stable expression and examined the alkaline phosphatase (ALP) activity and mineral deposition level in vitro. In situ hybridization method was used to observe miR-433-3p in primary osteoblasts. We built up an OVX rat model to mimic postmenopausal osteoporosis, and found aberrant circulating miR-433-3p and miR-106b, which were not reported previously. Results showed that miR-433-3p potentially regulated DKK1 mRNA, Furthermore, the correlation of serum DKK1 with circulating miR-433-3p level was significant (r = 0.7520, p = 0.046). In the luciferase reporter assay, we found that miR-433-3p siRNA decreased luminescence signal, indicating direct regulation of miR-433-3p on DKK1 mRNA. When the miR-433-3p binding site in DKK1 3’UTR was mutant, such reduction was prohibited. Western blotting result validated that miR-433-3p inhibited over 90% of DKK1 protein expression. Similarly, the change of protein expression was not observed in mutant group. The stable expression of lentivirus mediated miR-433-3p increased ALP activity and mineralization both in human and rat derived immortalized cells. We found that primary osteoblasts had higher miR-433-3p level compared with immortal cells through real-time PCR, as well as in situ hybridization experiment. Conclusively, our findings further emphasized the vital role of miR-433-3p in DKK1/WNT/β-catenin pathway through decreasing DKK1 expression and inducing osteoblasts differentiation.
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Affiliation(s)
- Xiaolin Tang
- Department of Medical Science, Shunde Polytechnic, Foshan, China
- * E-mail:
| | - Jiantao Lin
- Traditional Chinese Medicine and New Drug Research Institute, Guangdong Medical University, Dongguan, China
| | - Guanhai Wang
- Traditional Chinese Medicine and New Drug Research Institute, Guangdong Medical University, Dongguan, China
| | - Jianlin Lu
- Department of Medical Science, Shunde Polytechnic, Foshan, China
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Xu ML, Bi CWC, Liu EYL, Dong TTX, Tsim KWK. Wnt3a induces the expression of acetylcholinesterase during osteoblast differentiation via the Runx2 transcription factor. J Biol Chem 2017; 292:12667-12678. [PMID: 28607150 DOI: 10.1074/jbc.m117.777581] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 06/08/2017] [Indexed: 12/14/2022] Open
Abstract
Acetylcholinesterase (AChE) hydrolyzes acetylcholine to terminate cholinergic transmission in neurons. Apart from this AChE activity, emerging evidence suggests that AChE could also function in other, non-neuronal cells. For instance, in bone, AChE exists as a proline-rich membrane anchor (PRiMA)-linked globular form in osteoblasts, in which it is proposed to play a noncholinergic role in differentiation. However, this hypothesis is untested. Here, we found that in cultured rat osteoblasts, AChE expression was increased in parallel with osteoblastic differentiation. Because several lines of evidence indicate that AChE activity in osteoblast could be triggered by Wnt/β-catenin signaling, we added recombinant human Wnt3a to cultured osteoblasts and found that this addition induced expression of the ACHE gene and protein product. This Wnt3a-induced AChE expression was blocked by the Wnt-signaling inhibitor Dickkopf protein-1 (DKK-1). We hypothesized that the Runt-related transcription factor 2 (Runx2), a downstream transcription factor in Wnt/β-catenin signaling, is involved in AChE regulation in osteoblasts, confirmed by the identification of a Runx2-binding site in the ACHE gene promoter, further corroborated by ChIP. Of note, Runx2 overexpression in osteoblasts induced AChE expression and activity of the ACHE promoter tagged with the luciferase gene. Moreover, deletion of the Runx2-binding site in the ACHE promoter reduced its activity during osteoblastic differentiation, and addition of 5-azacytidine and trichostatin A to differentiating osteoblasts affected AChE expression, suggesting epigenetic regulation of the ACHE gene. We conclude that AChE plays a role in osteoblastic differentiation and is regulated by both Wnt3a and Runx2.
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Affiliation(s)
- Miranda L Xu
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong, China; HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518000, Guangdong Province, China
| | - Cathy W C Bi
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong, China; HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518000, Guangdong Province, China
| | - Etta Y L Liu
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong, China; HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518000, Guangdong Province, China
| | - Tina T X Dong
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong, China; HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518000, Guangdong Province, China
| | - Karl W K Tsim
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong, China; HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518000, Guangdong Province, China.
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50
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Baicalein enhances the osteogenic differentiation of human periodontal ligament cells by activating the Wnt/β-catenin signaling pathway. Arch Oral Biol 2017; 78:100-108. [DOI: 10.1016/j.archoralbio.2017.01.019] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 01/02/2017] [Accepted: 01/26/2017] [Indexed: 12/25/2022]
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