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Zhao L, Xiang S, Tang C, Liu W, Gao J, Li X, Cao Y. Sclerostin Transduced Bone Marrow Mesenchymal Stem Cells Promote Fracture Healing in Rats Through the Wnt/β-Catenin Signal Pathway. Stem Cells Dev 2024; 33:438-447. [PMID: 38814826 DOI: 10.1089/scd.2024.0061] [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] [Indexed: 06/01/2024] Open
Abstract
The prognosis of fracture is directly related to several factors. Due to the limitations of existing treatment strategies, there are still many fractures with poor healing. Bone marrow mesenchymal stem cells (BMSCs) have the potential to differentiate into osteoblasts and chondrocytes. Therefore, BMSC transplantation is promised as an effective method for treating bone fractures. We aim to explore whether silently expressing sclerostin gene (SOST) can promote bone formation through the SOST/Wnt/β-catenin signal pathway. We isolated rat BMSCs and the target gene (SOST shRNA) was transduced into them for osteogenic induction. The results showed that SOST significantly inhibited the proliferation and osteogenic differentiation of BMSCs during osteogenic induction, whereas silently expressing SOST not only increased the number of surviving BMSCs but also promoted the expression of osteogenesis-related proteins RUNX2, osteoprotegerin, Collagen I (COL-I), and bone morphogenetic protein-2 during osteogenic induction. The results of imaging examination in rats show that downregulating the expression of SOST can promote the formation of bony callus and the transformation of cartilage tissue into normal bone tissue, and then accelerate the healing of osteoporotic fracture. In addition, we also found that SOST silencing can activate the Wnt/β-catenin pathway to achieve these effects. In conclusion, SOST silencing can promote the proliferation and osteogenic differentiation of BMSCs in situ, and therefore may enhance the therapeutic efficiency of BMSC transplantation in OPF.
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Affiliation(s)
- Lili Zhao
- Department of Orthopedics, Guangdong Province, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Shouyu Xiang
- Department of Orthopedics, Guangdong Province, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Cheng Tang
- Department of Orthopedics, Guangdong Province, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Wei Liu
- Department of Orthopedics, Guangdong Province, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Jianliang Gao
- Department of Orthopedics, Guangdong Province, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Xing Li
- Department of Orthopedic Surgery, State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Yanming Cao
- Department of Orthopedics, Guangdong Province, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
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Wang H, Shan K, Li Y, Wu S, Zhou C, Tao S, Wang M, Kang X, Zhou L, Lyu Z, Li N. Therapeutic potential of Chinese medicinal herbs stimulating osteogenic differentiation of bone marrow-derived mesenchymal stem cells in osteoporosis. Front Pharmacol 2024; 15:1423555. [PMID: 39144620 PMCID: PMC11322149 DOI: 10.3389/fphar.2024.1423555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 07/16/2024] [Indexed: 08/16/2024] Open
Abstract
Osteoporosis (OP) is a common and complex chronic metabolic disease with an increasing incidence rate, which has markedly increased the human health burden worldwide. The predominant cause of OP is an imbalance between osteoblasts (OB) and osteoclasts (OC). Studies on the correlation between bone marrow-derived mesenchymal stem cells (BMSCs) and OP have indicated that BMSCs-induced OB differentiation is an important pathway for bone tissue renewal. Chinese medicinal herbs have been used for centuries to treat various types of OPs because they are safer and more effective. The in vivo and in vitro experiments have confirmed that these herbs or their primary phytochemicals may exert therapeutic effects by stimulating BMSCs differentiation, which restores OB and OP balance, inhibits adipocyte differentiation, exerts anti-inflammatory and antioxidant effects, regulates the immune system, etc. This review summarizes the research on how Chinese medicinal herbs or their primary phytochemicals treat OP by stimulating BMSC differentiation and provides a scientifically reliable basis and perspective for their future clinical application.
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Affiliation(s)
- Hui Wang
- Xi’an Hospital of Traditional Chinese Medicine, Xi’an, Shanxi, China
- Department of Traditional Chinese Medicine, The First Clinical Medical College of Shaanxi University of Chinese Medicine, Xianyang, Shanxi, China
| | - Kai Shan
- Qingdao Hospital of Traditional Chinese Medicine (Qingdao Hiser Hospital), Qingdao, Shandong, China
| | - Yan Li
- Xi’an Hospital of Traditional Chinese Medicine, Xi’an, Shanxi, China
- Department of Traditional Chinese Medicine, The First Clinical Medical College of Shaanxi University of Chinese Medicine, Xianyang, Shanxi, China
| | - Sinuo Wu
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Chunman Zhou
- Xi’an Hospital of Traditional Chinese Medicine, Xi’an, Shanxi, China
- Department of Traditional Chinese Medicine, The First Clinical Medical College of Shaanxi University of Chinese Medicine, Xianyang, Shanxi, China
| | - Shan Tao
- Xi’an Hospital of Traditional Chinese Medicine, Xi’an, Shanxi, China
- Department of Traditional Chinese Medicine, The First Clinical Medical College of Shaanxi University of Chinese Medicine, Xianyang, Shanxi, China
| | - Meijuan Wang
- Qingdao Hospital of Traditional Chinese Medicine (Qingdao Hiser Hospital), Qingdao, Shandong, China
| | - Xiaochun Kang
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Liang Zhou
- Acupuncture and Moxibustion Department, Nanchang Hongdu Hospital of Traditional Chinese Medicine, Nanchang, Jiangxi, China
| | - Zhongxi Lyu
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ningcen Li
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Mohammadzadeh M, Zarei M, Abbasi H, Webster TJ, Beheshtizadeh N. Promoting osteogenesis and bone regeneration employing icariin-loaded nanoplatforms. J Biol Eng 2024; 18:29. [PMID: 38649969 PMCID: PMC11036660 DOI: 10.1186/s13036-024-00425-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 04/15/2024] [Indexed: 04/25/2024] Open
Abstract
There is an increasing demand for innovative strategies that effectively promote osteogenesis and enhance bone regeneration. The critical process of bone regeneration involves the transformation of mesenchymal stromal cells into osteoblasts and the subsequent mineralization of the extracellular matrix, making up the complex mechanism of osteogenesis. Icariin's diverse pharmacological properties, such as anti-inflammatory, anti-oxidant, and osteogenic effects, have attracted considerable attention in biomedical research. Icariin, known for its ability to stimulate bone formation, has been found to encourage the transformation of mesenchymal stromal cells into osteoblasts and improve the subsequent process of mineralization. Several studies have demonstrated the osteogenic effects of icariin, which can be attributed to its hormone-like function. It has been found to induce the expression of BMP-2 and BMP-4 mRNAs in osteoblasts and significantly upregulate Osx at low doses. Additionally, icariin promotes bone formation by stimulating the expression of pre-osteoblastic genes like Osx, RUNX2, and collagen type I. However, icariin needs to be effectively delivered to bone to perform such promising functions.Encapsulating icariin within nanoplatforms holds significant promise for promoting osteogenesis and bone regeneration through a range of intricate biological effects. When encapsulated in nanofibers or nanoparticles, icariin exerts its effects directly at the cellular level. Recalling that inflammation is a critical factor influencing bone regeneration, icariin's anti-inflammatory effects can be harnessed and amplified when encapsulated in nanoplatforms. Also, while cell adhesion and cell migration are pivotal stages of tissue regeneration, icariin-loaded nanoplatforms contribute to these processes by providing a supportive matrix for cellular attachment and movement. This review comprehensively discusses icariin-loaded nanoplatforms used for bone regeneration and osteogenesis, further presenting where the field needs to go before icariin can be used clinically.
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Affiliation(s)
- Mahsa Mohammadzadeh
- Department of Materials Engineering, Isfahan University of Technology, Isfahan, 84156-83111, Iran
- Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Masoud Zarei
- Department of Materials Science and Engineering, Sharif University of Technology, Tehran, Iran
- Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hossein Abbasi
- Department of Mechanical Engineering, University of Michigan-Dearborn, Dearborn, MI, 48128, USA
| | - Thomas J Webster
- School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin, China
- School of Engineering, Saveetha University, Chennai, India
- Program in Materials Science, UFPI, Teresina, Brazil
| | - Nima Beheshtizadeh
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
- Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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Lei SS, Huang XW, Li LZ, Wang XP, Zhang Y, Li B, Shou D. Explorating the mechanism of Epimedii folium-Rhizoma drynariae herbal pair promoted bone defects healing through network pharmacology and experimental studies. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117329. [PMID: 37879510 DOI: 10.1016/j.jep.2023.117329] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 10/05/2023] [Accepted: 10/16/2023] [Indexed: 10/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Bone defects are difficult to treat and have a high incidence of nonunion. The Epimedii folium-Rhizoma drynariae herbal pair (EDP) is a traditional Chinese medicine (TCM) used for treating bone diseases. However, the mechanisms by which EDP promotes osteogenesis or bone formation remain largely unclear. AIM OF THE STUDY This study aimed to investigate the mechanism of EDP promoted bone formation in bone defects using network pharmacology and experiments. MATERIALS AND METHODS The chemical components of EDP were analyzed by UHPLC-MS. The hub target and pathway enrichment analysis was conducted using molecular docking or network pharmacology. The pharmacological actions of EDP were determined by μCT and histopathology examination using a bone defect rat model. The effects of EDP on the mRNA expression of Bmp2, Smad2/5, Runx2, and Alp genes were measured by RT-PCR, while changes in the protein expressions of BMP2, COL1A1, SPP1, ALP, and RUNX2in the tibia tissues of the rats in response to EDP were analyzed by immunohistochemical staining or Western blot. We also performed cell viability assays, Alizarin Red and ALP staining assays, and RT-PCR to better understand how EDP affected osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). RESULTS Identified 14 key compounds and 47 hub targets of EDP that may be involved in promoting osteogenesis to repair bone defects. And the BMP/Smad/Runx2 pathway was likely the key pathway through which EDP promoted bone defects repairing. The results of in vivo rat experiments indicated that EDP effectively promoted tibia repair in the model rats and activated the BMP/Smad/Runx2 pathway in the tibia tissue, with upregulating Bmp2, Bmpr1α, Smad2/5, Runx2, and Alp genes, and increased the protein expression of BMP2, COL1A1, RUNX2, and ALP. In vitro, EDP was found to increase the proliferation, differentiation, and mineralization in BMSCs- and also up-regulated the expression of key genes in the BMP/Smad/Runx2 pathway. CONCLUSION This study highlighted the ability of EDP to promote the osteogenic differentiation to enable bone repair by activating the BMP/Smad/Runx2 pathway.
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Affiliation(s)
- Shan Shan Lei
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310007, China
| | - Xiao Wen Huang
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310007, China
| | - Lin Zi Li
- Jingmen Central Hospital, 448000, Jingmen, China
| | - Xu Ping Wang
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310007, China
| | - Yang Zhang
- Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310053, China
| | - Bo Li
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang 310007, China.
| | - Dan Shou
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310007, China; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 311402, China.
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Tian S, Li YL, Wang J, Dong RC, Wei J, Ma Y, Liu YQ. Chinese Ecliptae herba (Eclipta prostrata (L.) L.) extract and its component wedelolactone enhances osteoblastogenesis of bone marrow mesenchymal stem cells via targeting METTL3-mediated m6A RNA methylation. JOURNAL OF ETHNOPHARMACOLOGY 2023; 312:116433. [PMID: 37004744 DOI: 10.1016/j.jep.2023.116433] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/05/2023] [Accepted: 03/19/2023] [Indexed: 05/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chinese Ecliptae herba (Eclipta prostrata (L.) L.) is an ethnomedicinal herb, which is used mainly to nourish kidney and thus strengthen bones according to traditional Chinese medicine theory. Pharmacological studies have supported the ethnomedicine use, showing that Ecliptae herba extract has an anti-osteoporotic effect in vivo and promoted osteoblast proliferation and activity in vitro. However, the molecular mechanism of Ecliptae herba on osteoblast differentiation from bone marrow mesenchymal stem cells (BMSC), the progenitors of osteoblasts, is still unclear. AIM OF THE STUDY N6-methyladenosine (m6A) mRNA epigenetic modification may play a key role in promoting osteoblastic differentiation, and thus treating osteoporosis. This study sought to assess the mechanism through which Eclipate herba and its component wedelolactone influence m6A modification during the process of osteoblastogenesis from BMSC. MATERIAL AND METHODS The alkaline phosphatase (ALP) and Alizarin red S (ARS) staining were applied to determine osteoblastogenesis from BMSC. Western blot and quantitative real-time PCR were performed. RNA sequencing analysis was used to determine the characteristics of m6A methylation. Stable knocking down of METTL3 using lentiviral-based shRNA was performed. RESULTS Upon 9 d treatment of BMSC with ethyl acetate extract of Ecliptae herba (MHL), ALP activity and ossification level increased in comparison with osteogenic medium (OS)-treated control. The expression of methyltransferase METTL3 and METTL14 was significantly increased, but WTAP expression had no change in response to MHL treatment. Knocking down of METTL3 resulted in a decrease in MHL-induced ALP activity, ossification level as well as mRNA expression of Osterix and Osteocalcin, two bone formation-related markers. The level of m6A increased when BMSC was treated with MHL for 9 d. RNA sequencing analysis indicated that MHL treatment altered mRNA m6A modification of genes associated with osteoblastogenesis. By kyoto encyclopedia of genes and genomes (KEGG) pathway analysis, HIF-1α, PI3K/Akt, and Hippo signaling pathways were enriched and associated with m6A modification. The expression of m6A-modified genes including HIF-1α, VEGF-A, and RASSF1, was upregulated by MHL, but the upregulation was reversed after METTL3 knockdown. Additionally, the enhanced expression of METTL3 was also observed after treatment with wedelolactone, a component from MHL. CONCLUSIONS These results suggested a previously uncharacterized mechanism of MHL and wedelolactone on osteoblastogenesis, by which METTL3-mediated m6A methylation is involved and thus contributes to the enhancement of osteoblastogenesis.
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Affiliation(s)
- Shuo Tian
- Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Yi-Lin Li
- Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Jie Wang
- Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Ren-Chao Dong
- Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Jun Wei
- Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Yu Ma
- Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Yan-Qiu Liu
- Shandong University of Traditional Chinese Medicine, Jinan, China.
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Xu X, Zhao L, Terry PD, Chen J. Reciprocal Effect of Environmental Stimuli to Regulate the Adipogenesis and Osteogenesis Fate Decision in Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs). Cells 2023; 12:1400. [PMID: 37408234 PMCID: PMC10216952 DOI: 10.3390/cells12101400] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 05/02/2023] [Accepted: 05/12/2023] [Indexed: 07/07/2023] Open
Abstract
Mesenchymal stem cells derived from bone marrow (BM-MSCs) can differentiate into adipocytes and osteoblasts. Various external stimuli, including environmental contaminants, heavy metals, dietary, and physical factors, are shown to influence the fate decision of BM-MSCs toward adipogenesis or osteogenesis. The balance of osteogenesis and adipogenesis is critical for the maintenance of bone homeostasis, and the interruption of BM-MSCs lineage commitment is associated with human health issues, such as fracture, osteoporosis, osteopenia, and osteonecrosis. This review focuses on how external stimuli shift the fate of BM-MSCs towards adipogenesis or osteogenesis. Future studies are needed to understand the impact of these external stimuli on bone health and elucidate the underlying mechanisms of BM-MSCs differentiation. This knowledge will inform efforts to prevent bone-related diseases and develop therapeutic approaches to treat bone disorders associated with various pathological conditions.
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Affiliation(s)
- Xinyun Xu
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, USA
| | - Ling Zhao
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, USA
| | - Paul D. Terry
- Department of Medicine, Graduate School of Medicine, The University of Tennessee, Knoxville, TN 37920, USA;
| | - Jiangang Chen
- Department of Public Health, The University of Tennessee, Knoxville, TN 37996, USA
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7
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Bai L, Liu Y, Zhang X, Chen P, Hang R, Xiao Y, Wang J, Liu C. Osteoporosis remission via an anti-inflammaging effect by icariin activated autophagy. Biomaterials 2023; 297:122125. [PMID: 37058900 DOI: 10.1016/j.biomaterials.2023.122125] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 03/14/2023] [Accepted: 04/09/2023] [Indexed: 04/16/2023]
Abstract
The pace of bone formation slows down with aging, which leads to the development of osteoporosis. In addition to senescent bone marrow mesenchymal stem cells (S-BMSCs), senescent macrophages (S-MΦs) present in the bone marrow produce numerous inflammatory cytokines that contribute to the inflammaged microenvironment and are involved in the development of osteoporosis. Although autophagy activation has shown a significant anti-aging effect, its influence on inflammaging and its role in osteoporosis treatment remain unclear. Traditional Chinese herbal medicine contains bioactive components that exhibit remarkable advantages in bone regeneration. We have demonstrated that icariin (ICA), a bioactive component of traditional Chinese herbal medicine, activates autophagy, exerts a significant anti-inflammaging effect on S-MΦs, and rejuvenates osteogenesis of S-BMSCs, thereby alleviating bone loss in osteoporotic mice. The transcriptomic analysis further reveals that the TNF-α signaling pathway, which is significantly associated with the level of autophagy, regulates this effect. Moreover, the expression of senescence-associated secretory phenotype (SASP) is significantly reduced after ICA treatment. In summary, our findings suggest that bioactive components/materials targeting autophagy can effectively modulate the inflammaging of S-MΦs, offering an innovative treatment strategy for osteoporosis remission and various age-related comorbidities.
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Affiliation(s)
- Long Bai
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, China; Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China; The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China; Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, China
| | - Yanpeng Liu
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, China; The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China; Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, China
| | - Xiaohui Zhang
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, China; The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China; Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, China
| | - Peiru Chen
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Institute of Lifeomics, Beijing, 102206, China
| | - Ruiqiang Hang
- Shanxi Key Laboratory of Biomedical Metal Materials, College of Materials Science and Engineering, Taiyuan University of Technology, Taiyuan, 030024, China
| | - Yin Xiao
- School of Medicine and Dentistry, Griffith University, Gold Coast, Australia; Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, Brisbane, Australia.
| | - Jing Wang
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, China; The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China; Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, China.
| | - Changsheng Liu
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, China; The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China; Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, China.
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8
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Bozorgi A, Khazaei M, Bozorgi M, Jamalpoor Z. Fabrication and characterization of apigenin-loaded chitosan/gelatin membranes for bone tissue engineering applications. J BIOACT COMPAT POL 2023. [DOI: 10.1177/08839115221149725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
Fabricating degradable polymer-based membranes has attracted much attention for guided bone regeneration. Chitosan/gelatin (Cs/Gel) composites are among the most known scaffolds with structural similarity to bone matrix and a high potential to support cell attachment and proliferation. Recently, plant-derived phenolic compound apigenin has been identified to direct the osteogenic differentiation of mesenchymal stem cells and retain osteoblast metabolic functions. We incorporated apigenin into Cs/Gel membranes to improve apigenin bioavailability and get proper concentrations for efficient biological activities. Apigenin-loaded Cs/Gel membranes were prepared using a solution casting method with various apigenin contents (0, 10, 25, 50, and 100 µM). Chemical composition, morphological characteristics, swelling behavior, degradation rate, and apigenin release from membranes were evaluated. Saos-2 osteoblasts were cultured on membranes to investigate cell-membrane interaction, proliferation, viability, and mineralization under the osteogenic culture condition. The results showed that membranes had homogeneous and moderate rough surfaces, facilitating osteoblast attachment and expansion. Swelling ratios exceeded 200%, reaching a stable rate in 24 h. Apigenin-loaded membranes degraded slower in vitro. Membranes containing lower apigenin concentrations exhibited a higher cargo release profile over 21 days. Apigenin improved osteoblast proliferation and viability, but the mineralization depended on apigenin dose, with optimized values at low concentrations. These data suggested that Cs/Gel membranes loaded with low apigenin contents improved osteoblast survival, proliferation, and mineralization.
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Affiliation(s)
- Azam Bozorgi
- Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mozafar Khazaei
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Maryam Bozorgi
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zahra Jamalpoor
- Trauma Research Center, AJA University of Medical Sciences, Tehran, Iran
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9
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Alipour M, Sharifi S, Samiei M, Shahi S, Aghazadeh M, Dizaj SM. Synthesis, characterization, and evaluation of Hesperetin nanocrystals for regenerative dentistry. Sci Rep 2023; 13:2076. [PMID: 36746996 PMCID: PMC9902453 DOI: 10.1038/s41598-023-28267-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 01/16/2023] [Indexed: 02/08/2023] Open
Abstract
Hesperetin (HS), a metabolite of hesperidin, is a polyphenolic component of citrus fruits. This ingredient has a potential role in bone strength and the osteogenic differentiation. The bone loss in the orofacial region may occur due to the inflammation response of host tissues. Nanotechnology applications have been harshly entered the field of regenerative medicine to improve the efficacy of the materials and substances. In the current study, the hesperetin nanocrystals were synthesized and characterized. Then, the anti-inflammatory and antioxidative effects of these nanocrystals were evaluated on inflamed human Dental Pulp Stem Cells (hDPSCs) and monocytes (U937). Moreover, the osteoinduction capacity of these nanocrystals was assessed by gene and protein expression levels of osteogenic specific markers including RUNX2, ALP, OCN, Col1a1, and BSP in hDPSCs. The deposition of calcium nodules in the presence of hesperetin and hesperetin nanocrystals was also assessed. The results revealed the successful fabrication of hesperetin nanocrystals with an average size of 100 nm. The levels of TNF, IL6, and reactive oxygen species (ROS) in inflamed hDPSCs and U937 significantly decreased in the presence of hesperetin nanocrystals. Furthermore, these nanocrystals induced osteogenic differentiation in hDPSCs. These results demonstrated the positive and effective role of fabricated nanocrystal forms of this natural ingredient for regenerative medicine purposes.
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Affiliation(s)
- Mahdieh Alipour
- Dental and Periodontal Research Center, Faculty of Dentistry, Tabriz University of Medical Sciences, Daneshgah St, Golgasht St, Tabriz, Iran
| | - Simin Sharifi
- Dental and Periodontal Research Center, Faculty of Dentistry, Tabriz University of Medical Sciences, Daneshgah St, Golgasht St, Tabriz, Iran
| | - Mohammad Samiei
- Department of Endodontics, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahriar Shahi
- Dental and Periodontal Research Center, Faculty of Dentistry, Tabriz University of Medical Sciences, Daneshgah St, Golgasht St, Tabriz, Iran
| | - Marziyeh Aghazadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Oral Medicine, Faculty of Dentistry, Tabriz University of Medical Sciences, Daneshgah St, Golgasht St, Tabriz, Iran.
| | - Solmaz Maleki Dizaj
- Dental and Periodontal Research Center, Faculty of Dentistry, Tabriz University of Medical Sciences, Daneshgah St, Golgasht St, Tabriz, Iran.
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10
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Zhang LB, Yan Y, He J, Wang PP, Chen X, Lan TY, Guo YX, Wang JP, Luo J, Yan ZR, Xu Y, Tao QW. Epimedii Herba: An ancient Chinese herbal medicine in the prevention and treatment of rheumatoid arthritis. Front Chem 2022; 10:1023779. [PMID: 36465876 PMCID: PMC9712800 DOI: 10.3389/fchem.2022.1023779] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 11/02/2022] [Indexed: 08/29/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic, progressive inflammatory and systemic autoimmune disease resulting in severe joint destruction, lifelong suffering and considerable disability. Diverse prescriptions of traditional Chinese medicine (TCM) containing Epimedii Herba (EH) achieve greatly curative effects against RA. The present review aims to systemically summarize the therapeutic effect, pharmacological mechanism, bioavailability and safety assessment of EH to provide a novel insight for subsequent studies. The search terms included were "Epimedii Herba", "yinyanghuo", "arthritis, rheumatoid" and "Rheumatoid Arthritis", and relevant literatures were collected on the database such as Google Scholar, Pubmed, Web of Science and CNKI. In this review, 15 compounds from EH for the treatment of RA were summarized from the aspects of anti-inflammatory, immunoregulatory, cartilage and bone protective, antiangiogenic and antioxidant activities. Although EH has been frequently used to treat RA in clinical practice, studies on mechanisms of these activities are still scarce. Various compounds of EH have the multifunctional traits in the treatment of RA, so EH may be a great complementary medicine option and it is necessary to pay more attention to further research and development.
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Affiliation(s)
- Liu-Bo Zhang
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship Clinical Medical College & School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yu Yan
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Jun He
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Pei-Pei Wang
- China-Japan Friendship Clinical Medical College & School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Xin Chen
- School of Chinese Medicine, Shenyang Pharmaceutical University, Shenyang, China
| | - Tian-Yi Lan
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship Clinical Medical College & School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yu-Xuan Guo
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship Clinical Medical College & School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Jin-Ping Wang
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Jing Luo
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Ze-Ran Yan
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Yuan Xu
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Qing-Wen Tao
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
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11
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Li C, Cui Z, Deng S, Chen P, Li X, Yang H. The potential of plant extracts in cell therapy. STEM CELL RESEARCH & THERAPY 2022; 13:472. [PMID: 36104798 PMCID: PMC9476258 DOI: 10.1186/s13287-022-03152-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 05/23/2022] [Indexed: 11/10/2022]
Abstract
Cell therapy is the frontier technology of biotechnology innovation and the most promising method for the treatment of refractory diseases such as tumours. However, cell therapy has disadvantages, such as toxicity and poor therapeutic effects. Plant extracts are natural, widely available, and contain active small molecule ingredients that are widely used in the treatment of various diseases. By studying the effect of plant extracts on cell therapy, active plant extracts that have positive significance in cell therapy can be discovered, and certain contributions to solving the current problems of attenuation and adjuvant therapy in cell therapy can be made. Therefore, this article reviews the currently reported effects of plant extracts in stem cell therapy and immune cell therapy, especially the effects of plant extracts on the proliferation and differentiation of mesenchymal stem cells and nerve stem cells and the potential role of plant extracts in chimeric antigen receptor T-cell immunotherapy (CAR-T) and T-cell receptor modified T-cell immunotherapy (TCR-T), in the hope of encouraging further research and clinical application of plant extracts in cell therapy.
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12
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Aloe vera gel as a stimulant for mesenchymal stem cells differentiation and a natural therapy for radiation induced liver damage. JOURNAL OF RADIATION RESEARCH AND APPLIED SCIENCES 2022. [DOI: 10.1016/j.jrras.2022.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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13
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Song K, Yang GM, Han J, Gil M, Dayem AA, Kim K, Lim KM, Kang GH, Kim S, Jang SB, Vellingiri B, Cho SG. Modulation of Osteogenic Differentiation of Adipose-Derived Stromal Cells by Co-Treatment with 3, 4'-Dihydroxyflavone, U0126, and N-Acetyl Cysteine. Int J Stem Cells 2022; 15:334-345. [PMID: 35769058 PMCID: PMC9396012 DOI: 10.15283/ijsc22044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/20/2022] [Accepted: 04/20/2022] [Indexed: 11/30/2022] Open
Abstract
Background and Objectives Flavonoids form the largest group of plant phenols and have various biological and pharmacological activities. In this study, we investigated the effect of a flavonoid, 3, 4’-dihydroxyflavone (3, 4’-DHF) on osteogenic differentiation of equine adipose-derived stromal cells (eADSCs). Methods and Results Treatment of 3, 4’-DHF led to increased osteogenic differentiation of eADSCs by increasing phosphorylation of ERK and modulating Reactive Oxygen Species (ROS) generation. Although PD98059, an ERK inhibitor, suppressed osteogenic differentiation, another ERK inhibitor, U0126, apparently increased osteogenic differentiation of the 3, 4’-DHF-treated eADSCs, which may indicate that the effect of U0126 on bone morphogenetic protein signaling is involved in the regulation of 3, 4’-DHF in osteogenic differentiation of eADSCs. We revealed that 3, 4’-DHF could induce osteogenic differentiation of eADSCs by suppressing ROS generation and co-treatment of 3, 4’-DHF, U0126, and/or N-acetyl cysteine (NAC) resulted in the additive enhancement of osteogenic differentiation of eADSCs. Conclusions Our results showed that co-treatment of 3, 4’-DHF, U0126, and/or NAC cumulatively regulated osteogenesis in eADSCs, suggesting that 3, 4’-DHF, a flavonoid, can provide a novel approach to the treatment of osteoporosis and can provide potential therapeutic applications in therapeutics and regenerative medicine for human and companion animals.
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Affiliation(s)
- Kwonwoo Song
- Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea
| | - Gwang-Mo Yang
- Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea
| | - Jihae Han
- Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea
| | - Minchan Gil
- Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea
| | - Ahmed Abdal Dayem
- Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea
| | - Kyeongseok Kim
- Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea
| | - Kyung Min Lim
- Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea
| | - Geun-Ho Kang
- Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea
| | - Sejong Kim
- Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea
| | - Soo Bin Jang
- Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea
| | - Balachandar Vellingiri
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India
| | - Ssang-Goo Cho
- Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea
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14
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Therapeutic Potential of Skin Stem Cells and Cells of Skin Origin: Effects of Botanical Drugs Derived from Traditional Medicine. Stem Cell Rev Rep 2022; 18:1986-2001. [PMID: 35648312 DOI: 10.1007/s12015-022-10388-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2022] [Indexed: 12/09/2022]
Abstract
Skin, the largest organ of the body, plays a vital role in protecting inner organs. Skin stem cells (SSCs) comprise a group of cells responsible for multiplication and replacement of damaged and non-functional skin cells; thereby help maintain homeostasis of skin functions. SSCs and differentiated cells of the skin such as melanocytes and keratinocytes, have a plethora of applications in regenerative medicine. However, as SSCs reside in small populations in specific niches in the skin, use of external stimulants for cell proliferation in vitro and in vivo is vital. Synthetic and recombinant stimulants though available, pose many challenges due to their exorbitant prices, toxicity issues and side effects. Alternatively, time tested traditional medicine preparations such as polyherbal formulations are widely tested as effective natural stimulants, to mainly stimulate proliferation, and melanogenesis/prevention of melanogenesis of both SSCs and cells of skin origin. Complex, multiple targets, synergistic bioactivities of the phytochemical constituents of herbal preparations amply justify these as natural stimulants. The use of these formulations in clinical applications such as in skin regeneration for burn wounds, wound healing acceleration, enhancement or decrease of melanin pigmentations will be in great demand. Although much multidisciplinary research is being conducted on the use of herbal formulas as stem cell stimulants, very few related clinical trials are yet registered with the NIH clinical trial registry. Therefore, identification/ discovery, in depth investigations culminating in clinical trials, as well as standardization and commercialization of such natural stimulants must be promoted, ensuring the sustainable use of medicinal plants.
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15
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Icariin and Icariside II Reciprocally Stimulate Osteogenesis and Inhibit Adipogenesis of Multipotential Stromal Cells through ERK Signaling. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:8069930. [PMID: 34956384 PMCID: PMC8702327 DOI: 10.1155/2021/8069930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 11/12/2021] [Accepted: 11/18/2021] [Indexed: 11/17/2022]
Abstract
Herba Epimedii is a famous Chinese herbal medicine for treating bone diseases. Icariin and icariside II, the main chemical constituents, have attracted great attention from scientists for their potential as antiosteoporosis agents. Our study aimed to evaluate their effects on the lineage commitment of multipotential stromal cells (MSCs). The osteogenesis and adipogenesis of MSCs were assessed by ALP activity, calcium deposition, and adipocyte formation. The expression profiles and levels of osteogenic and adipogenic specific genes were evaluated by cDNA microarray and quantitative real-time PCR. The involvement of extracellular signal-regulated kinase (ERK) signaling was studied by enzyme-linked immunosorbent assay. Icariin and icariside II significantly increased ALP activity and mineralization during osteogenic differentiation of MSCs. Runx2, Col1, and Bmp2 were upregulated in the presence of icariin and icariside II. Meanwhile, they downregulated Pparg, Adipsin, and Cebpb expression during adipogenic differentiation. cDNA microarray revealed 57 differentially expressed genes during lineage commitment of MSCs. In addition, icariin and icariside II enhanced the phosphorylation of ERK, and the above biological effects were blocked by ERK inhibitor U0126. Icariin and icariside II may drive the final lineage commitment of MSCs towards osteogenesis and inhibit adipogenesis through the ERK signaling pathway. Both of them exert multiple osteoprotective effects and deserve more attention for their medicinal and healthcare prospects.
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16
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Sharma A, Bhardwaj P, Arya SK. Naringin: A potential natural product in the field of biomedical applications. CARBOHYDRATE POLYMER TECHNOLOGIES AND APPLICATIONS 2021. [DOI: 10.1016/j.carpta.2021.100068] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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Abstract
Osteoporosis significantly impacts the normal life of the elderly and is reported to be closely related to dysfunction of osteoblastic differentiation. Runt-related transcription factor-2 (Runx2) is a critical transcriptional factor involved in the regulation of osteoblast differentiation. Omarigliptin is a novel dipeptidyl peptidase-4 (DDP-4) inhibitor and this study proposes to probe into its possible therapeutic function against Osteoporosis by investigating its impacts on osteoblastic differentiation. Osteogenic medium was used to induce osteoblastic differentiation in MC3T3‑E1 cells, and was verified by the increased alkaline phosphatase (ALP) activity, enhanced mineralization, and promoted expression level of osteoblastic differentiation-related factors, including bone morphogenetic protein-2 (BMP-2), ALP, osteocalcin (Ocn), collagen type I alpha 1 (Col1a1), Collagen Type I alpha 2 (Col1a2), Runx2, osterix (Sp7), fibroblast growth factor receptor 2 (Fgfr2), and fibroblast growth factor receptor 3 (Fgfr3), accompanied by the activation of the p38 and Akt pathways. After treatment with Omarigliptin, the ALP activity and mineralization were further promoted, accompanied by the further upregulation of osteoblastic differentiation-related factors, and activation of the p38 and Akt pathways. Lastly, Omarigliptin-induced osteoblastic differentiation, promoted ALP activity, and increased expression levels of Sp7, Fgfr2, Fgfr3, BMP-2, Ocn, ALP, Col1a1, and Col1a2, in the osteogenic medium- cultured MC3T3‑E1 cells were dramatically abolished by the knockdown of Runx2. Taken together, our data reveal that Omarigliptin promoted osteoblastic differentiation by regulating Runx2.
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Affiliation(s)
- Fake Liao
- Department of orthopedics, Longyan First Hospital Affiliated to Fujian Medical University, Longyan City, Fujian Province, No. 105, Jiuyi North Road, Zhongcheng, Xinluo District, 364000, China
| | - Xiunian Hu
- Department of orthopedics, Longyan First Hospital Affiliated to Fujian Medical University, Longyan City, Fujian Province, No. 105, Jiuyi North Road, Zhongcheng, Xinluo District, 364000, China
| | - Rijiang Chen
- Department of orthopedics, Longyan First Hospital Affiliated to Fujian Medical University, Longyan City, Fujian Province, No. 105, Jiuyi North Road, Zhongcheng, Xinluo District, 364000, China
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18
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Bhonde R, Sanap A, Joshi K. Mesenchymal stem cells as a platform for research on traditional medicine. J Ayurveda Integr Med 2021; 12:722-728. [PMID: 34740493 PMCID: PMC8642702 DOI: 10.1016/j.jaim.2021.08.012] [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: 02/16/2021] [Revised: 08/09/2021] [Accepted: 08/14/2021] [Indexed: 10/26/2022] Open
Abstract
The translation of Traditional Medicines (TMs) such as Ayurveda, and Traditional Chinese Medicine into clinical practice remains obstructed due to lack of scientific evidence by means of safety, quality, standardization, clinical efficacy, and mode of action. These limitations can be attributed to the lack of synonymous invitro models which reflect invivo features. Human mesenchymal stem cells (hMSCs) have emerged as an efficient cell source for regenerative medicine and tissue engineering. In this review, the authors discuss how hMSCs can be used as an invitro platform to screen herbs described in TMs using modern methods such as evaluation of its potential, safety, quality, mode of action, etc. Integration of traditional knowledge systems like Ayurveda and hMSCs as a platform to screen and study TMs using modern tools will effectively increase the validity of TMs as evidence-based medicine.
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Affiliation(s)
- Ramesh Bhonde
- Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, 411018, India
| | - Avinash Sanap
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Pimpri, Pune, 411018, India; Interdisciplinary School of Health Sciences, Savitribai Phule University of Pune, Pune, 411007, India
| | - Kalpana Joshi
- Department of Biotechnology, Sinhgad College of Engineering affiliated to Savitribai Phule Pune University, Pune, 411041, India.
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Yang X, Shao J, Wu XM, Pan FF, Yang SA, Pan XH, Jin AM. Troxerutin Stimulates Osteoblast Differentiation of Mesenchymal Stem Cell and Facilitates Bone Fracture Healing. Front Pharmacol 2021; 12:723145. [PMID: 34434113 PMCID: PMC8381475 DOI: 10.3389/fphar.2021.723145] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 07/29/2021] [Indexed: 11/23/2022] Open
Abstract
Troxerutin (TRX), a semi-synthetic derivative of the natural bioflavonoid rutin, is a bioactive flavonoid widely abundant in various fruits and vegetables. Known as vitamin P4, TRX has been demonstrated to have several activities including anti-inflammation, anti-oxidants, vasoprotection, and immune support in various studies. Although rutin, the precursor of troxerutin, was reported to have a protective role against bone loss, the function of TRX in skeletal system remains unknown. In the present study, we found that TRX promoted osteogenic differentiation of human mesenchymal stem cells (MSCs) in a concentration-dependent manner by stimulating the alkaline phosphatase (ALP) activity, calcium nodule formation and osteogenic marker genes expression in vitro. The further investigation demonstrated that TRX stimulated the expression of the critical transcription factor β-catenin and several downstream target genes of Wnt signaling, thus activated Wnt/β-catenin signaling. Using a femur fracture rats model, TRX was found to stimulate new bone formation and accelerate the fracture healing in vivo. Collectively, our data demonstrated that TRX could promote osteogenesis in vitro and facilitate the fracture healing in vivo, indicating that TRX may be a promising therapeutic candidate for bone fracture repair.
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Affiliation(s)
- Xiao Yang
- Department of Spinal Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jiang Shao
- Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiao-Min Wu
- Department of Orthopaedics, The Second School of Clinical Medicine, Southern Medical University, The Second Affiliated Hospital of Shenzhen University, The Clinical Medical College of Guangdong Medical University, People's Hospital of Shenzhen Baoan District, Shenzhen, China
| | - Fei-Fei Pan
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Shao-An Yang
- Department of Traumatic Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiao-Hua Pan
- Department of Orthopaedics, The Second School of Clinical Medicine, Southern Medical University, The Second Affiliated Hospital of Shenzhen University, The Clinical Medical College of Guangdong Medical University, People's Hospital of Shenzhen Baoan District, Shenzhen, China
| | - An-Min Jin
- Department of Spinal Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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Zhang Z, Zhou H, Sun F, Han J, Han Y. Circ_FBLN1 promotes the proliferation and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by regulating let-7i-5p/FZD4 axis and Wnt/β-catenin pathway. J Bioenerg Biomembr 2021; 53:561-572. [PMID: 34424449 DOI: 10.1007/s10863-021-09917-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 08/13/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND Recently, more and more circular RNAs (circRNAs) have been identified in osteogenesis. In this study, we aimed to explore the effect of circ_FBLN1 on the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). METHODS The protein levels of osteogenesis-related genes, let-7i-5p, frizzled class receptor 4 (FZD4), Ki67, Wnt6 and β-catenin were measured by western blot assay. The levels of circ_FBLN1, FBLN1 mRNA and FZD4 mRNA were determined by quantitative real-time polymerase chain reaction (qRT-PCR) assay. The feature of circ_FBLN1 was investigated by RNase R and Actinomycin D assays. Cell proliferation ability was evaluated by colony formation assay and 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The targeting relationship between let-7i-5p and circ_FBLN1 or FZD4 was verified by dual-luciferase reporter assay. RESULTS Circ_FBLN1 level was enhanced during the osteogenic differentiation of hBMSCs. Silencing of circ_FBLN1 repressed cell proliferation and osteogenic differentiation in hBMSCs. For mechanism analysis, circ_FBLN1 was found to act as a sponge for let-7i-5p and FZD4 served as a direct target gene of let-7i-5p. Let-7i-5p was downregulated during the osteogenic differentiation of hBMSCs and let-7i-5p inhibition restored the effects of circ_FBLN1 knockdown on the proliferation and osteogenesis of hBMSCs. Moreover, let-7i-5p overexpression suppressed cell proliferation and osteogenesis in hBMSCs through targeting FZD4. In addition, circ_FBLN1 knockdown reduced the levels of Wnt6 and β-catenin in hBMSCs, indicating the inactivation of Wnt/β-catenin pathway. CONCLUSION Knockdown of circ_FBLN1 inhibited the proliferation and osteogenesis of hBMSCs by regulating let-7i-5p/FZD4 axis and repressing Wnt/β-catenin pathway.
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Affiliation(s)
- Zilong Zhang
- Department of Spine, Zaozhuang Municipal Hospital, Zaozhuang City, Shandong Province, China
| | - Huachao Zhou
- Department of the Orthopaedic Trauma, Zaozhuang Mining Group Zaozhuang Hospital, Zaozhuang, Shandong, China
| | - Fei Sun
- Department of the Orthopaedic Trauma, Zaozhuang Mining Group Zaozhuang Hospital, Zaozhuang, Shandong, China
| | - Jianjian Han
- Department of the Orthopaedic Trauma, Qingdao Central Hospital, Qingdao, Shandong, China
| | - Yongyuan Han
- Department of Orthopedics, No.4 Hospital Beijing University of Chinese Medicine, No.202 Xuezhuang Community, Zhongxin Street, Zaozhuang, 277101, Shandong, China.
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21
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Bonnet C, Brahmbhatt A, Deng SX, Zheng JJ. Wnt signaling activation: targets and therapeutic opportunities for stem cell therapy and regenerative medicine. RSC Chem Biol 2021; 2:1144-1157. [PMID: 34458828 PMCID: PMC8341040 DOI: 10.1039/d1cb00063b] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 06/01/2021] [Indexed: 12/18/2022] Open
Abstract
Wnt proteins are secreted morphogens that play critical roles in embryonic development, stem cell proliferation, self-renewal, tissue regeneration and remodeling in adults. While aberrant Wnt signaling contributes to diseases such as cancer, activation of Wnt/β-catenin signaling is a target of interest in stem cell therapy and regenerative medicine. Recent high throughput screenings from chemical and biological libraries, combined with improved gene expression reporter assays of Wnt/β-catenin activation together with rational drug design, led to the development of a myriad of Wnt activators, with different mechanisms of actions. Among them, Wnt mimics, antibodies targeting Wnt inhibitors, glycogen-synthase-3β inhibitors, and indirubins and other natural product derivatives are emerging modalities to treat bone, neurodegenerative, eye, and metabolic disorders, as well as prevent ageing. Nevertheless, the creation of Wnt-based therapies has been hampered by challenges in developing potent and selective Wnt activators without off-target effects, such as oncogenesis. On the other hand, to avoid these risks, their use to promote ex vivo expansion during tissue engineering is a promising application.
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Affiliation(s)
- Clémence Bonnet
- Stein Eye Institute, University of California Los Angeles CA USA +1-3107947906 +1-3102062173
- INSERM, UMRS1138, Team 17, From Physiopathology of Ocular Diseases to Clinical Development, Paris University, Centre de Recherche des Cordeliers, and Cornea Departement, Cochin Hospital, AP-HP F-75014 Paris France
| | - Anvi Brahmbhatt
- Stein Eye Institute, University of California Los Angeles CA USA +1-3107947906 +1-3102062173
| | - Sophie X Deng
- Stein Eye Institute, University of California Los Angeles CA USA +1-3107947906 +1-3102062173
- Molecular Biology Institute, University of California Los Angeles CA USA
| | - Jie J Zheng
- Stein Eye Institute, University of California Los Angeles CA USA +1-3107947906 +1-3102062173
- Molecular Biology Institute, University of California Los Angeles CA USA
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22
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Mahmoudi Z, Saidi A, Iranshahi M, Dadgar N, Azizsoltani A, Behzad S, Mahmoudi L, Soleimani M, Parsa Khankandi H. In vitro evaluation of ferutinin on proliferation and osteogenesis differentiation in human unrestricted Somatic stem cells. Steroids 2021; 172:108862. [PMID: 34010709 DOI: 10.1016/j.steroids.2021.108862] [Citation(s) in RCA: 3] [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: 12/19/2020] [Revised: 04/01/2021] [Accepted: 05/10/2021] [Indexed: 11/25/2022]
Abstract
Osteoporosis is a common disease in post-menopausal women. The increased risk of breast cancer and malignancy with hormone replacement, hampers its wide-usage. Phytoestrogens are known to have selective estrogen receptor modulator activity. The present study aims to determine how ferutinin affects unrestricted human Somatic Stem Cells (USSCs) osteogenic differentiation. The effect of ferutinin on USSCs proliferation was assessed by MTT assay while osteogenesis was evaluated using Alkaline Phosphatase Activity (ALP), calcium deposition and Alizarin Red Staining. Quantitative real-time PCR was applied to examine the expression of bone specific genes such as osteocalcin, Runx2, and BMP-2. Ferutinin (5-15 µg/mL) could positively impact on the proliferation of cells in a dose-dependent manner. Also, ALP enzyme activity and calcium deposition were enhanced in the presence of ferutinin. Based on real-time PCR results, ferutinin could increase the expression of bone marker genes. The pattern of ferutinin effect on gene expression is similar to standard synthetic estrogen, 17-β-estradiol. In the presence of the estrogen activity inhibitor (ICI), the effect of ferutinin on ALP and gene level was diminished. In conclusion, ferutinin may be considered as a potential candidate for the stem cell therapy in osteoporosis.
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Affiliation(s)
- Zahra Mahmoudi
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| | - Abbas Saidi
- Department of Plant Sciences and Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Neda Dadgar
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Arezou Azizsoltani
- Department of Medical Biotechnology, Faculty of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran
| | - Sahar Behzad
- Evidence-based Phytotherapy and Complementary Medicine Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Ladan Mahmoudi
- Department of Food Science and Technology, Faculty of Agriculture, Tabriz University, Tabriz, Iran
| | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hamed Parsa Khankandi
- Department of Pharmacognosy, Facultyl of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran
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Oh Y, Ahn CB, Marasinghe MPCK, Je JY. Insertion of gallic acid onto chitosan promotes the differentiation of osteoblasts from murine bone marrow-derived mesenchymal stem cells. Int J Biol Macromol 2021; 183:1410-1418. [PMID: 34022306 DOI: 10.1016/j.ijbiomac.2021.05.122] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/06/2021] [Accepted: 05/17/2021] [Indexed: 12/16/2022]
Abstract
Chitosan, a naturally occurring biodegradable and biocompatible polymer, has found use as a food additive, nutraceuticals, and functional foods in recent years. In this study, gallic acid-g-chitosan (GAC) was prepared by the insertion of GA onto plain chitosan (PC) via free radical-mediated grafting and its osteogenic effects were investigated in murine bone marrow-derived mesenchymal stem cells (mBMMSCs). Structural characterization of PC and GAC was performed using 1H NMR and FT-IR spectroscopy. The amount of GA successfully grafted onto PC was 111 mg GA/g GAC via the Folin-Ciocalteu's method. While PC and GAC promoted the increase in alkaline phosphatase activity and mineralization, GAC increased these factors significantly more than PC, indicating that the grafting of GA onto chitosan increased its osteogenic potential. Mechanistic study revealed that GAC activated Wnt1 and Wnt3a mRNA and protein expression as well as increased the translocation of β-catenin into the nucleus and upregulated the expression of β-catenin targeted genes including Runx2, osterix, type I collagen and cyclin D1. In addition, DKK-1, a Wnt antagonist, decreased GAC-mediated osteoblast differentiation in mBMMSCs through blocking the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Yunok Oh
- Convergence Research Center for Smart Healthcare, Kyungsung University, Busan 48434, Republic of Korea
| | - Chang-Bum Ahn
- Division of Food and Nutrition, Chonnam National University, Gwangju 61186, Republic of Korea
| | - M P C K Marasinghe
- Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea
| | - Jae-Young Je
- Department of Marine-Bio Convergence Science, Pukyong National University, Busan 48547, Republic of Korea.
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24
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Shang F, Yu Y, Liu S, Ming L, Zhang Y, Zhou Z, Zhao J, Jin Y. Advancing application of mesenchymal stem cell-based bone tissue regeneration. Bioact Mater 2021; 6:666-683. [PMID: 33005830 PMCID: PMC7509590 DOI: 10.1016/j.bioactmat.2020.08.014] [Citation(s) in RCA: 157] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 08/07/2020] [Accepted: 08/15/2020] [Indexed: 12/11/2022] Open
Abstract
Reconstruction of bone defects, especially the critical-sized defects, with mechanical integrity to the skeleton is important for a patient's rehabilitation, however, it still remains challenge. Utilizing biomaterials of human origin bone tissue for therapeutic purposes has provided a facilitated approach that closely mimics the critical aspects of natural bone tissue with regard to its properties. However, not only efficacious and safe but also cost-effective and convenient are important for regenerative biomaterials to achieve clinical translation and commercial success. Advances in our understanding of regenerative biomaterials and their roles in new bone formation potentially opened a new frontier in the fast-growing field of regenerative medicine. Taking inspiration from the role and multicomponent construction of native extracellular matrix (ECM) for cell accommodation, the ECM-mimicking biomaterials and the naturally decellularized ECM scaffolds were used to create new tissues for bone restoration. On the other hand, with the going deep in understanding of mesenchymal stem cells (MSCs), they have shown great promise to jumpstart and facilitate bone healing even in diseased microenvironments with pharmacology-based endogenous MSCs rescue/mobilization, systemic/local infusion of MSCs for cytotherapy, biomaterials-based approaches, cell-sheets/-aggregates technology and usage of subcellular vesicles of MSCs to achieve scaffolds-free or cell-free delivery system, all of them have been shown can improve MSCs-mediated regeneration in preclinical studies and several clinical trials. Here, following an overview discussed autogenous/allogenic and ECM-based bone biomaterials for reconstructive surgery and applications of MSCs-mediated bone healing and tissue engineering to further offer principles and effective strategies to optimize MSCs-based bone regeneration.
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Affiliation(s)
- Fengqing Shang
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Department of Stomatology, The 306th Hospital of PLA, Beijing, 100101, China
| | - Yang Yu
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong, 250012, China
| | - Shiyu Liu
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Leiguo Ming
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Yongjie Zhang
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Zhifei Zhou
- Department of Stomatology, General Hospital of Tibetan Military Command, Lhasa, 850000, China
| | - Jiayu Zhao
- Bureau of Service for Veteran Cadres of PLA in Beijing, Beijing, 100001, China
| | - Yan Jin
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
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25
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Sabu BS, Chandrashekar KT, Mishra R, Tripathi VD, Khatri H, Deo A. Evaluation of Morinda citrifolia (noni) fruit extract as a bone regenerative material in the treatment of periodontal intrabony osseous defects: Clinical and cone-beam computed tomography assessment. J Indian Soc Periodontol 2021; 25:144-149. [PMID: 33888947 PMCID: PMC8041072 DOI: 10.4103/jisp.jisp_58_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 09/15/2020] [Accepted: 10/11/2020] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Nature and its products can be utilized for regeneration in periodontal destruction and damage to supporting tissues. We come across the use of various graft materials to reestablish the lost bone and for the long-term survival of teeth. The objective of this study was to evaluate the bone fill efficacy of Morinda citrifolia fruit extract in the periodontal bone defect. MATERIALS AND METHODS This randomized study included twenty patients indicated for periodontal regenerative therapy and were equally divided and assigned into the experimental and control group. Open flap debridement alone was performed in the control group, while placement of extract along with open flap debridement was done in the experimental group. Clinical parameters assessed were gingival index, probing pocket depth, and relative attachment level, and the amount of bone fill was assessed using cone-beam computed tomography (CBCT) at baseline and at 6-month interval. RESULTS From the values of clinical parameters, there was a mean reduction in probing pocket and gain in attachment level and a 27.7% increase in bone fill in experimental group as compared to the control group from CBCT analysis. CONCLUSIONS The use of M. citrifolia fruit extract in the intraosseous defect was found to be efficacious in terms of relative attachment level and the amount of bone fill, and it had shown some anti-inflammatory affect.
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Affiliation(s)
- Blessy Shin Sabu
- Department of Periodontics and Implantology, Hitkarini Dental College and Hospital, Hitkarini Hills, Dumna Airport Road, Affiliated to Madhya Pradesh Medical Science University (MPMSU), Jabalpur, Madhya Pradesh, 482002, India
| | - Kabbur Thippanna Chandrashekar
- Department of Periodontics and Implantology, Hitkarini Dental College and Hospital, Hitkarini Hills, Dumna Airport Road, Affiliated to Madhya Pradesh Medical Science University (MPMSU), Jabalpur, Madhya Pradesh, 482002, India
| | - Rohit Mishra
- Department of Periodontics and Implantology, Hitkarini Dental College and Hospital, Hitkarini Hills, Dumna Airport Road, Affiliated to Madhya Pradesh Medical Science University (MPMSU), Jabalpur, Madhya Pradesh, 482002, India
| | - Vandana Dubey Tripathi
- Department of Periodontics and Implantology, Hitkarini Dental College and Hospital, Hitkarini Hills, Dumna Airport Road, Affiliated to Madhya Pradesh Medical Science University (MPMSU), Jabalpur, Madhya Pradesh, 482002, India
| | - Honey Khatri
- Department of Periodontics and Implantology, Hitkarini Dental College and Hospital, Hitkarini Hills, Dumna Airport Road, Affiliated to Madhya Pradesh Medical Science University (MPMSU), Jabalpur, Madhya Pradesh, 482002, India
| | - Ankita Deo
- Department of Periodontics and Implantology, Hitkarini Dental College and Hospital, Hitkarini Hills, Dumna Airport Road, Affiliated to Madhya Pradesh Medical Science University (MPMSU), Jabalpur, Madhya Pradesh, 482002, India
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26
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Siu WS, Ko CH, Shiu HT, Li KK, Shum WT, Leung PC, Zhang JF. Green tea extract synergistically enhances the effectiveness of an antiresorptive drug on management of osteoporosis induced by ovariectomy in a rat model. Exp Ther Med 2021; 21:328. [PMID: 33732301 PMCID: PMC7903424 DOI: 10.3892/etm.2021.9759] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 09/25/2020] [Indexed: 11/05/2022] Open
Abstract
Antiresorptive drugs are effective for reducing bone loss in postmenopausal women, but their long-term application may be associated with adverse effects. The present study aimed to investigate the potential in vivo synergistic effects of green tea extract (GTE) and alendronate or raloxifene on the management of osteoporosis. Ovariectomized rats were fed orally with GTE, alendronate and raloxifene at different concentrations and various combinations for 4 weeks. Bone mineral density (BMD) at the lumbar spine, femur and tibia was monitored weekly using peripheral quantitative computed tomography. Bone microarchitecture in the left distal femur was analyzed using micro-CT, while serum biochemical levels were measured using ELISA kits at the end of the study. GTE alone effectively mitigated BMD loss and improved bone microarchitecture in rats. The co-administration of GTE and alendronate increased total BMD in the lumbar spine, femur and tibia. Particularly, GTE synergistically enhanced the effect of alendronate at a low dose on bone microarchitecture and decreased serum tartrate-resistant acid phosphatase. These findings imply that the dosage of certain antiresorptive agents could be reduced when they are administrated simultaneously with GTE, so that their adverse effects are minimized. The findings may be used to support the development of a new synergistic intervention between food therapy and pharmacotherapy on the management of osteoporosis in a long-term basis.
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Affiliation(s)
- Wing Sum Siu
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China.,State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China
| | - Chun Hay Ko
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China.,State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China
| | - Hoi Ting Shiu
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China.,State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China
| | - Kai Kai Li
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China.,State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China
| | - Wai Ting Shum
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China.,State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China
| | - Ping Chung Leung
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China.,State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China.,Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China
| | - Jin Fang Zhang
- Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P.R. China
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27
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Effect of immunosuppressants on a mouse model of osteogenesis imperfecta type V harboring a heterozygous Ifitm5 c.-14C > T mutation. Sci Rep 2020; 10:21197. [PMID: 33273604 PMCID: PMC7713238 DOI: 10.1038/s41598-020-78403-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 11/19/2020] [Indexed: 01/08/2023] Open
Abstract
Osteogenesis imperfecta (OI) type V is an autosomal dominant disorder caused by the c.-14C > T mutation in the interferon-induced transmembrane protein 5 gene (IFITM5), however, its onset mechanism remains unclear. In this study, heterozygous c.-14C > T mutant mice were developed to investigate the effect of immunosuppressants (FK506 and rapamycin) on OI type V. Among the mosaic mice generated by Crispr/Cas9-based technology, mice with less than 40% mosaic ratio of c.-14C > T mutation survived, whereas those with more than 48% mosaic ratio exhibited lethal skeletal abnormalities with one exception. All heterozygous mutants obtained by mating mosaic mice with wild-type mice exhibited a perinatal lethal phenotype due to severe skeletal abnormalities. Administration of FK506, a calcineurin inhibitor, in the heterozygous fetuses improved bone mineral content (BMC) of the neonates, although it did not save the neonates from the lethal effects of the mutation, whereas rapamycin, an mTOR inhibitor, reduced BMC, suggesting that mTOR signaling is involved in the bone mineralization of heterozygous mutants. These findings could clarify certain aspects of the onset mechanism of OI type V and enable development of therapeutics for this condition.
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28
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7-HYB, a Phenolic Compound Isolated from Myristica fragrans Houtt Increases Cell Migration, Osteoblast Differentiation, and Mineralization through BMP2 and β-catenin Signaling. Int J Mol Sci 2020; 21:ijms21218059. [PMID: 33137925 PMCID: PMC7663243 DOI: 10.3390/ijms21218059] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 10/23/2020] [Accepted: 10/26/2020] [Indexed: 12/14/2022] Open
Abstract
The seeds (nutmegs) of Myristica fragrans Houtt have been used as popular spices and traditional medicine to treat a variety of diseases. A phenolic compound, ((7S)-8′-(benzo[3′,4′]dioxol-1′-yl)-7-hydroxypropyl)benzene-2,4-diol (7-HYB) was isolated from the seeds of M. fragrans. This study aimed to investigate the anabolic effects of 7-HYB in osteogenesis and bone mineralization. In the present study, 7-HYB promotes the early and late differentiation of MC3T3-E1 preosteoblasts. 7-HYB also elevated cell migration rate during differentiation of the preosteoblasts with the increased phosphorylation of mitogen-activated protein kinases (MAPKs) including ERK1/2, p38, and JNK. In addition, 7-HYB induced the protein level of BMP2, the phosphorylation of Smad1/5/8, and the expression of RUNX2. 7-HYB also inhibited GSK3β and subsequently increased the level of β-catenin. However, in bone marrow macrophages (BMMs), 7-HYB has no biological effects in cell viability, TRAP-positive multinuclear osteoclasts, and gene expression (c-Fos and NF-ATc1) in receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. Our findings suggest that 7-HYB plays an important role in osteoblast differentiation through the BMP2 and β-catenin signaling pathway. It also indicates that 7-HYB might have a therapeutic effect for the treatment of bone diseases such as osteoporosis and periodontitis.
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29
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Oh Y, Ahn CB, Je JY. Blue Mussel-Derived Peptides PIISVYWK and FSVVPSPK Trigger Wnt/β-Catenin Signaling-Mediated Osteogenesis in Human Bone Marrow Mesenchymal Stem Cells. Mar Drugs 2020; 18:md18100510. [PMID: 33050263 PMCID: PMC7599581 DOI: 10.3390/md18100510] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/24/2020] [Accepted: 10/08/2020] [Indexed: 01/08/2023] Open
Abstract
Marine-derived bioactive peptides have shown potential bone health promoting effects. Although various marine-derived bioactive peptides have potential nutraceutical or pharmaceutical properties, only a few of them are commercially available. This study presented an osteogenic mechanism of blue mussel-derived peptides PIISVYWK and FSVVPSPK as potential bone health promoting agents in human bone marrow-derived mesenchymal stem cells (hBMMSCs). Alkaline phosphatase (ALP) activity and mineralization were stimulated using PIISVYWK and FSVVPSPK as early and late markers of osteogenesis in a concentration-dependent manner. Western blot and RT-qPCR results revealed that PIISVYWK and FSVVPSPK increased osteoblast differentiation of hBMMSCs by activating canonical Wnt/β-catenin signaling-related proteins and mRNAs. Immunofluorescence images confirmed nuclear translocation of β-catenin in osteogenic differentiation. Treatment with the pharmacological inhibitor DKK-1 blocked PIISVYWK- and FSVVPSPK-induced ALP activity and mineralization, as well as mRNA expression of the canonical Wnt/β-catenin signaling pathway in hBMMSC differentiation into osteoblasts. These findings suggested that PIISVYWK and FSVVPSPK promoted the canonical Wnt/β-catenin signaling pathway in osteogenesis of hBMMSCs. Blue mussel-derived PIISVYWK and FSVVPSPK might help develop peptide-based therapeutic agents for bone-related diseases.
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Affiliation(s)
- Yunok Oh
- Institute of Marine Life Sciences, Pukyong National University, Busan 48613, Korea;
| | - Chang-Bum Ahn
- Division of Food and Nutrition, Chonnam National University, Gwangju 61186, Korea;
| | - Jae-Young Je
- Department of Marine-Bio Convergence Science, Pukyong National University, Busan 48547, Korea
- Correspondence: ; Tel.: +82-51-629-6871
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30
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Oh Y, Ahn CB, Je JY. Ark shell protein-derived bioactive peptides promote osteoblastic differentiation through upregulation of the canonical Wnt/β-catenin signaling in human bone marrow-derived mesenchymal stem cells. J Food Biochem 2020; 44:e13440. [PMID: 32808363 DOI: 10.1111/jfbc.13440] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 07/30/2020] [Accepted: 07/30/2020] [Indexed: 01/13/2023]
Abstract
In this study, the stimulating effect of ark shell protein-derived peptides AWLNH and PHDL on osteoblast differentiation in human bone marrow-derived mesenchymal stem cells (hBMMSCs) and its molecular mechanism was investigated. The hBMMSCs were cultured with two peptides and osteogenic markers were analyzed. Results showed that enhanced ALP activity and calcification were detected in the presence of AWLNH and PHDL. Based on western blotting, RT-qPCR, and immunostaining analysis, AWLNH and PHDL are specific for osteoblast differentiation of hBMMSCs through activating the canonical Wnt/β-catenin signaling pathway followed by activating Runx2, osterix, and type I collagen. Loss-of-function assay with DKK-1, a Wnt antagonist, showed that the canonical Wnt/β-catenin signaling was essential for AWLNH and PHDL-induced osteogenesis in hBMMSCs. These findings suggested that AWLNH and PHDL can stimulate osteoblast differentiation of hBMMSCs via upregulating the canonical Wnt/β-catenin signaling and may be useful for a potential nutraceuticals or pharmaceuticals to treat osteoporosis. PRACTICAL APPLICATIONS: Ark shell is a popular foodstuff in Korea. However, biological effects of its protein and peptide have not been explored in many ways. This study demonstrated that ark shell protein-derived peptides promoted osteoblast differentiation in hBMMSCs through upregulating the canonical Wnt/β-catenin signaling. The results of this study could be a basis to promote its application as functional foods and/or nutraceuticals.
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Affiliation(s)
- Yunok Oh
- Institute of Marine Life Sciences, Pukyong National University, Busan, Republic of Korea
| | - Chang-Bum Ahn
- Division of Food and Nutrition, Chonnam National University, Gwangju, Republic of Korea
| | - Jae-Young Je
- Department of Marine-Bio Convergence Science, Pukyong National University, Busan, Republic of Korea
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31
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TMARg, a Novel Anthraquinone Isolated from Rubia cordifolia Nakai, Increases Osteogenesis and Mineralization through BMP2 and β-Catenin Signaling. Int J Mol Sci 2020; 21:ijms21155332. [PMID: 32727092 PMCID: PMC7432489 DOI: 10.3390/ijms21155332] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/22/2020] [Accepted: 07/22/2020] [Indexed: 12/24/2022] Open
Abstract
Background: Plant extracts have long been regarded as useful medicines in the treatment of human diseases. Rubia cordifolia Nakai has been used as a traditional medicine, as it has pharmacological properties such as antioxidant and anti-inflammatory activity. However, the biological functions of TMARg, isolated from the roots of R. cordifolia, in osteoblast differentiation remain unknown. This study was performed to investigate the pharmacological effects and intracellular signaling of TMARg in the osteoblast differentiation of pre-osteoblast MC3T3-E1 cells and mesenchymal precursor C2C12 cells. Methods: Cell viability was evaluated using an MTT assay. Early and late osteoblast differentiation was examined by analyzing the activity of alkaline phosphatase (ALP), and by staining it with Alizarin red S (ARS). Cell migration was determined by using migration assays. Western blot analysis and immunocytochemical analysis were used to examine the intracellular signaling pathways and differentiation proteins. Results: In the present study, TMARg showed no cytotoxicity and increased the osteoblast differentiation in pre-osteoblasts, as assessed from the alkaline phosphate (ALP) staining and activity and ARS staining. TMARg also induced BMP2 expression and increased the p-smad1/5/8-RUNX2 and β-catenin pathways in both MC3T3-E1 and C2C12 cells. Furthermore, TMARg activated mitogen-activated protein kinases (MAPKs) and increased the cell migration rate. In addition, the TMARg-mediated osteoblast differentiation was suppressed by BMP and Wnt inhibitors with the downregulation of BMP2 expression. Conclusion: These findings demonstrate that TMARg exerts pharmacological and biological effects on osteoblast differentiation through the activation of BMP2 and β-catenin signaling pathways, and suggest that TMARg might be a potential phytomedicine for the treatment of bone diseases.
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32
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Ion R, Necula MG, Mazare A, Mitran V, Neacsu P, Schmuki P, Cimpean A. Drug Delivery Systems Based on Titania Nanotubes and Active Agents for Enhanced Osseointegration of Bone Implants. Curr Med Chem 2020; 27:854-902. [PMID: 31362646 DOI: 10.2174/0929867326666190726123229] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 01/16/2019] [Accepted: 05/04/2019] [Indexed: 12/31/2022]
Abstract
TiO2 nanotubes (TNTs) are attractive nanostructures for localized drug delivery. Owing to their excellent biocompatibility and physicochemical properties, numerous functionalizations of TNTs have been attempted for their use as therapeutic agent delivery platforms. In this review, we discuss the current advances in the applications of TNT-based delivery systems with an emphasis on the various functionalizations of TNTs for enhancing osteogenesis at the bone-implant interface and for preventing implant-related infection. Innovation of therapies for enhancing osteogenesis still represents a critical challenge in regeneration of bone defects. The overall concept focuses on the use of osteoconductive materials in combination with the use of osteoinductive or osteopromotive factors. In this context, we highlight the strategies for improving the functionality of TNTs, using five classes of bioactive agents: growth factors (GFs), statins, plant derived molecules, inorganic therapeutic ions/nanoparticles (NPs) and antimicrobial compounds.
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Affiliation(s)
- Raluca Ion
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Madalina Georgiana Necula
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Anca Mazare
- University of Erlangen-Nuremberg, Department of Materials Science, Erlangen, Germany
| | - Valentina Mitran
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Patricia Neacsu
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Patrik Schmuki
- University of Erlangen-Nuremberg, Department of Materials Science, Erlangen, Germany
| | - Anisoara Cimpean
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
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33
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Yoon Y, Jung T, Afan Shahid M, Khan IU, Kim WH, Kweon OK. Frozen-thawed gelatin-induced osteogenic cell sheets of canine adipose-derived mesenchymal stromal cells improved fracture healing in canine model. J Vet Sci 2020; 20:e63. [PMID: 31775190 PMCID: PMC6883194 DOI: 10.4142/jvs.2019.20.e63] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 09/03/2019] [Accepted: 09/03/2019] [Indexed: 12/16/2022] Open
Abstract
We assessed the efficacy of frozen-thawed gelatin-induced osteogenic cell sheet (FT-GCS) compared to that of fresh gelatin-induced osteogenic cell sheet (F-GCS) with adipose-derived mesenchymal stromal cells (Ad-MSCs) used as the control. The bone differentiation capacity of GCS has already been studied. On that basis, the experiment was conducted to determine ease of use of GCS in the clinic. In vitro evaluation of F-GCS showed 3–4 layers with an abundant extracellular matrix (ECM) formation; however, cryopreservation resulted in a reduction of FT-GCS layers to 2–3 layers. Cellular viabilities of F-GCS and FT-GCS did not vary significantly. Moreover, there was no significant difference in mRNA expressions of Runx2, β-catenin, OPN, and BMP-7 between F-GCS and FT-GCS. In an in vivo experiment, both legs of six dogs with transverse radial fractures were randomly assigned to one of three groups: F-GCS, FT-GCS, or control. Fracture sites were wrapped with the respective cell sheets and fixed with 2.7 mm locking plates and six screws. At 8 weeks after the operations, bone samples were collected and subjected to micro computed tomography and histopathological examination. External volumes of callus as a portion of the total bone volume in control, F-GCS, and FT-GCS groups were 49.6%, 45.3%, and 41.9%, respectively. The histopathological assessment showed that both F-GCS and FT-GCS groups exhibited significantly (p < 0.05) well-organized, mature bone with peripheral cartilage at the fracture site compared to that of the control group. Based on our results, we infer that the cryopreservation process did not significantly affect the osteogenic ability of gelatin-induced cell sheets.
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Affiliation(s)
- Yongseok Yoon
- BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Taeseong Jung
- BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Muhammad Afan Shahid
- BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Imdad Ullah Khan
- BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Wan Hee Kim
- BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Oh Kyeong Kweon
- BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea.
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Blagodatski A, Klimenko A, Jia L, Katanaev VL. Small Molecule Wnt Pathway Modulators from Natural Sources: History, State of the Art and Perspectives. Cells 2020; 9:cells9030589. [PMID: 32131438 PMCID: PMC7140537 DOI: 10.3390/cells9030589] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 02/25/2020] [Accepted: 02/28/2020] [Indexed: 02/07/2023] Open
Abstract
The Wnt signaling is one of the major pathways known to regulate embryonic development, tissue renewal and regeneration in multicellular organisms. Dysregulations of the pathway are a common cause of several types of cancer and other diseases, such as osteoporosis and rheumatoid arthritis. This makes Wnt signaling an important therapeutic target. Small molecule activators and inhibitors of signaling pathways are important biomedical tools which allow one to harness signaling processes in the organism for therapeutic purposes in affordable and specific ways. Natural products are a well known source of biologically active small molecules with therapeutic potential. In this article, we provide an up-to-date overview of existing small molecule modulators of the Wnt pathway derived from natural products. In the first part of the review, we focus on Wnt pathway activators, which can be used for regenerative therapy in various tissues such as skin, bone, cartilage and the nervous system. The second part describes inhibitors of the pathway, which are desired agents for targeted therapies against different cancers. In each part, we pay specific attention to the mechanisms of action of the natural products, to the models on which they were investigated, and to the potential of different taxa to yield bioactive molecules capable of regulating the Wnt signaling.
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Affiliation(s)
- Artem Blagodatski
- School of Biomedicine, Far Eastern Federal University, Vladivostok 690090, Russia;
- Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
- Correspondence: (A.B.); (V.L.K.)
| | - Antonina Klimenko
- School of Biomedicine, Far Eastern Federal University, Vladivostok 690090, Russia;
| | - Lee Jia
- Institute of Oceanography, Minjiang University, Fuzhou 350108, China;
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou 350108, China
| | - Vladimir L. Katanaev
- School of Biomedicine, Far Eastern Federal University, Vladivostok 690090, Russia;
- Institute of Oceanography, Minjiang University, Fuzhou 350108, China;
- Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Correspondence: (A.B.); (V.L.K.)
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Yuliati A, Hartono M, Suardita K. Proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cell after exposure to red flesh dragon fruit extract. Dent Res J (Isfahan) 2020. [DOI: 10.4103/1735-3327.280885] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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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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Deng X, Tan S, Zhu D, Sun Y, Yu J, Meng X, Zheng L, Liu Y. The combined effect of oleonuezhenide and wedelolactone on proliferation and osteoblastogenesis of bone marrow mesenchymal stem cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 65:153103. [PMID: 31805425 DOI: 10.1016/j.phymed.2019.153103] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 09/28/2019] [Accepted: 09/29/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Regulation of the survival and differentiation of bone marrow mesenchymal stem cells is an essential consideration in the development of targeted drugs for treatment of osteoporosis. PURPOSE The present study aimed to evaluate the combined effect of wedelolactone and oleonuezhenide, two compounds from Chinese formula Er-Zhi-Wan, on osteoblastogenesis and the underlying molecular mechanisms. METHODS MTT assay was taken to evaluate cell proliferation. The alkaline phosphatase (ALP) activity assay was used to determine the activity of ALP. Alizarin red S (ARS) staining was taken to indicate the intensity of the calcium deposits. Quantitative real-time PCR and Western blot were performed to the levels of Runx2, Osteocalcin, and Osterix expression in mouse bone marrow mesenchymal stem cells (BMSCs). Ovariectomized mouse model and bone histomorphometric analysis were also used to research the effects of wedelolactone and oleonuezhenide on bone loss caused by ovariectomy. RESULTS Wedelolactone combined with oleonuezhenide enhanced osteoblast differentiation and bone mineralization. Osteoblastogenesis-related marker genes including osteocalcin, Runx2, and osteorix were upregulated in the presence of wedelolactone and oleonuezhenide. At the molecular level, oleonuezhenide did not affect GSK-3β phosphorylation induced by wedelolactone, but elevated casein kinase 2-alpha (CK2α) expression, resulting in β-catenin and Runx2 nuclear translocation. In addition, 30 µM wedelolactone-induced cytotoxicity in bone marrow mesenchymal stem cells was relieved by 9 µM oleonuezhenide. These cells were protected by oleonuezhenide and maintained osteoblastic activity. Oleonuezhenide increased Wnt5a and CK2α expression. Wedelolactone-reduced extracellular signal-regulated kinase (ERK) phosphorylation was reversed by oleonuezhenide. In ovariectomized mice, administration of wedelolactone and oleonuezhenide prevented ovariectomy-induced bone loss by enhancing osteoblastic activity. CONCLUSION These results suggested that oleonuezhenide enhanced the effects of wedelolactone on osteoblastogenesis. These two compounds could be developed as a combined therapeutic agent for osteoporosis.
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Affiliation(s)
- Xue Deng
- Institute (College) of Integrative Medicine, Dalian Medical University, No.9 West Section Lvshun South Road, Dalian 116044, China
| | - Suming Tan
- Institute (College) of Integrative Medicine, Dalian Medical University, No.9 West Section Lvshun South Road, Dalian 116044, China
| | - Di Zhu
- Institute (College) of Integrative Medicine, Dalian Medical University, No.9 West Section Lvshun South Road, Dalian 116044, China
| | - Yujiao Sun
- Institute (College) of Integrative Medicine, Dalian Medical University, No.9 West Section Lvshun South Road, Dalian 116044, China
| | - Jinghua Yu
- Institute of Virology and AIDS Research, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province 130000, China
| | - Xiangling Meng
- Institute of Virology and AIDS Research, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province 130000, China
| | - Luping Zheng
- Institute (College) of Integrative Medicine, Dalian Medical University, No.9 West Section Lvshun South Road, Dalian 116044, China
| | - Yanqiu Liu
- Institute (College) of Integrative Medicine, Dalian Medical University, No.9 West Section Lvshun South Road, Dalian 116044, China,.
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Zadegan S, Nourmohammadi J, Vahidi B, Haghighipour N. An investigation into osteogenic differentiation effects of silk fibroin-nettle (Urtica dioica L.) nanofibers. Int J Biol Macromol 2019; 133:795-803. [PMID: 31028813 DOI: 10.1016/j.ijbiomac.2019.04.165] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 03/28/2019] [Accepted: 04/23/2019] [Indexed: 01/23/2023]
Abstract
The purpose of this study was to investigate physical, mechanical, and osteogenic properties of silk fibroin (SF) nanofibers containing Urtica dioica L. (nettle) extract at different concentrations. In this respect, the successful incorporation of nettle in SF nanofibers was analyzed and then confirmed through Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The mean fiber diameter, water uptake, breaking strain, cellular attachment, and proliferation of the given nanofibers also increased as the nettle content was added, while this trend was opposite in terms of tensile strength and modulus. The in vitro release studies correspondingly demonstrated that the nettle release had been controlled according to Fickian diffusion and it was faster in the samples including more nettle. Furthermore, both ARS staining and real-time RT-PCR results suggested that nettle had enhanced the expression of both early and late markers of osteoblast differentiation in a dose-dependent manner.
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Affiliation(s)
- Sara Zadegan
- Division of Biomedical Engineering, Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| | - Jhamak Nourmohammadi
- Division of Biomedical Engineering, Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.
| | - Bahman Vahidi
- Division of Biomedical Engineering, Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
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Long H, Zhu Y, Lin Z, Wan J, Cheng L, Zeng M, Tang Y, Zhao R. miR-381 modulates human bone mesenchymal stromal cells (BMSCs) osteogenesis via suppressing Wnt signaling pathway during atrophic nonunion development. Cell Death Dis 2019; 10:470. [PMID: 31209205 PMCID: PMC6572824 DOI: 10.1038/s41419-019-1693-z] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 05/19/2019] [Accepted: 05/23/2019] [Indexed: 12/19/2022]
Abstract
The osteogenic differentiation of human bone mesenchymal stromal cells (BMSCs) has been considered as a central issue in fracture healing. Wnt signaling could promote BMSC osteogenic differentiation through inhibiting PPARγ. During atrophic nonunion, Wnt signaling-related factors, WNT5A and FZD3 proteins, were significantly reduced, along with downregulation of Runx2, ALP, and Collagen I and upregulation of PPARγ. Here, we performed a microarray analysis to identify differentially expressed miRNAs in atrophic nonunion tissues that were associated with Wnt signaling through targeting related factors. Of upregulated miRNAs, miR-381 overexpression could significantly inhibit the osteogenic differentiation in primary human BMSCs while increase in PPARγ protein level. Through binding to the 3'UTR of WNT5A and FZD3, miR-381 modulated the osteogenic differentiation via regulating β-catenin nucleus translocation. Moreover, PPARγ, an essential transcription factor inhibiting osteogenic differentiation, could bind to the promoter region of miR-381 to activate its expression. Taken together, PPARγ-induced miR-381 upregulation inhibits the osteogenic differentiation in human BMSCs through miR-381 downstream targets, WNT5A and FZD3, and β-catenin nucleus translocation in Wnt signaling. The in vivo study also proved that inhibition of miR-381 promoted the fracture healing. Our finding may provide a novel direction for atrophic nonunion treatment.
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Affiliation(s)
- Haitao Long
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yong Zhu
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhangyuan Lin
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jun Wan
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Liang Cheng
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Min Zeng
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yifu Tang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ruibo Zhao
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China.
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Goonoo N, Bhaw-Luximon A. Mimicking growth factors: role of small molecule scaffold additives in promoting tissue regeneration and repair. RSC Adv 2019; 9:18124-18146. [PMID: 35702423 PMCID: PMC9115879 DOI: 10.1039/c9ra02765c] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 06/02/2019] [Indexed: 12/31/2022] Open
Abstract
The primary aim of tissue engineering scaffolds is to mimic the in vivo environment and promote tissue growth. In this quest, a number of strategies have been developed such as enhancing cell-material interactions through modulation of scaffold physico-chemical parameters. However, more is required for scaffolds to relate to the cell natural environment. Growth factors (GFs) secreted by cells and extracellular matrix (ECM) are involved in both normal repair and abnormal remodeling. The direct use of GFs on their own or when incorporated within scaffolds represent a number of challenges such as release rate, stability and shelf-life. Small molecules have been proposed as promising alternatives to GFs as they are able to minimize or overcome many shortcomings of GFs, in particular immune response and instability. Despite the promise of small molecules in various TE applications, their direct use is limited by nonspecific adverse effects on non-target tissues and organs. Hence, they have been incorporated within scaffolds to localize their actions and control their release to target sites. However, scanty rationale is available which links the chemical structure of these molecules with their mode of action. We herewith review various small molecules either when used on their own or when incorporated within polymeric carriers/scaffolds for bone, cartilage, neural, adipose and skin tissue regeneration.
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Affiliation(s)
- Nowsheen Goonoo
- Biomaterials, Drug Delivery and Nanotechnology (BDDN) Unit, Centre for Biomedical and Biomaterials Research, University of Mauritius Réduit Mauritius
| | - Archana Bhaw-Luximon
- Biomaterials, Drug Delivery and Nanotechnology (BDDN) Unit, Centre for Biomedical and Biomaterials Research, University of Mauritius Réduit Mauritius
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Xiang-Lin L, Le-Ping L, Rong H, Shu-Qi Z, Zi-Yi Z, Ting P, Hui-Ping L, Guo-Min Z. Effects of Zhuang Gu Zhi Tong Formula on Wnt/β-catenin Osteoporosis Pathway Antagonist SOST in Osteoporosis. DIGITAL CHINESE MEDICINE 2019. [DOI: 10.1016/j.dcmed.2019.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Asperosaponin VI stimulates osteogenic differentiation of rat adipose-derived stem cells. Regen Ther 2019; 11:17-24. [PMID: 31193169 PMCID: PMC6518317 DOI: 10.1016/j.reth.2019.03.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 02/14/2019] [Accepted: 03/20/2019] [Indexed: 12/20/2022] Open
Abstract
In the aging population, the decrease on osteogenic differentiation resulted into a significant reduction in bone formation. Bone tissue engineering has been a successful technique for treatment of bone defects. It is reported that adipose-derived stem cells (ADSCs) have pluripotency to differentiate into adipocytes and osteoblasts. However little is revealed about the effect of the herbal medicine Asperosaponin VI (ASA VI) on ADSCs differentiation. In our study, we isolated and identified ADSCs from rats. We examined the effect of different concentrations of ASA VI in ADSCs on alkaline phosphatase (ALP) activity, calcium deposition, the expression of bone-related proteins and the release of inflammatory cytokines. Flowcytometry assay showed ADSCs were highly expressed CD44 and CD105, but hardly expressed CD34 and CD45, suggesting ADSCs were successfully isolated for follow-up experiments. ALP activity examination and Alizarin red (AR) stain showed that ASA VI enhanced the ALP activity and promoted matrix mineralization in ADSCs. In addition, bone-related protein OCN and RUNX2, and Smad2/3 phosphorylation was upregulated after ASA VI treatment in ADSCs. ELISA results showed that ASA VI blocked the release of TNF-α, IL-6 and IL-1β in ADSCs. Considering this results, we concluded that ASA VI promotes osteogenic differentiation of ADSCs through inducing the expression of bone-related proteins. These findings enriched the function of ASA VI as a regenerative medicine and shed new light for the treatment of bone defects in clinical research.
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Hokmabad VR, Davaran S, Aghazadeh M, Alizadeh E, Salehi R, Ramazani A. Effect of incorporating Elaeagnus angustifolia extract in PCL-PEG-PCL nanofibers for bone tissue engineering. Front Chem Sci Eng 2019. [DOI: 10.1007/s11705-018-1742-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Liu L, Wang D, Qin Y, Xu M, Zhou L, Xu W, Liu X, Ye L, Yue S, Zheng Q, Li D. Astragalin Promotes Osteoblastic Differentiation in MC3T3-E1 Cells and Bone Formation in vivo. Front Endocrinol (Lausanne) 2019; 10:228. [PMID: 31040823 PMCID: PMC6476984 DOI: 10.3389/fendo.2019.00228] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 03/21/2019] [Indexed: 12/24/2022] Open
Abstract
Astragalin (AG) is a biologically active flavonoid compound that can be extracted from a number of medicinal plants. However, the effects of AG on osteoblastic differentiation in mouse MC3T3-E1 cells and on bone formation in vivo have not been studied fully. In this study, we found that the activities of alkaline phosphatase (ALP) and mineralized nodules in MC3T3-E1 cells were both significantly increased after treatment with AG (5, 10, and 20 μM). Meanwhile, the mRNA and protein levels of osteoblastic marker genes in MC3T3-E1 cells after AG treatment were markedly increased compared with a control group. In addition, the levels of BMP-2, p-Smad1/5/9, and Runx2 were significantly elevated in AG-treated MC3T3-E1 cells. Moreover, we found that the protein levels of Erk1/2, p-Erk1/2, p38, p-p38, and p-JNK were also significantly increased in AG-treated MC3T3-E1 cells compared to those in the control group. Finally, in vivo experiments demonstrated that AG significantly promoted bone formation in an ovariectomized (OVX)-induced osteoporotic mouse model. This was evidenced by significant increases in the values of osteoblast-related parameters (BFR/BS, MAR, Ob.S/BS, and Ob.N/B.Pm) and bone histomorphometric parameters (BMD, BV/TV, Tb.Th, and Tb.N.) in OVX mice after AG treatment (5, 10, and 20 mg/kg). Collectively, these results demonstrated that AG may promote osteoblastic differentiation in MC3T3-E1 cells via the activation of the BMP and MAPK pathways and promote bone formation in vivo. These novel findings indicated that AG may be a useful bone anabolic agent for the prevention and treatment of osteoporosis.
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Affiliation(s)
- Li Liu
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
- School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Dan Wang
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Yao Qin
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Maolei Xu
- School of Pharmacy, Binzhou Medical University, Yantai, China
| | - Ling Zhou
- School of Pharmacy, Binzhou Medical University, Yantai, China
| | - Wenjuan Xu
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Xiaona Liu
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Lei Ye
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Shijun Yue
- School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Qiusheng Zheng
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
- Key Laboratory of Xinjiang Endemic Phytomedicine Resources, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi, China
| | - Defang Li
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
- *Correspondence: Defang Li
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Eyvazi M, Farahzadi R, Karimian Fathi N, Karimipour M, Soleimani Rad J, Montaseri A. Mummy Material Can Promote Differentiation of Adipose Derived Stem Cells into Osteoblast through Enhancement of Bone Specific Transcription Factors Expression. Adv Pharm Bull 2018; 8:457-464. [PMID: 30276142 PMCID: PMC6156472 DOI: 10.15171/apb.2018.053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Revised: 07/17/2018] [Accepted: 07/19/2018] [Indexed: 12/20/2022] Open
Abstract
Purpose: Application of Mummy material for treatment of different diseases such as bone fracture, cutaneous wounds and joint inflammation has been advised since hundred years ago in Persian traditional medicine. Due to the claims of indigenous people and advice of traditional medicine for application of this material in healing of bone fractures, this study has been designed to evaluate whether Mummy material can promote the differentiation of mesenchymal stem cells into osteoblasts and enhance the expression of bone specific genes and proteins. Methods: Adipose derived stem cells (ASCs) at fourth cell passage were divided into control, osteogenesis group (received osteogenic medium), Mummy group (received Mummy at concentration of 500 µg/ml). ASCs in the fourth group were treated with both osteogenic medium and Mummy (500µg/ml). Cells in all groups were harvested on days 7, 14 and 21 days for further evaluation through Real time RT-PCR, Von kossa staining, Immunocytochemistry and flowcytometery. Results: Treatment of ASCs with Mummy at concentration of 500µg/ml promotes the expression level of Osteocalcin, RUNX-2 and β1-integrin genes in different time points but that of the Osterix did not changed. Furthermore the expression of Osteocalcin protein enhanced significantly in ASCs treated with Mummy detected by Immunocytochemistry and flowcytometery technique compared to the control groups. The results of this study also showed that treatment of ASCs with Mummy resulted in formation of mineral deposits which was evaluated by Von Kossa staining method. Conclusion: Obtained data from this study reveals that Mummy is a potent enhancer for differentiation of ASCs into osteoblasts in in vitro system, probably through increasing the level of bone specific genes and proteins.
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Affiliation(s)
- Maryam Eyvazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Raheleh Farahzadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nahid Karimian Fathi
- Biochemistry Department, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Karimipour
- Anatomical Sciences Department, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jafar Soleimani Rad
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Azadeh Montaseri
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Xi J, Li Q, Luo X, Li J, Guo L, Xue H, Wu G. Epigallocatechin‑3‑gallate protects against secondary osteoporosis in a mouse model via the Wnt/β‑catenin signaling pathway. Mol Med Rep 2018; 18:4555-4562. [PMID: 30221714 DOI: 10.3892/mmr.2018.9437] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 11/03/2017] [Indexed: 11/05/2022] Open
Abstract
Epigallocatechin‑3‑gallate (EGCG) is a polyphenolic compound extracted and isolated from green tea, which has a variety of important biological activities in vitro and in vivo, including anti‑tumor, anti‑oxidation, anti‑inflammation and lowering blood pressure. The aim of the present study was to investigate the protective effect of EGCG against secondary osteoporosis in a mouse model via the Wnt/β‑catenin signaling pathway. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting were used to analyze runt‑related transcription factor 2 and osterix mRNA expression, and the protein expression of cyclin D1, Wnt and β‑catenin, and suppressed peroxisome proliferator‑activated receptor γ protein expression. The protective effect of EGCG against secondary osteoporosis was examined and its potential mechanism was analyzed. Treatment with EGCG significantly decreased serum calcium, urinary calcium, body weight and body fat, and increased leptin levels in mice with secondary osteoporosis. In addition, EGCG treatment significantly inhibited the structure score of articular cartilage and cancellous bone in proximal tibia metaphysis in mice with secondary osteoporosis. Treatment also significantly decreased alkaline phosphatase activity, runt‑related transcription factor 2 and osterix mRNA expression. EGCG also significantly induced the protein expression of cyclin D1, Wnt and β‑catenin, and suppressed peroxisome proliferator‑activated receptor γ protein expression in mice with secondary osteoporosis. Taken together, these results suggest that EGCG may be a possible new drug in clinical settings.
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Affiliation(s)
- Jiancheng Xi
- Department of Minimally Invasive Spinal Surgery, The 309th Hospital of The People's Liberation Army, Beijing 100091, P.R. China
| | - Qinggui Li
- Department of Orthopedics, The Fourth Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Xiaobo Luo
- Department of Minimally Invasive Spinal Surgery, The 309th Hospital of The People's Liberation Army, Beijing 100091, P.R. China
| | - Jinlong Li
- Department of Minimally Invasive Spinal Surgery, The 309th Hospital of The People's Liberation Army, Beijing 100091, P.R. China
| | - Lixin Guo
- Department of Minimally Invasive Spinal Surgery, The 309th Hospital of The People's Liberation Army, Beijing 100091, P.R. China
| | - Haibin Xue
- Department of Minimally Invasive Spinal Surgery, The 309th Hospital of The People's Liberation Army, Beijing 100091, P.R. China
| | - Guangsen Wu
- Department of Minimally Invasive Spinal Surgery, The 309th Hospital of The People's Liberation Army, Beijing 100091, P.R. China
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Ma HP, Deng X, Chen DY, Zhu D, Tong JL, Zhao T, Ma JH, Liu YQ. A microfluidic chip-based co-culture of fibroblast-like synoviocytes with osteoblasts and osteoclasts to test bone erosion and drug evaluation. ROYAL SOCIETY OPEN SCIENCE 2018; 5:180528. [PMID: 30839692 PMCID: PMC6170564 DOI: 10.1098/rsos.180528] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 08/21/2018] [Indexed: 05/04/2023]
Abstract
Targeting fibroblast-like synoviocyte (FLS) migration and invasion-mediated bone erosion is a promising clinical strategy for the treatment of rheumatoid arthritis (RA). Drug sensitivity testing is fundamental to this scheme. We designed a microfluidic chip-based, cell co-cultured platform to mimic RA FLS-mediated bone erosion and perform drug-sensitive assay. Human synovium SW982 cells were cultured in the central channel and migrated to flow through matrigel-coated side channels towards cell culture chamber where RANKL-stimulated osteoclastic RAW264.7 and osteogenic medium (OS)-stimulated bone marrow mesenchymal stem cells (BMSC) were cultured in the microfluidic chip device, mimicking FLS migration and invasion-mediated bone erosion in RA. These SW982 cells showed different migration potentials to osteoclasts and BMSC. The migration of SW982 cells with high expression of cadherin-11 was more potent when SW982 cells were connected with the co-culture of RAW264.7 and BMSC. Simultaneously, in the co-cultured chamber, tartrate-resistant acid phosphatase (TRAP) activity of RANKL-stimulated RAW264.7 cells was enhanced, but alkaline phosphatase (ALP) activity was decreased in comparison with mono-cultured chamber. Furthermore, it was confirmed that celastrol, a positive drug for the treatment of RA, inhibited SW982 cell migration as well as TRAP activity in the cell-cultured microfluidic chips. Thus, the migration and invasion to bone-related cells was reconstituted on the microfluidic model. It may provide an effective anti-RA drug screen model for targeting FLS migration-mediated bone erosion.
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Affiliation(s)
- Hui-Peng Ma
- College of Laboratory Medicine, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Xue Deng
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Deng-Yi Chen
- College of Laboratory Medicine, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Di Zhu
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Jin-Ling Tong
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Ting Zhao
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Jin-Hui Ma
- People's Liberation Army No. 202 Hospital, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Yan-Qiu Liu
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian 116044, People's Republic of China
- Author for correspondence: Yan-Qiu Liu e-mail:
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Xue W, Yu J, Chen W. Plants and Their Bioactive Constituents in Mesenchymal Stem Cell-Based Periodontal Regeneration: A Novel Prospective. BIOMED RESEARCH INTERNATIONAL 2018; 2018:7571363. [PMID: 30175141 PMCID: PMC6098897 DOI: 10.1155/2018/7571363] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 06/12/2018] [Accepted: 07/04/2018] [Indexed: 12/24/2022]
Abstract
Periodontitis is a common chronic inflammatory disease, which causes the destruction of both the soft and mineralized tissues. However, current treatments such as bone graft materials, barrier membranes, and protein products all have difficulties in regenerating the complete periodontal tissue structure. Stem cell-based tissue engineering has now emerged as one of the most effective treatments for the patients suffering from periodontal diseases. Plants not only can be substrates for life processes, but also contain hormones or functional molecules. Numbers of preclinical studies have revealed that products from plant can be successfully applied in modulating proliferation and differentiation of human mesenchymal stem cells. Plant-derived substances can induce stem cells osteogenic differentiation, and they also possess angiogenic potency. Furthermore, in the field of tissue engineering, plant-derived compounds or plant extracts can be incorporated with biomaterials or utilized as biomaterials for cell transplantation. So it is speculated that botanical products may become a new perspective in stem cell-based periodontal regeneration. However, the lack of achieving predict clinical efficacy and quality control has been the major impediment to its extensive application. This review gives an overview of the prospect of applying different plant-derived substances in various human mesenchymal stem cells-based periodontal regeneration.
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Affiliation(s)
- Wenqing Xue
- Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China
- Department of Periodontics, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, Jiangsu 210029, China
| | - Jinhua Yu
- Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China
- Department of Endodontics, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, Jiangsu 210029, China
| | - Wu Chen
- Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China
- Department of Periodontics, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, Jiangsu 210029, China
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Zhang H, Wang H, Wei J, Chen X, Sun M, Ouyang H, Hao J, Chang Y, Dou Z, He J. Comparison of the Active Compositions between Raw and Processed Epimedium from Different Species. Molecules 2018; 23:E1656. [PMID: 29986486 PMCID: PMC6099698 DOI: 10.3390/molecules23071656] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 07/03/2018] [Accepted: 07/06/2018] [Indexed: 11/17/2022] Open
Abstract
Epimedium herb is one of the most vital traditional Chinese medicines (TCMs), which is used for “nourishing the kidney and reinforcing the Yang”. In the guidance of TCM theory, Epimedium herb is usually processed with lamb oil to increase its efficacy. The contents of active ingredients in different Epimedium are significantly varied, which may derive from their different species, regions and processing methods. In this research, 13 batches of raw Epimedium collected from 6 provinces were identified. After optimization of the processing method of Epimedium, a liquid chromatography⁻mass spectrometry (LC⁻MS/MS) method for simultaneous determination of 16 compounds was established to evaluate the quality of raw and processed. Then the multivariate statistical technique was applied to compare different batches of Epimedium based on the LC⁻MS/MS data. As a conclusion, the herbs collected from 6 areas were ascribed to 5 species by microscopic and appearance features. Meanwhile, all of the raw and processed samples were classified by partial least squares discriminant analysis (PLS-DA) based on the 16 analyzed compounds. The comparison results indicate that processing and species both have important influences on Epimedium compositions contents.
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Affiliation(s)
- Huamei Zhang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China.
| | - Hui Wang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China.
| | - Juan Wei
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China.
| | - Xiaopeng Chen
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China.
| | - Mengjie Sun
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China.
| | - Huizi Ouyang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China.
| | - Jia Hao
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China.
| | - Yanxu Chang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China.
| | - Zhiying Dou
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China.
| | - Jun He
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China.
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Iqbal M, Zhang H, Mehmood K, Li A, Jiang X, Wang Y, Zhang J, Iqbal MK, Rehman MU, Yao W, Yang S, Li J. Icariin: a Potential Compound for the Recovery of Tibial Dyschondroplasia Affected Chicken Via Up-Regulating BMP-2 Expression. Biol Proced Online 2018; 20:15. [PMID: 29988477 PMCID: PMC6026509 DOI: 10.1186/s12575-018-0080-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 05/24/2018] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Tibial dyschondroplasia (TD) is a skeletal disease of fast growing chicken and other avian species. It is characterized by an avascular and non-mineralized growth plate, which leads to a deformed tibial bone and lameness. Unfortunately, this disease is not only responsible for causing huge economic losses but also raises animal welfare concerns. Icariin is a flavonoid, which is isolated from Epimedium pubescens herb, and it has been used to cure different diseases including bone fractures and osteoporosis. RESULTS We designed this experiment to use icariin for the treatment of TD affect chickens; for this purpose, a total of 180 chicks were equally divided into three groups: control, TD and icariin. All the three groups were offered ad libitum same normal standard diet with an addition of thiram (50 mg/kg) from 3rd day to 7th day in TD and icariin group in order to induce TD in chickens. After the induction of TD, the chickens in icariin groups were fed standard diet with an addition of icariin at the rate of 10 mg/kg in drinking water to check the therapeutic effect of this flavonoid on TD. Our results showed that the icariin helped in restoring the TD lesion into a normal structure with significantly (P < 0.05) up-regulating the bone morphogenetic protein-2 (BMP-2) expression in the tibial growth plates (GP). CONCLUSIONS Icariin increased the vascular area in the growth plate and decreased the average TD score. In conclusion, this study shows that icariin is a potential compound for the recovery of TD affected chickens via up-regulating the BMP-2 expression without posing a threat of ingestion of toxic veterinary drug residues to human beings upon the consumption of treated chickens.
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Affiliation(s)
- Mujahid Iqbal
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070 People’s Republic of China
| | - Hui Zhang
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070 People’s Republic of China
| | - Khalid Mehmood
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070 People’s Republic of China
- University College of Veterinary and Animal Sciences, The Islamia University of Bahawalpur, Punjab, Pakistan
| | - Aoyun Li
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070 People’s Republic of China
| | - Xiong Jiang
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070 People’s Republic of China
| | - Yaping Wang
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070 People’s Republic of China
| | - Jialu Zhang
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070 People’s Republic of China
| | - Muhammad Kashif Iqbal
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070 People’s Republic of China
| | - Mujeeb Ur Rehman
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070 People’s Republic of China
| | - Wangyuan Yao
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070 People’s Republic of China
| | - Shijin Yang
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070 People’s Republic of China
| | - Jiakui Li
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070 People’s Republic of China
- College of Animal Husbandry and Veterinary Medicine, Tibet Agricultural and Animal Husbandry University, Linzhi, Tibet 860000 People’s Republic of China
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