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Li C, Ji H, Zhuang S, Xie X, Cui D, Zhang C. Update on the correlation between mitochondrial function and osteonecrosis of the femoral head osteocytes. Redox Rep 2025; 30:2491846. [PMID: 40249372 PMCID: PMC12010656 DOI: 10.1080/13510002.2025.2491846] [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: 04/19/2025] Open
Abstract
Mitochondrial health is maintained in a steady state through mitochondrial dynamics and autophagy processes. Recent studies have identified healthy mitochondria as crucial regulators of cellular function and survival. This process involves adenosine triphosphate (ATP) synthesis by mitochondrial oxidative phosphorylation (OXPHOS), regulation of calcium metabolism and inflammatory responses, and intracellular oxidative stress management. In the skeletal system, they participate in the regulation of cellular behaviors and the responses of osteoblasts, osteoclasts, chondrocytes, and osteocytes to external stimuli. Indeed, mitochondrial damage or dysfunction occurs in the development of a few bone diseases. For example, mitochondrial damage may lead to an imbalance in osteoblasts and osteoclasts, resulting in osteoporosis, osteomalacia, or poor bone production, and chondrocyte death and inflammatory infiltration in osteoarthritis are the main causes of cartilage degeneration due to mitochondrial damage. However, the opposite exists for osteosarcoma, where overactive mitochondrial metabolism is able to accelerate the proliferation and migration of osteosarcoma cells, which is a major disease feature. Bone is a dynamic organ and osteocytes play a fundamental role in all regions of bone tissue and are involved in regulating bone integrity. This review examines the impact of mitochondrial physiological function on osteocyte health and summarizes the microscopic molecular mechanisms underlying its effects. It highlights that targeted therapies focusing on osteocyte mitochondria may be beneficial for osteocyte survival, providing a new insight for the diagnosis, prevention, and treatment of diseases associated with osteocyte death.
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Affiliation(s)
- Chengming Li
- Department of Orthopedics, Zhongda Hospital Southeast University, Nanjing, People’s Republic of China
| | - Hangyu Ji
- Department of Orthopedics, Zhongda Hospital Southeast University, Nanjing, People’s Republic of China
| | - Suyang Zhuang
- Department of Orthopedics, Zhongda Hospital Southeast University, Nanjing, People’s Republic of China
| | - Xinhui Xie
- Department of Orthopedics, Zhongda Hospital Southeast University, Nanjing, People’s Republic of China
| | - Daping Cui
- Department of Orthopedics, Shenzhen Bao’an District Central Hospital, Shenzhen, People’s Republic of China
| | - Cong Zhang
- Department of Orthopedics, Zhongda Hospital Southeast University, Nanjing, People’s Republic of China
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Ruan W, Li T, Bang IH, Lee J, Deng W, Ma X, Luo C, Du F, Yoo SH, Kim B, Li J, Yuan X, Figarella K, An YA, Wang YY, Liang Y, DeBerge M, Zhang D, Zhou Z, Wang Y, Gorham JM, Seidman JG, Seidman CE, Aranki SF, Nair R, Li L, Narula J, Zhao Z, Gorfe AA, Muehlschlegel JD, Tsai KL, Eltzschig HK. BMAL1-HIF2A heterodimer modulates circadian variations of myocardial injury. Nature 2025; 641:1017-1028. [PMID: 40269168 PMCID: PMC12095075 DOI: 10.1038/s41586-025-08898-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 03/14/2025] [Indexed: 04/25/2025]
Abstract
Acute myocardial infarction is a leading cause of morbidity and mortality worldwide1. Clinical studies have shown that the severity of cardiac injury after myocardial infarction exhibits a circadian pattern, with larger infarcts and poorer outcomes in patients experiencing morning-onset events2-7. However, the molecular mechanisms underlying these diurnal variations remain unclear. Here we show that the core circadian transcription factor BMAL17-11 regulates circadian-dependent myocardial injury by forming a transcriptionally active heterodimer with a non-canonical partner-hypoxia-inducible factor 2 alpha (HIF2A)12-16-in a diurnal manner. To substantiate this finding, we determined the cryo-EM structure of the BMAL1-HIF2A-DNA complex, revealing structural rearrangements within BMAL1 that enable cross-talk between circadian rhythms and hypoxia signalling. BMAL1 modulates the circadian hypoxic response by enhancing the transcriptional activity of HIF2A and stabilizing the HIF2A protein. We further identified amphiregulin (AREG)16,17 as a rhythmic target of the BMAL1-HIF2A complex, critical for regulating daytime variations of myocardial injury. Pharmacologically targeting the BMAL1-HIF2A-AREG pathway provides cardioprotection, with maximum efficacy when aligned with the pathway's circadian phase. These findings identify a mechanism governing circadian variations of myocardial injury and highlight the therapeutic potential of clock-based pharmacological interventions for treating ischaemic heart disease.
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Affiliation(s)
- Wei Ruan
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA.
- Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, China.
| | - Tao Li
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - In Hyuk Bang
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Jaewoong Lee
- Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA
| | - Wankun Deng
- Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Xinxin Ma
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Cong Luo
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
- Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Fang Du
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Seung-Hee Yoo
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Boyun Kim
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
- Major in Aquaculture and Applied Life Sciences, College of Fisheries Science, Pukyong National University, Busan, Republic of Korea
| | - Jiwen Li
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
- Department of Cardiac Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoyi Yuan
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Katherine Figarella
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Yu A An
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Yin-Ying Wang
- Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yafen Liang
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
- Center for Outcomes Research, UTHealth Houston, Houston, TX, USA
| | - Matthew DeBerge
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Dongze Zhang
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Zhen Zhou
- Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Yanyu Wang
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Joshua M Gorham
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | | | | | - Sary F Aranki
- Department of Surgery, Division of Cardiac Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ragini Nair
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Lei Li
- Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, China
| | - Jagat Narula
- Division of Cardiology, Department of Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Memorial Hermann Hospital, Houston, TX, USA
| | - Zhongming Zhao
- Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Alemayehu A Gorfe
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Jochen D Muehlschlegel
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kuang-Lei Tsai
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA.
- MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
| | - Holger K Eltzschig
- Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA.
- Center for Outcomes Research, UTHealth Houston, Houston, TX, USA.
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Fan Y, Chen Z, Wang H, Jiang M, Lu H, Wei Y, Hu Y, Mo L, Liu Y, Zhou C, He W, Chen Z. Isovitexin targets SIRT3 to prevent steroid-induced osteonecrosis of the femoral head by modulating mitophagy-mediated ferroptosis. Bone Res 2025; 13:18. [PMID: 39865068 PMCID: PMC11770138 DOI: 10.1038/s41413-024-00390-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 09/18/2024] [Accepted: 11/13/2024] [Indexed: 01/30/2025] Open
Abstract
The death of osteoblasts induced by glucocorticoid (GC)-mediated oxidative stress plays a crucial role in the development of steroid-induced osteonecrosis of the femoral head (SIONFH). Improving bone formation driven by osteoblasts has shown promising outcomes in the prognosis of SIONFH. Isovitexin has demonstrated antioxidant properties, but its therapeutic effects on GC-induced oxidative stress and SIONFH remain unexplored. In this study, we analyzed clinical samples obtained from SIONFH patients using proteomic and bioinformatic approaches. We found an imbalance in mitochondrial homeostasis and ferroptosis-induced impairment of osteogenic capacity in SIONFH. Subsequently, we investigated the cause-and-effect relationship between mitochondria and ferroptosis, as well as the regulatory role of mitophagy in maintaining mitochondrial homeostasis and controlling ferroptosis. We then identified the critical involvement of SIRT3 in modulating mitochondrial homeostasis and ferroptosis. Furthermore, molecular docking and co-immunoprecipitation confirmed the strong interaction between SIRT3 and BNIP3. Strikingly, restoring SIRT3 expression significantly inhibited pathological mitophagy mediated by the BNIP3/NIX pathway. Additionally, we discovered that Isovitexin, by promoting SIRT3 expression, effectively regulated mitophagy, preserved mitochondrial homeostasis in osteoblasts, suppressed ferroptosis, and restored osteogenic capacity, leading to remarkable improvements in SIONFH. These findings reveal the effects and molecular mechanisms of Isovitexin on SIONFH and highlight the potential of targeting SIRT3 as a promising strategy to suppress mitophagy-mediated ferroptosis in osteoblasts and against SIONFH.
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Affiliation(s)
- Yinuo Fan
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhiwen Chen
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Haixing Wang
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Mengyu Jiang
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hongduo Lu
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yangwenxiang Wei
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yunhao Hu
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liang Mo
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuhao Liu
- The Department of Orthopedics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Chi Zhou
- The Department of Orthopedics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Wei He
- The Department of Orthopedics, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
| | - Zhenqiu Chen
- The Department of Orthopedics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
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Fahad Almulhim B, Sherif FE, Younis NS, Safwat Y, Khattab S. Foliar spraying with zinc oxide nanoparticles enhances the anti-osteoporotic efficacy of the fruit extracts of Silybum marianum L. by stimulating silybin production. FRONTIERS IN PLANT SCIENCE 2025; 15:1421485. [PMID: 39840357 PMCID: PMC11747799 DOI: 10.3389/fpls.2024.1421485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 11/28/2024] [Indexed: 01/23/2025]
Abstract
Introduction Silybum marianum is a medicinal plant that produces silymarin, which has been demonstrated to possess antiviral, anti-neurodegenerative, and anticancer activities. Silybin (A+B) are two major hepatoprotective flavonolignans produced predominantly in S. marianum fruits. Several attempts have been made to increase the synthesis of silymarin, or its primary components, silybin (A+B). Zinc oxide nanoparticles (ZnO-NPs) are considered a highly efficient Zn source widely used to promote crop development and productivity. Methods In this study, we aimed to investigate the effects of the foliar application of ZnO-NPs on the growth, yield, photosynthetic pigment content, silybin (A+B) content, and the expression of the chalcone synthase (CHS) gene in S. marianum plants. Different concentrations of ZnO-NPs were administered as foliar sprays to S. marianum plants growing in greenhouse conditions. Furthermore, we evaluated the anti-osteoporotic efficacy of the corresponding fruit extract against dexamethasone (Dex)-induced osteoporosis. Results and discussion Foliar treatment at all ZnO-NP concentrations increased the amounts of bioactive components of silybin (A+B), which enhanced the growth and yield of S. marianum plants while increasing the levels of N, P, K, and Zn in their leaves, roots, and fruits; the levels of photosynthetic pigments in their leaves; and silybin (A+B) content in their fruits, thereby increasing the medicinal value of S. marianum. The highest gains were observed in plants sprayed with the highest ZnO-NP concentration (20.0 mg/L). In addition, gene expression studies revealed that ZnO-NPs stimulated silybin (A+B) production by activating CHS genes. The administration of S. marianum extracts to Dex-administered rats increased osteoblast and bone formation while inhibiting osteoclast and bone resorption, thereby protecting the animals against Dex-induced osteoporosis.
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Affiliation(s)
- Bedoor Fahad Almulhim
- Department of Biological Sciences, College of Science, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Fadia El Sherif
- Department of Biological Sciences, College of Science, King Faisal University, Al-Ahsa, Saudi Arabia
- Department of Horticulture, Faculty of Agriculture, Suez Canal University, Ismalia, Egypt
| | - Nancy S. Younis
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Yamen Safwat
- Department of Orthopedic Surgery, Zagazig University, Zagazig, Egypt
| | - Salah Khattab
- Department of Biological Sciences, College of Science, King Faisal University, Al-Ahsa, Saudi Arabia
- Department of Horticulture, Faculty of Agriculture, Suez Canal University, Ismalia, Egypt
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Cekuc MS, Ergul YS, Pius AK, Meagan M, Shinohara I, Murayama M, Susuki Y, Ma C, Morita M, Chow SKH, Bunnell BA, Lin H, Gao Q, Goodman SB. Metformin Modulates Cell Oxidative Stress to Mitigate Corticosteroid-Induced Suppression of Osteogenesis in a 3D Model. J Inflamm Res 2024; 17:10383-10396. [PMID: 39654863 PMCID: PMC11625639 DOI: 10.2147/jir.s498888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 11/26/2024] [Indexed: 12/12/2024] Open
Abstract
Background Corticosteroids provide well-established therapeutic benefits; however, they are also accompanied by adverse effects on bone. Metformin is a widely used medication for managing type 2 diabetes mellitus. Recent studies have highlighted additional therapeutic benefits of metformin, particularly concerning bone health and oxidative stress. Objective This research investigates the effects of prednisolone on cellular metabolic functions and bone formation using a 3D in vitro model. Then, we demonstrate the potential therapeutic effects of metformin on oxidative stress and the formation of calcified matrix due to corticosteroids. Methods Human mesenchymal stem cells (MSCs) and macrophages were cultured in a 3D GelMA scaffold and stimulated with prednisolone, with and without metformin. The adverse effects of prednisolone and metformin's therapeutic effect(s) were assessed by analyzing cell viability, osteogenesis markers, bone mineralization, and inflammatory markers. Oxidative stress was measured by evaluating reactive oxygen species (ROS) levels and ATP production. Results Prednisolone exhibited cytotoxic effects, reducing the viability of MSCs and macrophages. Lower osteogenesis potential was also detected in the MSC group. Metformin positively affected cell functions, including enhanced osteoblast activity and increased bone mineralization. Furthermore, metformin effectively reduced oxidative stress, as evidenced by decreased ROS levels and increased ATP production. These findings indicate that metformin protects against oxidative damage, thus supporting osteogenesis. Conclusion Metformin exhibits promising therapeutic potential beyond its role in diabetes management. The capacity to alleviate oxidative stress highlights the potential of metformin in supporting bone formation in inflammatory environments.
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Affiliation(s)
- Mehmet Sertac Cekuc
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Yasemin Sude Ergul
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Alexa K Pius
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Makarcyzk Meagan
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA
| | - Issei Shinohara
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Masatoshi Murayama
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Yosuke Susuki
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Chao Ma
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Mayu Morita
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Simon Kwoon-Ho Chow
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Bruce A Bunnell
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
| | - Hang Lin
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA
| | - Qi Gao
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Stuart B Goodman
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
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Yang Y, Jian Y, Liu Y, Ma M, Guo J, Xu B, Yue C. Mitochondrial maintenance as a novel target for treating steroid-induced osteonecrosis of femoral head: a narrative review. EFORT Open Rev 2024; 9:1013-1022. [PMID: 39513701 PMCID: PMC11619724 DOI: 10.1530/eor-24-0023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2024] Open
Abstract
The pathogenesis of steroid-induced osteonecrosis of the femoral head (SONFH) remains unclear; however, emerging evidence suggests that mitochondrial injury plays a significant role. This review aims to elucidate the involvement of mitochondrial dysfunction in SONFH and explore potential therapeutic targets. A comprehensive literature search was conducted in PubMed, Web of Science, and Elsevier ScienceDirect, focusing on mitochondrial homeostasis, including mitophagy, mitochondrial biogenesis, mitochondrial dynamics, and oxidative stress in SONFH. Ultimately, we included and analyzed a total of 16 studies. Glucocorticoids initially promote but later inhibit mitochondrial biogenesis in osteoblasts, leading to excessive ROS production and mitochondrial dysfunction. This dysfunction impairs osteoblast survival and bone formation, contributing to SONFH progression. Key proteins such as mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α) are potential therapeutic targets for promoting mitochondrial biogenesis and reducing ROS-induced damage. Enhancing mitochondrial function and reducing oxidative stress in osteoblasts may prevent or slow the progression of SONFH. Future research should focus on developing these strategies.
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Affiliation(s)
- Yidan Yang
- Henan University of Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China
| | - Yi Jian
- Department of Orthopedics, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan Province, People’s Republic of China
| | - Youwen Liu
- Henan University of Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China
- Department of Orthopedics, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan Province, People’s Republic of China
| | - Maoxiao Ma
- Department of Orthopedics, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan Province, People’s Republic of China
| | - Jiayi Guo
- Department of Orthopedics, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan Province, People’s Republic of China
| | - Bin Xu
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Chen Yue
- Department of Orthopedics, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan Province, People’s Republic of China
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Zheng X, Ye FC, Sun T, Liu FJ, Wu MJ, Zheng WH, Wu LF. Delay the progression of glucocorticoid-induced osteoporosis: Fraxin targets ferroptosis via the Nrf2/GPX4 pathway. Phytother Res 2024; 38:5203-5224. [PMID: 39192711 DOI: 10.1002/ptr.8310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 07/09/2024] [Accepted: 07/24/2024] [Indexed: 08/29/2024]
Abstract
Glucocorticoid-induced osteoporosis (GIOP) commonly accelerates bone loss, increasing the risk of fractures and osteonecrosis more significantly than traditional menopausal osteoporosis. The extracellular environment influenced by glucocorticoids heightens fracture and osteonecrosis risks. Fraxin (Fra), a key component of the traditional Chinese herbal remedy Cortex Fraxini, is known for its wide-ranging pharmacological effects, but its impact on GIOP remains unexplored. This investigation aims to delineate the effects and underlying mechanisms of Fra in combating dexamethasone (Dex)-induced ferroptosis and GIOP. We established a mouse model of GIOP via intraperitoneal injections of Dex and cultured osteoblasts with Dex treatment for in vitro analysis. We evaluated the impact of Fra on Dex-treated osteoblasts through assays such as C11-BODIPY and FerroOrange staining, mitochondrial functionality tests, and protein expression analyses via Western blot and immunofluorescence. The influence of Fra on bone microarchitecture of GIOP in mice was assessed using microcomputerized tomography, hematoxylin and eosin staining, double-labeling with Calcein-Alizarin Red S, and immunohistochemistry at imaging and histological levels. Based on our data, Fra prevented Dex-induced ferroptosis and bone loss. In vitro, glutathione levels increased and malondialdehyde, lipid peroxidation, and mitochondrial reactive oxygen species decreased. Fra treatment also increases nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and COL1A1 expression and promotes bone formation. To delve deeper into the mechanism, the findings revealed that Fra triggered the activation of Nrf2/GPX4 signaling. Moreover, the use of siRNA-Nrf2 blocked the beneficial effect of Fra in osteoblasts cultivated with Dex. Fra effectively combats GIOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.
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Affiliation(s)
- Xiang Zheng
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Fang-Chen Ye
- The First School of Medicine, Nanfang Medical University, Guangzhou, China
| | - Tao Sun
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Fei-Jun Liu
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Ming-Jian Wu
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Wen-Hao Zheng
- Department of Orthopaedic, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ling-Feng Wu
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
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Rong Y, Liang X, Jiang K, Jia H, Li H, Lu B, Li G. Global Trends in Research of Programmed Cell Death in Osteoporosis: A Bibliometric and Visualized Analysis (2000-2023). Orthop Surg 2024; 16:1783-1800. [PMID: 38923347 PMCID: PMC11293941 DOI: 10.1111/os.14133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/28/2024] Open
Abstract
Osteoporosis (OP) is a systemic metabolic bone disease that is characterized by decreased bone mineral density and microstructural damage to bone tissue. Recent studies have demonstrated significant advances in the research of programmed cell death (PCD) in OP. However, there is no bibliometric analysis in this research field. This study searched the Web of Science Core Collection (WoSCC) database for literature related to OP and PCD from 2000 to 2023. This study used VOSviewers 1.6.20, the "bibliometrix" R package, and CiteSpace (6.2.R3) for bibliometric and visualization analysis. A total of 2905 articles from 80 countries were included, with China and the United States leading the way. The number of publications related to PCD in OP is increasing year by year. The main research institutions are Shanghai Jiao Tong University, Chinese Medical University, Southern Medical University, Zhejiang University, and Soochow University. Bone is the most popular journal in the field of PCD in OP, and the Journal of Bone and Mineral Research is the most co-cited journal. These publications come from 14,801 authors, with Liu Zong-Ping, Yang Lei, Manolagas Stavros C, Zhang Wei, and Zhao Hong-Yan having published the most papers. Ronald S. Weinstein was co-cited most often. Oxidative stress and autophagy are the current research hot spots for PCD in OP. This bibliometric study provides the first comprehensive summary of trends and developments in PCD research in OP. This information identifies the most recent research frontiers and hot directions, which will provide a definitive reference for scholars studying PCD in OP.
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Affiliation(s)
- Yi‐fa Rong
- The First College of Clinical MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Xue‐Zhen Liang
- The First College of Clinical MedicineShandong University of Traditional Chinese MedicineJinanChina
- Orthopaedic MicrosurgeryAffiliated Hospital of Shandong University of Traditional Chinese MedicineJinanChina
| | - Kai Jiang
- The First College of Clinical MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Hai‐Feng Jia
- The First College of Clinical MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Han‐Zheng Li
- The First College of Clinical MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Bo‐Wen Lu
- The First College of Clinical MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Gang Li
- Orthopaedic MicrosurgeryAffiliated Hospital of Shandong University of Traditional Chinese MedicineJinanChina
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9
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Pal China S, Kalyanaraman H, Zhuang S, Cabriales JA, Sah RL, Pilz RB. Protein kinase G2 activation restores Wnt signaling and bone mass in glucocorticoid-induced osteoporosis in mice. JCI Insight 2024; 9:e175089. [PMID: 38885330 PMCID: PMC11383176 DOI: 10.1172/jci.insight.175089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 05/31/2024] [Indexed: 06/20/2024] Open
Abstract
Osteoporotic fractures are a major complication of long-term glucocorticoid therapy. Glucocorticoids transiently increase bone resorption, but they predominantly inhibit bone formation and induce osteocyte apoptosis, leading to bone loss. Current treatments of glucocorticoid-induced osteoporosis aim mainly at reducing bone resorption and are, therefore, inadequate. We previously showed that signaling via the NO/cGMP/protein kinase G pathway plays a key role in skeletal homeostasis. Here, we show that pharmacological PKG activation with the guanylyl cyclase-1 activator cinaciguat or expression of a constitutively active, mutant PKG2R242Q restored proliferation, differentiation, and survival of primary mouse osteoblasts exposed to dexamethasone. Cinaciguat treatment of WT mice or osteoblast-specific expression of PKG2R242Q in transgenic mice prevented dexamethasone-induced loss of cortical bone mass and strength. These effects of cinaciguat and PKG2R242Q expression were due to preserved bone formation parameters and osteocyte survival. The basis for PKG2's effects appeared to be through recovery of Wnt/β-catenin signaling, which was suppressed by glucocorticoids but critical for proliferation, differentiation, and survival of osteoblast-lineage cells. Cinaciguat reduced dexamethasone activation of osteoclasts, but this did not occur in the PKG2R242Q transgenic mice, suggesting a minor role in osteoprotection. We propose that existing PKG-targeting drugs could represent a novel therapeutic approach to prevent glucocorticoid-induced osteoporosis.
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Affiliation(s)
| | | | | | | | - Robert L Sah
- Department of Bioengineering, UCSD, La Jolla, California, USA
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10
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Przewłócka K, Korewo-Labelle D, Berezka P, Karnia MJ, Kaczor JJ. Current Aspects of Selected Factors to Modulate Brain Health and Sports Performance in Athletes. Nutrients 2024; 16:1842. [PMID: 38931198 PMCID: PMC11206260 DOI: 10.3390/nu16121842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/10/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
This review offers a comprehensive evaluation of current aspects related to nutritional strategies, brain modulation, and muscle recovery, focusing on their applications and the underlying mechanisms of physiological adaptation for promoting a healthy brain, not only in athletes but also for recreationally active and inactive individuals. We propose that applying the rule, among others, of good sleep, regular exercise, and a properly balanced diet, defined as "SPARKS", will have a beneficial effect on the function and regeneration processes of the gut-brain-muscle axis. However, adopting the formula, among others, of poor sleep, stress, overtraining, and dysbiosis, defined as "SMOULDER", will have a detrimental impact on the function of this axis and consequently on human health as well as on athletes. Understanding these dynamics is crucial for optimizing brain health and cognitive function. This review highlights the significance of these factors for overall well-being, suggesting that adopting the "SPARKS" approach may benefit not only athletes but also older adults and individuals with health conditions.
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Affiliation(s)
- Katarzyna Przewłócka
- Division of Physiology, Gdansk University of Physical Education and Sport, 80-336 Gdansk, Poland;
| | - Daria Korewo-Labelle
- Department of Physiology, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland;
| | - Paweł Berezka
- Department of Animal and Human Physiology, Faculty of Biology, University of Gdansk, 80-309 Gdansk, Poland; (P.B.); (M.J.K.)
| | - Mateusz Jakub Karnia
- Department of Animal and Human Physiology, Faculty of Biology, University of Gdansk, 80-309 Gdansk, Poland; (P.B.); (M.J.K.)
| | - Jan Jacek Kaczor
- Department of Animal and Human Physiology, Faculty of Biology, University of Gdansk, 80-309 Gdansk, Poland; (P.B.); (M.J.K.)
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11
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Kikuchi T, Udagawa K, Sasazaki Y. High-molecular-weight Hyaluronan Administration Inhibits Bone Resorption and Promotes Bone Formation in Young-age Osteoporosis Rats. J Histochem Cytochem 2024; 72:373-385. [PMID: 38804525 PMCID: PMC11179592 DOI: 10.1369/00221554241255724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/29/2024] [Indexed: 05/29/2024] Open
Abstract
Osteoporosis poses a significant global health concern, affecting both the elderly and young individuals, including athletes. Despite the development of numerous antiosteoporotic drugs, addressing the unique needs of young osteoporosis patients remains challenging. This study focuses on young rats subjected to ovariectomy (OVX) to explore the impact of high-molecular-weight hyaluronan (HA) on preventing OVX-induced osteoporosis. Twenty-four rats underwent OVX, while 12 underwent sham procedures (sham control group). Among the OVX rats, half received subcutaneous injections of HA (MW: 2700 kDa) at 10 mg/kg/week into their backs (OVX-HA group), whereas the other half received saline injections (0.5 ml/week) at the same site (OVX-saline group). OVX-HA group exhibited significantly higher percentages of osteoclast surface (Oc. S/BS), osteoblast surface per bone surface (Ob. S/BS), and bone volume/tissue volume (BV/TV) compared with OVX-saline group at the same age. The proportions of Ob. S/BS and BV/TV in the OVX-HA group closely resembled those of the sham control group, whereas the proportion of Oc. S/BS in the OVX-HA group was notably higher than that in the sham control group. In summary, the administration of HA significantly mitigated bone resorption and enhanced bone formation, suggesting a crucial role for HA in the treatment of young adult osteoporosis.
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Affiliation(s)
- Toshiyuki Kikuchi
- National Hospital Organization Murayama Medical Center, Tokyo, Japan
| | - Kazuhiko Udagawa
- Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
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12
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Goto K, Watanabe D, Kawae N, Nakamura T, Yanagida K, Yoshida T, Kajihara H, Mizushima A. Relationship between Femoral Proximal Bone Quality Assessment by MRI IDEAL-IQ Sequence and Body Mass Index in Elderly Men. Tomography 2024; 10:816-825. [PMID: 38787022 PMCID: PMC11125441 DOI: 10.3390/tomography10050062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/08/2024] [Accepted: 05/16/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND Bone assessment using the MRI DEAL-IQ sequence may have the potential to serve as a substitute for evaluating bone strength by quantifying the bone marrow hematopoietic region (R2*) and marrow adiposity (proton density fat fraction: PDFF). Higher body mass index (BMI) is associated with increased bone mineral density (BMD) in the proximal femur; however, the relationship between BMI and R2* or PDFF remains unclear. Herein, we investigated the correlation between BMI and MRI IDEAL-IQ based R2* or PDFF of the proximal femur. METHODS A retrospective single-cohort study was conducted on 217 patients diagnosed with non-metastatic prostate cancer between September 2019 and December 2022 who underwent MRI. The correlation between BMI and R2* or PDFF of the proximal femur was analyzed using Spearman's rank correlation test. RESULTS Among 217 patients (median age, 74 years; median BMI, 23.8 kg/m2), there was a significant positive correlation between BMI and R2* at the right and left proximal femur (r = 0.2686, p < 0.0001; r = 0.2755, p < 0.0001, respectively). Furthermore, BMI and PDFF showed a significant negative correlation (r = -0.239, p = 0.0004; r = -0.2212, p = 0.001, respectively). CONCLUSION In elderly men, the increased loading on the proximal femur due to elevated BMI was observed to promote a decrease in bone marrow adiposity in the proximal femur, causing a tendency for a transition from fatty marrow to red marrow with hematopoietic activity. These results indicate that the MRI IDEAL-IQ sequence may be valuable for assessing bone quality deterioration in the proximal femur.
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Affiliation(s)
- Kashia Goto
- Department of Palliative Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (K.G.); (N.K.); (A.M.)
| | - Daisuke Watanabe
- Department of Palliative Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (K.G.); (N.K.); (A.M.)
- Department of Urology, Koto Hospital, Tokyo 136-0072, Japan; (K.Y.); (T.Y.)
- Department of Molecular and Cellular Therapeutics, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Norikazu Kawae
- Department of Palliative Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (K.G.); (N.K.); (A.M.)
- Department of Radiology, Koto Hospital, Tokyo 136-0072, Japan;
| | | | - Kazuki Yanagida
- Department of Urology, Koto Hospital, Tokyo 136-0072, Japan; (K.Y.); (T.Y.)
| | - Takahiro Yoshida
- Department of Urology, Koto Hospital, Tokyo 136-0072, Japan; (K.Y.); (T.Y.)
| | - Hajime Kajihara
- Department of Orthopedic Surgery, Koto Hospital, Tokyo 136-0072, Japan;
| | - Akio Mizushima
- Department of Palliative Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (K.G.); (N.K.); (A.M.)
- Department of Molecular and Cellular Therapeutics, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
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13
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Rahimi K, Nourishirazi A, Delaviz H, Ghotbeddin Z. Antinociceptive effects of gamma-linolenic acid in the formalin test in the rats. Ann Med Surg (Lond) 2024; 86:2677-2683. [PMID: 38694379 PMCID: PMC11060212 DOI: 10.1097/ms9.0000000000002001] [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: 01/20/2024] [Accepted: 03/13/2024] [Indexed: 05/04/2024] Open
Abstract
Background Gamma-linolenic acid (GLA) is found in animals and plants that play a role in brain function and metabolism. Objective This study aimed to investigate the analgesic effects of GLA on peripheral formalin injection. Methods Wistar rats were randomly assigned to four groups: Sham, formalin, formalin/GLA 100 mg/kg, and formalin/GLA 150 mg/kg. The Formalin test was utilized to create a pain model. A tissue sample was prepared from the spinal cords of rats to measure oxidative stress parameters and pro-inflammatory cytokines. Furthermore, the authors analyzed the expression of c-Fos protein in the spinal cords. Results Our findings demonstrate that GLA has a reliable pain-relieving effect in the formalin test. GLA 100 increased superoxide dismutase (SOD) (P<0.05), glutathione (GSH) (P<0.001), and catalase (CAT) (P<0.05), and decreased the levels of c-Fos (P<0.001), interleukin-1 beta (IL-1β) (P<0.001), tumour necrosis factor-alpha (TNF-α) (P<0.001), and malondialdehyde (MDA) (P<0.001) in the spinal cord. Also GLA 150 increased SOD (P<0.05), GSH (P<0.001), and CAT (P<0.05) and decreased the levels of c-Fos (P<0.001), IL-1β (P<0.001), TNF-α (P<0.001), and MDA (P<0.001) in the spinal cord. Conclusion The findings have validated the antinociceptive impact of GLA and hinted towards its immunomodulatory influence in the formalin test.
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Affiliation(s)
- Kaveh Rahimi
- Department of Basic Sciences, Faculty of Veterinary Medicine
| | | | | | - Zohreh Ghotbeddin
- Department of Basic Sciences, Faculty of Veterinary Medicine
- Stem Cell and Transgenic Technology Research Center, Shahid Chamran University of Ahvaz, Ahvaz, Iran
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14
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Mou K, Chan SMH, Vlahos R. Musculoskeletal crosstalk in chronic obstructive pulmonary disease and comorbidities: Emerging roles and therapeutic potentials. Pharmacol Ther 2024; 257:108635. [PMID: 38508342 DOI: 10.1016/j.pharmthera.2024.108635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 02/13/2024] [Accepted: 03/11/2024] [Indexed: 03/22/2024]
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is a multifaceted respiratory disorder characterized by progressive airflow limitation and systemic implications. It has become increasingly apparent that COPD exerts its influence far beyond the respiratory system, extending its impact to various organ systems. Among these, the musculoskeletal system emerges as a central player in both the pathogenesis and management of COPD and its associated comorbidities. Muscle dysfunction and osteoporosis are prevalent musculoskeletal disorders in COPD patients, leading to a substantial decline in exercise capacity and overall health. These manifestations are influenced by systemic inflammation, oxidative stress, and hormonal imbalances, all hallmarks of COPD. Recent research has uncovered an intricate interplay between COPD and musculoskeletal comorbidities, suggesting that muscle and bone tissues may cross-communicate through the release of signalling molecules, known as "myokines" and "osteokines". We explored this dynamic relationship, with a particular focus on the role of the immune system in mediating the cross-communication between muscle and bone in COPD. Moreover, we delved into existing and emerging therapeutic strategies for managing musculoskeletal disorders in COPD. It underscores the development of personalized treatment approaches that target both the respiratory and musculoskeletal aspects of COPD, offering the promise of improved well-being and quality of life for individuals grappling with this complex condition. This comprehensive review underscores the significance of recognizing the profound impact of COPD on the musculoskeletal system and its comorbidities. By unravelling the intricate connections between these systems and exploring innovative treatment avenues, we can aspire to enhance the overall care and outcomes for COPD patients, ultimately offering hope for improved health and well-being.
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Affiliation(s)
- Kevin Mou
- Centre for Respiratory Science and Health, School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Stanley M H Chan
- Centre for Respiratory Science and Health, School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Ross Vlahos
- Centre for Respiratory Science and Health, School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia.
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15
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Parveen B, Penumallu NR, Shaik AR, Parveen A, Parveen R, Vohora D. The impact of antiseizure medication on bone heath: A systematic review of animal studies. Epilepsy Res 2024; 200:107302. [PMID: 38280331 DOI: 10.1016/j.eplepsyres.2024.107302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 12/01/2023] [Accepted: 01/11/2024] [Indexed: 01/29/2024]
Abstract
BACKGROUND Antiseizure medications (ASMs) are known to potentially impact bone health, but existing literature presents conflicting results regarding their specific effects on bone mineralization, metabolism, and quality. OBJECTIVE This systematic review aims to establish a consensus regarding the influence of ASMs on bone health based on existing preclinical studies. METHODS Following SYRCLE and PRISMA guidelines, we conducted a systematic search in PubMed, Science Direct, and Google Scholar to identify relevant studies. Ultimately, 21 articles were selected for inclusion in this review. RESULTS Among the chosen studies, approximately half involved Wistar rats as experimental subjects. Levetiracetam and sodium valproate were the most frequently investigated drugs, with a typical treatment duration of 10-12 weeks. These studies exhibited a low risk of bias in aspects like sequence generation, random housing, random outcome assessment, and reporting bias. However, blinding in performance, allocation concealment, and detection were often rated as having a high risk of bias. The collective findings suggest that prolonged ASM use leads to reduced bone mineral density, altered bone turnover marker levels (including hypovitaminosis D, hypocalcemia, and secondary hyperparathyroidism), deterioration of bone microarchitecture, and decreased mechanical strength. CONCLUSION The adverse effects on bone associated with ASMs are not limited to enzyme-inducing drugs, as newer generation ASMs may also contribute to these effects. Hypovitaminosis D alone may not be solely responsible for ASM-induced bone issues, suggesting the involvement of other mechanisms. Furthermore, substantial variations were observed in the results of different preclinical studies on individual ASMs, highlighting the need to standardize animal study methodologies to enhance reproducibility and reduce variation.
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Affiliation(s)
- Bushra Parveen
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India; Centre of Excellence in Unani Medicine (Pharmacognosy & Pharmacology), Bioactive Natural Product Laboratory, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.
| | - Naveen Reddy Penumallu
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India; Centre of Excellence in Unani Medicine (Pharmacognosy & Pharmacology), Bioactive Natural Product Laboratory, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Abdul Rahaman Shaik
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Abida Parveen
- Centre of Excellence in Unani Medicine (Pharmacognosy & Pharmacology), Bioactive Natural Product Laboratory, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Rabea Parveen
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Divya Vohora
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.
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16
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Sandor LF, Ragacs R, Gyori DS. Local Effects of Steroid Hormones within the Bone Microenvironment. Int J Mol Sci 2023; 24:17482. [PMID: 38139309 PMCID: PMC10744126 DOI: 10.3390/ijms242417482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 12/05/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Steroid hormone production via the adrenal cortex, gonads, and placenta (so-called glandular steroidogenesis) is responsible for the endocrine control of the body's homeostasis and is organized by a feedback regulatory mechanism based on the hypothalamus-pituitary-steroidogenic gland axis. On the other hand, recently discovered extraglandular steroidogenesis occurring locally in different tissues is instead linked to paracrine or autocrine signaling, and it is independent of the control by the hypothalamus and pituitary glands. Bone cells, such as bone-forming osteoblasts, osteoblast-derived osteocytes, and bone-resorbing osteoclasts, respond to steroid hormones produced by both glandular and extraglandular steroidogenesis. Recently, new techniques to identify steroid hormones, as well as synthetic steroids and steroidogenesis inhibitors, have been introduced, which greatly empowered steroid hormone research. Based on recent literature and new advances in the field, here we review the local role of steroid hormones in regulating bone homeostasis and skeletal lesion formation. The novel idea of extraglandular steroidogenesis occurring within the skeletal system raises the possibility of the development of new therapies for the treatment of bone diseases.
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Affiliation(s)
| | | | - David S. Gyori
- Department of Physiology, School of Medicine, Semmelweis University, 1085 Budapest, Hungary
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17
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Peng P, He M, Fang W, Lai M, Xiao F, He W, Xiao H, Wei Q. Plasma 8-OHdG act as a biomarker for steroid-induced osteonecrosis of the femoral head. BMC Musculoskelet Disord 2023; 24:808. [PMID: 37828532 PMCID: PMC10568778 DOI: 10.1186/s12891-023-06804-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 08/16/2023] [Indexed: 10/14/2023] Open
Abstract
BACKGROUND Oxidative stress was closely related to the occurrence and development of Steroid-induced osteonecrosis of the femoral head (SIONFH). 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a important index of oxidative stress. The aim of this study is to investigate the role of 8-OHdG in the development of SIONFH. METHODS From May 2021 and November 2021, 33 patients diagnosed with SIONFH and 26 healthy controls were recruited in this study. Assessment included the radiography and pathology evaluation of clinical bone tissue, expression position and level of 8-OHdG, level of plasma 8-OHdG, as well as the receiver operating characteristic (ROC) curve. RESULTS We observed that expression levels of 8-OHdG in bone samples decreased with Association Research Circulation Osseous (ARCO) stages. Plasma 8-OHdG levels were significantly increased in the SIONFH group compared to the healthy control group. Plasma 8-OHdG level of pre-collapse patients was higher than that of post-collapse patients, the decreased plasma 8-OHdG level was related to higher ARCO stages. CONCLUSION Plasma 8-OHdG may represent potential biomarkers during SIONFH at different stages. Higher plasma 8-OHdG levels indicated early stage of SIONFH. The current study provided new clues for early diagnosis and treatment for SIONFH.
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Affiliation(s)
- Peng Peng
- Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Mincong He
- Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, Guangzhou, 510378, China
- Department of Orthopaedics, The Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510378, China
| | - Weihua Fang
- Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Mengqi Lai
- Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Fangjun Xiao
- Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Wei He
- Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, Guangzhou, 510378, China
- Department of Orthopaedics, The Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510378, China
| | - Huan Xiao
- Department of Orthopedics, Bijie Traditional Chinese Medicine Hospital, Bijie, 551700, China.
| | - Qiushi Wei
- Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, Guangzhou, 510378, China.
- Department of Orthopaedics, The Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510378, China.
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18
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Shen Y, Jiang B, Lu W, Luo B, Zhou Y, Qian G. Dexamethasone-induced mitochondrial ROS-mediated inhibition of AMPK activity facilitates osteoblast necroptosis. Toxicol Res (Camb) 2023; 12:922-929. [PMID: 37915480 PMCID: PMC10615823 DOI: 10.1093/toxres/tfad080] [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: 03/16/2023] [Revised: 08/15/2023] [Accepted: 08/28/2023] [Indexed: 11/03/2023] Open
Abstract
Long-term or high-dose glucocorticoid use can lead to serious orthopedic complications, including femoral head necrosis. Both basic and clinical studies have shown that high doses dexamethasone (Dex) can directly induce osteoblasts death. This study investigated the mechanism underlying Dex induced osteoblast death. In this study, we showed that Dex induces osteoblast necroptosis, rather than apoptosis, through the inhibition of AMP-activated protein kinase (AMPK) activity. We also demonstrated that inactivation of AMPK-mediated necroptosis is through receptor-interacting protein kinase 3 (RIP3), but not RIP1. Furthermore, we found that Dex-induced necroptosis is dependent on mitochondrial reactive oxygen species (ROS) following with directly activation of RIP1 and inactivation of AMPK. These findings provide new insights into the mechanism of Dex-induced osteoblast death and may have implications for the development of new therapies for osteoporosis and other bone-related diseases.
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Affiliation(s)
- Yingchao Shen
- Department of Orthopaedics, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, No. 6, Huanghe Road, Changshu, Jiangsu 215500, China
| | - Bo Jiang
- Department of Hand and Foot Surgery, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, Jiangsu 215004, China
| | - Wei Lu
- Department of Orthopaedics, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, No. 6, Huanghe Road, Changshu, Jiangsu 215500, China
| | - Bin Luo
- Department of Orthopaedics, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, No. 6, Huanghe Road, Changshu, Jiangsu 215500, China
| | - Yuan Zhou
- Department of Orthopaedics, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, No. 6, Huanghe Road, Changshu, Jiangsu 215500, China
| | - Guiying Qian
- Department of Orthopaedics, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, No. 6, Huanghe Road, Changshu, Jiangsu 215500, China
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19
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Liu Y, Mo L, Lu H, Wei Y, Zhang J, Bennett S, Xu J, Zhou C, Fang B, Chen Z. Dragon blood resin ameliorates steroid-induced osteonecrosis of femoral head through osteoclastic pathways. Front Cell Dev Biol 2023; 11:1202888. [PMID: 37675145 PMCID: PMC10477996 DOI: 10.3389/fcell.2023.1202888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 08/09/2023] [Indexed: 09/08/2023] Open
Abstract
Objective: Dragon's Blood resin (DBR) is a traditional medicinal substance renowned for its diverse pharmacological effects, which consists of potent anti-inflammatory, antioxidant and angiogenic properties. This study aimed to elucidate its therapeutic mechanism in alleviating steroid-induced osteonecrosis of the femoral head (SIONFH). Methods: Techniques such as SPR and LC-MS were employed to identify and analyze the target proteins of DBR in bone marrow macrophages (BMMs). In vitro, BMMs were treated with RANKL and DBR, and TRAcP staining and actin belt staining were utilized to assess osteoclast activity. The inhibitory effects and underlying mechanisms of DBR on osteoclastogenesis and reactive oxygen species (ROS) generation were determined using real-time PCR, western blotting and immunofluorescence staining. An in vivo SIONFH rat model was set up to assess the curative impacts of DBR using micro-CT scanning and pathological staining. Results: Bioinformatic tools revealed a pivotal role of osteoclast differentiation in SIONFH. Proteomic analysis identified 164 proteins binding in BMMs. In vitro assessments demonstrated that DBR hindered osteoclastogenesis by modulating the expression of specific genes and proteins, along with antioxidant proteins including TRX1 and Glutathione Reductase. Notably, the resin effectively inhibited the expression of crucial proteins, such as the phosphorylation of JNK and the nuclear localization of p65 within the TRAF6/JNK and NFκB signaling pathways. In vivo experiments further confirmed that DBR mitigated the onset of SIONFH in rats by curbing osteoclast and ROS activities. Conclusion: These findings underscore the potential of Dragon's Blood as an effective administration for early-stage SIONFH, shedding light on its therapeutic influence on ROS-mediated osteoclastic signaling pathways.
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Affiliation(s)
- Yuhao Liu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liang Mo
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hongduo Lu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yangwenxiang Wei
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiahao Zhang
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Samuel Bennett
- School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Jiake Xu
- School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
- Shenzhen institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Chi Zhou
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bin Fang
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhenqiu Chen
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
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20
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Plotnikov MB, Chernysheva GA, Smol’yakova VI, Aliev OI, Anishchenko AM, Ulyakhina OA, Trofimova ES, Ligacheva AA, Anfinogenova ND, Osipenko AN, Kovrizhina AR, Khlebnikov AI, Schepetkin IA, Drozd AG, Plotnikov EV, Atochin DN, Quinn MT. Neuroprotective Effects of Tryptanthrin-6-Oxime in a Rat Model of Transient Focal Cerebral Ischemia. Pharmaceuticals (Basel) 2023; 16:1057. [PMID: 37630972 PMCID: PMC10457995 DOI: 10.3390/ph16081057] [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: 06/09/2023] [Revised: 07/13/2023] [Accepted: 07/22/2023] [Indexed: 08/27/2023] Open
Abstract
The activation of c-Jun N-terminal kinase (JNK) plays an important role in stroke outcomes. Tryptanthrin-6-oxime (TRYP-Ox) is reported to have high affinity for JNK and anti-inflammatory activity and may be of interest as a promising neuroprotective agent. The aim of this study was to investigate the neuroprotective effects of TRYP-Ox in a rat model of transient focal cerebral ischemia (FCI), which involved intraluminal occlusion of the left middle cerebral artery (MCA) for 1 h. Animals in the experimental group were administered intraperitoneal injections of TRYP-Ox 30 min before reperfusion and 23 and 47 h after FCI. Neurological status was assessed 4, 24, and 48 h following FCI onset. Treatment with 5 and 10 mg/kg of TRYP-Ox decreased mean scores of neurological deficits by 35-49 and 46-67% at 24 and 48 h, respectively. At these doses, TRYP-Ox decreased the infarction size by 28-31% at 48 h after FCI. TRYP-Ox (10 mg/kg) reduced the content of interleukin (IL) 1β and tumor necrosis factor (TNF) in the ischemic core area of the MCA region by 33% and 38%, respectively, and attenuated cerebral edema by 11% in the left hemisphere, which was affected by infarction, and by 6% in the right, contralateral hemisphere 24 h after FCI. TRYP-Ox reduced c-Jun phosphorylation in the MCA pool at 1 h after reperfusion. TRYP-Ox was predicted to have high blood-brain barrier permeability using various calculated descriptors and binary classification trees. Indeed, reactive oxidant production was significantly lower in the brain homogenates from rats treated with TRYP-Ox versus that in control animals. Our data suggest that the neuroprotective activity of TRYP-Ox may be due to the ability of this compound to inhibit JNK and exhibit anti-inflammatory and antioxidant activity. Thus, TRYP-Ox may be considered a promising neuroprotective agent that potentially could be used for the development of new treatment strategies in cerebral ischemia.
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Affiliation(s)
- Mark B. Plotnikov
- Department of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634028, Russia; (M.B.P.); (G.A.C.); (V.I.S.); (O.I.A.); (A.M.A.); (O.A.U.); (E.S.T.); (A.A.L.)
- Faculty of Radiophysics, National Research Tomsk State University, Tomsk 634050, Russia
| | - Galina A. Chernysheva
- Department of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634028, Russia; (M.B.P.); (G.A.C.); (V.I.S.); (O.I.A.); (A.M.A.); (O.A.U.); (E.S.T.); (A.A.L.)
| | - Vera I. Smol’yakova
- Department of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634028, Russia; (M.B.P.); (G.A.C.); (V.I.S.); (O.I.A.); (A.M.A.); (O.A.U.); (E.S.T.); (A.A.L.)
| | - Oleg I. Aliev
- Department of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634028, Russia; (M.B.P.); (G.A.C.); (V.I.S.); (O.I.A.); (A.M.A.); (O.A.U.); (E.S.T.); (A.A.L.)
| | - Anna M. Anishchenko
- Department of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634028, Russia; (M.B.P.); (G.A.C.); (V.I.S.); (O.I.A.); (A.M.A.); (O.A.U.); (E.S.T.); (A.A.L.)
- Department of Pharmacology, Siberian State Medical University, Tomsk 634050, Russia;
| | - Olga A. Ulyakhina
- Department of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634028, Russia; (M.B.P.); (G.A.C.); (V.I.S.); (O.I.A.); (A.M.A.); (O.A.U.); (E.S.T.); (A.A.L.)
| | - Eugene S. Trofimova
- Department of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634028, Russia; (M.B.P.); (G.A.C.); (V.I.S.); (O.I.A.); (A.M.A.); (O.A.U.); (E.S.T.); (A.A.L.)
- Department of Pharmacology, Siberian State Medical University, Tomsk 634050, Russia;
| | - Anastasia A. Ligacheva
- Department of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634028, Russia; (M.B.P.); (G.A.C.); (V.I.S.); (O.I.A.); (A.M.A.); (O.A.U.); (E.S.T.); (A.A.L.)
| | - Nina D. Anfinogenova
- Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634012, Russia;
| | - Anton N. Osipenko
- Department of Pharmacology, Siberian State Medical University, Tomsk 634050, Russia;
| | - Anastasia R. Kovrizhina
- Kizhner Research Center, Tomsk Polytechnic University, Tomsk 634050, Russia; (A.R.K.); (A.I.K.)
| | - Andrei I. Khlebnikov
- Kizhner Research Center, Tomsk Polytechnic University, Tomsk 634050, Russia; (A.R.K.); (A.I.K.)
| | - Igor A. Schepetkin
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA;
| | - Anastasia G. Drozd
- Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk 634050, Russia; (A.G.D.); (E.V.P.)
| | - Evgenii V. Plotnikov
- Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk 634050, Russia; (A.G.D.); (E.V.P.)
- Mental Health Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634014, Russia
| | - Dmitriy N. Atochin
- Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02115, USA
| | - Mark T. Quinn
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA;
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21
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Wu J, Li J, Wu Y, Yang M, Chen Y, Wang N, Wang J, Yuan Z, Yi J, Yang C. Betulinic acid mitigates zearalenone-induced liver injury by ERS/MAPK/Nrf2 signaling pathways in mice. Food Chem Toxicol 2023; 177:113811. [PMID: 37179046 DOI: 10.1016/j.fct.2023.113811] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 04/29/2023] [Accepted: 05/03/2023] [Indexed: 05/15/2023]
Abstract
Zearalenone (ZEA) is a mycotoxin commonly found in cereals and feedstuffs, which can induce oxidative stress and inflammation to cause liver damage in humans and animals. Betulinic acid (BA) is extracted from pentacyclic triterpenoids of many natural plants and has anti-inflammatory, and anti-oxidation biological activities in many studies. However, the protective effect of BA on liver injury induced by ZEA has not been reported. Therefore, this study aims to explore the protective effect of BA on ZEA-induced liver injury and its possible mechanism. In the mice experiment, ZEA exposure increased the liver index and caused histopathological impairment, oxidative damage, hepatic inflammatory responses, and increased hepatocyte apoptosis. However, when combined with BA, it could inhibit the production of ROS, up-regulate the proteins expression of Nrf2 and HO-1 and down-regulate the expression of Keap1, and alleviate oxidative damage and inflammation in the liver of mice. In addition, BA could alleviate ZEA-induced apoptosis and liver injury in mice by inhibiting the endoplasmic reticulum stress (ERS) and MAPK signaling pathways. In conclusion, this study revealed the protective effect of BA on the hepatotoxicity of ZEA for the first time, providing a new perspective for the development of ZEA antidote and the application of BA.
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Affiliation(s)
- Jing Wu
- College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China; Hunan Engineering Research Center of Livestock and Poultry Health Care, Hunan Agricultural University, Changsha, 410128, China
| | - Jiayan Li
- College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China; Hunan Engineering Research Center of Livestock and Poultry Health Care, Hunan Agricultural University, Changsha, 410128, China
| | - You Wu
- College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China; Hunan Engineering Research Center of Livestock and Poultry Health Care, Hunan Agricultural University, Changsha, 410128, China
| | - Mengran Yang
- College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China; Hunan Engineering Research Center of Livestock and Poultry Health Care, Hunan Agricultural University, Changsha, 410128, China
| | - Yunqin Chen
- College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China; Hunan Engineering Research Center of Livestock and Poultry Health Care, Hunan Agricultural University, Changsha, 410128, China
| | - Naidong Wang
- College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China; Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, Laboratory of Functional Proteomics, Research Center of Reverse Vaccinology, Changsha, 410128, China
| | - Ji Wang
- College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China; Hunan Engineering Research Center of Livestock and Poultry Health Care, Hunan Agricultural University, Changsha, 410128, China
| | - Zhihang Yuan
- College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China; Hunan Engineering Research Center of Livestock and Poultry Health Care, Hunan Agricultural University, Changsha, 410128, China
| | - Jine Yi
- College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China; Hunan Engineering Research Center of Livestock and Poultry Health Care, Hunan Agricultural University, Changsha, 410128, China.
| | - Chenglin Yang
- College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China; Hunan Engineering Research Center of Livestock and Poultry Health Care, Hunan Agricultural University, Changsha, 410128, China.
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22
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Li Q, Tian C, Liu X, Li D, Liu H. Anti-inflammatory and antioxidant traditional Chinese Medicine in treatment and prevention of osteoporosis. Front Pharmacol 2023; 14:1203767. [PMID: 37441527 PMCID: PMC10335577 DOI: 10.3389/fphar.2023.1203767] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 06/13/2023] [Indexed: 07/15/2023] Open
Abstract
A metabolic bone disorder called osteoporosis is characterized by decreased bone mass and compromised microarchitecture. This condition can deteriorate bones and raise the risk of fractures. The two main causes of osteoporosis are an increase in osteoclast activity or quantity and a decrease in osteoblast viability. Numerous mechanisms, including estrogen shortage, aging, chemical agents, and decreased mechanical loads, have been linked to osteoporosis. Inflammation and oxidative stress have recently been linked to osteoporosis, according to an increasing number of studies. The two primary medications used to treat osteoporosis at the moment are bisphosphonates and selective estrogen receptor modulators (SERMs). These medications work well for osteoporosis brought on by aging and estrogen deprivation, however, they do not target inflammation and oxidative stress-induced osteoporosis. In addition, these drugs have some limitations that are attributed to various side effects that have not been overcome. Traditional Chinese medicine (TCM) has been applied in osteoporosis for many years and has a high safety profile. Therefore, in this review, literature related to botanical drugs that have an effect on inflammation and oxidative stress-induced osteoporosis was searched for. Moreover, the pharmacologically active ingredients of these herbs and the pathways were discussed and may contribute to the discovery of more safe and effective drugs for the treatment of osteoporosis.
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Affiliation(s)
- Qian Li
- Laboratory of Metabolic Abnormalities and Vascular Aging, Liyuan Hospital Affiliated to Huazhong University of Science and Technology, Department of Integrated Chinese and Western Medicine, City Wuhan, Hubei Province, China
| | - Ciqiu Tian
- Hubei University of Chinese Medicine, City Wuhan, Hubei Province, China
| | - Xiangjie Liu
- Liyuan Hospital Affiliated to Huazhong University of Science and Technology, Geriatric Department, City Wuhan, Hubei Province, China
| | - Dinglin Li
- Laboratory of Metabolic Abnormalities and Vascular Aging, Liyuan Hospital Affiliated to Huazhong University of Science and Technology, Department of Integrated Chinese and Western Medicine, City Wuhan, Hubei Province, China
| | - Hao Liu
- Laboratory of Metabolic Abnormalities and Vascular Aging, Liyuan Hospital Affiliated to Huazhong University of Science and Technology, Department of Integrated Chinese and Western Medicine, City Wuhan, Hubei Province, China
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23
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Rapone B, Ferrara E, Qorri E, Inchingolo F, Isola G, Dongiovanni P, Tartaglia GM, Scarano A. Research efficacy of gaseous ozone therapy as an adjuvant to periodontal treatment on oxidative stress mediators in patients with type 2 diabetes: a randomized clinical trial. BMC Oral Health 2023; 23:278. [PMID: 37170229 PMCID: PMC10176779 DOI: 10.1186/s12903-023-02985-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/24/2023] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND Chronic inflammation and cumulative oxidative stress have been theorized as two common pathways of the interconnection between periodontitis and diabetes. Improvement in oxidizing status has been demonstrated in periodontal patients with diabetes treated with proper non-surgical periodontal treatment. In addition to periodontal treatment, Gaseous ozone therapy has been reported to possess anti-inflammatory properties and the ability to stimulate the endogenous antioxidant defence mechanism. To date, the antioxidant effect of gaseous ozone, in addition with periodontal treatment in diabetic patients, has been examined in only one study. The aim of this study was to determine the efficacy of gaseous ozone therapy as an alternative approach to supporting non-surgical periodontal therapy (NSPT), aimed at improving antioxidant machinery and interfering with ROS production on plasma levels in diabetic individuals diagnosed with moderate or severe periodontitis. METHODS One hundred and eighty patients with periodontitis and type 2 diabetes mellitus were randomly assigned to receive non-surgical periodontal treatment (NSPT) plus gaseous ozone therapy (A) NSPT alone (B). Clinical and periodontal parameters -Bleeding on probing (BOP), Periodontal pocket depth (PPD), and Clinical attachment Level (CAL)- and plasma levels of oxidant-antioxidant (TOS- TAOS) levels, glutathione (GSH), and malondialdehyde (MDA) were recorded at baseline and at 3- (T1) and at 6-months (T2) after treatment. RESULTS Both treatments were efficacious in reducing clinical parameters. However, there were no significant differences regarding oxidative stress parameters in group A compared to group B. CONCLUSIONS In the present study, gaseous ozone therapy did not enhance the effect of periodontal treatment in reducing oxidative stress in plasma levels of periodontitis patients with type II diabetes. TRIAL REGISTRATION The study was registered with ISRCTN1728169 (23/07/2022).
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Affiliation(s)
- Biagio Rapone
- Interdisciplinary Department of Medicine, “Aldo Moro” University of Bari, Bari, 70121 Italy
| | - Elisabetta Ferrara
- Department of Medical, Oral and Biotechnological Sciences, University G. d’Annunzio, Chieti, 66100 Italy
| | - Erda Qorri
- Dean Faculty of Medical Sciences, Albanian University, Bulevardi Zogu I, Tirana, 1000 Albania
| | - Francesco Inchingolo
- Interdisciplinary Department of Medicine, “Aldo Moro” University of Bari, Bari, 70121 Italy
| | - Gaetano Isola
- Department of General Surgery and Medical Surgery Specialties, School of Dentistry, University of Catania, 95123 Catania, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, Milan, 20122 Italy
| | - Gianluca Martino Tartaglia
- UOC Maxillo-Facial Surgery and Dentistry, Ospedale Maggiore Policlinico, Fondazione IRCCS Ca Granda, Milan, 20122 Italy
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, 20122 Italy
| | - Antonio Scarano
- Department of Innovative Technologies in Medicine and Dentistry, University of Chieti-Pescara, Chieti, 66100 Italy
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24
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Chen M, Fu W, Xu H, Liu CJ. Pathogenic mechanisms of glucocorticoid-induced osteoporosis. Cytokine Growth Factor Rev 2023; 70:54-66. [PMID: 36906448 PMCID: PMC10518688 DOI: 10.1016/j.cytogfr.2023.03.002] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/21/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023]
Abstract
Glucocorticoid (GC) is one of the most prescribed medicines to treat various inflammatory and autoimmune diseases. However, high doses and long-term use of GCs lead to multiple adverse effects, particularly glucocorticoid-induced osteoporosis (GIO). Excessive GCs exert detrimental effects on bone cells, including osteoblasts, osteoclasts, and osteocytes, leading to impaired bone formation and resorption. The actions of exogenous GCs are considered to be strongly cell-type and dose dependent. GC excess inhibits the proliferation and differentiation of osteoblasts and enhances the apoptosis of osteoblasts and osteocytes, eventually contributing to reduced bone formation. Effects of GC excess on osteoclasts mainly include enhanced osteoclastogenesis, increased lifespan and number of mature osteoclasts, and diminished osteoclast apoptosis, which result in increased bone resorption. Furthermore, GCs have an impact on the secretion of bone cells, subsequently disturbing the process of osteoblastogenesis and osteoclastogenesis. This review provides timely update and summary of recent discoveries in the field of GIO, with a particular focus on the effects of exogenous GCs on bone cells and the crosstalk among them under GC excess.
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Affiliation(s)
- Meng Chen
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA; School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Wenyu Fu
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Huiyun Xu
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.
| | - Chuan-Ju Liu
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA; Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, USA.
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25
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The Impact of Plasma Membrane Ion Channels on Bone Remodeling in Response to Mechanical Stress, Oxidative Imbalance, and Acidosis. Antioxidants (Basel) 2023; 12:antiox12030689. [PMID: 36978936 PMCID: PMC10045377 DOI: 10.3390/antiox12030689] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 03/14/2023] Open
Abstract
The extracellular milieu is a rich source of different stimuli and stressors. Some of them depend on the chemical–physical features of the matrix, while others may come from the ‘outer’ environment, as in the case of mechanical loading applied on the bones. In addition to these forces, a plethora of chemical signals drives cell physiology and fate, possibly leading to dysfunctions when the homeostasis is disrupted. This variety of stimuli triggers different responses among the tissues: bones represent a particular milieu in which a fragile balance between mechanical and metabolic demands should be tuned and maintained by the concerted activity of cell biomolecules located at the interface between external and internal environments. Plasma membrane ion channels can be viewed as multifunctional protein machines that act as rapid and selective dual-nature hubs, sensors, and transducers. Here we focus on some multisensory ion channels (belonging to Piezo, TRP, ASIC/EnaC, P2XR, Connexin, and Pannexin families) actually or potentially playing a significant role in bone adaptation to three main stressors, mechanical forces, oxidative stress, and acidosis, through their effects on bone cells including mesenchymal stem cells, osteoblasts, osteoclasts, and osteocytes. Ion channel-mediated bone remodeling occurs in physiological processes, aging, and human diseases such as osteoporosis, cancer, and traumatic events.
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26
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Motafeghi F, Mortazavi P, Ghassemi-Barghi N, Zahedi M, Shokrzadeh M. Dexamethasone as an anti-cancer or hepatotoxic. Toxicol Mech Methods 2023; 33:161-171. [PMID: 35866224 DOI: 10.1080/15376516.2022.2105183] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The linkage between inflammation and oxidative stress in liver damage has been proven and is undeniable; dexamethasone with some antioxidants can reduce the toxicity of liver tissue. Due to the importance of cancer treatment, glucocorticoids' synergistic effect in inhibiting cancer cell growth is also investigated. Dexamethasone alone and combined with etoposide were tested at concentrations of 1, 5, and 10 μM to evaluate the potency of dexamethasone in inhibiting the growth of A549 cells using oxidative stress factors and DNA damage. Also, intraperitoneal injection of dexamethasone in rats was used to induce liver toxicity. Coenzyme Q10 at different concentrations (1, 10, and 50 mg/kg) was used as an antioxidant to assess the oxidative stress factors and measure Caspase-3 activity. The results showed that dexamethasone combined with etoposide could significantly inhibit the growth of cancer cells and induce apoptosis. Treatment of A549 cells using dexamethasone also inhibits cancer cells' growth by inducing oxidative stress and DNA damage. Dexamethasone also, by inducing oxidative stress and activation of caspase 3, ultimately causes hepatotoxicity. Treatment with different concentrations of CoQ10 showed improved mitochondrial function, antioxidant defense, and liver enzyme. The best effect of coenzyme Q10 on dexamethasone-induced hepatotoxicity is 50 mg/kg. As a result, dexamethasone (alone and combined with etoposide) has an anti-cancer effect by damaging DNA and inducing oxidative stress. Also, CoQ10 has antioxidant effects against dexamethasone-induced hepatotoxicity by improving mitochondrial function and reducing caspase-3 activity.
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Affiliation(s)
- Farzaneh Motafeghi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Parham Mortazavi
- Department of Pharmacology and Toxicology, Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Nasrin Ghassemi-Barghi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Zahedi
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Shokrzadeh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
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27
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Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation. Signal Transduct Target Ther 2023; 8:16. [PMID: 36627278 PMCID: PMC9832009 DOI: 10.1038/s41392-022-01227-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 09/30/2022] [Accepted: 10/10/2022] [Indexed: 01/12/2023] Open
Abstract
Lkb1 deficiency confers the Kras-mutant lung cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation (AST). However, it remains largely unknown how Lkb1 deficiency dynamically regulates AST. Using the classical AST mouse model (Kras LSL-G12D/+;Lkb1flox/flox, KL), we here comprehensively analyze the temporal transcriptomic dynamics of lung tumors at different stages by dynamic network biomarker (DNB) and identify the tipping point at which the Wnt signaling is abruptly suppressed by the excessive accumulation of reactive oxygen species (ROS) through its downstream effector FOXO3A. Bidirectional genetic perturbation of the Wnt pathway using two different Ctnnb1 conditional knockout mouse strains confirms its essential role in the negative regulation of AST. Importantly, pharmacological activation of the Wnt pathway before but not after the tipping point inhibits squamous transdifferentiation, highlighting the irreversibility of AST after crossing the tipping point. Through comparative transcriptomic analyses of mouse and human tumors, we find that the lineage-specific transcription factors (TFs) of adenocarcinoma and squamous cell carcinoma form a "Yin-Yang" counteracting network. Interestingly, inactivation of the Wnt pathway preferentially suppresses the adenomatous lineage TF network and thus disrupts the "Yin-Yang" homeostasis to lean towards the squamous lineage, whereas ectopic expression of NKX2-1, an adenomatous lineage TF, significantly dampens such phenotypic transition accelerated by the Wnt pathway inactivation. The negative correlation between the Wnt pathway and AST is further observed in a large cohort of human lung adenosquamous carcinoma. Collectively, our study identifies the tipping point of AST and highlights an essential role of the ROS-Wnt axis in dynamically orchestrating the homeostasis between adeno- and squamous-specific TF networks at the AST tipping point.
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Ekeuku SO, Chin KY, Mohd Ramli ES. Effects of Piper sarmentosum on Bone Health and Fracture Healing: A Scoping Review. Endocr Metab Immune Disord Drug Targets 2023; 23:908-916. [PMID: 36453484 DOI: 10.2174/1871530323666221130152737] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 09/08/2022] [Accepted: 10/18/2022] [Indexed: 12/04/2022]
Abstract
BACKGROUND Piper sarmentosum (PS) is a traditional herb used by Southeast Asian communities to treat various illnesses. Recent pharmacological studies have discovered that PS possesses antioxidant and anti-inflammatory activities. Since oxidative stress and inflammation are two important processes driving the pathogenesis of bone loss, PS may have potential therapeutic effects against osteoporosis. OBJECTIVE This review systematically summarised the therapeutic effects of PS on preventing osteoporosis and promoting fracture healing. METHODS A systematic literature search was performed in November 2021 using 4 electronic databases and the search string "Piper sarmentosum" AND (bone OR osteoporosis OR osteoblasts OR osteoclasts OR osteocytes). RESULTS Nine unique articles were identified from the literature. The efficacy of PS has been studied in animal models of osteoporosis induced by ovariectomy and glucocorticoids, as well as bone fracture models. PS prevented deterioration of bone histomorphometric indices, improved fracture healing and restored the biomechanical properties of healed bone in ovariectomised rats. PS also prevented osteoblast/osteocyte apoptosis, increased bone formation and mineralisation and subsequently improved trabecular bone microstructures and strength of rats with osteoporosis induced by glucocorticoids. Apart from its antioxidant and anti-inflammatory activity, PS also suppressed circulating and skeletal expression of corticosterone and skeletal expression of 11β hydroxysteroid dehydrogenase type 1 but increased the enzyme activity in the glucocorticoid osteoporosis model. This review also identified several research gaps about the skeletal effects of PS and suggested future studies to bridge these gaps. CONCLUSION PS may be of therapeutic benefit to bone health. However, further research is required to validate this claim.
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Affiliation(s)
- Sophia Ogechi Ekeuku
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
| | - Kok-Yong Chin
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
| | - Elvy Suhana Mohd Ramli
- Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
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Rong X, Kou Y, Zhang Y, Yang P, Tang R, Liu H, Li M. ED-71 Prevents Glucocorticoid-Induced Osteoporosis by Regulating Osteoblast Differentiation via Notch and Wnt/β-Catenin Pathways. Drug Des Devel Ther 2022; 16:3929-3946. [PMID: 36411860 PMCID: PMC9675334 DOI: 10.2147/dddt.s377001] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 11/03/2022] [Indexed: 08/27/2023] Open
Abstract
PURPOSE Long-term glucocorticoid- usage can lead to glucocorticoid-induced osteoporosis (GIOP). The study focused on the preventative effects of a novel active vitamin D3 analog, eldecalcitol (ED-71), against GIOP and explored the underlying molecular mechanisms. METHODS Intraperitoneal injection of methylprednisolone (MPED) or dexamethasone (DEX) induced the GIOP model within C57BL/6 mice in vivo. Simultaneously, ED-71 was orally supplemented. Bone histological alterations, microstructure parameters, novel bone formation rates, and osteogenic factor changes were evaluated by hematoxylin-eosin (HE) staining, micro-computed tomography, calcein/tetracycline labeling, and immunohistochemical (IHC) staining. The osteogenic differentiation level and mineralization in pre-osteoblast MC3T3-E1 cells were evaluated in vitro using alkaline phosphatase (ALP) staining, alizarin red (AR) staining, quantitative polymerase chain reaction (qPCR), Western blotting, and immunofluorescence staining. RESULTS ED-71 partially prevented bone mass reduction and microstructure parameter alterations among GIOP-induced mice. Moreover, ED-71 also promoted new bone formation and osteoblast activity while inhibiting osteoclasts. In vitro, ED-71 promoted osteogenic differentiation and mineralization in DEX-treated MC3T3-E1 cells and boosted the levels of osteogenic-related factors. Additionally, GSK3-β and β-catenin expression levels were elevated after ED-71 was added to cells and were accompanied by reduced Notch expression. The Wnt signaling inhibitor XAV939 and Notch overexpression reversed the ED-71 promotional effects toward osteogenic differentiation and mineralization. CONCLUSION ED-71 prevented GIOP by enhancing osteogenic differentiation through Notch and Wnt/GSK-3β/β-catenin signaling. The results provide a novel translational direction for the clinical application of ED-71 against GIOP.
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Affiliation(s)
- Xing Rong
- Department of Bone Metabolism, 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, People’s Republic of China
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People’s Republic of China
| | - Yuying Kou
- Department of Bone Metabolism, 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, People’s Republic of China
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People’s Republic of China
| | - Yuan Zhang
- Department of Bone Metabolism, 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, People’s Republic of China
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People’s Republic of China
| | - Panpan Yang
- Department of Bone Metabolism, 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, People’s Republic of China
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People’s Republic of China
| | - Rong Tang
- Department of Bone Metabolism, 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, People’s Republic of China
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People’s Republic of China
| | - Hongrui Liu
- Department of Bone Metabolism, 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, People’s Republic of China
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People’s Republic of China
| | - Minqi Li
- Department of Bone Metabolism, 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, People’s Republic of China
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People’s Republic of China
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Yang K, Li J, Tao L. Purine metabolism in the development of osteoporosis. Biomed Pharmacother 2022; 155:113784. [DOI: 10.1016/j.biopha.2022.113784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/17/2022] Open
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Tocotrienol as a Protecting Agent against Glucocorticoid-Induced Osteoporosis: A Mini Review of Potential Mechanisms. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27185862. [PMID: 36144598 PMCID: PMC9506150 DOI: 10.3390/molecules27185862] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/03/2022] [Accepted: 09/08/2022] [Indexed: 11/18/2022]
Abstract
Glucocorticoid-induced osteogenic dysfunction is the main pathologyical mechanism underlying the development of glucocorticoid-induced osteoporosis. Glucocorticoids promote adipogenic differentiation and osteoblast apoptosis through various pathways. Various ongoing studies are exploring the potential of natural products in preventing glucocorticoid-induced osteoporosis. Preclinical studies have consistently shown the bone protective effects of tocotrienol through its antioxidant and anabolic effects. This review aims to summarise the potential mechanisms of tocotrienol in preventing glucocorticoid-induced osteoporosis based on existing in vivo and in vitro evidence. The current literature showed that tocotrienol prevents oxidative damage on osteoblasts exposed to high levels of glucocorticoids. Tocotrienol reduces lipid peroxidation and increases oxidative stress enzyme activities. The reduction in oxidative stress protects the osteoblasts and preserves the bone microstructure and biomechanical strength of glucocorticoid-treated animals. In other animal models, tocotrienol has been shown to activate the Wnt/β-catenin pathway and lower the RANKL/OPG ratio, which are the targets of glucocorticoids. In conclusion, tocotrienol enhances osteogenic differentiation and bone formation in glucocorticoid-treated osteoblasts while improving structural integrity in glucocorticoid-treated rats. This is achieved by preventing oxidative stress and osteoblast apoptosis. However, these preclinical results should be validated in a randomised controlled trial.
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Zhang L, Zheng YL, Wang R, Wang XQ, Zhang H. Exercise for osteoporosis: A literature review of pathology and mechanism. Front Immunol 2022; 13:1005665. [PMID: 36164342 PMCID: PMC9509020 DOI: 10.3389/fimmu.2022.1005665] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Osteoporosis (OP) is a disease that weakens bones and has a high morbidity rate worldwide, which is prevalent among the elderly, particularly, women of postmenopausal age. The dynamic balance between bone formation and resorption is necessary for normal bone metabolism. Many factors, including aging, estrogen deficiency, and prolonged immobilization, disrupt normal apoptosis, autophagy, and inflammation, leading to abnormal activation of osteoclasts, which gradually overwhelm bone formation by bone resorption. Moderate exercise as an effective non-drug treatment helps increase bone formation and helps relieve OP. The possible mechanisms are that exercise affects apoptosis and autophagy through the release of exercise-stimulated myohormone and the secretion of anti-inflammatory cytokines via mechanical force. In addition, exercise may also have an impact on the epigenetic processes involved in bone metabolism. Mechanical stimulation promotes bone marrow mesenchymal stem cells (BMSCs) to osteogenic differentiation by altering the expression of non-coding RNAs. Besides, by reducing DNA methylation, the mechanical stimulus can also alter the epigenetic status of osteogenic genes and show associated increased expression. In this review, we reviewed the possible pathological mechanisms of OP and summarized the effects of exercise on bone metabolism, and the mechanisms by which exercise alleviates the progression of OP, to provide a reference for the prevention and treatment of OP.
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Affiliation(s)
- Lin Zhang
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
| | - Yi-Li Zheng
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
| | - Rui Wang
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
| | - Xue-Qiang Wang
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
- Department of Rehabilitation Medicine, Shanghai Shangti Orthopaedic Hospital, Shanghai, China
- *Correspondence: Xue-Qiang Wang, ; Hao Zhang,
| | - Hao Zhang
- Department of Orthopedics, Changhai Hospital Affiliated to the Navy Military Medical University, Shanghai, China
- *Correspondence: Xue-Qiang Wang, ; Hao Zhang,
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Rai D, Tripathi AK, Sardar A, Pandey AR, Sinha S, Chutani K, Dhaniya G, Kothari P, Sashidhara KV, Trivedi R. A novel BMP2 secretagogue ameliorates glucocorticoid induced oxidative stress in osteoblasts by activating NRF2 dependent survival while promoting Wnt/β-catenin mediated osteogenesis. Free Radic Biol Med 2022; 190:124-147. [PMID: 35963563 DOI: 10.1016/j.freeradbiomed.2022.08.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/25/2022] [Accepted: 08/03/2022] [Indexed: 01/16/2023]
Abstract
In our previous study, a novel BMP2 secretagogue was synthesized belonging to a class of galloyl conjugates of flavanones, with remarkable osteogenic potential that promoted bone regeneration. We aimed to establish the protective effect of our compound against bone loss that co-exists with excess Glucocorticoid (GC) therapy. GC therapy induces osteoblast damage leading to apoptosis by increasing reactive oxygen species (ROS). Our results delineate that compound 5e (a BMP2 secretagogue) activates NRF2 signalling to counter the disturbed cellular redox homeostasis and escalate osteoblast survival as assessed by Western blot and immunocytochemistry. Depletion of NRF2 by siRNA blocked activation of the NRF2/HO-1 pathway, magnified oxidative stress, increased apoptosis and abrogated the protective effects of compound 5e. 5e, on the other hand, increased ALP, mineralization activity, and promoted osteoblast differentiation by activating WNT/β-catenin signalling in BMP2 dependent manner, validated by Western blot of WNT3A, SOST, GSK3-β and β-catenin nuclear translocation. Treatment of 5e in presence of BMP inhibitor noggin attenuated the osteogenic efficacy and minimized Wnt//β-catenin signalling in presence of dexamethasone. Our compound prevents GC challenged trabecular and cortical bone loss assessed by micro-CT and promotes bone formation and osteocyte survival determined by calcein labelling and TUNEL assay in GC treated animals. The osteogenic potential of the compound was authenticated by bone turnover markers. On a concluding note, compounds with BMP upregulation can be potential therapeutics for the prevention and treatment of glucocorticoid-induced osteoporosis.
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Affiliation(s)
- Divya Rai
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
| | - Ashish Kumar Tripathi
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Anirban Sardar
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
| | - Alka Raj Pandey
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
| | - Shradha Sinha
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
| | - Kunal Chutani
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
| | - Geeta Dhaniya
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Priyanka Kothari
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Koneni V Sashidhara
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
| | - Ritu Trivedi
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India.
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Abstract
Glucocorticoid use is ubiquitous and is associated with multiple adverse reactions. Among them, osteoporosis and bone fractures are of our concern. In this review, we present current evidence on the effect of glucocorticoids on bone mineral density and the risk of fractures, the mechanisms underlying those effects, and the recommendations for monitoring and treating patients who take them. The bone mineral density of the lumbar spine and total hip is lower, and the risk of fractures is higher in glucocorticoid users than non-users. These effects have a rapid onset, are dose-dependent, and improve soon after discontinuation of glucocorticoids. They also appear to occur even with non-systemic routes of administration and with low doses. Glucocorticoids reduce bone mineral density by increasing osteoclast activity and decreasing osteoblast and osteocyte activity. Calcium metabolism and parathyroid hormone activity are less important than was initially thought. Treatment decisions are on risk stratification using clinical, radiographic, and prediction tools. Our armamentarium for the treatment and prevention of glucocorticoid-induced osteoporosis includes calcium and vitamin D, bisphosphonates, recombinant parathyroid hormone, monoclonal antibodies against receptor activator of nuclear factor kappa-B ligand, and hormone treatments.
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Affiliation(s)
- Mariana Urquiaga
- Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, AL, USA.
| | - Kenneth G Saag
- Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, AL, USA
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35
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de Vasconcelos RF, Costa V, Araujo B, Maia TAC, Dias R, Vasconcelos L, Silveira H, Carneiro B, Thiers D, Costa FWG, Kurita L, Ayala A, Leitão R, Pereira KMA, Gondim DV, Goes P. Milk kefir therapy improves the skeletal response to resistance exercise in rats submitted to glucocorticoid-induced osteoporosis. Exp Gerontol 2022; 167:111921. [PMID: 35964897 DOI: 10.1016/j.exger.2022.111921] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 08/03/2022] [Accepted: 08/06/2022] [Indexed: 11/04/2022]
Abstract
Glucocorticoid-induced osteoporosis (GIO) has emerged as a challenge after long-term glucocorticoids (GCs) administration. Exercise has been an important non-pharmacological option, while medications modulate bone remodeling despite adverse effects. In this way, milk Kefir (MK) therapy stands out as a safe alternative to improve bone metabolism. Our study aimed to investigate the effect of MK associated to resistance exercise on bone loss in rats with GIO. For this, sixty male Wistar rats were divided into 2 groups: normal (N) and subjected to GIO, which was subdivided into 4 groups: control (C), milk kefir therapy (K), Exercise (Ex), and Exercise+K (ExK). GIO was induced by dexamethasone (7 mg/kg - i.m.; 1×/wk, 5 wk). MK was administered daily (1×/day; 0.7 ml/animal) and the climb exercise with load was performed 3×/wk; both for 16 wk. Femur was collected for assessment of bone microarchitecture, quality and metabolism. GIO markedly reduced trabecular bone volume density (BV/TV) (-35 %), trabecular thickness (Tb.Th) (-33 %), mineral content of femur (-26 %) as well as bone collagen content (-56 %). Bone strength and its biomechanical properties given by flexural strength (-81 %), fracture load (-80 %), and the number of osteocytes (-84 %) were lowered after GIO. GCs reduced osteoblast number and function while increased osteoclast number, altering bone remodeling (p < 0.05). On the other hand, ExK significantly improved bone microarchitecture and quality, marked by fractal dimension increase (+38 %), cortical volume (+34 %), BV/TV (+34 %), Tb.Th (+33 %), mineral content and collagen maturity, while reduced the space between trabecula (-34 %). The Ex and ExK increased the number of osteocytes (p < 0.05) and they were able to reverse the lower osteoblast number. Both treatments used alone significantly enhanced bone biomechanical properties, but the ExK showed a more significant improvement. ExK ameliorated bone strength and biomechanics (p < 0.05) and stimulated bone formation and modulated bone remodeling (p < 0.05). MK and exercise administered isolated or in association increased the percentage of collagen bone filling after GIO (p < 0.05), but only ExK improved collagen maturity. Our results showed that MK associated to resistance exercise enhanced bone microarchitecture, quality and metabolism, being therefore an interesting tool to improve skeletal response during GIO.
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Affiliation(s)
- Raquel Felipe de Vasconcelos
- Post-Graduation Program in Morphofunctional Science, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Nucleus of Study and Research in Pain, Inflammation and Osteoimmunology (NEPDIO), School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Vanessa Costa
- Post-Graduation Program in Morphofunctional Science, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Nucleus of Study and Research in Pain, Inflammation and Osteoimmunology (NEPDIO), School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Bruno Araujo
- Nucleus of Study and Research in Pain, Inflammation and Osteoimmunology (NEPDIO), School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Thays Allane Cordeiro Maia
- Nucleus of Study and Research in Pain, Inflammation and Osteoimmunology (NEPDIO), School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Romero Dias
- Nucleus of Study and Research in Pain, Inflammation and Osteoimmunology (NEPDIO), School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Lorena Vasconcelos
- Post-Graduation Program in Morphofunctional Science, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Nucleus of Study and Research in Pain, Inflammation and Osteoimmunology (NEPDIO), School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Helson Silveira
- Post-Graduation Program in Morphofunctional Science, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Nucleus of Study and Research in Pain, Inflammation and Osteoimmunology (NEPDIO), School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Bárbara Carneiro
- Nucleus of Study and Research in Pain, Inflammation and Osteoimmunology (NEPDIO), School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Post-Graduation Program in Dentistry, Department of Clinical Dentistry, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceará, Fortaleza, Brazil
| | - Diego Thiers
- Post-Graduation Program in Morphofunctional Science, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Nucleus of Study and Research in Pain, Inflammation and Osteoimmunology (NEPDIO), School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Fábio Wildson Gurgel Costa
- Post-Graduation Program in Dentistry, Department of Clinical Dentistry, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceará, Fortaleza, Brazil; Oral Radiology Unit, Department of Dental Clinic, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceará, Fortaleza, Brazil
| | - Lúcio Kurita
- Oral Radiology Unit, Department of Dental Clinic, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceará, Fortaleza, Brazil
| | - Alejandro Ayala
- Post-graduation Program in Physics, Department of Physics, Federal University of Ceará, Fortaleza, Brazil
| | - Renata Leitão
- Post-Graduation Program in Morphofunctional Science, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Department of Morphology, Medical School, Federal University of Ceará, Fortaleza, Brazil
| | - Karuza Maria Alves Pereira
- Post-Graduation Program in Morphofunctional Science, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Nucleus of Study and Research in Pain, Inflammation and Osteoimmunology (NEPDIO), School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Department of Morphology, Medical School, Federal University of Ceará, Fortaleza, Brazil
| | - Delane Viana Gondim
- Post-Graduation Program in Morphofunctional Science, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Nucleus of Study and Research in Pain, Inflammation and Osteoimmunology (NEPDIO), School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Department of Morphology, Medical School, Federal University of Ceará, Fortaleza, Brazil
| | - Paula Goes
- Post-Graduation Program in Morphofunctional Science, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Nucleus of Study and Research in Pain, Inflammation and Osteoimmunology (NEPDIO), School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Department of Pathology and Legal Medicine, Medical School, Federal University of Ceará, Fortaleza, Brazil.
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Thompson MA, Zuniga K, Sousse L, Christy R, Gurney J. The Role of Vitamin E in Thermal Burn Injuries, Infection, and Sepsis: A Review. J Burn Care Res 2022; 43:1260-1270. [PMID: 35863690 PMCID: PMC9629418 DOI: 10.1093/jbcr/irac100] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Thermal burn injuries are still a serious public health concern in the United States, due to the initial insult and resulting comorbidities. Burned patients are increasingly susceptible to colonization by endogenous and exogenous microorganisms after having lost skin, which acts as the primary protective barrier to environmental contaminants. Furthermore, the onset of additional pathophysiologies, specifically sepsis, becomes more likely in burned patients compared to other injuries. Despite improvements in the early care of burn patients, infections, and sepsis, these pathophysiologies remain major causes of morbidity and mortality and warrant further investigation of potential therapies. Vitamin E may be one such therapy. We aimed to identify publications of studies that evaluated the effectiveness of vitamin E as it pertains to thermal burn injuries, infection, and sepsis. Several investigations ranging from in vitro bench work to clinical studies have examined the impact on, or influence of, vitamin E in vitro, in vivo, and in the clinical setting. To the benefit of subjects it has been shown that enteral or parenteral vitamin E supplementation can prevent, mitigate, and even reverse the effects of thermal burn injuries, infection, and sepsis. Therefore, a large-scale prospective observational study to assess the potential benefits of vitamin E supplementation in patients is warranted and could result in clinical care practice paradigm changes.
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Affiliation(s)
- Marc A Thompson
- US Army Institute of Surgical Research, JBSA Ft Sam Houston, San Antonio, TX
| | - Kameel Zuniga
- US Army Institute of Surgical Research, JBSA Ft Sam Houston, San Antonio, TX
| | - Linda Sousse
- US Army Institute of Surgical Research, JBSA Ft Sam Houston, San Antonio, TX
| | - Robert Christy
- US Army Institute of Surgical Research, JBSA Ft Sam Houston, San Antonio, TX
| | - Jennifer Gurney
- Burn Center, United States Army Institute of Surgical Research, JBSA Ft. Sam Houston, TX, USA
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Brazão V, Colato RP, Santello FH, Duarte A, Goulart A, Sampaio PA, Pacheco Silva CB, Tirapelli CR, Costa RM, Tostes RC, do Prado JC. Melatonin regulates antioxidant defense and inflammatory response by activating Nrf2-dependent mechanisms and inhibiting NFkappaB expression in middle-aged T. cruzi infected rats. Exp Gerontol 2022; 167:111895. [PMID: 35843349 DOI: 10.1016/j.exger.2022.111895] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 07/05/2022] [Accepted: 07/11/2022] [Indexed: 12/29/2022]
Abstract
Oxidative stress with higher levels of leptin and inflammatory response are key processes related to pathogenesis of both T. cruzi infection and aging. Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the expression of several genes implicated in the oxidative stress response in many pathological conditions. Melatonin is a pleiotropic hormone with, antioxidant, anti-inflammatory and anti-aging actions. Then, we hypothesized that Nrf2 response is impaired during the acute T. cruzi (9 days) infection and that melatonin rescues Nrf2 responses. Young (5 weeks-old) and middle-aged (18 months-old) male Wistar rats were infected with T. cruzi. Nrf2 translocation and markers of inflammation and oxidative stress were analyzed in blood and spleen. Increased apoptosis levels and oxidative stress indicators were observed in the rat spleen during T. cruzi infection. These responses were accompanied by decreased Nrf2 expression and increased expression of nuclear factor kappa B (NFκB). Melatonin (5 mg/kg/day; p.o. gavage) attenuated the superoxide anion (O2-) and hydrogen peroxide (H2O2) production induced by T. cruzi infection. Increased expressions of catalase and superoxide dismutase (SOD) were detected in the spleen of melatonin-treated rats infected with T. cruzi. Melatonin treatment inhibited the spleen NF-κB activation and downregulates the levels of circulating interleukin (IL)-4, IL-10 and tumor necrosis factor (TNF)-α in T. cruzi middle-aged infected rats. Increased levels of the chemokine CXCL1 in middle-aged control rats was observed, confirming that aging alters the production of this chemokine. In T. cruzi infected young animals, CXCL1 was up-regulated when compared to non-infected young ones. For young or middle-aged animals, melatonin treatment had no significant effect on CXCL1 levels. Our findings demonstrate an important role for Nrf2/NF-kB regulation as a possible mechanism by which melatonin attenuates oxidative stress, and provide new insights for further studies of this indoleamine as a therapeutic co-adjuvant agent against T. cruzi infection.
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Affiliation(s)
- Vânia Brazão
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil.
| | - Rafaela Pravato Colato
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Fabricia Helena Santello
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Andressa Duarte
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Amanda Goulart
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Pedro Alexandre Sampaio
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Carla B Pacheco Silva
- Department of Psychiatric Nursing and Human Sciences, Laboratory of Pharmacology, College of Nursing of Ribeirão Preto, USP, Ribeirão Preto, SP, Brazil
| | - Carlos Renato Tirapelli
- Department of Psychiatric Nursing and Human Sciences, Laboratory of Pharmacology, College of Nursing of Ribeirão Preto, USP, Ribeirão Preto, SP, Brazil
| | - Rafael M Costa
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirao Preto, SP, Brazil; Special Academic Unit of Health Sciences, Federal University of Jatai, Jatai, GO, Brazil
| | - Rita C Tostes
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirao Preto, SP, Brazil
| | - José Clóvis do Prado
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
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Mohamed MM, Gunasekera WM, Glew D, Bell C, Bhalla AK. Teriparatide therapy for medication-related osteonecrosis of the jaw: case report and literature review. Clin Med (Lond) 2022; 22 Suppl 4:20-21. [PMID: 38614567 PMCID: PMC9600819 DOI: 10.7861/clinmed.22-4-s20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
| | | | - David Glew
- Royal National Hospital for Rheumatic Diseases, Bath, UK
| | | | - Ashok K Bhalla
- Royal National Hospital for Rheumatic Diseases, Bath, UK
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Schwed-Gross A, Hamiel H, Faber GP, Angel M, Ben-Yishay R, Benichou JIC, Ishay-Ronen D, Shav-Tal Y. Glucocorticoids enhance chemotherapy-driven stress granule assembly and impair granule dynamics leading to cell death. J Cell Sci 2022; 135:276097. [PMID: 35713120 PMCID: PMC9450892 DOI: 10.1242/jcs.259629] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 06/13/2022] [Indexed: 11/20/2022] Open
Abstract
Stress granules (SGs) can assemble in cancer cells upon chemotoxic stress. Glucocorticoids function during stress responses and are administered with chemotherapies. The roles of glucocorticoids in SG assembly and disassembly pathways are unknown. We examined whether combining glucocorticoids such as cortisone with chemotherapies from the vinca alkaloid family, which dismantle the microtubule network, affects SG assembly and disassembly pathways and influences cell viability in cancer cells and human-derived organoids. Cortisone augmented SG formation when combined with vinorelbine (VRB). Live-cell imaging showed that cortisone increased SG assembly rates but reduced SG clearance rates after stress, by increasing protein residence times within the SGs. Mechanistically, VRB and cortisone signaled through the integrated stress response mediated by eIF2α (also known as EIF2S1), yet induced different kinases, with cortisone activating the GCN2 kinase (also known as EIF2AK4). Cortisone increased VRB-induced cell death and reduced the population of cells trapped in mitotic catastrophe. These effects were mediated by the core SG proteins G3BP1 and G3BP2. In conclusion, glucocorticoids induce SG assembly and cell death when administered with chemotherapies, suggesting that combining glucocorticoids with chemotherapies can enhance cancer cell chemosensitivity. Summary: Combining cortisone with the chemotherapy vinorelbine enhances the assembly of stress granules that are less likely to be cleared from the cells, augmenting vinorelbine-induced cell death.
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Affiliation(s)
- Avital Schwed-Gross
- The Mina & Everard Goodman Faculty of Life Sciences & Institute of Nanotechnology, Bar-Ilan University, Ramat Gan 5290002, Israel
| | - Hila Hamiel
- The Mina & Everard Goodman Faculty of Life Sciences & Institute of Nanotechnology, Bar-Ilan University, Ramat Gan 5290002, Israel
| | - Gabriel P Faber
- The Mina & Everard Goodman Faculty of Life Sciences & Institute of Nanotechnology, Bar-Ilan University, Ramat Gan 5290002, Israel
| | - Mor Angel
- The Mina & Everard Goodman Faculty of Life Sciences & Institute of Nanotechnology, Bar-Ilan University, Ramat Gan 5290002, Israel
| | - Rakefet Ben-Yishay
- Oncology Institute, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
| | - Jennifer I C Benichou
- The Mina & Everard Goodman Faculty of Life Sciences & Institute of Nanotechnology, Bar-Ilan University, Ramat Gan 5290002, Israel
| | - Dana Ishay-Ronen
- Oncology Institute, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
| | - Yaron Shav-Tal
- The Mina & Everard Goodman Faculty of Life Sciences & Institute of Nanotechnology, Bar-Ilan University, Ramat Gan 5290002, Israel
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40
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Quque M, Ferreira C, Sosa S, Schull Q, Zahn S, Criscuolo F, Bleu J, Viblanc VA. Cascading effects of conspecific aggression on oxidative status and telomere length in zebra finches. Physiol Biochem Zool 2022; 95:416-429. [DOI: 10.1086/721252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Huang Y, Wang Z, Peng Y, Xu R, Yan J, Xiong C, Ma J, Zhong K, Lu H. Carboxin can induce cardiotoxicity in zebrafish embryos. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 233:113318. [PMID: 35182799 DOI: 10.1016/j.ecoenv.2022.113318] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 06/14/2023]
Abstract
Carboxin is a heterocyclic systemic fungicide, mainly used to prevent and control grain smut and wheat rust. Although its mammalian toxicity has been reported, its toxicity to acute exposure to aquatic animals is unknown. In our study, we used zebrafish as aquatic organisms to study Carboxin toxicity. Carboxin can cause developmental toxicity and cardiotoxicity in zebrafish embryos. Histopathological staining of cardiac sections reveals structural changes in zebrafish hearts, and fluorescence quantitative PCR results shows the heart developmental genes mRNA expression levels were disrupted significantly. Besides, carboxin can also cause oxidative stress and reactive oxygen species (ROS) accumulation in zebrafish embryos. The accumulation of ROS causes mitochondrial damage, which is where ATP energy is produced. So ATPase activities and gene expression level were measured and significantly decreased after exposure to carboxin. From the confocal images, the number of blood cells in the heart were decreased significantly after carboxin exposure. Besides, Carboxin exposure can inhibit myocardial cell proliferation. These are all causes to the heart failure, eventually leading to embryos death.
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Affiliation(s)
- Yong Huang
- Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, Jiangxi, China; College of Chemistry and Chemical Engineering, Gannan Normal University, Ganzhou 341000, Jiangxi, China
| | - Ziqin Wang
- Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, Jiangxi, China
| | - Yuyang Peng
- Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, Jiangxi, China
| | - Rong Xu
- The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi, China
| | - Jiajie Yan
- Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, Jiangxi, China
| | - Cong Xiong
- Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, Jiangxi, China
| | - Jinze Ma
- Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, Jiangxi, China
| | - Keyuan Zhong
- Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, Jiangxi, China
| | - Huiqiang Lu
- Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, Jiangxi, China; College of Chemistry and Chemical Engineering, Gannan Normal University, Ganzhou 341000, Jiangxi, China.
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Tripathi AK, Rai D, Kothari P, Kushwaha P, Sashidhara KV, Trivedi R. Benzofuran pyran hybrid prevents glucocorticoid induced osteoporosis in mice via modulation of canonical Wnt/β-catenin signaling. Apoptosis 2022; 27:90-111. [PMID: 35107658 PMCID: PMC8808472 DOI: 10.1007/s10495-021-01702-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2021] [Indexed: 11/26/2022]
Abstract
Glucocorticoid induced osteoporosis (GIOP) is the second most leading cause of osteoporosis. We have identified a compound, a benzofuran pyran hybrid compound 4e that has osteogenic potential and we wanted to assess its efficacy in GIOP in male mice. We assessed the effect of dexamethasone and compound 4e on primary osteoblasts using various cell based and immunofluorescence assays. For in vivo studies we administered methylprednisolone and compound 4e as a prophylactic measure in male Balb/c mice for 28 days and then evaluated the effect on bone microarchitecture by microCT, bone formation by histology along with clinically relevant bone markers. Compound 4e preserved osteoblast differentiation as evident by higher ALP positive cells and mineralization in compound treated groups. Compound 4e also increased the expression of osteogenic genes. This compound guarded β-catenin expression both in vitro and in vivo as confirmed by western blot and immunofluorescence assays. This led to the preservation of bone microarchitecture and cortical thickness at 2.5 mg kg−1 and 5 mg kg−1 doses. Further compound 4e enhanced bone formation rate and regulated osteocyte death. The osteogenic potential of compound 4e was reflected by an increased level of serum marker osteocalcin and decreased levels of SOST and CTX-I. Overall, Compound 4e is able to overcome the catabolic effect of dexamethasone on bone by targeting the canonical WNT/β-catenin signaling as evidenced by both in vitro and in vivo studies.
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Affiliation(s)
- Ashish Kumar Tripathi
- Endocrinology Division, CSIR-Central Drug Research Institute, 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh, 226031, India
| | - Divya Rai
- Endocrinology Division, CSIR-Central Drug Research Institute, 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Priyanka Kothari
- Endocrinology Division, CSIR-Central Drug Research Institute, 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh, 226031, India
| | - Pragati Kushwaha
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Koneni V Sashidhara
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Ritu Trivedi
- Endocrinology Division, CSIR-Central Drug Research Institute, 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh, 226031, India.
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43
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Huang W, Wu Y, Qiao M, Xie Z, Cen X, Huang X, Zhao Z. CircRNA-miRNA networks in regulating bone disease. J Cell Physiol 2022; 237:1225-1244. [PMID: 34796958 DOI: 10.1002/jcp.30625] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/21/2021] [Accepted: 10/26/2021] [Indexed: 02/05/2023]
Abstract
Circular RNA (circRNA) is a class of endogenous noncoding RNA (ncRNA), presenting as a special covalent closed loop without a 5' cap or 3' tail, maintaining resistance to RNA exonuclease and keeping high stability. Although lowly expressed in most situations, circRNA makes an active difference in regulating physiological or pathological processes by modulating gene expression by regulation of transcription, protein, and miRNA functions through various mechanisms in particular tissues. Recent studies have demonstrated the roles of the miRNA-circRNA network in the development of several bone diseases such as osteoporosis, a multiple-mechanism disease resulting from defective bone quality and low bone mass, osteoarthritis, whose main pathomechanism is inflammation and articular cartilage degradation, as well as osteosarcoma, known as one of the most common bone cancers. However, the specific mechanism of how circRNA along with miRNA influences those diseases is not well documented, showing potential for the development of new therapies for those bone diseases.
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Affiliation(s)
- Wei Huang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, People's Republic of China
| | - Yongyao Wu
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, People's Republic of China
| | - MingXin Qiao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, People's Republic of China
| | - Zhuojun Xie
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, People's Republic of China
| | - Xiao Cen
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, People's Republic of China
| | - Xinqi Huang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, People's Republic of China
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, People's Republic of China
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Pierce JL, Sharma AK, Roberts RL, Yu K, Irsik DL, Choudhary V, Dorn JS, Bensreti H, Benson RD, Kaiser H, Khayrullin A, Davis C, Wehrle CJ, Johnson MH, Bollag WB, Hamrick MW, Shi X, Isales CM, McGee-Lawrence ME. The Glucocorticoid Receptor in Osterix-Expressing Cells Regulates Bone Mass, Bone Marrow Adipose Tissue, and Systemic Metabolism in Female Mice During Aging. J Bone Miner Res 2022; 37:285-302. [PMID: 34747055 PMCID: PMC9976194 DOI: 10.1002/jbmr.4468] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 09/23/2021] [Accepted: 10/17/2021] [Indexed: 12/18/2022]
Abstract
Hallmarks of aging-associated osteoporosis include bone loss, bone marrow adipose tissue (BMAT) expansion, and impaired osteoblast function. Endogenous glucocorticoid levels increase with age, and elevated glucocorticoid signaling, associated with chronic stress and dysregulated metabolism, can have a deleterious effect on bone mass. Canonical glucocorticoid signaling through the glucocorticoid receptor (GR) was recently investigated as a mediator of osteoporosis during the stress of chronic caloric restriction. To address the role of the GR in an aging-associated osteoporotic phenotype, the current study utilized female GR conditional knockout (GR-CKO; GRfl/fl :Osx-Cre+) mice and control littermates on the C57BL/6 background aged to 21 months and studied in comparison to young (3- and 6-month-old) mice. GR deficiency in Osx-expressing cells led to low bone mass and BMAT accumulation that persisted with aging. Surprisingly, however, GR-CKO mice also exhibited alterations in muscle mass (reduced % lean mass and soleus fiber size), accompanied by reduced voluntary physical activity, and also exhibited higher whole-body metabolic rate and elevated blood pressure. Moreover, increased lipid storage was observed in GR-CKO osteoblastic cultures in a glucocorticoid-dependent fashion despite genetic deletion of the GR, and could be reversed via pharmacological inhibition of the mineralocorticoid receptor (MR). These findings provide evidence of a role for the GR (and possibly the MR) in facilitating healthy bone maintenance with aging in females. The effects of GR-deficient bone on whole-body physiology also demonstrate the importance of bone as an endocrine organ and suggest evidence for compensatory mechanisms that facilitate glucocorticoid signaling in the absence of osteoblastic GR function; these represent new avenues of research that may improve understanding of glucocorticoid signaling in bone toward the development of novel osteogenic agents. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Jessica L Pierce
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Anuj K Sharma
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Rachel L Roberts
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Kanglun Yu
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Debra L Irsik
- Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, GA, USA.,Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - Vivek Choudhary
- Department of Physiology, Augusta University, Augusta, GA, USA
| | - Jennifer S Dorn
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Husam Bensreti
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Reginald D Benson
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Helen Kaiser
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Andrew Khayrullin
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Colleen Davis
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Chase J Wehrle
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Maribeth H Johnson
- Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, GA, USA
| | - Wendy B Bollag
- Charlie Norwood VA Medical Center, Augusta, GA, USA.,Department of Physiology, Augusta University, Augusta, GA, USA
| | - Mark W Hamrick
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Xingming Shi
- Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, GA, USA
| | - Carlos M Isales
- Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, GA, USA
| | - Meghan E McGee-Lawrence
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA.,Department of Orthopaedic Surgery, Augusta University, Augusta, GA, USA
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45
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Endocrine Fibroblast Growth Factors in Relation to Stress Signaling. Cells 2022; 11:cells11030505. [PMID: 35159314 PMCID: PMC8834311 DOI: 10.3390/cells11030505] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/30/2022] [Accepted: 01/31/2022] [Indexed: 01/10/2023] Open
Abstract
Fibroblast growth factors (FGFs) play important roles in various growth signaling processes, including proliferation, development, and differentiation. Endocrine FGFs, i.e., atypical FGFs, including FGF15/19, FGF21, and FGF23, function as endocrine hormones that regulate energy metabolism. Nutritional status is known to regulate the expression of endocrine FGFs through nuclear hormone receptors. The increased expression of endocrine FGFs regulates energy metabolism processes, such as fatty acid metabolism and glucose metabolism. Recently, a relationship was found between the FGF19 subfamily and stress signaling during stresses such as endoplasmic reticulum stress and oxidative stress. This review focuses on endocrine FGFs and the recent progress in FGF studies in relation to stress signaling. In addition, the relevance of the stress-FGF pathway to disease and human health is discussed.
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46
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Transforming Growth Factor-Beta in Skeletal Muscle Wasting. Int J Mol Sci 2022; 23:ijms23031167. [PMID: 35163088 PMCID: PMC8835446 DOI: 10.3390/ijms23031167] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/11/2022] [Accepted: 01/19/2022] [Indexed: 12/21/2022] Open
Abstract
Transforming growth factor-beta (TGF-β) is part of a family of molecules that is present in many body tissues and performs many different functions. Evidence has been obtained from mice and human cancer patients with bony metastases and non-metastatic disease, as well as pediatric burn patients, that inflammation leads to bone resorption and release of TGF-β from the bone matrix with paracrine effects on muscle protein balance, possibly mediated by the generation of reactive oxygen species. Whether immobilization, which confounds the etiology of bone resorption in burn injury, also leads to the release of TGF-β from bone contributing to muscle wasting in other conditions is unclear. The use of anti-resorptive therapy in both metastatic cancer patients and pediatric burn patients has been successful in the prevention of muscle wasting, thereby creating an additional therapeutic niche for this class of drugs. The liberation of TGF-β may be one way in which bone helps to control muscle mass, but further investigation will be necessary to assess whether the rate of bone resorption is the determining factor for the release of TGF-β. Moreover, whether different resorptive conditions, such as immobilization and hyperparathyroidism, also involve TGF-β release in the pathogenesis of muscle wasting needs to be investigated.
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47
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Gado M, Baschant U, Hofbauer LC, Henneicke H. Bad to the Bone: The Effects of Therapeutic Glucocorticoids on Osteoblasts and Osteocytes. Front Endocrinol (Lausanne) 2022; 13:835720. [PMID: 35432217 PMCID: PMC9008133 DOI: 10.3389/fendo.2022.835720] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
Despite the continued development of specialized immunosuppressive therapies in the form of monoclonal antibodies, glucocorticoids remain a mainstay in the treatment of rheumatological and auto-inflammatory disorders. Therapeutic glucocorticoids are unmatched in the breadth of their immunosuppressive properties and deliver their anti-inflammatory effects at unparalleled speed. However, long-term exposure to therapeutic doses of glucocorticoids decreases bone mass and increases the risk of fractures - particularly in the spine - thus limiting their clinical use. Due to the abundant expression of glucocorticoid receptors across all skeletal cell populations and their respective progenitors, therapeutic glucocorticoids affect skeletal quality through a plethora of cellular targets and molecular mechanisms. However, recent evidence from rodent studies, supported by clinical data, highlights the considerable role of cells of the osteoblast lineage in the pathogenesis of glucocorticoid-induced osteoporosis: it is now appreciated that cells of the osteoblast lineage are key targets of therapeutic glucocorticoids and have an outsized role in mediating their undesirable skeletal effects. As part of this article, we review the molecular mechanisms underpinning the detrimental effects of supraphysiological levels of glucocorticoids on cells of the osteoblast lineage including osteocytes and highlight the clinical implications of recent discoveries in the field.
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Affiliation(s)
- Manuel Gado
- Center for Regenerative Therapies TU Dresden, Technische Universität Dresden, Dresden, Germany
| | - Ulrike Baschant
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Lorenz C. Hofbauer
- Center for Regenerative Therapies TU Dresden, Technische Universität Dresden, Dresden, Germany
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Holger Henneicke
- Center for Regenerative Therapies TU Dresden, Technische Universität Dresden, Dresden, Germany
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- *Correspondence: Holger Henneicke,
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Abstract
Osteocytes, former osteoblasts encapsulated by mineralized bone matrix, are far from being passive and metabolically inactive bone cells. Instead, osteocytes are multifunctional and dynamic cells capable of integrating hormonal and mechanical signals and transmitting them to effector cells in bone and in distant tissues. Osteocytes are a major source of molecules that regulate bone homeostasis by integrating both mechanical cues and hormonal signals that coordinate the differentiation and function of osteoclasts and osteoblasts. Osteocyte function is altered in both rare and common bone diseases, suggesting that osteocyte dysfunction is directly involved in the pathophysiology of several disorders affecting the skeleton. Advances in osteocyte biology initiated the development of novel therapeutics interfering with osteocyte-secreted molecules. Moreover, osteocytes are targets and key distributors of biological signals mediating the beneficial effects of several bone therapeutics used in the clinic. Here we review the most recent discoveries in osteocyte biology demonstrating that osteocytes regulate bone homeostasis and bone marrow fat via paracrine signaling, influence body composition and energy metabolism via endocrine signaling, and contribute to the damaging effects of diabetes mellitus and hematologic and metastatic cancers in the skeleton.
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Affiliation(s)
- Jesus Delgado-Calle
- 1Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas,2Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Teresita Bellido
- 1Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas,2Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas,3Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
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49
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Brotto M, Invernizzi M, Ireland A, Klein GL. Editorial: Osteoporosis and the Role of Muscle. Front Endocrinol (Lausanne) 2022; 13:951298. [PMID: 35832428 PMCID: PMC9271953 DOI: 10.3389/fendo.2022.951298] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 05/30/2022] [Indexed: 01/09/2023] Open
Affiliation(s)
- Marco Brotto
- Director of Bone-Muscle Research Center, University of Texas at Arlington, Arlington, TX, United States
| | - Marco Invernizzi
- Department of Health Sciences, University of Eastern Piedmont, Novara, Italy
| | - Alex Ireland
- Senior Lecturer, Manchester Metropolitan University, Manchester, United Kingdom
| | - Gordon L. Klein
- Senior Scientist and Adjunct Professor, Department of Orthopaedic Surgery and Rehabilitation, University of Texas Medical Branch, Galveston, TX, United States
- *Correspondence: Gordon L. Klein,
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50
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Oh S, Choi CH, Lee BJ, Park JH, Son KH, Byun K. Fermented Oyster Extract Attenuated Dexamethasone-Induced Muscle Atrophy by Decreasing Oxidative Stress. Molecules 2021; 26:molecules26237128. [PMID: 34885708 PMCID: PMC8658907 DOI: 10.3390/molecules26237128] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/12/2021] [Accepted: 11/22/2021] [Indexed: 12/25/2022] Open
Abstract
It is well known that oxidative stress induces muscle atrophy, which decreases with the activation of Nrf2/HO-1. Fermented oyster extracts (FO), rich in γ-aminobutyric acid (GABA) and lactate, have shown antioxidative effects. We evaluated whether FO decreased oxidative stress by upregulating Nrf2/HO-1 and whether it decreased NF-κB, leading to decreased IL-6 and TNF-α. Decreased oxidative stress led to the downregulation of Cbl-b ubiquitin ligase, which increased IGF-1 and decreased FoxO3, atrogin1, and Murf1, and eventually decreased muscle atrophy in dexamethasone (Dexa)-induced muscle atrophy animal model. For four weeks, mice were orally administered with FO, GABA, lactate, or GABA+Lactate, and then Dexa was subcutaneously injected for ten days. During Dexa injection period, FO, GABA, lactate, or GABA+Lactate were also administered, and grip strength test and muscle harvesting were performed on the day of the last Dexa injection. We compared the attenuation effect of FO with GABA, lactate, and GABA+lactate treatment. Nrf2 and HO-1 expressions were increased by Dexa but decreased by FO; SOD activity and glutathione levels were decreased by Dexa but increased by FO; NADPH oxidase activity was increased by Dexa but decreased by FO; NF-κB, IL-6, and TNF-α activities were increased by Dexa were decreased by FO; Cbl-b expression was increased by Dexa but restored by FO; IGF-1 expression was decreased by Dexa but increased by FO; FoxO3, Atrogin-1, and MuRF1 expressions were increased by Dexa but decreased by FO. The gastrocnemius thickness and weight were decreased by Dexa but increased by FO. The cross-sectional area of muscle fiber and grip strength were decreased by Dexa but increased by FO. In conclusion, FO decreased Dexa-induced oxidative stress through the upregulation of Nrf2/HO-1. Decreased oxidative stress led to decreased Cbl-b, FoxO3, atrogin1, and MuRF1, which attenuated muscle atrophy.
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Affiliation(s)
- Seyeon Oh
- Functional Cellular Networks Laboratory, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon 21999, Korea;
| | - Chang Hu Choi
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Korea;
| | - Bae-Jin Lee
- Marine Bioprocess Co., Ltd., Smart Marine BioCenter, Busan 46048, Korea; (B.-J.L.); (J.-H.P.)
| | - Joung-Hyun Park
- Marine Bioprocess Co., Ltd., Smart Marine BioCenter, Busan 46048, Korea; (B.-J.L.); (J.-H.P.)
| | - Kuk-Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Korea;
- Correspondence: (K.-H.S.); (K.B.); Tel.: +82-32-460-3666 (K.-H.S.); +82-32-899-6511 (K.B.)
| | - Kyunghee Byun
- Functional Cellular Networks Laboratory, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon 21999, Korea;
- Department of Anatomy and Cell Biology, Gachon University College of Medicine, Incheon 21936, Korea
- Correspondence: (K.-H.S.); (K.B.); Tel.: +82-32-460-3666 (K.-H.S.); +82-32-899-6511 (K.B.)
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