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Jiang YS, Wei WS, Xie DT, Guo G. Circular RNAs inducing the osteogenic differentiation of dental mesenchymal stem cells via microRNA sponging. World J Stem Cells 2025; 17:101638. [DOI: 10.4252/wjsc.v17.i5.101638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 11/24/2024] [Accepted: 04/14/2025] [Indexed: 05/26/2025] Open
Abstract
Circular RNAs (circRNAs) are a distinct type of nonlinear and noncoding RNAs endogenously expressed by pre-mRNA back-splicing and crucial in transcriptional and posttranscriptional regulation. CircRNAs can regulate cellular and molecular pathways through various mechanisms, such as microRNA sponging. Numerous studies have indicated the regulatory roles of circRNAs in the osteogenic differentiation of stem cells (SCs) isolated from different sources. Dental tissue-derived mesenchymal SCs (MSCs) have received considerable attention in artificial bone engineering, in which SCs are used to manufacture functional bone tissues to repair bone defects. Recently, studies have reported the regulatory roles of circRNAs in the osteogenic differentiation of dental-derived MSCs, such as apical papillae, dental pulp, and dental follicle SCs. This review aimed to discuss the findings of studies evaluating the contribution of circRNAs to the osteogenic differentiation of dental-derived MSCs.
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Affiliation(s)
- Yong-Song Jiang
- Department of Orthopedic, The Central Hospital of Yongzhou, Yongzhou 425000, Hunan Province, China
- Department of Orthopedic, Yongzhou Hospital Affiliated to University of South China, Yongzhou 425000, Hunan Province, China
| | - Wei-Sheng Wei
- Department of Orthopedic, The Central Hospital of Yongzhou, Yongzhou 425000, Hunan Province, China
- Department of Orthopedic, Yongzhou Hospital Affiliated to University of South China, Yongzhou 425000, Hunan Province, China
| | - Dao-Tao Xie
- Norxin International Technology Innovation Cooperation Platform, Xi’an 710032, Shaanxi Province, China
| | - Gang Guo
- Norxin International Technology Innovation Cooperation Platform, Xi’an 710032, Shaanxi Province, China
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Zhu R, Xiong L, Dan Z, Shi X, Shu C, Wang Y, Zhu H. Palmitic acid induces cardiomyocyte apoptosis by enhancing the KLF4/cMLCK signaling pathway. Gene 2025; 943:149270. [PMID: 39855370 DOI: 10.1016/j.gene.2025.149270] [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: 10/10/2024] [Revised: 12/11/2024] [Accepted: 01/20/2025] [Indexed: 01/27/2025]
Abstract
Hyperlipidemia and myocardial apoptosis caused by myocardial ischemia are the main causes of high mortality rates in cardiovascular diseases. Previous studies have indicated that Krüppel-like factor 4 (KLF4) is involved in the induction of cardiac myocyte apoptosis under various stress conditions. In current study, we discovered that KLF4 also participates in palmitic acid (PA)-induced cardiac myocyte apoptosis. However, the specific mechanisms by which KLF4 regulates cardiac myocyte apoptosis remain unclear. Cardiac myosin light-chain kinase (cMLCK) is a crucial enzyme involved in regulating cardiac myocyte contraction and is closely associated with the regulation of apoptosis. Here, we employed the lipotoxicity in vitro and in vivo models to explore the potential synergistic role of KLF4 and cMLCK in cardiac myocyte apoptosis. Our findings demonstrate that under the influence of PA, upregulation of KLF4 expression accompanied by downregulation of cMLCK expression leads to cardiomyocyte apoptosis and cell proliferation inhibition. Selective knockdown and overexpression of KLF4 in cardiomyocytes further confirmed the involvement of KLF4 in PA-induced cardiomyocyte apoptosis. Likewise, overexpression of cMLCK alleviated PA-induced cardiac myocyte apoptosis. Our study reveals the pro-apoptotic effect of KLF4 and elucidates the specific mechanism by which the KLF4/cMLCK signaling pathway is involved in PA-induced cardiac myocyte apoptosis, providing new therapeutic targets for cardiovascular disease treatment.
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Affiliation(s)
- Rumeng Zhu
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Lei Xiong
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Zhangyong Dan
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Xiaorui Shi
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Chuanlin Shu
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Yi Wang
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Sciences, Anhui Medical University, Hefei, China; Department of Biological Engineering, School of Life Sciences, Anhui Medical University, Hefei 230032, China; Anhui Province Key Laboratory of Cancer Translational Medicine, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Huaqing Zhu
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
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3
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Gao D, Yi WW, Liu B, Zhang CE, Yang CC, Zeng L, Li L, Luo G, Zhang L, Ju ZY, Wang JB. Tetrahydroxy stilbene glucoside rejuvenates aging hematopoietic stem cells with predilection for lymphoid differentiation via AMPK and Tet2. J Adv Res 2025; 70:515-529. [PMID: 38704089 PMCID: PMC11976424 DOI: 10.1016/j.jare.2024.04.027] [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: 12/28/2023] [Revised: 03/26/2024] [Accepted: 04/26/2024] [Indexed: 05/06/2024] Open
Abstract
INTRODUCTION Aging of hematopoietic stem cells (HSCs) has emerged as an important challenge to human health. Recent advances have raised the prospect of rejuvenating aging HSCs via specific medical interventions, including pharmacological treatments. Nonetheless, efforts to develop such drugs are still in infancy until now. OBJECTIVES We aimed to screen the prospective agents that can rejuvenate aging HSCs and explore the potential mechanisms. METHODS We screened a set of natural anti-aging compounds through oral administration to sub-lethally irradiated mice, and identified 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) as a potent rejuvenating agent for aging HSCs. Then naturally aged mice were used for the follow-up assessment to determine the HSC rejuvenating potential of TSG. Finally, based on the transcriptome and DNA methylation analysis, we validated the role of the AMP-activated protein kinase (AMPK)-ten-eleven-translocation 2 (Tet2) axis (the AMPK-Tet2 axis) as the underlying mechanisms of TSG for ameliorating HSCs aging. RESULTS TSG treatment not only significantly increased the absolute number of common lymphoid progenitors (CLPs) along with B lymphocytes, but also boosted the HSCs/CLPs repopulation potential of aging mice. Further elaborated mechanism research demonstrated that TSG supplementation restored the stemness of aging HSCs, as well as promoted an epigenetic reprograming that was associated with an improved regenerative capacity and an increased rate of lymphopoiesis. Such effects were diminished when the mice were co-treated with an AMPK inhibitor, or when it was performed in Tet2 knockout mice as well as senescent cells assay. CONCLUSION TSG is effective in rejuvenating aging HSCs by modulating the AMPK- Tet2 axis and thus represents a potential candidate for developing effective HSC rejuvenating therapies.
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Affiliation(s)
- Dan Gao
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China; Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang 550004, China
| | - Wei-Wei Yi
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Bo Liu
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Cong-En Zhang
- Department of Pharmacy, Beijing Friendship Hospital of Capital Medical University, Beijing 100050, China
| | - Cui-Cui Yang
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China
| | - Li Zeng
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China
| | - Lin Li
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China
| | - Guangbin Luo
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106-1712, USA; Centre for Translational Medicine, Shenzhen Bao'an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen 518101, China.
| | - Lan Zhang
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China.
| | - Zhen-Yu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, Guangdong 510632, China.
| | - Jia-Bo Wang
- School of Chinese Medicine, Capital Medical University, Beijing 100069, China.
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Zhang Y, Wang Y, Cheng X, Guo H, Ma D, Song Y, Zhang Y, Wang H, Du H. Cardioprotective Effects of Phlorizin on Hyperlipidemia-induced Myocardial Injury: Involvement of Suppression in Pyroptosis via Regulating HK1/NLRP3/Caspase-1 Signaling Pathway. Appl Biochem Biotechnol 2025; 197:754-770. [PMID: 39223343 DOI: 10.1007/s12010-024-05056-5] [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] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
Hyperlipidemia (HLP) is a prevalent and intricate condition that plays a pivotal role in impairing heart function. The primary objective of this study was to assess the lipid-lowering and cardioprotective properties of phlorizin (PHZ) and to investigate its potential molecular mechanisms in rats. In this investigation, Sprague-Dawley rats were subjected to a high-fat diet for a period of 28 days to induce an HLP model. Subsequently, the rats received oral doses of PHZ or metformin from day 14 to day 28. We assessed various parameters using commercially available kits, including serum lipid deposition, myocardial injury biomarkers, oxidative stress markers, and inflammatory cytokine levels. We also employed electron microscopy to examine myocardial ultrastructural changes and conducted Western blot analyses to assess apoptosis factors and pyroptosis markers. Comparing the PHZ group with the model group, we observed significant improvements in blood lipid deposition and heart injury biomarkers. Furthermore, PHZ demonstrated a clear reduction in myocardial tissue oxidative stress and inflammatory factors, as well as a suppression of cell apoptosis. Subsequent investigations indicated that PHZ treatment led to a decreased inflammatory response and lowered levels of hexokinase 1 (HK1), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and Caspase-1. In summary, PHZ proved to be an effective remedy for alleviating HLP-induced cardiac damage by reducing blood lipid levels, mitigating oxidative stress, curbing inflammation, and suppressing pyroptosis. The inhibition of pyroptosis by PHZ appears to be linked to the regulation of the HK1/NLRP3/Caspase-1 signaling pathway.
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Affiliation(s)
- Yuling Zhang
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China
| | - Yanan Wang
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China
| | - Xizhen Cheng
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China
| | - Haochuan Guo
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China
| | - Donglai Ma
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China
- Hebei Technology Innovation Center of TCM Formula Preparations, Shijiazhuang, 050200, Hebei, China
- Traditional Chinese Medicine Processing Technology Innovation Center of Hebei Province, Shijiazhuang, 050091, Hebei, China
| | - Yongxing Song
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China
- Traditional Chinese Medicine Processing Technology Innovation Center of Hebei Province, Shijiazhuang, 050091, Hebei, China
| | - Yajing Zhang
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China.
- Hebei Technology Innovation Center of TCM Formula Preparations, Shijiazhuang, 050200, Hebei, China.
| | - Hongfang Wang
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China.
- Hebei Technology Innovation Center of TCM Formula Preparations, Shijiazhuang, 050200, Hebei, China.
| | - Huiru Du
- Hebei Technology Innovation Center of TCM Formula Preparations, Shijiazhuang, 050200, Hebei, China.
- Department of Pharmaceutical Engineering, Hebei Chemical & Pharmaceutical College, Shijiazhuang, 050026, Hebei, China.
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Wang LF, Li Q, Le Zhao J, Wen K, Zhang YT, Zhao QH, Ding Q, Li JH, Guan XH, Xiao YF, Deng KY, Xin HB. CD38 deficiency prevents diabetic nephropathy by inhibiting lipid accumulation and oxidative stress through activation of the SIRT3 pathway. Biochem Cell Biol 2025; 103:1-12. [PMID: 39116458 DOI: 10.1139/bcb-2024-0058] [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: 08/10/2024] Open
Abstract
Diabetic nephropathy (DN) is one of the most common complications of diabetes. Our previous study showed that CD38 knockout (CD38KO) mice had protective effects on many diseases. However, the roles and mechanisms of CD38 in DN remain unknown. Here, DN mice were generated by high-fat diet (HFD) feeding plus streptozotocin (STZ) injection in male CD38KO and CD38flox mice. Mesangial cells (SV40 MES 13 cells) were used to mimic the injury of DN with palPagination Donemitic acid (PA) treatment in vitro. Our results showed that CD38 expression was significantly increased in kidney of diabetic CD38flox mice and SV40 MES 13 cells treated with PA. CD38KO mice were significantly resistant to diabetes-induced renal injury. Moreover, CD38 deficiency markedly decreased HFD/STZ-induced lipid accumulation, fibrosis, and oxidative stress in kidney tissue. In contrast, overexpression of CD38 aggravated PA-induced lipid accumulation and oxidative stress. CD38 deficiency increased expression of SIRT3, while overexpression of CD38 decreased its expression. More importantly, 3-TYP, an inhibitor of SIRT3, significantly enhanced PA-induced lipid accumulation and oxidative stress in CD38 overexpressing cell lines. In conclusion, our results demonstrated that CD38 deficiency prevented DN by inhibiting lipid accumulation and oxidative stress through activation of the SIRT3 pathway.
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Affiliation(s)
- Ling-Fang Wang
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Qian Li
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Jia Le Zhao
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Ke Wen
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Ya-Ting Zhang
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Qi-Hang Zhao
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Qi Ding
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Jia-Hui Li
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Xiao-Hui Guan
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Yun-Fei Xiao
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Ke-Yu Deng
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Hong-Bo Xin
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
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Aghaei SM, Hosseini SM. Inflammation-related miRNAs in obesity, CVD, and NAFLD. Cytokine 2024; 182:156724. [PMID: 39106574 DOI: 10.1016/j.cyto.2024.156724] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 07/08/2024] [Accepted: 08/01/2024] [Indexed: 08/09/2024]
Abstract
Obesity, cardiovascular diseases (CVD), and nonalcoholic fatty liver disease (NAFLD) pose significant worldwide health challenges, characterized by complex interplay among inflammatory pathways that underlie their development. In this review, we examine the contribution of inflammation and associated signaling molecules to the pathogenesis of these conditions, while also emphasizing the significant participation of non-coding RNAs (ncRNAs) in modulating inflammatory pathways. In the context of obesity, aberrant expression patterns of inflammatory-associated miRNAs play a contributory role in adipose tissue inflammation and insulin resistance, thereby exacerbating disturbances in metabolic homeostasis. Similarly, in CVD, dysregulated miRNA expression alters inflammatory reactions, disrupts endothelial function, and induces cardiac remodeling, thereby impacting the advancement of the disease. Moreover, in the context of NAFLD, inflammatory-associated miRNAs are implicated in mediating hepatic inflammation, lipid deposition, and fibrosis, underscoring their candidacy as promising therapeutic targets. Additionally, the competing endogenous RNA (ceRNA) network has emerged as a novel regulatory mechanism in the etiology of CVD, obesity, and NAFLD, wherein ncRNAs assume pivotal roles in facilitating communication across diverse molecular pathways. Moreover, in the concluding section, we underscored the potential efficacy of directing interventions towards inflammatory-related miRNAs utilizing herbal remedies and therapies based on exosome delivery systems as a promising strategy for ameliorating pathologies associated with inflammation in obesity, CVD, and NAFLD.
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Affiliation(s)
- Sayed Mohsen Aghaei
- Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Sayed Mostafa Hosseini
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Talebi SF, Kooshki A, Zarein M, Seify M, Dolatshahi B, Shoorei H, Bhandari RK. Protective effect of hesperidin on malathion-induced ovarian toxicity in mice: The role of miRNAs, inflammation, and apoptosis. Toxicol Rep 2024; 12:469-476. [PMID: 40094084 PMCID: PMC11907194 DOI: 10.1016/j.toxrep.2024.04.003] [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: 02/29/2024] [Revised: 04/06/2024] [Accepted: 04/11/2024] [Indexed: 03/19/2025] Open
Abstract
Malathion, a widely used organophosphate, is known for its relatively low toxicity and extensive application. However, it has been found to act as a female reproductive toxicant by causing oxidative stress, apoptosis, autophagy, and hormonal imbalances. Hesperidin, a flavonoid belonging to the flavanone class, exhibits various beneficial properties such as antioxidant and anti-inflammatory effects, which can potentially counteract harmful effects. The objective of this study was to examine how hesperidin and malathion impact the expression of miRNAs and genes linked to apoptosis and inflammation. Balb/c mice (n = 40) were divided into four groups: hesperidin (20 mg/kg), malathion (3 mg/kg), hesperidin+malathion, and control. After a 35-day intraperitoneal treatment, the mice were sacrificed. The left ovaries were used for analyzing the expression of miRNA-146a-5p, miRNA-129-3p, miRNA-96-5p, NF-κB, Bax, and Bcl-2 through RT-qPCR, as well as the levels of several cytokines using the ELISA method. The right ovaries were examined through histological and immunohistochemical techniques using H&E and NF-κB staining. Malathion exposure led to an increased Bax/Bcl-2 ratio, upregulated expression of Bax and NF-κB, elevated levels of IFN-γ, IL-2, and IL-6, enhanced expression of miRNA-146a-5p, decreased expression of miRNA-129-3p and miRNA-96-5p, and reduced levels of IL-4 and IL-10. Additionally, malathion-exposed ovaries exhibited structural abnormalities and disrupted architecture, accompanied by heightened NF-κB immunoreactivity. Conversely, treatment with hesperidin showed its capacity to counteract the detrimental consequences of malathion on the ovaries by alleviating or reversing these changes. In conclusion, hesperidin showed protective effects against malathion-induced ovarian toxicity by modulating cytokine production, apoptosis, inflammation, and miRNA expression.
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Affiliation(s)
- Seyedeh Fahimeh Talebi
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Islamic Republic of Iran
- Department of Pharmacology, Birjand University of Medical Sciences, Birjand, Islamic Republic of Iran
| | - Alireza Kooshki
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Islamic Republic of Iran
| | - Mahnaz Zarein
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Islamic Republic of Iran
| | - Mohammad Seify
- Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Islamic Republic of Iran
| | - Baharan Dolatshahi
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Islamic Republic of Iran
| | - Hamed Shoorei
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Islamic Republic of Iran
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
- Rooyesh Infertility Center, Birjand University of Medical Sciences, Birjand, Islamic Republic of Iran
| | - Ramji Kumar Bhandari
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211, USA
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Zhou J, Tang CK. Cytoplasmic Polyadenylation Element Binding Protein 1 and Atherosclerosis: Prospective Target and New Insights. Curr Vasc Pharmacol 2024; 22:95-105. [PMID: 38284693 DOI: 10.2174/0115701611258090231221082502] [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: 05/12/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 01/30/2024]
Abstract
The ribonucleic acid (RNA)-binding protein Cytoplasmic Polyadenylation Element Binding Protein 1 (CPEB1), a key member of the CPEB family, is essential in controlling gene expression involved in both healthy physiological and pathological processes. CPEB1 can bind to the 3'- untranslated regions (UTR) of substrate messenger ribonucleic acid (mRNA) and regulate its translation. There is increasing evidence that CPEB1 is closely related to the pathological basis of atherosclerosis. According to recent investigations, many pathological processes, including inflammation, lipid metabolism, endothelial dysfunction, angiogenesis, oxidative stress, cellular senescence, apoptosis, and insulin resistance, are regulated by CPEB1. This review considers the prevention and treatment of atherosclerotic heart disease in relation to the evolution of the physiological function of CPEB1, recent research breakthroughs, and the potential participation of CPEB1 in atherosclerosis.
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Affiliation(s)
- Jing Zhou
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, School of Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Chao-Ke Tang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, School of Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
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9
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Rates ADB, Cesarino I. Pour some sugar on me: The diverse functions of phenylpropanoid glycosylation. JOURNAL OF PLANT PHYSIOLOGY 2023; 291:154138. [PMID: 38006622 DOI: 10.1016/j.jplph.2023.154138] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 11/06/2023] [Indexed: 11/27/2023]
Abstract
The phenylpropanoid metabolism is the source of a vast array of specialized metabolites that play diverse functions in plant growth and development and contribute to all aspects of plant interactions with their surrounding environment. These compounds protect plants from damaging ultraviolet radiation and reactive oxygen species, provide mechanical support for the plants to stand upright, and mediate plant-plant and plant-microorganism communications. The enormous metabolic diversity of phenylpropanoids is further expanded by chemical modifications known as "decorative reactions", including hydroxylation, methylation, glycosylation, and acylation. Among these modifications, glycosylation is the major driving force of phenylpropanoid structural diversification, also contributing to the expansion of their properties. Phenylpropanoid glycosylation is catalyzed by regioselective uridine diphosphate (UDP)-dependent glycosyltransferases (UGTs), whereas glycosyl hydrolases known as β-glucosidases are the major players in deglycosylation. In this article, we review how the glycosylation process affects key physicochemical properties of phenylpropanoids, such as molecular stability and solubility, as well as metabolite compartmentalization/storage and biological activity/toxicity. We also summarize the recent knowledge on the functional implications of glycosylation of different classes of phenylpropanoid compounds. A balance of glycosylation/deglycosylation might represent an essential molecular mechanism to regulate phenylpropanoid homeostasis, allowing plants to dynamically respond to diverse environmental signals.
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Affiliation(s)
- Arthur de Barros Rates
- Departamento de Botânica, Instituto de Biociências, Universidade de São Paulo, Rua do Matão 277, 05508-090, São Paulo, Brazil
| | - Igor Cesarino
- Departamento de Botânica, Instituto de Biociências, Universidade de São Paulo, Rua do Matão 277, 05508-090, São Paulo, Brazil; Synthetic and Systems Biology Center, InovaUSP, Avenida Professor Lucio Martins Rodrigues 370, 05508-020, São Paulo, Brazil.
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10
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Al-Khayri JM, Mascarenhas R, Harish HM, Gowda Y, Lakshmaiah VV, Nagella P, Al-Mssallem MQ, Alessa FM, Almaghasla MI, Rezk AAS. Stilbenes, a Versatile Class of Natural Metabolites for Inflammation-An Overview. Molecules 2023; 28:molecules28093786. [PMID: 37175197 PMCID: PMC10180133 DOI: 10.3390/molecules28093786] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/21/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Stilbenes are polyphenolic allelochemicals synthesized by plants, especially grapes, peanuts, rhubarb, berries, etc., to defend themselves under stressful conditions. They are now exploited in medicine for their antioxidant, anti-proliferative and anti-inflammatory properties. Inflammation is the immune system's response to invading bacteria, toxic chemicals or even nutrient-deprived conditions. It is characterized by the release of cytokines which can wreak havoc on healthy tissues, worsening the disease condition. Stilbenes modulate NF-κB, MAPK and JAK/STAT pathways, and reduce the transcription of inflammatory factors which result in maintenance of homeostatic conditions. Resveratrol, the most studied stilbene, lowers the Michaelis constant of SIRT1, and occupies the substrate binding pocket. Gigantol interferes with the complement system. Besides these, oxyresveratrol, pterostilbene, polydatin, viniferins, etc., are front runners as drug candidates due to their diverse effects from different functional groups that affect bioavailability and molecular interactions. However, they each have different thresholds for toxicity to various cells of the human body, and thus a careful review of their properties must be conducted. In animal models of autoinflammatory diseases, the mode of application of stilbenes is important to their absorption and curative effects, as seen with topical and microemulsion gel methods. This review covers the diversity seen among stilbenes in the plant kingdom and their mechanism of action on the different inflammatory pathways. In detail, macrophages' contribution to inflamed conditions in the liver, the cardiac, connective and neural tissues, in the nephrons, intestine, lungs and in myriad other body cells is explored, along with detailed explanation on how stilbenes alleviate the symptoms specific to body site. A section on the bioavailability of stilbenes is included for understanding the limitations of the natural compounds as directly used drugs due to their rapid metabolism. Current delivery mechanisms include sulphonamides, or using specially designed synthetic drugs. It is hoped that further research may be fueled by this comprehensive work that makes a compelling argument for the exploitation of these compounds in medicine.
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Affiliation(s)
- Jameel M Al-Khayri
- Department of Agricultural Biotechnology, College of Agriculture and Food Sciences, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Roseanne Mascarenhas
- Department of Life Sciences, CHRIST (Deemed to Be University), Bangalore 560029, India
| | | | - Yashwanth Gowda
- Department of Life Sciences, CHRIST (Deemed to Be University), Bangalore 560029, India
| | | | - Praveen Nagella
- Department of Life Sciences, CHRIST (Deemed to Be University), Bangalore 560029, India
| | - Muneera Qassim Al-Mssallem
- Department of Food Science and Nutrition, College of Agriculture and Food Sciences, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Fatima Mohammed Alessa
- Department of Food Science and Nutrition, College of Agriculture and Food Sciences, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Mustafa Ibrahim Almaghasla
- Department of Arid Land Agriculture, College of Agriculture and Food Sciences, King Faisal University, Al-Ahsa 31982, Saudi Arabia
- Plant Pests, and Diseases Unit, College of Agriculture and Food Sciences, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Adel Abdel-Sabour Rezk
- Department of Agricultural Biotechnology, College of Agriculture and Food Sciences, King Faisal University, Al-Ahsa 31982, Saudi Arabia
- Department of Virus and Phytoplasma, Plant Pathology Institute, Agricultural Research Center, Giza 12619, Egypt
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11
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Zhu H, Xu C, Dong Y, Lu S, Guo L. Chai-Gui Decoction and its representative components ameliorate spontaneous hypertension rats by modulating lipid metabolism and gut microbiota. JOURNAL OF ETHNOPHARMACOLOGY 2023; 305:116116. [PMID: 36603783 DOI: 10.1016/j.jep.2022.116116] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/22/2022] [Accepted: 12/26/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hypertension coincides with the category of "vertigo" and/or "headache" on the basis clinical manifestations and traditional Chinese medicine (TCM) theory. Chai-Gui Decoction (CGD), which is in usage for relieving "vertigo" and/or "headache", had been demonstrated to be useful in ameliorating hypertension. AIM OF STUDY This study was planned to investigate the mechanism of CGD and its components in hypertension by using spontaneous hypertension rat (SHR). MATERIALS AND METHODS CGD extract and its classification component samples (compounds in plasma, CP; compounds in gut, CG; compounds in plasma and gut, CPG) were prepared for animal experiment. SHR rats were induced with CGD extract (3 g/kg/d BW, 5 g/kg/d BW, 15 g/kg/d BW) and CGD-component classes (CP = 19.501 mg/kg/d, CG = 5.240 mg/kg/d, CPG = 24.741 mg/kg/d) for 4 weeks. Blood pressure (BP) and indexes of renin-angiotensin-aldosterone system (RAAS system) were measured. Histopathology was carried out to assess the efficacy of CGD and its components on aorta tissues. Untargeted metabolomics of lipid from rat serum samples were applied by Ultra-High performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and chemometric analysis to explore the relationship between metabolic pathways and hypertension. 16S rRNA gene sequencing of rat colon content and bioinformatics analysis were used to characterize the effects of CGD and its components on the gut microbiota composition of SHR rats. RESULTS CGD and its component mixtures showed antihypertensive effect on SHR rats, decreased the blood pressure and reduced the aortic wall thickness in SHR rats. CGD and its component mixtures could improve the RAAS in SHR rats, including increase the percentage of angiotensin 1-7 (Ang 1-7), decrease the percentage of angiotensin II (Ang II), and decrease the Ang Ⅱ/Ang 1-7 ratio. CGD and its component mixtures could regulate the metabolome in SHR rats, mainly as decreasing the higher serum levels of Lysophosphatidylcholine (LPC) 16: 0, LPC 20: 4, and LPC 22: 6. In addition, bacteria from family S24-7 were negatively correlated with levels of LPE 16:0, LPE 18:0, LPE 18:1, and LPE 18:2. CONCLUSION CGD and its component mixtures exhibited antihypertensive effect on SHR rats. The underlying mechanism could be related to modulation on RAAS, LPC metabolism and the bacterial abundance of family S24-7 in gut.
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Affiliation(s)
- Hongjun Zhu
- Nanjing University of Chinese Medicine Wuxi Affiliated Hospital: Wuxi Hospital of Traditional Chinese Medicine, Wuxi, 214000, China
| | - Chen Xu
- Nanjing University of Chinese Medicine Wuxi Affiliated Hospital: Wuxi Hospital of Traditional Chinese Medicine, Wuxi, 214000, China
| | - Yun Dong
- Nanjing University of Chinese Medicine Wuxi Affiliated Hospital: Wuxi Hospital of Traditional Chinese Medicine, Wuxi, 214000, China
| | - Shu Lu
- Nanjing University of Chinese Medicine Wuxi Affiliated Hospital: Wuxi Hospital of Traditional Chinese Medicine, Wuxi, 214000, China
| | - Linxiu Guo
- College of Agronomy, Henan Agricultural University, Zhengzhou, 450046, China.
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12
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Chen S, Liang Y, Shen Y, Wang X. lncRNA XIST/miR‑129‑2‑3p axis targets CCP110 to regulate the proliferation, invasion and migration of endometrial cancer cells. Exp Ther Med 2023; 25:159. [PMID: 36911384 PMCID: PMC9996364 DOI: 10.3892/etm.2023.11858] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 01/06/2023] [Indexed: 02/24/2023] Open
Abstract
Centromere coiled-coil protein 110 (CCP110) plays a role in the development of several types of cancer; however, its regulatory mechanism and role in endometrial cancer is unclear. The present study revealed that CCP110 is regulated by a signaling pathway involving microRNA (miR/miRNA)-129-2-3p and the long non-coding RNA (lncRNA) X-inactive-specific transcript (XIST), and plays a role in controlling the proliferation, migration and invasion of endometrial cancer cells. CCP110 was upregulated in human endometrial cancer tissues, as revealed by immunohistochemistry, and high expression of the protein was related to reduced overall survival of the patients. Genetic knockdown of CCP110 by small interfering RNA promoted apoptosis and suppressed the proliferation, migration, invasion and colony formation of endometrial cancer cells significantly in the endometrial cancer Ishikawa and HEC-1B cell lines, as assessed by flow cytometry, and Cell Counting Kit-8, Transwell and colony formation assays. A bioinformatics analysis and luciferase reporter assay revealed that CCP110 is a target of miR-129-2-3p. Overexpression of miR-129-2-3p mimic fragments inhibited the proliferation, migration and invasion of endometrial cancer cells significantly, while co-overexpression of CCP110 counteracted these inhibitory effects. The expression level of the lncRNA XIST was upregulated significantly in endometrial cancer tissues, as assessed by reverse transcription-quantitative PCR assay, while that of miR-129-2-3p was downregulated significantly. A bioinformatics analysis and luciferase reporter assay showed that XIST could inhibit miR-129-2-3p via a miRNA sponge effect. Furthermore, co-overexpression of XIST antagonized the inhibitory effect of the miR-129-2-3p mimic on the luciferase reporter gene signal and protein expression of CCP110. Co-overexpression of XIST also abolished the inhibitory effect of the miR-129-2-3p mimic on the proliferation, migration and invasion of endometrial cancer cells. Overall, these data identified a novel regulatory mechanism of CCP110 involving XIST and miR-129-2-3p, which affected the development of endometrial carcinoma. CCP110, XIST and miR-129-2-3p could represent novel targets for the clinical treatment of endometrial cancer.
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Affiliation(s)
- Shu Chen
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Yaozhong Liang
- Department of Orthopedics, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Yuan Shen
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Xiaoyu Wang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
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13
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Zhang H, Zhou Y, Wen D, Wang J. Noncoding RNAs: Master Regulator of Fibroblast to Myofibroblast Transition in Fibrosis. Int J Mol Sci 2023; 24:1801. [PMID: 36675315 PMCID: PMC9861037 DOI: 10.3390/ijms24021801] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 01/11/2023] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
Myofibroblasts escape apoptosis and proliferate abnormally under pathological conditions, especially fibrosis; they synthesize and secrete a large amount of extracellular matrix (ECM), such as α-SMA and collagen, which leads to the distortion of organ parenchyma structure, an imbalance in collagen deposition and degradation, and the replacement of parenchymal cells by fibrous connective tissues. Fibroblast to myofibroblast transition (FMT) is considered to be the main source of myofibroblasts. Therefore, it is crucial to explore the influencing factors regulating the process of FMT for the prevention, treatment, and diagnosis of FMT-related diseases. In recent years, non-coding RNAs, including microRNA, long non-coding RNAs, and circular RNAs, have attracted extensive attention from scientists due to their powerful regulatory functions, and they have been found to play a vital role in regulating FMT. In this review, we summarized ncRNAs which regulate FMT during fibrosis and found that they mainly regulated signaling pathways, including TGF-β/Smad, MAPK/P38/ERK/JNK, PI3K/AKT, and WNT/β-catenin. Furthermore, the expression of downstream transcription factors can be promoted or inhibited, indicating that ncRNAs have the potential to be a new therapeutic target for FMT-related diseases.
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Affiliation(s)
| | | | | | - Jie Wang
- Department of Immunology, Xiangya School of Medicine, Central South University, Xiangya Road, Changsha 410000, China
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14
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Zhang K, Gu X, Xia Y, Zhao X, Khoso Pervez A, Li S. MiR-129-3p regulates ferroptosis in the liver of Selenium-deficient broilers by targeting SLC7A11. Poult Sci 2022; 102:102271. [PMID: 36436380 PMCID: PMC9700304 DOI: 10.1016/j.psj.2022.102271] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 10/12/2022] [Accepted: 10/15/2022] [Indexed: 11/23/2022] Open
Abstract
Selenium (Se) has been proven to be an essential trace element for organism. Se deficiency in poultry can cause widespread damage, such as exudative diathesis. The liver is not only the main organ of metabolism, but also one of the organs with high Se content in organism. Recent studies have shown that solute carrier family 7 member 11 (SLC7A11) plays a key role in the negative regulation of ferroptosis. In order to explore the mechanism of Se deficiency induces liver ferroptosis in broilers, and the role of microRNAs (miRNAs) in this process, we divided broilers into 2 groups: control group (0.2 mg/kg Se) and Se deficiency group (0.03 mg/kg Se). Hematoxylin-Eosin staining detected liver tissue damage in broilers. Predicted and verified the targeting relationship between miR-129-3p and SLC7A11 through miRDB and dual luciferase report experiments. The genes related to ferroptosis were detected by qRT-PCR and Western Blot. The results showed that the expression level of miR-129-3p mRNA in Se-deficient liver was significantly increased. To understand whether the miR-129-3p/SLC7A11 axis could involve in the process of ferroptosis, our further research showed that overexpression of miR-129-3p could reduce the expression of SLC7A11 and its downstream GCL, GSS, and GPX4, thereby inducing ferroptosis. These data indicates that miR-129-3p affected ferroptosis under Se deficiency conditions through the SLC7A11 pathway. Our research provides a new perspective for the mechanism of Se deficiency on the liver damage.
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Affiliation(s)
- Kaixin Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Xuedie Gu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Yu Xia
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Xiaochun Zhao
- Animal Disease Control and Prevention of Heilongjiang Province, Harbin 150069, China
| | - Ahmed Khoso Pervez
- Shaheed Benazir Bhutto, University of Veterinary and Animal Sciences, Sakrand, Pakistan
| | - Shu Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China.
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15
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Huang TT, Chen CM, Chen LG, Lan YW, Huang TH, Choo KB, Chong KY. 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside ameliorates bleomycin-induced pulmonary fibrosis via regulating pro-fibrotic signaling pathways. Front Pharmacol 2022; 13:997100. [PMID: 36267283 PMCID: PMC9577370 DOI: 10.3389/fphar.2022.997100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 09/12/2022] [Indexed: 12/01/2022] Open
Abstract
2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-Glucoside (THSG) is the main active ingredient extracted from Polygonum multiflorum Thunb. (PMT), which has been reported to possess extensive pharmacological properties. Nevertheless, the exact role of THSG in pulmonary fibrosis has not been demonstrated yet. The main purpose of this study was to investigate the protective effect of THSG against bleomycin (BLM)-induced lung fibrosis in a murine model, and explore the underlying mechanisms of THSG in transforming growth factor-beta 1 (TGF-β1)-induced fibrogenesis using MRC-5 human lung fibroblast cells. We found that THSG significantly attenuated lung injury by reducing fibrosis and extracellular matrix deposition. THSG treatment significantly downregulated the expression levels of TGF-β1, fibronectin, α-SMA, CTGF, and TGFBR2, however, upregulated the expression levels of antioxidants (SOD-1 and catalase) and LC3B in the lungs of BLM-treated mice. THSG treatment decreased the expression levels of fibronectin, α-SMA, and CTGF in TGF-β1-stimulated MRC-5 cells. Conversely, THSG increased the expression levels of SOD-1 and catalase. Furthermore, treatment of THSG profoundly reduced the TGF-β1-induced generation of reactive oxygen species (ROS). In addition, THSG restored TGF-β1-induced impaired autophagy, accompany by increasing the protein levels of LC3B-II and Beclin 1. Mechanism study indicated that THSG significantly reduced TGF-β1-induced increase of TGFBR2 expression and phosphorylation of Smad2/3, Akt, mTOR, and ERK1/2 in MRC-5 cells. These findings suggest that THSG may be considered as an anti-fibrotic drug for the treatment of pulmonary fibrosis.
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Affiliation(s)
- Tsung-Teng Huang
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chuan-Mu Chen
- Department of Life Sciences, Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
- The iEGG and Animal Biotechnology Center and the Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Lih-Geeng Chen
- Department of Microbiology, Immunology and Biopharmaceuticals, National Chiayi University, Chiayi, Taiwan
| | - Ying-Wei Lan
- Division of Pulmonary Biology, The Perinatal Institute of Cincinnati Children’s Research Foundation, Cincinnati, OH, United States
| | - Tse-Hung Huang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan
| | - Kong Bung Choo
- Centre for Stem Cell Research, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang, Selangor, Malaysia
| | - Kowit-Yu Chong
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan
- Centre for Stem Cell Research, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang, Selangor, Malaysia
- Hyperbaric Oxygen Medical Research Lab, Bone and Joint Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- *Correspondence: Kowit-Yu Chong,
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16
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Zhang ZL, Li YZ, Wu GQ, Zhang DD, Deng C, Wang ZM, Song XM, Wang W. A comprehensive review of traditional uses, phytochemistry and pharmacology of Reynoutria genus. J Pharm Pharmacol 2022; 74:1718-1742. [DOI: 10.1093/jpp/rgac068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 08/22/2022] [Indexed: 11/14/2022]
Abstract
Abstract
Objectives
The genus Reynoutria belonging to the family Polygonaceae is widely distributed in the north temperate zone and used in folk medicine. It is administered as a sedative, tonic and digestive, also as a treatment for canities and alopecia. Herein, we reported a review on traditional uses, phytochemistry and pharmacology reported from 1985 up to early 2022. All the information and studies concerning Reynoutria plants were summarized from the library and digital databases (e.g. ScienceDirect, SciFinder, Medline PubMed, Google Scholar, and CNKI).
Key findings
A total of 185 articles on the genus Reynoutria have been collected. The phytochemical investigations of Reynoutria species revealed the presence of more than 277 chemical components, including stilbenoids, quinones, flavonoids, phenylpropanoids, phospholipids, lactones, phenolics and phenolic acids. Moreover, the compounds isolated from the genus Reynoutria possess a wide spectrum of pharmacology such as anti-atherosclerosis, anti-inflammatory, antioxidative, anticancer, neuroprotective, anti-virus and heart protection.
Summary
In this paper, the traditional uses, phytochemistry and pharmacology of genus Reynoutria were reviewed. As a source of traditional folk medicine, the Reynoutria genus have high medicinal value and they are widely used in medicine. Therefore, we hope our review can help genus Reynoutria get better development and utilization.
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Affiliation(s)
- Zi-Long Zhang
- School of Pharmacy, Shaanxi University of Chinese Medicine , Xian Yang, Shaanxi 712046 , China
| | - Yu-Ze Li
- School of Pharmacy, Shaanxi University of Chinese Medicine , Xian Yang, Shaanxi 712046 , China
| | - Guo-Qing Wu
- School of Pharmacy, Shaanxi University of Chinese Medicine , Xian Yang, Shaanxi 712046 , China
| | - Dong-Dong Zhang
- School of Pharmacy, Shaanxi University of Chinese Medicine , Xian Yang, Shaanxi 712046 , China
| | - Chong Deng
- School of Pharmacy, Shaanxi University of Chinese Medicine , Xian Yang, Shaanxi 712046 , China
| | - Zhi-Min Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences , BeiJing 100700 , China
| | - Xiao-Mei Song
- School of Pharmacy, Shaanxi University of Chinese Medicine , Xian Yang, Shaanxi 712046 , China
| | - Wei Wang
- School of Pharmacy, Shaanxi University of Chinese Medicine , Xian Yang, Shaanxi 712046 , China
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17
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The role of some lipids and their metabolites in programmed cell death (lipoapoptosis). ACTA BIOMEDICA SCIENTIFICA 2022. [DOI: 10.29413/abs.2022-7.4.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
In recent years, the understanding of the mechanisms involved in the regulation of lipoapoptosis signaling pathways has expanded considerably. However, many mechanisms of apoptosis induction by lipids as well as molecules mediating intracellular and systemic signals belonging to AOS/enzyme-dependent phospholipid metabolites are not completely clear.This review summarizes the current understanding of the mechanisms of apoptotic cell death induction by some lipid molecules. Literature search was performed in the database “PubMed”, “eLIBRARY” using key words: “apoptosis”, “lipids”, “fatty acids”, “eicosanoids”, “reactive oxygen species”.A brief characterization of the signaling pathways of apoptosis is given. The role of reactive oxygen species and their dependent products of lipid peroxidation in the regulation of the main signaling pathways of apoptosis are shown. Particular attention is paid to the product of phospholipid metabolism – 4-hydroxynonenal.Pro- and anti-apoptotic effects of some prostaglandins are demonstrated. Arguments are presented that prostaglandins of series J and D are pro-apoptotic in most cells, and this effect depends on activation of the prostanoid receptor DP2 and on reduction of AKT kinase activity. In contrast, the E-series prostaglandins and hydroxyecosatetraenoic acid act opposite to the J-series and D-series prostaglandins, reducing apoptosis by activating AKT and increasing Bcl-2 protein expression.The role of individual fatty acids involved in the initiation and transduction of pro-apoptotic and anti-apoptotic signals is assessed. It was shown that saturated fatty acids have the maximum damaging potential than their unsaturated counterparts. An in-depth understanding and deciphering of the mechanisms by which lipids and their metabolites modulate the activation of signaling pathways of programmed cell death can help to develop therapeutic strategies to prevent a number of diseases associated with impaired regulation of apoptosis.
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18
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Long Q, Li L, Yang H, Lu Y, Yang H, Zhu Y, Tang Y, Liu C, Yuan J. SGLT2 inhibitor, canagliflozin, ameliorates cardiac inflammation in experimental autoimmune myocarditis. Int Immunopharmacol 2022; 110:109024. [PMID: 35841866 DOI: 10.1016/j.intimp.2022.109024] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 06/29/2022] [Accepted: 07/01/2022] [Indexed: 12/19/2022]
Abstract
Myocarditis is an inflammatory cardiovascular disease which contributes to dilated cardiomyopathy (DCM) and heart failure. Canagliflozin (CANA) exerts anti-inflammatory and cardioprotective effects in heart failure besides its hypoglycemic effect. However, the role of CANA in myocarditis has not been elucidated. In this work, CANA treatment markedly alleviated cardiac inflammation and improved cardiac function in experimental autoimmune myocarditis (EAM) mice induced by α-myosin-heavy chain peptides. The expressions of NLRP3 inflammasome complexes (NLRP3, ASC, and Caspase-1) and their downstream molecules (IL-1β, IL-18) were significantly downregulated by CANA, accompanied with reduced Th17 cell infiltration in hearts. Furthermore, Bax/Bcl-2 ratio, Cleaved Caspase-3 protein level and the percentage of TUNEL-positive myocardial cells, which usually indicated apoptosis, were reduced by CANA treatment. These findings suggest CANA could be a valuable medication for myocarditis treatment.
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Affiliation(s)
- Qi Long
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Lixia Li
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongmin Yang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Lu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Han Yang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaoxi Zhu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaohan Tang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Changhu Liu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Yuan
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Wang C, Dai S, Gong L, Fu K, Ma C, Liu Y, Zhou H, Li Y. A Review of Pharmacology, Toxicity and Pharmacokinetics of 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-Glucoside. Front Pharmacol 2022; 12:791214. [PMID: 35069206 PMCID: PMC8769241 DOI: 10.3389/fphar.2021.791214] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/10/2021] [Indexed: 12/20/2022] Open
Abstract
Polygonum multiflorum Thunb. (He-shou-wu in Chinese), a Chinese botanical drug with a long history, is widely used to treat a variety of chronic diseases in clinic, and has been given the reputation of “rejuvenating and prolonging life” in many places. 2,3,4′,5-tetrahydroxystilbene-2-O-β-D-glucoside (TSG, C20H22O9) is the main and unique active ingredient isolated from Polygonum multiflorum Thunb., which has extensive pharmacological activities. Modern pharmacological studies have confirmed that TSG exhibits significant activities in treating various diseases, including inflammatory diseases, neurodegenerative diseases, cardiovascular diseases, hepatic steatosis, osteoporosis, depression and diabetic nephropathy. Therefore, this review comprehensively summarizes the pharmacological and pharmacokinetic properties of TSG up to 2021 by searching the databases of Web of Science, PubMed, ScienceDirect and CNKI. According to the data, TSG shows remarkable anti-inflammation, antioxidation, neuroprotection, cardiovascular protection, hepatoprotection, anti-osteoporosis, enhancement of memory and anti-aging activities through regulating multiple molecular mechanisms, such as NF-κB, AMPK, PI3K-AKT, JNK, ROS-NO, Bcl-2/Bax/Caspase-3, ERK1/2, TGF-β/Smad, Nrf2, eNOS/NO and SIRT1. In addition, the toxicity and pharmacokinetics of TSG are also discussed in this review, which provided direction and basis for the further development and clinical application of TSG.
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Affiliation(s)
- Cheng Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shu Dai
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lihong Gong
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ke Fu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanfang Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Honglin Zhou
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Procyanidin B2 Alleviates Palmitic Acid-Induced Injury in HepG2 Cells via Endoplasmic Reticulum Stress Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:8920757. [PMID: 34956386 PMCID: PMC8702323 DOI: 10.1155/2021/8920757] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 11/21/2021] [Accepted: 11/26/2021] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome featuring ectopic lipid accumulation in hepatocytes. NAFLD has been a severe threat to humans with a global prevalence of over 25% yet no approved drugs for the treatment to date. Previous studies showed that procyanidin B2 (PCB2), an active ingredient from herbal cinnamon, has an excellent hepatoprotective effect; however, the mechanism remains inconclusive. The present study aimed to investigate the protective effect and underlying mechanism of PCB2 on PA-induced cellular injury in human hepatoma HepG2 cells. Our results showed that PA-induced oxidative stress, calcium disequilibrium, and subsequent endoplasmic reticulum stress (ERS) mediated cellular injury, with elevated protein levels of GRP78, GRP94, CHOP, and hyperphosphorylation of PERK and IRE1α as well as the increased ratio of Bax/Bcl-2, which was restored by PCB2 in a concentration-dependent manner, proving the excellent antiapoptosis effect. In addition, 4-phenylbutyric acid (4-PBA), the ER stress inhibitor, increased cell viability and decreased protein levels of GRP78 and CHOP, which is similar to PCB2, and thapsigargin (TG), the ER stress agonist, exhibited conversely meanwhile partly counteracted the hepatic protection of PCB2. What is more, upregulated protein expression of p-IKKα/β, p-NF-κB p65, NLRP3, cleaved caspase 1, and mature IL-1β occurred in HepG2 cells in response to PA stress while rescued with the PCB2 intervention. In conclusion, our study demonstrated that PA induces ERS in HepG2 cells and subsequently activates downstream NLRP3 inflammasome-mediated cellular injury, while PCB2 inhibits NLRP3/caspase 1/IL-1β pathway, inflammation, and apoptosis with the presence of ERS, thereby promoting cell survival, which may provide pharmacological evidence for clinical approaches on NAFLD.
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Dai ZH, Jiang ZM, Tu H, Mao L, Song GL, Yang ZB, Liu F, Ali Sheikh MS. miR-129 Attenuates Myocardial Ischemia Reperfusion Injury by Regulating the Expression of PTEN in Rats. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5535788. [PMID: 34435045 PMCID: PMC8382530 DOI: 10.1155/2021/5535788] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/13/2021] [Accepted: 07/22/2021] [Indexed: 12/12/2022]
Abstract
PTEN/AKT signaling plays pivotal role in myocardial ischemia reperfusion injury (MIRI), and miRNAs are involved in the regulation of AKT signaling. This study was designed to investigate the interaction between miR-129 and PTEN in MIRI. A MIRI rat model and a hypoxia reoxygenation (H/R) H9C2 cell model were constructed to simulate myocardial infarction clinically. TTC staining, creatine kinase (CK) activity, TUNEL/Hoechst double staining, Hoechst staining and flow cytometer were used for evaluating myocardial infarction or cell apoptosis. miR-129 mimic transfection experiment and luciferase reporter gene assay were conducted for investigating the function of miR-129 and the interaction between miR-129 and PTEN, respectively. Real-time PCR and western blotting were performed to analyze the gene expression. Compared to the control, MIRI rats presented obvious myocardial infarction, higher CK activity, increased expression of caspase-3 and PTEN, decreased expression of miR-129, and insufficient AKT phosphorylation. Consistently, H/R significantly increased the apoptosis of H9C2 cells, concomitant with the downregulation of miR-129, upregulation of PTEN and caspase-3, and insufficient phosphorylation of AKT, while miR-129 mimic obviously inhibited the expression of PTEN and caspase-3, increased the AKT phosphorylation, and decreased the cell apoptosis. Additionally, miR-129 mimic obviously decreased the relative luciferase activity in H9C2 cells. To our best knowledge, this study firstly found that the low expression of miR-129 accelerates the myocardial cell apoptosis by directly targeting 3'UTR of PTEN. miR-129 is an important biomarker for MIRI, as well as a potential therapy target.
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Affiliation(s)
- Zhao-Hui Dai
- The Affiliated Changsha Hospital of Hunan Normal University, Changsha, Hunan 410006, China
- Chest Pain Center of Changsha, Changsha, China
| | - Zhi-Ming Jiang
- The Affiliated Changsha Hospital of Hunan Normal University, Changsha, Hunan 410006, China
- Chest Pain Center of Changsha, Changsha, China
| | - Hua Tu
- The Affiliated Changsha Hospital of Hunan Normal University, Changsha, Hunan 410006, China
| | - Li Mao
- Department of Basic Medicine, Changsha Health Vocational College, Changsha, Hunan 410600, China
| | - Gui-Lin Song
- The Affiliated Changsha Hospital of Hunan Normal University, Changsha, Hunan 410006, China
- Institute of Emergency and Critical Care Medicine of Changsha, Changsha, China
| | - Zhong-Bao Yang
- The Affiliated Changsha Hospital of Hunan Normal University, Changsha, Hunan 410006, China
- Institute of Emergency and Critical Care Medicine of Changsha, Changsha, China
| | - Fang Liu
- The Affiliated Changsha Hospital of Hunan Normal University, Changsha, Hunan 410006, China
- College of Medicine, Hunan Normal University, Changsha, Hunan 410006, China
| | - Md Sayed Ali Sheikh
- Internal Medicine Department, Cardiology, College of Medicine, Jouf University, Sakaka, Aljouf, Saudi Arabia
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22
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Tan H, Song W, Liu S, Song Q, Zhou T, Wang Y, Hou Y. Molecular Mechanism of Palmitic Acid on Myocardial Contractility in Hypertensive Rats and Its Relationship with Neural Nitric Oxide Synthase Protein in Cardiomyocytes. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6657476. [PMID: 33954193 PMCID: PMC8060086 DOI: 10.1155/2021/6657476] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 03/09/2021] [Accepted: 04/03/2021] [Indexed: 01/07/2023]
Abstract
OBJECTIVE It is aimed at investigating the mechanism of palmitic acid (PA) on myocardial contractility in hypertensive rats and its relationship with myocardial neural nitric oxide synthase (nNOS) protein. METHODS The rats were randomly divided into sham operation group and hypertensive group, with thirty rats in each group, to prepare angiotensin II-induced hypertensive model rats. The blood pressure of rats was measured by the multianimal multichannel tail cuff noninvasive blood pressure system of Kent Coda, USA. The Ionoptix single-cell contraction detection system was used to detect myocardial cells. ATP level of left ventricular cardiomyocytes was determined by luminescence method, and protein was measured by Western blot. RESULTS Compared with the sham group, systolic blood pressure and diastolic blood pressure were increased in the hypertensive group over 4 weeks; PA increased the contractility of left ventricular cardiomyocytes in normal rats, but not in hypertensive rats, and PA increased the intracellular ATP level of rats in the sham group but not in the hypertension group. In the hypertension group, the expression of nNOS in the cardiomyocytes was significantly increased, and specific nNOS inhibitor S-methyl-L-thiocitrulline (SMTC) was found to restore the positive inotropic effect of PA in the myocardium of the hypertension group. PA was supplemented after using CPT-1 inhibitor etomoxir (ETO); it was found that ETO inhibited the positive inotropic effect of PA on left ventricular cardiomyocytes in the sham group, and PA was supplemented after using SMTC and ETO, it was found that SMTC + ETO could inhibit the positive inotropic effect of PA on left ventricular cardiomyocytes in myocardium of hypertensive rats. CONCLUSION PA could increase the contractility of healthy cardiomyocytes, but had no obvious positive effect on the cardiomyocytes of hypertensive rats, PA enhanced the contractility of cardiomyocytes by increasing ATP level in them, and the inhibitory effect of PA on myocardial contractility in hypertensive rats may be related to the increased nNOS and CPT-1 in cardiomyocytes.
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Affiliation(s)
- Haibo Tan
- Department of Critical Care Medicine, Zibo Central Hospital, Zibo, 2553000 Shandong Province, China
| | - Weiwei Song
- Department of Critical Care Medicine, Zibo Central Hospital, Zibo, 2553000 Shandong Province, China
| | - Sha Liu
- Department of Critical Care Medicine, Zibo Central Hospital, Zibo, 2553000 Shandong Province, China
| | - Qing Song
- Department of Critical Care Medicine, Zibo Central Hospital, Zibo, 2553000 Shandong Province, China
| | - Tiangang Zhou
- Department of Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014 Shandong Province, China
| | - Yidan Wang
- Department of Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014 Shandong Province, China
| | - Yunfeng Hou
- Department of Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014 Shandong Province, China
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MicroRNA-129-5p alleviates spinal cord injury in mice via suppressing the apoptosis and inflammatory response through HMGB1/TLR4/NF-κB pathway. Biosci Rep 2021; 40:222205. [PMID: 32096822 PMCID: PMC7069919 DOI: 10.1042/bsr20193315] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 02/15/2020] [Accepted: 02/17/2020] [Indexed: 12/15/2022] Open
Abstract
Secondary injury after spinal cord injury (SCI) is one reversible pathological change mainly involving excessive inflammatory response and neuro-apoptosis. Since in recent years, microRNAs (miRNAs) have been proposed as novel regulators of inflammation in different disease conditions. However, the role of miRNAs in the inflammatory response and apoptosis of secondary injury after SCI remains to be fully elucidated. Here, we tried to explore the influence and mechanism of miRNAs on the neuron inflammatory response and apoptosis after SCI. The expression profiles of miRNA were examined using miRNA microarray, and among the candidate miRNAs, miR-129-5p was found to be the most down-regulated miRNA in spinal tissues. Overexpression of miR-129-5p using agomir-miR-129-5p promoted injury mice functional recovery, suppressed the apoptosis and alleviated inflammatory response in spinal tissues. Using LPS-induced BV-2 cell model, we found miR-129-5p was also proved in protecting inflammatory response and cell apoptosis in vitro. High-mobility group protein B1 (HMGB1), a well-known inflammatory mediator, was found to be directly targeted by miR-129-5p and it was associated with the inhibitory effect of miR-129-5p on the activation of toll-like receptor (TLR)-4 (TLR4)/ nuclear factor-κB (NF-κB) pathway in vitro and in vivo. Further experiments revealed that the anti-apoptosis and anti-inflammatory effects of miR-129-5p were reversed by HMGB1 overexpression in BV-2 cells. Collectively, these data revealed that miR-129-5p alleviated SCI in mice via suppressing the apoptosis and inflammatory response through HMGB1//TLR4/NF-κB pathway. Our data suggest that up-regulation of miR-129-5p may be a novel therapeutic target for SCI.
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Wang B, Li Y, You C. miR-129-3p Targeting of MCU Protects Against Glucose Fluctuation-Mediated Neuronal Damage via a Mitochondrial-Dependent Intrinsic Apoptotic Pathway. Diabetes Metab Syndr Obes 2021; 14:153-163. [PMID: 33488104 PMCID: PMC7815084 DOI: 10.2147/dmso.s285179] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 12/12/2020] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Glucose fluctuations have an adverse effect on several diabetes-related complications, especially for the nervous system, but the underlying mechanisms are not clear. MicroRNAs are critical regulators of posttranscription in many physiological processes, such as apoptosis. Our study clarified the neuroprotective effects of miR-129-3p targeting mitochondrial calcium uniporter (MCU) in glucose fluctuation-mediated neuronal damage and the specific mechanisms involved. METHODS The expression of MCU and miR-129-3p was examined by real-time PCR and Western blot in the glucose fluctuation cell model. Dual-luciferase reporter assay was performed to confirm the transcriptional regulation of miR-129-3p by MCU. Fluorescent probe and assay kit assay was used to determine oxidative stress condition. Mitochondrial-dependent intrinsic apoptotic factors were examined by flow cytometry assay, enzyme-linked immunosorbent assay (ELISA), and gene and protein expression assays. RESULTS We found an upregulation of MCU and downregulation of miR-129-3p in glucose fluctuation-treated primary hippocampal neuronal cells, and miR-129-3p directly targeted MCU. miR-129-3p overexpression produced a dramatic reduction in calcium overload, reactive oxygen species (ROS) generation, GSH-to-GSSG ratio, MMP-2 expression in the mitochondrial-dependent intrinsic apoptosis pathway and an increase in MnSOD activity. Increasing MCU expression rescued the effects of miR-129-3p overexpression. miR-129-3p downregulation produced a significant increase in calcium overload, reactive oxygen species (ROS) generation, MMP-2 expression, cytochrome c release and cell apoptosis, and antioxidant N-acetyl cysteine (NAC) rescued the effects of miR-129-3p downregulation. CONCLUSION Therefore, miR-129-3p suppressed glucose fluctuation-mediated neuronal damage by targeting MCU via a mitochondrial-dependent intrinsic apoptotic pathway. The miR-129-3p/MCU axis may be a promising therapeutic target for glucose fluctuation-mediated neuronal damage.
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Affiliation(s)
- Bo Wang
- Department of Neurosurgery, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan610041, People’s Republic of China
- Department of Neurosurgery, Kunming Medical University First Affiliated Hospital, Kunming, Yunnan650032, People’s Republic of China
| | - Yang Li
- Intensive Care Unit, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan610041, People’s Republic of China
| | - Chao You
- Department of Neurosurgery, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan610041, People’s Republic of China
- Correspondence: Chao You Department of Neurosurgery, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan610041, People’s Republic of ChinaTel +86 28-85422026 Email
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25
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Chen R, Ye B, Xie H, Huang Y, Wu Z, Wu H, Wang X, Miao H, Liang W. miR-129-3p alleviates chondrocyte apoptosis in knee joint fracture-induced osteoarthritis through CPEB1. J Orthop Surg Res 2020; 15:552. [PMID: 33228708 PMCID: PMC7684967 DOI: 10.1186/s13018-020-02070-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 11/04/2020] [Indexed: 12/13/2022] Open
Abstract
Background Osteoarthritis (OA), a refractory disease, is one of the leading contributors for disability worldwide. Since chondrocyte is the only resident cell in cartilage, this study aims to explore the roles of miR-129-3p and CPEB1 in chondrocyte apoptosis in knee joint fracture-induced OA. Methods Cartilage was collected from 20 OA patients who underwent total knee replacement (OA group) and 20 patients with knee contusion (normal group). Then, miR-129-3p and CPEB1 levels in the cartilage were quantified by qRT-PCR. Primary rat chondrocytes in the knee were isolated and identified by toluidine blue staining and immunofluorescent staining of type II collagen. OA cellular models were induced by TNF-α treatment, in which miR-129-3p and CPEB1 expressions were assessed. Subsequently, cell viability, apoptosis, and the expression levels of apoptotic protein and caspase-3 were measured. Dual luciferase reporter assay identified the interaction between miR-129-3p and CPEB1. Results Patients in the OA group had decreased miR-129-3p expression and increased CPEB1 expression than those in the normal group. TNF-α treatment successfully induced the OA cellular model. Downregulated miR-129-3p and upregulated CPEB1 expressions were found in OA-treated chondrocytes. miR-129-3p overexpression or CPEB1 knockdown improved chondrocyte viability and attenuated apoptosis, and vice versa. miR-129-3p negatively regulated CPEB1, thus ameliorating apoptosis and enhancing cell viability. Conclusion miR-129-3p negatively targeted CPEB1 to facilitate chondrocyte viability and hamper apoptosis. Supplementary Information The online version contains supplementary material available at 10.1186/s13018-020-02070-1.
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Affiliation(s)
- Ruixiong Chen
- Department of Orthopedics, Guangzhou Red Cross Hospital Affiliated to Jinan University, No. 396, Mid Tongfu Road, Haizhu District, Guangzhou, 510000, Guangdong, People's Republic of China
| | - Baoqing Ye
- Department of Orthopedics, Guangzhou Red Cross Hospital Affiliated to Jinan University, No. 396, Mid Tongfu Road, Haizhu District, Guangzhou, 510000, Guangdong, People's Republic of China
| | - Han Xie
- Department of Orthopedics, Huizhou Central People's Hospital, Huizhou, 516000, Guangdong, People's Republic of China
| | - Yuliang Huang
- Department of Orthopedics, Huizhou Central People's Hospital, Huizhou, 516000, Guangdong, People's Republic of China
| | - Zhehui Wu
- Department of Orthopedics, Huizhou Central People's Hospital, Huizhou, 516000, Guangdong, People's Republic of China
| | - Hongbo Wu
- Department of Orthopedics, Huizhou Central People's Hospital, Huizhou, 516000, Guangdong, People's Republic of China
| | - Xiaofeng Wang
- Department of Orthopedics, Huizhou Central People's Hospital, Huizhou, 516000, Guangdong, People's Republic of China
| | - Haixiong Miao
- Department of Orthopedics, Guangzhou Red Cross Hospital Affiliated to Jinan University, No. 396, Mid Tongfu Road, Haizhu District, Guangzhou, 510000, Guangdong, People's Republic of China.
| | - Weiguo Liang
- Department of Orthopedics, Guangzhou Red Cross Hospital Affiliated to Jinan University, No. 396, Mid Tongfu Road, Haizhu District, Guangzhou, 510000, Guangdong, People's Republic of China.
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Liu J, Wang S, Zhang Q, Li X, Xu S. Selenomethionine alleviates LPS-induced chicken myocardial inflammation by regulating the miR-128-3p-p38 MAPK axis and oxidative stress. Metallomics 2020; 12:54-64. [PMID: 31720660 DOI: 10.1039/c9mt00216b] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Selenium is closely related to the occurrence of heart disease, and an appropriate amount of selenium can alleviate inflammatory changes caused by various factors. Lipopolysaccharide (LPS), as a specific component of the cell wall of Gram-negative bacteria, is often used to construct various inflammatory models. In order to explore the effect of selenium on LPS-induced myocardial inflammation in chickens, we chose 4-month-old laying hens to be fed with a selenium-rich diet containing 0.5 g kg-1 Se, and injected LPS into the abdominal cavity at the age of 8 months to establish an inflammation model. We observed the myocardial tissue lesions by light microscopy, and detected miR-128-3p, p38MAPK, and NF-κB pathway-associated inflammatory factors and Th1/Th2 related factors by qRT-PCR and Western blot. The results showed that LPS stimulation inhibited miR-128-3p, which increased the expression of p38MAPK and NF-κB, while the expression of TNF-α, IL-1, PTGE, COX-2 and iNOS increased. Additionally, the expression of IL-4 and IL-6 increased and IFN-γ decreased, suggesting an imbalance of Th1/Th2. We also found that LPS treatment not only increased the content of H2O2 and MDA in the myocardium, but also increased the expression of HSP60, HSP70 and HSP90, while the activity of SOD, GPX and CAT and the content of GSH decreased. Interestingly, the addition of selenium can alleviate the changes in the above indicators. Finally, we concluded that selenium inhibits the occurrence of oxidative stress and ultimately alleviates myocardial inflammation induced by LPS through the miR-128-3p-p38MAPK-NF-κB pathway.
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Affiliation(s)
- Jing Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China.
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Ge X, Li Z, Zhou Z, Xia Y, Bian M, Yu J. Circular RNA SIPA1L1 promotes osteogenesis via regulating the miR-617/Smad3 axis in dental pulp stem cells. Stem Cell Res Ther 2020; 11:364. [PMID: 32831141 PMCID: PMC7444204 DOI: 10.1186/s13287-020-01877-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/12/2020] [Accepted: 08/05/2020] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Bone regeneration is preferred for bone loss caused by tumors, bone defects, fractures, etc. Recently, mesenchymal stem cells are considered as optimistic tools for bone defect therapy. Dental pulp stem cells (DPSCs) are a promising candidate for regenerative medicine and bone regeneration. Our previous study showed that upregulated circSIPA1L1 during osteogenesis of DPSCs is of significance. In this paper, the potential role of circSIPA1L1 in osteogenesis of DPSCs and its underlying mechanisms are explored. METHODS The circular structure of circSIPA1L1 was identified by Sanger sequencing and PCR. Regulatory effects of circSIPA1L1 and miR-617 on mineral deposition in DPSCs were assessed by alkaline phosphatase (ALP) and alizarin red S (ARS) staining and in vivo bone formation assay were conducted to verify the biological influences of circSIPA1L1 on DPSCs. Western blot was performed to detect the protein expression of Smad3. Localization of circSIPA1L1 and miR-617 was confirmed by FISH. Dual-luciferase reporter assay and rescue experiments were conducted to investigate the role of the circSIPA1L1/miR-617/Smad3 regulatory axis in osteogenesis of DPSCs. RESULTS Sanger sequencing and back-to-back primer experiments confirmed the closed-loop structure of circSIPA1L1. CircSIPA1L1 could promote the committed differentiation of DPSCs. MiR-617 was predicted to be the target binding circSIPA1L1 through MiRDB, miRTarBase, and TargetScan database analyses, which was further confirmed by dual-luciferase reporter assay. FISH results showed that circSIPA1L1 and miR-617 colocalize in the cytoplasm of DPSCs. MiR-617 exerted an inhibitory effect on the osteogenesis of DPSCs. Knockdown of circSIPA1L1 or upregulation of miR-617 downregulated phosphorylated Smad3. In addition, rescue experiments showed that knockdown of miR-617 reversed the inhibitory effect of circSIPA1L1 on osteogenesis of DPSCs. CONCLUSION CircRNASIPA1L1 promotes osteogenesis of DPSCs by adsorbing miR-617 and further targeting Smad3.
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Affiliation(s)
- Xingyun Ge
- Institute of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029, Jiangsu, China.,Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China
| | - Zehan Li
- Institute of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029, Jiangsu, China.,Peninsula Dental School, Faculty of Medicine and Dentistry, University of Plymouth, Plymouth, UK
| | - Zhou Zhou
- Institute of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029, Jiangsu, China.,Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China
| | - Yibo Xia
- Institute of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029, Jiangsu, China.,Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China
| | - Minxia Bian
- Institute of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029, Jiangsu, China.,Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China
| | - Jinhua Yu
- Institute of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029, Jiangsu, China. .,Endodontic Department, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, China.
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Tong R, Jia T, Shi R, Yan F. Inhibition of microRNA-15 protects H9c2 cells against CVB3-induced myocardial injury by targeting NLRX1 to regulate the NLRP3 inflammasome. Cell Mol Biol Lett 2020; 25:6. [PMID: 32099552 PMCID: PMC7031959 DOI: 10.1186/s11658-020-00203-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 02/06/2020] [Indexed: 02/07/2023] Open
Abstract
Background Viral myocarditis (VMC) is a type of cardiac inflammation that is generally caused by coxsackievirus B3 (CVB3) infection. Several MicroRNAs (miRNAs) are known to play crucial roles in VMC pathogenesis. MiR-15 is reportedly associated with myocardial injury, inflammatory responses and viral infection. Whether miR-15 affects the occurrence and development of VMC remains largely unknown. The roles of miR-15 and their underlying mechanisms in CVB3-stimulated H9c2 cells were assessed in this study. Methods We infected H9c2 cells with CVB3 to establish a VMC cellular model. We then determined the effects of miR-15 inhibition on three cardiomyocyte injury markers: lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) and cardiac troponin-I (cTn-I). The impact on CVB3-induced cell apoptosis and pro-inflammatory cytokines was also investigated. The effects of miR-15 inhibition on NLRP3 inflammasome activation were also assessed. The target relationship between miR-15 and NOD-like receptor X1 (NLRX1) was determined using a luciferase reporter assay. Results MiR-15 expression was significantly upregulated in H9c2 cells after CVB3 infection. Inhibition of miR-15 significantly decreased the CVB3-induced levels of LDH, CK-MB and cTn-I. It also elevated cell viability, reduced CVB3-induced cell apoptosis and decreased the generation of the interleukins IL-1β, IL-6 and IL-18. Furthermore, we determined that miR-15 inhibition suppressed NLRP3 inflammasome activation by downregulating NLRP3 and caspase-1 p20 expression. We found a direct target relationship between miR-15 and NLRX1. Additionally, inhibition of NLRX1 reversed the protective effects of miR-15 inhibition against CVB3-induced myocardial cell injury by regulating the NLRP3 inflammasome. Conclusion Our results indicate that miR-15 inhibition alleviates CVB3-induced myocardial inflammation and cell injury. This may be partially due to NLRX1-mediated NLRP3 inflammasome inactivation.
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Affiliation(s)
- Ru Tong
- 1Laboratory Dept., Second Hospital of Shanxi Medical University, Taiyuan, 030001 Shanxi China
| | - Tiewen Jia
- 1Laboratory Dept., Second Hospital of Shanxi Medical University, Taiyuan, 030001 Shanxi China
| | - Ruijie Shi
- 2Laboratory Dept., Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, 710068 Shaanxi province China
| | - Futang Yan
- 2Laboratory Dept., Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, 710068 Shaanxi province China
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Xie SC, Yang L, Shu T, Liu Q, Wang W. miR-149-5p mitigates tumor necrosis factor-α-induced chondrocyte apoptosis by inhibiting TRADD. Arch Med Sci 2020; 20:602-611. [PMID: 38757032 PMCID: PMC11094839 DOI: 10.5114/aoms.2020.92324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 11/27/2019] [Indexed: 05/18/2024] Open
Abstract
Introduction Chondrocyte apoptosis as a prominent characteristic is usually accompanied by cartilage degeneration in osteoarthritis (OA). Herein, we aimed to determine the roles of miR-149-5p in tumor necrosis factor-α (TNF-α)-induced chondrocyte apoptosis. Material and methods Human chondrocytes were cultured with TNF-α to establish an apoptosis cell model in vitro. After transfection with miR-149-5p mimics or co-expression with TRADD in chondrocytes, cell viability, apoptosis, inflammatory cytokines, mRNA and protein expression were measured using CCK8, Annexin V-FITC double staining, ELISA assays, RT-qPCR and western blotting, respectively. Results TNF-α-induced chondrocyte apoptosis occurred in association with the inhibition of cell proliferation, the elevation of inflammatory cytokine levels and the activation of TRADD and caspase-3/8 signaling. The post-transcriptional regulatory mechanism suggested that TRADD was a direct target of miR-149-5p, and overexpression of miR-149-5p resulted in the down-regulation of TRADD protein expression in chondrocytes. In addition, miR-149-5p mimics had the ability to attenuate TNF-α-induced inflammation and apoptosis, while transfection with TRADD vector neutralized the protective effects of miR-149-5p on TNF-α-induced chondrocyte dysfunction. Conclusions miR-149-5p inversely regulated TNF-α-mediated chondrocyte damage by inhibiting TRADD-modulated caspases signaling. The miR-149-5p/TRADD signaling pathway might be a promising therapeutic target for the treatment of OA.
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Affiliation(s)
- Shi-cheng Xie
- Department of Joint Surgery, the Affiliated Hospital of Jining Medical University, Jining, China
| | - Lin Yang
- Department of Orthopedics, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Taipengfei Shu
- Department of Endocrinology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qin Liu
- Department of Radiology, Tancheng Traditional Chinese Medicine Hospital, Tancheng, China
| | - Wenbo Wang
- Department of Orthopedics, the First Affiliated Hospital of Harbin Medical University, Harbin, China
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Bartoszewski R, Sikorski AF. Editorial focus: understanding off-target effects as the key to successful RNAi therapy. Cell Mol Biol Lett 2019; 24:69. [PMID: 31867046 PMCID: PMC6902517 DOI: 10.1186/s11658-019-0196-3] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 12/03/2019] [Indexed: 12/21/2022] Open
Abstract
With the first RNA interference (RNAi) drug (ONPATTRO (patisiran)) on the market, we witness the RNAi therapy field reaching a critical turning point, when further improvements in drug candidate design and delivery pipelines should enable fast delivery of novel life changing treatments to patients. Nevertheless, ignoring parallel development of RNAi dedicated in vitro pharmacological profiling aiming to identify undesirable off-target activity may slow down or halt progress in the RNAi field. Since academic research is currently fueling the RNAi development pipeline with new therapeutic options, the objective of this article is to briefly summarize the basics of RNAi therapy, as well as to discuss how to translate basic research into better understanding of related drug candidate safety profiles early in the process.
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Affiliation(s)
- Rafal Bartoszewski
- Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Gdansk, Poland
| | - Aleksander F. Sikorski
- Department of Cytobiochemistry, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
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In Vitro Evaluation of Chemically Analyzed Hypericum Triquetrifolium Extract Efficacy in Apoptosis Induction and Cell Cycle Arrest of the HCT-116 Colon Cancer Cell Line. Molecules 2019; 24:molecules24224139. [PMID: 31731693 PMCID: PMC6891740 DOI: 10.3390/molecules24224139] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 10/26/2019] [Accepted: 11/12/2019] [Indexed: 12/19/2022] Open
Abstract
Naturally derived drugs and plant-based products are attractive commodities that are being explored for cancer treatment. This in vitro study aimed to investigate the role of Hypericum triquetrifolium (50% ethanol: 50% water) extract (HTE) treatment on apoptosis, cell cycle modulation, and cell cycle arrest in human colon cancer cell line (HCT-116). HTE induced cell death via an apoptotic process, as assayed by an Annexin V-Cy3 assay. Exposing HCT-116 cells to 0.064, 0.125, 0.25, and 0.5 mg/mL of HTE for 24 h led to 50 ± 9%, 71.6 ± 8%, 85 ± 5%, and 96 ± 1.5% apoptotic cells, respectively. HCT-116 cells treated with 0.25 and 0.5 mg/mL HTE for 3 h resulted in 38.9 ± 1.5% and 57.2 ± 3% cleavage of caspase-3-specific substrate, respectively. RT-PCR analysis revealed that the HTE extract had no effect on mRNA levels of Apaf-1 and NOXA. Moreover, the addition of 0.125 mg/mL and 0.25 mg/mL HTE for 24 h was clearly shown to attenuate the cell cycle progression machinery in HCT-116 cells. GC/MS analysis of the extract identified 21 phytochemicals that are known as apoptosis inducers and cell cycle arrest agents. All the compounds detected are novel in H. triquetrifolium. These results suggest that HTE-induced apoptosis of human colon cells is mediated primarily through the caspase-dependent pathway. Thus, HTE appears to be a potent therapeutic agent for colon cancer treatment.
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