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Zheng XZ, Yu HY, Chen YR, Fang JS. Aucubin mitigates the elevation of microglial aerobic glycolysis and inflammation in diabetic neuropathic pain via aldose reductase. World J Diabetes 2025; 16:103915. [DOI: 10.4239/wjd.v16.i5.103915] [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: 12/04/2024] [Revised: 01/26/2025] [Accepted: 02/24/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Treatment of diabetic neuropathy is often limited by side effects. Aucubin, an iridoid glycoside derived from natural plants, exhibits notable anti-inflammatory and antioxidant properties.
AIM To investigate the effects of aucubin on diabetic neuropathic pain (DNP) and glycolysis and inflammation in microglia.
METHODS Streptozotocin (STZ) was used to establish a DNP animal model. Blood glucose levels and body weight of mice were measured following STZ administration. Paw withdrawal threshold was calculated for mechanical allodynia. Paw withdrawal latency was recorded for thermal hyperalgesia. The open field test and elevated plus maze was used to assess locomotor activity and anxiety-like behavior. Western blotting was utilized for analysis of protein expression. Immunofluorescence staining was measured for morphometric analysis of microglia. Glycolysis and ATP synthesis in BV-2 cell lines were detected by metabolic extracellular flux analysis. The SwissTargetPrediction and STRING databases were used for comprehensive screening to identify potential target proteins for aucubin. The molecular docking between the possible target proteins and aucubin was investigated using Auto Dock Tool. The BV-2 cell line was transfected with lentiviral AKR1B1-shRNA to further ascertain the function of AKR1B1 in the impact of aucubin on aerobic glycolysis and inflammation during high glucose stimulation.
RESULTS Aucubin significantly improved pain and anxiety-like behavior in STZ-induced diabetic mice and restored microglial aerobic glycolysis and inflammation. Several public databases and molecular docking studies suggested that AKR1B1, MMP2 and MMP9 are involved in the effect of aucubin on DNP. Aucubin failed to restore aerobic glycolysis and inflammation in the context of AKR1B1 deficiency.
CONCLUSION Aucubin has potential as a therapeutic agent for alleviating DNP by inhibiting expression of AKR1B1.
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Affiliation(s)
- Xue-Zhen Zheng
- Department of Anesthesiology, The First People's Hospital of Chun'an County, Hangzhou 311700, Zhejiang Province, China
| | - Hong-Yan Yu
- Department of Anesthesiology, The First People's Hospital of Chun'an County, Hangzhou 311700, Zhejiang Province, China
| | - Ye-Ru Chen
- Department of Anaesthesiology, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou 310058, Zhejiang Province, China
| | - Jian-Sheng Fang
- Department of Anesthesiology, The First People's Hospital of Chun'an County, Hangzhou 311700, Zhejiang Province, China
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Fukuyama Y, Kubo M, Harada K. Neurotrophic Natural Products. PROGRESS IN THE CHEMISTRY OF ORGANIC NATURAL PRODUCTS 2024; 123:1-473. [PMID: 38340248 DOI: 10.1007/978-3-031-42422-9_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/12/2024]
Abstract
Neurotrophins (NGF, BDNF, NT3, NT4) can decrease cell death, induce differentiation, as well as sustain the structure and function of neurons, which make them promising therapeutic agents for the treatment of neurodegenerative disorders. However, neurotrophins have not been very effective in clinical trials mostly because they cannot pass through the blood-brain barrier owing to being high-molecular-weight proteins. Thus, neurotrophin-mimic small molecules, which stimulate the synthesis of endogenous neurotrophins or enhance neurotrophic actions, may serve as promising alternatives to neurotrophins. Small-molecular-weight natural products, which have been used in dietary functional foods or in traditional medicines over the course of human history, have a great potential for the development of new therapeutic agents against neurodegenerative diseases such as Alzheimer's disease. In this contribution, a variety of natural products possessing neurotrophic properties such as neurogenesis, neurite outgrowth promotion (neuritogenesis), and neuroprotection are described, and a focus is made on the chemistry and biology of several neurotrophic natural products.
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Affiliation(s)
- Yoshiyasu Fukuyama
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, 770-8514, Japan.
| | - Miwa Kubo
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, 770-8514, Japan
| | - Kenichi Harada
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, 770-8514, Japan
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Park JH, Lee TK, Kim DW, Ahn JH, Lee CH, Lim SS, Kim YH, Cho JH, Kang IJ, Won MH. Aucubin Exerts Neuroprotection against Forebrain Ischemia and Reperfusion Injury in Gerbils through Antioxidative and Neurotrophic Effects. Antioxidants (Basel) 2023; 12:antiox12051082. [PMID: 37237948 DOI: 10.3390/antiox12051082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/07/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Aucubin is an iridoid glycoside that displays various pharmacological actions including antioxidant activity. However, there are few reports available on the neuroprotective effects of aucubin against ischemic brain injury. Thus, the aim of this study was to investigate whether aucubin protected against damage to hippocampal function induced by forebrain ischemia-reperfusion injury (fIRI) in gerbils, and to examine whether aucubin produced neuroprotection in the hippocampus against fIRI and to explore its mechanisms by histopathology, immunohistochemistry, and Western analysis. Gerbils were given intraperitoneal injections of aucubin at doses of 1, 5, and 10 mg/kg, respectively, once a day for seven days before fIRI. As assessed by the passive avoidance test, short-term memory function following fIRI significantly declined, whereas the decline in short-term memory function due to fIRI was ameliorated by pretreatment with 10 mg/kg, but not 1 or 5 mg/kg, of aucubin. Most of the pyramidal cells (principal cells) of the hippocampus died in the Cornu Ammonis 1 (CA1) area four days after fIRI. Treatment with 10 mg/kg, but not 1 or 5 mg/kg, of aucubin protected the pyramidal cells from IRI. The treatment with 10 mg/kg of aucubin significantly reduced IRI-induced superoxide anion production, oxidative DNA damage, and lipid peroxidation in the CA1 pyramidal cells. In addition, the aucubin treatment significantly increased the expressions of superoxide dismutases (SOD1 and SOD2) in the pyramidal cells before and after fIRI. Furthermore, the aucubin treatment significantly enhanced the protein expression levels of neurotrophic factors, such as brain-derived neurotrophic factor and insulin-like growth factor-I, in the hippocampal CA1 area before and after IRI. Collectively, in this experiment, pretreatment with aucubin protected CA1 pyramidal cells from forebrain IRI by attenuating oxidative stress and increasing neurotrophic factors. Thus, pretreatment with aucubin can be a promising candidate for preventing brain IRI.
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Affiliation(s)
- Joon Ha Park
- Department of Anatomy, College of Korean Medicine, Dongguk University, Gyeongju 38066, Republic of Korea
| | - Tae-Kyeong Lee
- Department of Food Science and Nutrition, Hallym University, Chuncheon 24252, Republic of Korea
| | - Dae Won Kim
- Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangnung-Wonju National University, Gangneung 25457, Republic of Korea
| | - Ji Hyeon Ahn
- Department of Physical Therapy, College of Health Science, Youngsan University, Yangsan 50510, Republic of Korea
| | - Choong-Hyun Lee
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea
| | - Soon Sung Lim
- Department of Food Science and Nutrition, Hallym University, Chuncheon 24252, Republic of Korea
| | - Yang Hee Kim
- Department of Surgery, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon 24289, Republic of Korea
| | - Jun Hwi Cho
- Department of Emergency Medicine, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon 24289, Republic of Korea
| | - Il Jun Kang
- Department of Food Science and Nutrition, Hallym University, Chuncheon 24252, Republic of Korea
| | - Moo-Ho Won
- Department of Emergency Medicine, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon 24289, Republic of Korea
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Yang P, Zhang Q, Shen H, Bai X, Liu P, Zhang T. Research progress on the protective effects of aucubin in neurological diseases. PHARMACEUTICAL BIOLOGY 2022; 60:1088-1094. [PMID: 35634723 PMCID: PMC9154787 DOI: 10.1080/13880209.2022.2074057] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 03/29/2022] [Accepted: 05/01/2022] [Indexed: 06/15/2023]
Abstract
CONTEXT Aucubin (AU), an iridoid glycoside that is one of the active constituents of Eucommia ulmoides Oliv. (EUO) (Eucommiaceae), a traditional Chinese medicine, has been extensively studied in the management of neurological diseases (NDs). However, a comprehensive review of its effects and mechanisms in this regard is currently not available. OBJECTIVE To compile the protective effects and mechanisms of AU in NDs and provide a basis for further research. METHODS We used 'aucubin' as the 'All Fields' or 'MeSH' in PubMed, Web of Science and China National Knowledge Infrastructure without any limitation to search all relevant articles as comprehensively as possible; we selected the articles on AU treatment of NDs for summary. RESULTS Studies reviewed herein reported that AU improved the symptoms or prognosis of Parkinson's disease, Alzheimer's disease, intracerebral haemorrhage, diabetic encephalopathy, epilepsy, anxiety and depression, and traumatic brain injury. The pharmacological mechanisms involved in repairing neuronal loss were postulated to include increasing γ-aminobutyric acid (GABA) content in the synapse, promoting differentiation of neural precursor cells into GABAergic neurons, providing antioxidant and anti-neuroinflammation activities, as well as enhancing autophagy and anti-apoptotic actions. DISCUSSION AND CONCLUSIONS The protective effects of AU on some NDs have been confirmed. According to the pharmacological effects, AU is also highly likely to have protective effects on other NDs, which can be realized by further in vivo and in vitro basic research, and clinical trials. In the future, AU may be used for clinical prevention or treatment of patients with neurological diseases.
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Affiliation(s)
- Ping Yang
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Clinical Pharmacy, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Qiaoyue Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Clinical Pharmacy, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Hengyan Shen
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Clinical Pharmacy, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Xinyu Bai
- Department of Clinical Pharmacy, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Ping Liu
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Tao Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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Xu Z, Yang H, Li X, Xu X, Tan H, Leng X. Dietary effects of aucubin on growth and flesh quality of grass carp (Ctenopharyngodon idellus) based on metabolomics. J Anim Sci 2022; 100:skac273. [PMID: 35985277 PMCID: PMC9615150 DOI: 10.1093/jas/skac273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
This aim of this study was to investigate the effects of dietary aucubin on the growth, flesh quality, and metabolomics of grass carp (Ctenopharyngodon idella). Five diets were designed with the aucubin inclusion of 0 (control diet), 0.2, 0.4, 0.6, and 0.8 g/kg (Auc-0.2, Auc-0.4, Auc-0.6, Auc-0.8) and were fed to grass carp with an initial body weight of 17.0 ± 0.2 g for 60 d. The results indicated that dietary aucubin did not significantly affect the growth performance of grass carp (P > 0.05). Compared to the control, dietary supplementation with 0.2 to 0.8 g/kg aucubin increased flesh hardness, chewiness, the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and the contents of total free amino acids (TFAA) and n-3 polyunsaturated fatty acids (n-3 PUFA) (P < 0.05). The contents of malondialdehyde (MDA) and lactic acid (LD) in the flesh were significantly decreased by the addition of 0.4 to 0.6 g/kg aucubin and by the addition of 0.6 to 0.8 g/kg aucubin (P < 0.05), respectively, while the content of delicious amino acids (DAA) was significantly enhanced by the addition of 0.4 to 0.8 g/kg aucubin (P < 0.05). Moreover, the contents of collagen and C22:6n3 (DHA) in the flesh of the Auc-0.8 group were significantly higher than those of the control (P < 0.05). In the metabolomics profiling of flesh, 133 and 135 named differential metabolites were identified in the Auc-0.4 and Auc-0.8 groups, respectively, compared to the control, and these metabolites were found to be involved in the second-grade pathways of "lipid metabolism" and "amino acid metabolism". Regarding gene expression, the mRNA levels of CuZn-SOD, CAT, COL1A1, COL1A2, Smad4, and FAS in flesh were upregulated in the Auc-0.4 and Auc-0.8 groups, and the expression levels of GPx, Nrf2, and TGF-β1 mRNA were also upregulated in the Auc-0.8 group (P < 0.05). In summary, dietary aucubin did not promote growth, but improved the flesh quality of grass carp, which might be associated with the TGF-β/Smad and Nrf2 pathways. The recommended supplementation level of aucubin in the diet of grass carp was 0.6 to 0.8 g/kg.
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Affiliation(s)
- Zhen Xu
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China
- Centre for Research on Environmental Ecology and Fish Nutrition (CREEFN) of the Ministry of Agriculture, Shanghai Ocean University, Shanghai 201306, China
- Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, Shanghai Ocean University, Shanghai 201306, China
| | - Hang Yang
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China
- Centre for Research on Environmental Ecology and Fish Nutrition (CREEFN) of the Ministry of Agriculture, Shanghai Ocean University, Shanghai 201306, China
- Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, Shanghai Ocean University, Shanghai 201306, China
| | - Xiaoqin Li
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China
- Centre for Research on Environmental Ecology and Fish Nutrition (CREEFN) of the Ministry of Agriculture, Shanghai Ocean University, Shanghai 201306, China
- Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, Shanghai Ocean University, Shanghai 201306, China
| | - Xiaoying Xu
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China
- Centre for Research on Environmental Ecology and Fish Nutrition (CREEFN) of the Ministry of Agriculture, Shanghai Ocean University, Shanghai 201306, China
- Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, Shanghai Ocean University, Shanghai 201306, China
| | - Hongxin Tan
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China
- Centre for Research on Environmental Ecology and Fish Nutrition (CREEFN) of the Ministry of Agriculture, Shanghai Ocean University, Shanghai 201306, China
- Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, Shanghai Ocean University, Shanghai 201306, China
| | - Xiangjun Leng
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China
- Centre for Research on Environmental Ecology and Fish Nutrition (CREEFN) of the Ministry of Agriculture, Shanghai Ocean University, Shanghai 201306, China
- Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, Shanghai Ocean University, Shanghai 201306, China
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Park SB, Jung WK, Yu HY, Kim YH, Kim J. Effect of Aucubin-Containing Eye Drops on Tear Hyposecretion and Lacrimal Gland Damage Induced by Urban Particulate Matter in Rats. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27092926. [PMID: 35566278 PMCID: PMC9104073 DOI: 10.3390/molecules27092926] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 04/26/2022] [Accepted: 04/28/2022] [Indexed: 11/16/2022]
Abstract
Exposure to particulate matter is a causative factor of dry eye disease. We aimed to investigate the beneficial effect of eye drops containing aucubin on dry eye disease induced by urban particulate matter (UPM). Dry eye was induced in male SD rats (6 weeks old) by topical exposure to UPM thrice a day for 5 d. Eye drops containing 0.1% aucubin or 0.5% aucubin were topically administered directly into the eye after UPM exposure for an additional 5 d. Tear secretion was evaluated using a phenol red thread tear test and corneal irregularity. The oxidative damage in the lacrimal gland was evaluated using TUNEL and immunohistochemical staining. The topical administration of aucubin significantly attenuated UPM-induced tear hyposecretion (control group: 9.25 ± 0.62 mm, UPM group: 4.55 ± 0.25 mm, 0.1% aucubin: 7.12 ± 0.58 mm, and 0.5% aucubin: 7.88 ± 0.75 mm) and corneal irregularity (control group: 0.00 ± 0.00, UPM group: 3.40 ± 0.29, 0.1% aucubin: 1.80 ± 0.27, and 0.5% aucubin: 1.15 ± 0.27). In addition, aucubin also reduced the UPM-induced apoptotic injury of lacrimal gland cells induced by oxidative stress through the increased expression of HMGB1 and RAGE. These findings indicate that the topical administration of aucubin eye drops showed a beneficial effect against UPM-induced abnormal ocular changes, such as tear hyposecretion and lacrimal gland damage. Therefore, our results reveal the pharmacological activities of aucubin in dry eye disease.
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Affiliation(s)
| | | | | | | | - Junghyun Kim
- Correspondence: ; Tel.: +82-63-270-4032; Fax: +82-63-270-4025
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Li M, Zheng Y, Deng S, Yu T, Ma Y, Ge J, Li J, Li X, Ma L. Potential therapeutic effects and applications of Eucommiae Folium in secondary hypertension. J Pharm Anal 2021; 12:711-718. [PMID: 36320603 PMCID: PMC9615539 DOI: 10.1016/j.jpha.2021.10.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 10/12/2021] [Accepted: 10/20/2021] [Indexed: 11/27/2022] Open
Abstract
Eucommiae Folium (EF), a traditional Chinese medicine, has been used to treat secondary hypertension, including renal hypertension and salt-sensitive hypertension, as well as hypertension caused by thoracic aortic endothelial dysfunction, a high-fat diet, and oxidized low-density lipoprotein. The antihypertensive components of EF are divided into four categories: flavonoids, iridoids, lignans, and phenylpropanoids, such as chlorogenic acid, geniposide acid and pinoresinol diglucoside. EF regulates the occurrence and development of hypertension by regulating biological processes, such as inhibiting inflammation, regulating the nitric oxide synthase pathway, reducing oxidative stress levels, regulating endothelial vasoactive factors, and lowering blood pressure. However, its molecular antihypertensive mechanisms are still unclear and require further investigation. In this review, by consulting the relevant literature on the antihypertensive effects of EF and using network pharmacology, we summarized the active ingredients and pharmacological mechanisms of EF in the treatment of hypertension to clarify how EF is associated with secondary hypertension, the related components, and underlying mechanisms. The results of the network pharmacology analysis indicated that EF treats hypertension through a multi-component, multi-target and multi-pathway mechanism. In particular, we discussed the role of EF targets in the treatment of hypertension, including epithelial sodium channel, heat shock protein70, rho-associated protein kinase 1, catalase, and superoxide dismutase. The relevant signal transduction pathways, the ras homolog family member A (RhoA)/Rho-associated protein kinase (ROCK) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase/eNOS/NO/Ca2+ pathways, are also discussed.
Eucommiae Folium (EF) treats secondary hypertension via the RhoA/ROCK1 and NO/sGC/cGMP pathways. EF inhibits oxidative stress and improves endothelial dysfunction to treat hypertension. EF's antihypertensive components are phenylpropanoids, flavonoids, lignans, iridoids. KEGG analysis showed EF treated hypertension through the MAPK and TNF signaling pathways.
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Li YC, Hao JC, Shang B, Zhao C, Wang LJ, Yang KL, He XZ, Tian QQ, Wang ZL, Jing HL, Li Y, Cao YJ. Neuroprotective effects of aucubin on hydrogen peroxide-induced toxicity in human neuroblastoma SH-SY5Y cells via the Nrf2/HO-1 pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 87:153577. [PMID: 33994055 DOI: 10.1016/j.phymed.2021.153577] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 03/21/2021] [Accepted: 04/15/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND When redox balance is lost in the brain, oxidative stress can cause serious damage that leads to neuronal loss, in congruence with neurodegenerative diseases. Aucubin (AU) is an iridoid glycoside and that is one of the active constituents of Eucommia ulmoides, has many pharmacological effects such as anti-inflammation, anti-liver fibrosis, and anti-atherosclerosis. PURPOSE The present study aimed to evaluate the inhibitory effects of AU on cell oxidative stress against hydrogen peroxide (H2O2)-induced injury in SH-SY5Y cells in vitro. METHODS SH-SY5Y cells were simultaneously treated with AU and H2O2 for 24 h. Cell viability was measured by CCK-8. Additionally, mitochondrial membrane depolarization, reactive oxygen species (ROS) generation, and cell apoptosis were measured by flow cytometry. RESULTS The results showed that AU can significantly increase the H2O2-induced cell viability and the mitochondrial membrane potential, decrease the ROS generation, malondialdehyde (MDA), and increase glutathione (GSH) contents and the superoxide dismutase (SOD) activity. We also found that H2O2 stimulated the production of nitric oxide (NO), which could be reduced by treatment with AU through inhibiting the inducible nitric oxide synthase (iNOS) protein expression. In H2O2-induced SH-SY5Y cells, the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) content and cell apoptosis were significantly reduced by AU treatment through nuclear factor E2-related factor 2/hemo oxygenase-1 (Nrf2/HO-1) activation, inhibiting the expression of p-NF-κB/NF-κB and down-regulating MAPK and Bcl-2/Bax pathways. CONCLUSION These results indicate that AU can reduce inflammation and oxidative stress through the NF-κB, Nrf2/HO-1, and MAPK pathways.
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Affiliation(s)
- Ying Chun Li
- Biomedicine Key Laboratory of Shaanxi Province, School of Pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Jin Cheng Hao
- Biomedicine Key Laboratory of Shaanxi Province, School of Pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Bo Shang
- Biomedicine Key Laboratory of Shaanxi Province, School of Pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Cheng Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Li Juan Wang
- Biomedicine Key Laboratory of Shaanxi Province, School of Pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Kai Lin Yang
- Biomedicine Key Laboratory of Shaanxi Province, School of Pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Xiao Zhou He
- Biomedicine Key Laboratory of Shaanxi Province, School of Pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Qian Qian Tian
- Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Zhao Liang Wang
- Biomedicine Key Laboratory of Shaanxi Province, School of Pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Hui Ling Jing
- Department of Dermatology, Xi'an Hospital of Traditional Chinese Medicine, Xi'an, China
| | - Yang Li
- Biomedicine Key Laboratory of Shaanxi Province, School of Pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China.
| | - Yan Jun Cao
- Biomedicine Key Laboratory of Shaanxi Province, School of Pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China.
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Wang H, Zhou XM, Wu LY, Liu GJ, Xu WD, Zhang XS, Gao YY, Tao T, Zhou Y, Lu Y, Wang J, Deng CL, Zhuang Z, Hang CH, Li W. Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury. J Neuroinflammation 2020; 17:188. [PMID: 32539839 PMCID: PMC7294631 DOI: 10.1186/s12974-020-01863-9] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 06/02/2020] [Indexed: 12/16/2022] Open
Abstract
Background Aucubin (Au), an iridoid glycoside from natural plants, has antioxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored the potential role of Au in an H2O2-induced oxidant damage in primary cortical neurons and weight-drop induced-TBI in a mouse model. Methods In vitro experiments, the various concentrations of Au (50 μg/ml, 100 μg/ml, or 200 μg/ml) were added in culture medium at 0 h and 6 h after neurons stimulated by H2O2 (100 μM). After exposed for 12 h, neurons were collected for western blot (WB), immunofluorescence, and M29,79-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. In vivo experiments, Au (20 mg/kg or 40 mg/kg) was administrated intraperitoneally at 30 min, 12 h, 24 h, and 48 h after modeling. Brain water content, neurological deficits, and cognitive functions were measured at specific time, respectively. Cortical tissue around focal trauma was collected for WB, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl staining, quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry, and enzyme linked immunosorbent assay (ELISA) at 72 h after TBI. RNA interference experiments were performed to determine the effects of nuclear factor erythroid-2 related factor 2 (Nrf2) on TBI mice with Au (40 mg/kg) treatment. Mice were intracerebroventricularly administrated with lentivirus at 72 h before TBI establishment. The cortex was obtained at 72 h after TBI and used for WB and q-PCR. Results Au enhanced the translocation of Nrf2 into the nucleus, activated antioxidant enzymes, suppressed excessive generation of reactive oxygen species (ROS), and reduced cell apoptosis both in vitro and vivo experiments. In the mice model of TBI, Au markedly attenuated brain edema, histological damages, and improved neurological and cognitive deficits. Au significantly suppressed high mobility group box 1 (HMGB1)-mediated aseptic inflammation. Nrf2 knockdown in TBI mice blunted the antioxidant and anti-inflammatory neuroprotective effects of the Au. Conclusions Taken together, our data suggest that Au provides a neuroprotective effect in TBI mice model by inhibiting oxidative stress and inflammatory responses; the mechanisms involve triggering Nrf2-induced antioxidant system.
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Affiliation(s)
- Han Wang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321# Zhongshan Road, Nanjing, 210008, China.,Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Xiao-Ming Zhou
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Ling-Yun Wu
- Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321# Zhongshan Road, Nanjing, 210008, China
| | - Guang-Jie Liu
- Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321# Zhongshan Road, Nanjing, 210008, China
| | - Wei-Dong Xu
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Xiang-Sheng Zhang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321# Zhongshan Road, Nanjing, 210008, China
| | - Yong-Yue Gao
- Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321# Zhongshan Road, Nanjing, 210008, China
| | - Tao Tao
- Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321# Zhongshan Road, Nanjing, 210008, China
| | - Yan Zhou
- Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321# Zhongshan Road, Nanjing, 210008, China
| | - Yue Lu
- Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321# Zhongshan Road, Nanjing, 210008, China
| | - Juan Wang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321# Zhongshan Road, Nanjing, 210008, China
| | - Chu-Lei Deng
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Zong Zhuang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321# Zhongshan Road, Nanjing, 210008, China
| | - Chun-Hua Hang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321# Zhongshan Road, Nanjing, 210008, China.
| | - Wei Li
- Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321# Zhongshan Road, Nanjing, 210008, China.
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Immunoregulation and antioxidant activities of a novel acidic polysaccharide from Radix Paeoniae Alba. Glycoconj J 2020; 37:361-371. [DOI: 10.1007/s10719-020-09916-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 02/09/2020] [Accepted: 02/18/2020] [Indexed: 01/18/2023]
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11
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A review of the pharmacology and toxicology of aucubin. Fitoterapia 2020; 140:104443. [DOI: 10.1016/j.fitote.2019.104443] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 11/25/2019] [Accepted: 11/29/2019] [Indexed: 12/12/2022]
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12
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Ma B, Zhang J, Zhu Z, Bao X, Zhang M, Ren C, Zhang Q. Aucubin, a natural iridoid glucoside, attenuates oxidative stress-induced testis injury by inhibiting JNK and CHOP activation via Nrf2 up-regulation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 64:153057. [PMID: 31419730 DOI: 10.1016/j.phymed.2019.153057] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 06/28/2019] [Accepted: 07/26/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Eucommia ulmoides has been used for many years as a successful strategy to treat male infertility. Aucubin (AU) is the active ingredient extracted from Eucommia ulmoides. However, its protective action and exact mechanism on testicular injury is not yet known. PURPOSE Here, the protective effect and the mechanism of action of AU on testis damage under oxidative stress was investigated in vivo and in vitro. METHODS As regard the in vivo experiment, male mice were divided into five groups and testicular injury model was established by Triptolide (TP) (120 μg/kg) intraperitoneal injection for two weeks. Animals in the treatment group were pretreated with an intraperitoneal injection of AU at different doses (5, 10 and 20 mg/kg) for 1 h and subsequently treated with TP (120 μg/kg). At the end of the experimental period, the testis was collected for biochemical and histological examination. As regard the in vitro experiment, Sertoli cells (SCs) were used to investigate the protective effect and mechanism of action of AU against disruption of the blood-testis-barrier (BTB) and apoptosis induced by TP via apoptosis detection, western blot, immunofluorescence analysis, and siRNA transient transfection. RESULTS TP-treated animals showed testicular atrophy, BTB disruption, increased ROS levels and spermatogenic dysfunction. Pre-administration of AU resulted in a significant protection on keeping a normal testicular weight, sperm morphology, BTB integrity, and a normal level of oxidative stress markers and antioxidants. Furthermore, AU prevented apoptosis through an effective inhibition of PERK/CHOP and JNK dependent apoptosis pathway, as well as protected the integrity of BTB by up-regulating the expression of tight junction proteins (ZO-1, Occludin, Claudin-11) and gap junction protein (Cx43). The mechanistic study revealed that AU significantly triggered Nrf2 translocation, thus increasing nuclear Nrf2 accumulation and then induced antioxidant enzymes expression in the testis and SCs. Furthermore, Nrf2 silencing unsuccessfully reversed the increased CHOP and p-JNK expression induced by TP, abolishing the protective effect of AU. CONCLUSION These results indicate that AU might be considered as a potential protective agent against testicular injury.
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Affiliation(s)
- Bo Ma
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China
| | - Jie Zhang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China
| | - Zhiming Zhu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China
| | - Xiaowen Bao
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China
| | - Mingya Zhang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China
| | - Chaoxing Ren
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China
| | - Qi Zhang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China.
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13
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Jung E, Park SB, Jung WK, Kim HR, Kim J. Antiglycation Activity of Aucubin In Vitro and in Exogenous Methylglyoxal Injected Rats. Molecules 2019; 24:molecules24203653. [PMID: 31658696 PMCID: PMC6832881 DOI: 10.3390/molecules24203653] [Citation(s) in RCA: 6] [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: 09/05/2019] [Revised: 09/30/2019] [Accepted: 10/08/2019] [Indexed: 11/16/2022] Open
Abstract
Advanced glycation end products (AGEs) is a causative factor of various chronic diseases, including chronic kidney disease and atherosclerosis. AGE inhibitors, such as aminoguanidine and pyridoxamine, have the therapeutic activities for reversing the increase in AGEs burden. This study evaluated the inhibitory effects of aucubin on the formation of methylglyoxal (MGO)-modified AGEs in vitro. We also determined the potential activity of aucubin in reducing the AGEs burden in the kidney, blood vessel, heart, and retina of exogenously MGO-injected rats. Aucubin inhibited the formation of MGO-modified AGE-bovine serum albumin (IC50 = 0.57 ± 0.04 mmol/L) and its cross-links to collagen (IC50 = 0.55 ± 0.02 mmol/L) in a dose-dependent manner. In addition, aucubin directly trapped MGO (IC50 = 0.22 ± 0.01 mmol/L) in vitro. In exogenous MGO-injected rats, aucubin suppressed the formation of circulating AGEs and its accumulation in various tissues. These activities of aucubin on the MGO-derived AGEs in vitro and in vivo showed its pharmacological potential for inhibiting AGEs-related various chronic diseases.
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Affiliation(s)
- Eunsoo Jung
- Laboratory of Toxicology, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea.
| | - Su-Bin Park
- Department of Oral Pathology, School of Dentistry, Chonbuk National University, Jeonju 54896, Korea.
| | - Woo Kwon Jung
- Department of Oral Pathology, School of Dentistry, Chonbuk National University, Jeonju 54896, Korea.
| | - Hyung Rae Kim
- Department of Oral Pathology, School of Dentistry, Chonbuk National University, Jeonju 54896, Korea.
| | - Junghyun Kim
- Department of Oral Pathology, School of Dentistry, Chonbuk National University, Jeonju 54896, Korea.
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Oveissi V, Ram M, Bahramsoltani R, Ebrahimi F, Rahimi R, Naseri R, Belwal T, Devkota HP, Abbasabadi Z, Farzaei MH. Medicinal plants and their isolated phytochemicals for the management of chemotherapy-induced neuropathy: therapeutic targets and clinical perspective. Daru 2019; 27:389-406. [PMID: 30852764 PMCID: PMC6593128 DOI: 10.1007/s40199-019-00255-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 02/26/2019] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Chemotherapy, as one of the main approaches of cancer treatment, is accompanied with several adverse effects, including chemotherapy-induced peripheral neuropathy (CIPN). Since current methods to control the condition are not completely effective, new treatment options should be introduced. Medicinal plants can be suitable candidates to be assessed regarding their effects in CIPN. Current paper reviews the available preclinical and clinical studies on the efficacy of herbal medicines in CIPN. METHODS Electronic databases including PubMed, Scopus, and Cochrane library were searched with the keywords "neuropathy" in the title/abstract and "plant", "extract", or "herb" in the whole text. Data were collected from inception until April 2018. RESULTS Plants such as chamomile (Matricaria chamomilla L.), sage (Salvia officinalis L.), cinnamon (Cinnamomum cassia (L.) D. Don), and sweet flag (Acorus calamus L.) as well as phytochemicals like matrine, curcumin, and thioctic acid have demonstrated beneficial effects in animal models of CIPN via prevention of axonal degeneration, decrease in total calcium level, improvement of endogenous antioxidant defense mechanisms such as superoxide dismutase and reduced glutathione, and regulation of neural cell apoptosis, nuclear factor-ĸB, cyclooxygenase-2, and nitric oxide signaling. Also, five clinical trials have evaluated the effect of herbal products in patients with CIPN. CONCLUSIONS There are currently limited clinical evidence on medicinal plants for CIPN which shows the necessity of future mechanistic studies, as well as well-designed clinical trial for further confirmation of the safety and efficacy of herbal medicines in CIPN. Graphical abstract Schematic mechanisms of medicinal plants to prevent chemotherapy-induced neuropathy: NO: nitric oxide, TNF: tumor necrosis factor, PG: prostaglandin, NF-ĸB: nuclear factor kappa B, LPO: lipid peroxidation, ROS: reactive oxygen species, COX: cyclooxygenase, IL: interleukin, ERK: extracellular signal-related kinase, X: inhibition, ↓: induction.
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Affiliation(s)
- Vahideh Oveissi
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mahboobe Ram
- Student Research Committee, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Roodabeh Bahramsoltani
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Farnaz Ebrahimi
- Pharmacy Students' Research Committee, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Roja Rahimi
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Rozita Naseri
- Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Tarun Belwal
- G. B. Pant National Institute of Himalayan Environment and Sustainable Development, Kosi-Katarmal, Almora, Uttarakhand, 263643, India
| | - Hari Prasad Devkota
- School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo ku, Kumamoto, 862-0973, Japan
- Program for Leading Graduate Schools, Health life science: Interdisciplinary and Glocal Oriented (HIGO) Program, Kumamoto University, 5-1 Oe-honmachi, Chuo ku, Kumamoto, 862-0973, Japan
| | - Zahra Abbasabadi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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15
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Kang WS, Jung E, Kim J. Aucuba japonica Extract and Aucubin Prevent Desiccating Stress-Induced Corneal Epithelial Cell Injury and Improve Tear Secretion in a Mouse Model of Dry Eye Disease. Molecules 2018; 23:molecules23102599. [PMID: 30314275 PMCID: PMC6222834 DOI: 10.3390/molecules23102599] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/05/2018] [Accepted: 10/08/2018] [Indexed: 11/16/2022] Open
Abstract
Dry eye disease is affected by a broad range of causes such as age, lifestyle, environment, medication and autoimmune diseases. These causes induce tear instability that activates immune cells and promotes expression of inflammatory molecules. In this study, we investigated the therapeutic effects of an ethanolic extract of Aucuba japonica (AJE) and its bioactive compound, aucubin, on dry eye disease. The human corneal cells were exposed to desiccation stress induced by exposing cells to air, so that viability was decreased. On the other hand, pre-treatment of AJE and aucubin restored cell survival rate depending on the dose under the dry condition. This result was confirmed again by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The mRNA expression of inflammatory molecules was reduced by the pretreatment of AJE and aucubin under the dry state. The therapeutic effects of AJE and aucubin were examined in the animal model for dry eye induced by unilateral excision of the exorbital lacrimal gland. Declined tear volumes and corneal irregularity in the dry eye group were fully recovered by the administration of AJE and aucubin. The apoptotic cells on the cornea were also decreased by AJE and aucubin. Therefore, this study suggests that administration of AJE can be a novel therapeutic for dry eye disease and that the pharmacological activities of AJE may be in part due to its bioactive compound, aucubin.
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Affiliation(s)
- Wan Seok Kang
- College Department of Oral Pathology, School of Dentistry, Chonbuk National University, Jeonju 54896, Korea.
| | - Eunsoo Jung
- Laboratory of Toxicology, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea.
| | - Junghyun Kim
- College Department of Oral Pathology, School of Dentistry, Chonbuk National University, Jeonju 54896, Korea.
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Zhu Z, Xie Q, Huang Y, Zhang S, Chen Y. Aucubin suppresses Titanium particles‑mediated apoptosis of MC3T3‑E1 cells and facilitates osteogenesis by affecting the BMP2/Smads/RunX2 signaling pathway. Mol Med Rep 2018; 18:2561-2570. [PMID: 30015916 PMCID: PMC6102688 DOI: 10.3892/mmr.2018.9286] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 03/28/2018] [Indexed: 11/06/2022] Open
Abstract
Aucubin represents an iridoid glucoside separated from multiple Chinese herbs, which has been demonstrated to possess numerous pharmacological activities. In the present study, the aim was to investigate the roles and mechanisms of aucubin in the suppression of mouse MC3T3-E1 osteoblast apoptosis induced by Titanium particles and the promotion of bone formation. MTT assay and flow cytometry were performed to analyze cell viability and apoptosis, respectively. ELISA and para-nitrophenyl phosphate colorimetry were carried out to evaluate the oxidative stress markers and alkaline phosphatase (ALP). Western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to evaluate the associated mRNA and protein expression. The results revealed that aucubin enhanced the cell activity of MC3T3-E1 cells treated with Ti particles. Aucubin suppressed the apoptosis of Ti particles-induced MC3T3-E1 cells and facilitated osteogenesis by affecting the B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein, ALP and associated osteogenic factors expression. Aucubin reduced the oxidative stress in Ti particles-induced MC3T3-E1 cells. In addition, aucubin upregulated the bone morphogenetic protein 2 (BMP2)/Smads/runt related transcription factor 2 (RunX2) pathway in Ti particles-induced MC3T3-E1 cells. In conclusion, the present study confirmed that aucubin suppressed the Ti particles-mediated apoptosis of MC3T3-E1 cells and facilitated osteogenesis by affecting the BMP2/Smads/RunX2 signaling pathway.
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Affiliation(s)
- Ziguan Zhu
- Department of Hand Surgery and Reconstruction Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Qingping Xie
- Department of Hand Surgery and Reconstruction Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Yazeng Huang
- Department of Orthopaedics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Shuijun Zhang
- Department of Orthopaedics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Yu Chen
- Department of Orthopaedics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
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17
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Zhou Y, Li P, Duan JX, Liu T, Guan XX, Mei WX, Liu YP, Sun GY, Wan L, Zhong WJ, Ouyang DS, Guan CX. Aucubin Alleviates Bleomycin-Induced Pulmonary Fibrosis in a Mouse Model. Inflammation 2018; 40:2062-2073. [PMID: 28785877 DOI: 10.1007/s10753-017-0646-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Pulmonary fibrosis is a life-threatening disease characterized by progressive dyspnea and worsening of pulmonary function. No effective therapeutic strategy for pulmonary fibrosis has been established. Aucubin is a natural constituent with a monoterpene cyclic ring system. The potency of aucubin in protecting cellular components against inflammation, oxidative stress, and proliferation effects is well documented. In this study, we investigated the protective effect of aucubin against pulmonary fibrosis in mice. A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (BLM), and aucubin was administered for 21 days after BLM injection. We found that aucubin decreased the breathing frequency and increased the lung dynamic compliance of BLM-stimulated mice detected by Buxco pulmonary function testing system. Histological examination showed that aucubin alleviated BLM-induced lung parenchymal fibrotic changes. Aucubin also reduced the intrapulmonary collagen disposition and inflammatory injury induced by BLM. In addition, aucubin reduced the expression of pro-fibrotic protein transforming growth factor (TGF)-β1 and α-smooth muscle actin (α-SMA) of pulmonary fibrosis mice induced by BLM. Furthermore, the effect of aucubin on the proliferation and differentiation of fibroblast was investigated in vitro. Aucubin inhibited the mRNA and protein expression of Ki67 and proliferating cell nuclear antigen (PCNA) induced by TGF-β1 and reduced the cell proliferation in a murine fibroblast cell NIH3T3. Aucubin also reduced the collagen syntheses and α-SMA expression induced by TGF-β1 in fibroblast. Our results indicate that aucubin inhibits inflammation, fibroblast proliferation, and differentiation, exerting protective effects against BLM-induced pulmonary fibrosis in a mouse model. This study provides an evidence that aucubin may be a novel drug for pulmonary fibrosis.
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Affiliation(s)
- Yong Zhou
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Ping Li
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Jia-Xi Duan
- Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Tian Liu
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Xin-Xin Guan
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Wen-Xiu Mei
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Yong-Ping Liu
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Guo-Ying Sun
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Li Wan
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Wen-Jing Zhong
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Dong-Sheng Ouyang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Cha-Xiang Guan
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China.
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Aucubin Protects against Myocardial Infarction-Induced Cardiac Remodeling via nNOS/NO-Regulated Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:4327901. [PMID: 30046377 PMCID: PMC6036820 DOI: 10.1155/2018/4327901] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 05/15/2018] [Indexed: 12/07/2022]
Abstract
Whether aucubin could protect myocardial infarction- (MI-) induced cardiac remodeling is not clear. In this study, in a mouse model, cardiac remodeling was induced by left anterior descending coronary artery ligation surgery. Mice were intraperitoneally injected with aucubin (10 mg/kg) 3 days post-MI. Two weeks post-MI, mice in the aucubin treatment group showed decreased mortality, decreased infarct size, and improved cardiac function. Aucubin also decreased cardiac remodeling post-MI. Consistently, aucubin protected cardiomyocytes against hypoxic injury in vitro. Mechanistically, we found that aucubin inhibited the ASK1/JNK signaling. These effects were abolished by the JNK activator. Moreover, we found that the oxidative stress was attenuated in both in vivo aucubin-treated mice heart and in vitro-treated cardiomyocytes, which caused decreased thioredoxin (Trx) consumption, leading to ASK1 forming the inactive complex with Trx. Aucubin increased nNOS-derived NO production in vivo and vitro. The protective effects of aucubin were reversed by the NOS inhibitors L-NAME and L-VINO in vitro. Furthermore, nNOS knockout mice also reversed the protective effects of aucubin on cardiac remodeling. Taken together, aucubin protects against cardiac remodeling post-MI through activation of the nNOS/NO pathway, which subsequently attenuates the ROS production, increases Trx preservation, and leads to inhibition of the ASK1/JNK pathway.
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Song M, Kim H, Park S, Kwon H, Joung I, Kim Kwon Y. Aucubin Promotes Differentiation of Neural Precursor Cells into GABAergic Neurons. Exp Neurobiol 2018; 27:112-119. [PMID: 29731677 PMCID: PMC5934542 DOI: 10.5607/en.2018.27.2.112] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 02/26/2018] [Accepted: 02/28/2018] [Indexed: 12/13/2022] Open
Abstract
Aucubin is a small compound naturally found in traditional medicinal herbs with primarily anti-inflammatory and protective effects. In the nervous system, aucubin is reported to be neuroprotective by enhancing neuronal survival and inhibiting apoptotic cell death in cultures and disease models. Our previous data, however, suggest that aucubin facilitates neurite elongation in cultured hippocampal neurons and axonal regrowth in regenerating sciatic nerves. Here, we investigated whether aucubin facilitates the differentiation of neural precursor cells (NPCs) into specific types of neurons. In NPCs cultured primarily from the rat embryonic hippocampus, aucubin significantly elevated the number of GAD65/67 immunoreactive cells and the expression of GAD65/67 proteins was upregulated dramatically by more than three-fold at relatively low concentrations of aucubin (0.01 µM to 10 µM). The expression of both NeuN and vGluT1 of NPCs, the markers for neurons and glutamatergic cells, respectively, and the number of vGluT1 immunoreactive cells also increased with higher concentrations of aucubin (1 µM and 10 µM), but the ratio of the increases was largely lower than GAD expression and GAD immunoreactive cells. The GABAergic differentiation of pax6-expressing late NPCs into GABA-producing cells was further supported in cortical NPCs primarily cultured from transgenic mouse brains, which express recombinant GFP under the control of pax6 promoter. The results suggest that aucubin can be developed as a therapeutic candidate for neurodegenerative disorders caused by the loss of inhibitory GABAergic neurons.
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Affiliation(s)
- Miyeoun Song
- Department of Life and Nanopharmarceutical Science, Kyung Hee University, Seoul 02447, Korea
| | - Hyomin Kim
- Department of Life and Nanopharmarceutical Science, Kyung Hee University, Seoul 02447, Korea
| | - Sujin Park
- Department of Life and Nanopharmarceutical Science, Kyung Hee University, Seoul 02447, Korea
| | - Hyockman Kwon
- Department of Biosciences and Biotechnology, Hankuk University of Foreign Studies, Yongin 17035, Korea
| | - Insil Joung
- Department of Biological Sciences, Hanseo University, Seosan 31962, Korea
| | - Yunhee Kim Kwon
- Department of Life and Nanopharmarceutical Science, Kyung Hee University, Seoul 02447, Korea.,Department of Biology, Kyung Hee University, Seoul 02447, Korea
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Song M, Han M, Kim Kwon Y. Effect of aucubin on neural precursor cell survival during neuronal differentiation. Int J Neurosci 2018; 128:899-905. [PMID: 29384407 DOI: 10.1080/00207454.2018.1435535] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF THE STUDY Aucubin (ACB) is an iridoid glycoside with various biological activities. Previously, it is reported that ACB reduces cell survival and proliferation in many human tumors, whereas it facilitates cell survival and neuroprotection in damaged neuronal cells and disease models. However, its effects on cell survival in the non-proliferating or differentiated neurons are not known. MATERIALS AND METHODS We examined whether ACB facilitated cell survival in differentiating neural precursor cells, HiB5, compared with the proliferating HiB5 cells at various concentrations. RESULTS The cell viabilities were evaluated by measuring MTT values, cell numbers, amounts of neurotransmittersD1 and protein amounts of neuronal markers. Here, we showed that ACB promotes cell survival in differentiated neurons (10-200 μg/mL), but reduces it in proliferating NPCs (200-400 μg/mL). Protein amounts of neurofilament proteins, NF-H, NF-M, PSD-95 in post-synaptic density, GAP-43 in growing neurites and NeuN in differentiated neurons were upregulated by addition of ACB, indicating that cell survival increased in differentiated neurons, shown by immunoblot analysis. Especially, when PDGF was added into N2 media to facilitate neuronal differentiation of HiB5 cells, the viability of differentiated HiB5 cells was significantly elevated following the increase of ACB concentration. Furthermore, ACB promoted cell survival of specific neuron types, such as GABAergic neurons and glutamatergic neurons. When differentiated neurons were immunostained with markers for specific neurons, neuronal subtypes producing GABA and GAD 65/67 were immunostained more than subtypes producing glutamate and vGluT1. CONCLUSION These results indicate that ACB improves neuronal cell survival in differentiated cells, suggesting it may be a therapeutic compound for neurodegenerative disorders.
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Affiliation(s)
- Miyeoun Song
- a Department of Life and Nanopharmaceutical Science , Kyung Hee University , Seoul , Republic of Korea
| | - Maeum Han
- a Department of Life and Nanopharmaceutical Science , Kyung Hee University , Seoul , Republic of Korea
| | - Yunhee Kim Kwon
- a Department of Life and Nanopharmaceutical Science , Kyung Hee University , Seoul , Republic of Korea.,b Department of Biology, Kyung Hee University , Seoul , Republic of Korea
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Lee GH, Lee HY, Choi MK, Choi AH, Shin TS, Chae HJ. Eucommia ulmoides leaf (EUL) extract enhances NO production in ox-LDL-treated human endothelial cells. Biomed Pharmacother 2018; 97:1164-1172. [DOI: 10.1016/j.biopha.2017.11.035] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 10/30/2017] [Accepted: 11/03/2017] [Indexed: 01/20/2023] Open
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Andoh T, Uta D, Kato M, Toume K, Komatsu K, Kuraishi Y. Prophylactic Administration of Aucubin Inhibits Paclitaxel-Induced Mechanical Allodynia via the Inhibition of Endoplasmic Reticulum Stress in Peripheral Schwann Cells. Biol Pharm Bull 2017; 40:473-478. [PMID: 28381802 DOI: 10.1248/bpb.b16-00899] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Paclitaxel is a chemotherapeutic agent that causes peripheral neuropathy as its major dose-limiting side effect. However, the peripheral neuropathy is difficult to manage. A study we recently conducted showed that repetitive administration of aucubin as a prophylactic inhibits paclitaxel-induced mechanical allodynia. However, the mechanisms underlying the anti-allodynic activity of aucubin, which is a major component of Plantaginis Semen, was unclear. In addition to mechanical allodynia, aucubin inhibited spontaneous and mechanical stimuli-induced firing in spinal dorsal horn neurons; however, catalpol, a metabolite of aucubin, did not show these effects. Furthermore, paclitaxel induced the expression of CCAAT/enhancer-binding protein homologous protein, a marker of endoplasmic reticulum (ER) stress, in the sciatic nerve and a Schwann cell line (LY-PPB6 cells); however, this effect was inhibited by aucubin. These results suggest that aucubin inhibits paclitaxel-induced mechanical allodynia through the inhibition of ER stress in peripheral Schwann cells.
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Affiliation(s)
- Tsugunobu Andoh
- Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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Wang J, Li Y, Huang WH, Zeng XC, Li XH, Li J, Zhou J, Xiao J, Xiao B, Ouyang DS, Hu K. The Protective Effect of Aucubin from Eucommia ulmoides Against Status Epilepticus by Inducing Autophagy and Inhibiting Necroptosis. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2017; 45:557-573. [PMID: 28387136 DOI: 10.1142/s0192415x17500331] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Eucommia ulmoides Oliv. is a famous traditional Chinese medicine which exhibits anti-oxidative stress ability and neuro-protective effects. Aucubin is the predominant component of Eucommia ulmoides Oliv. Our present study is intended to investigate aucubin's potential protective effects on neurons against epilepsy in the hippocampus by establishing the lithium-pilocarpine induced status epilepticus (SE) rat model in vivo. Aucubin (at a low dose and a high dose of 5[Formula: see text]mg/kg and 10[Formula: see text]mg/kg, respectively) was administered through gavage for two weeks before lithium-pilocarpine injection. Rats were sacrificed at 4, 24 and 72[Formula: see text]h after SE induction. Pretreatment with both low-dose and high-dose aucubin significantly reduced the number of death neurons ([Formula: see text]) and increased the number of surviving neurons ([Formula: see text]) in DG, Hilus, CA1 and CA3 hippocampal regions post SE. Meanwhile, it significantly inhibited necroptosis proteins (MLKL and RIP-1) ([Formula: see text] or [Formula: see text]) and enhanced autophagy protein (Beclin-1 and LC3BII/LC3BI) prevalence in the hippocampus ([Formula: see text] or [Formula: see text]). In conclusion, aucubin appeared to ameliorate damages in lithium-pilocarpine induced SE in hippocampus, reduce the number of apoptotic neurons, and increased the number of survival neurons by inducing autophagy and inhibiting necroptosis. These original findings might provide an important basis for the further investigation of the therapeutic role of aucubin in treatment or prevention of epilepsy-related neuronal damages.
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Affiliation(s)
- Jin Wang
- ** Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha 410000, P.R. China
| | - Ying Li
- †† Department of Healthy Management Center, The Third Xiangya Hospital, Central South University, Changsha 410013, P.R. China
| | - Wei-Hua Huang
- † Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P.R. China.,∥ Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P.R. China
| | - Xiang-Chang Zeng
- † Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P.R. China.,∥ Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P.R. China
| | - Xiao-Hui Li
- ** Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha 410000, P.R. China
| | - Jian Li
- ‡ Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha 410008, P.R. China
| | - Jun Zhou
- § Medical Science Research Center, Xiangya Hospital, Central South University, Changsha 410008, P.R. China
| | - Jian Xiao
- ¶ Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, P.R. China
| | - Bo Xiao
- * Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, P.R. China
| | - Dong-Sheng Ouyang
- † Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P.R. China.,∥ Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P.R. China
| | - Kai Hu
- * Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, P.R. China
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Yang J, Ju B, Yan Y, Xu H, Wu S, Zhu D, Cao D, Hu J. Neuroprotective effects of phenylethanoid glycosides in an in vitro model of Alzheimer's disease. Exp Ther Med 2017; 13:2423-2428. [PMID: 28565858 DOI: 10.3892/etm.2017.4254] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 01/06/2017] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate the neuroprotective effects of phenylethanol glycosides (PhGs) on H2O2- and β-amyloid peptide (Aβ)1-42-induced injury of PC12 cells as an in vitro model of Alzheimer's disease (AD). The optimal induction conditions were established through screening of various incubation times and concentrations. PC12 cells were treated with 0.5 µM Aβ1-42 and H2O2 in the presence of PhGs for 24 h and the cell viability was then evaluated by an MTT assay; lactate dehydrogenase (LDH) release and malondialdehyde (MDA) content were also measured. The optimal conditions for establishing the AD model were the treatment of PC12 cells with 0.5 µM Aβ1-42 for 48 h, or with 25 µM H2O2 dissolved in DMEM with PBS. PhGs at concentrations of 5, 25 and 50 µg/ml increased the viability and decreased LDH and MDA release by PC12 cells injured with Aβ1-42 or H2O2. In conclusion, the model of Aβ1-42- and H2O2-induced PC12 cell injury was successfully established. PhGs were shown to have a significant neuroprotective effect against Aβ1-42- or H2O2-induced cell injury.
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Affiliation(s)
- Jianhua Yang
- Department of Pharmacy, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Bowei Ju
- Department of Pharmacy, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China.,Department of Natural Medicines, College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Yao Yan
- Department of Pharmacy, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Huanhuan Xu
- Department of Pharmacy, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Shanshan Wu
- Department of Pharmacy, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Dandan Zhu
- Department of Pharmacy, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Dandan Cao
- Department of Pharmacy, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Junping Hu
- Department of Natural Medicines, College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
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Young IC, Chuang ST, Hsu CH, Sun YJ, Liu HC, Chen YS, Lin FH. Protective effects of aucubin on osteoarthritic chondrocyte model induced by hydrogen peroxide and mechanical stimulus. Altern Ther Health Med 2017; 17:91. [PMID: 28153003 PMCID: PMC5288878 DOI: 10.1186/s12906-017-1581-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 01/13/2017] [Indexed: 01/06/2023]
Abstract
Background During the onset of osteoarthritis (OA), certain biochemical events have been shown to accelerate cartilage degradation, including the dysregulation of cartilage ECM anabolism, abnormal generation of reactive oxygen species (ROS) and overproduction of proteolytic enzymes and inflammatory cytokines. The potency of aucubin in protecting cellular components against oxidative stress, inflammation and apoptosis effects are well documented, which makes it a potential candidate for OA treatment. In this study, we aimed to evaluate the protective benefits of aucubin against OA using H2O2 and compression induced OA-like chondrocyte models. Methods The effects of aucubin were studied in porcine chondrocytes after 1 mM H2O2 stimulation for 30 min or sustained compression for 24 h. Effects of aucubin on cell proliferation and cytotoxicity of chondrocytes were measured with WST-1 and LDH assays. ROS production was evaluated by the Total ROS/Superoxide Detection Kit. Caspase-3 activity was evaluated by the CaspACE assay system. The levels of apoptosis were evaluated by the Annexin V-FITC apoptosis detection kit. OA-related gene expression was measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Total DNA quantification was evaluated by the DNeasy Blood and Tissue kit. Sulfated-glycosaminoglycans (sGAGs) production and content were evaluated by DMMB assay and Alcian blue staining. Results The results showed that the ROS scavenge effects of aucubin appeared after 1 h of pretreatment. Aucubin could reduce the caspase-3 activity induced by H2O2, and reduced the apoptosis cell population in flowcytometry. In RT-qPCR results, aucubin could maintain ACAN and COL2A1 gene expressions, and prevent IL6 and MMP13 gene up-regulation induced by H2O2 and compression stimulations. In the DMMB assay and Alcian blue staining, aucubin could maintain the sGAG content and protect chondrocytes against compressive stress, but not oxidative stress from H2O2. Conclusions These results indicated that aucubin has protective effects in an osteoarthritic chondrocyte model induced by H2O2 and mechanical stimulus.
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Xie X, Zou G, Li C. Purification, characterization and in vitro antioxidant activities of polysaccharide from Chaenomeles speciosa. Int J Biol Macromol 2016; 92:702-707. [DOI: 10.1016/j.ijbiomac.2016.07.086] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 07/13/2016] [Accepted: 07/24/2016] [Indexed: 11/16/2022]
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Andoh T, Kato M, Kitamura R, Mizoguchi S, Uta D, Toume K, Komatsu K, Kuraishi Y. Prophylactic administration of an extract from Plantaginis Semen and its major component aucubin inhibits mechanical allodynia caused by paclitaxel in mice. J Tradit Complement Med 2016; 6:305-8. [PMID: 27419098 PMCID: PMC4936767 DOI: 10.1016/j.jtcme.2015.12.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 11/06/2015] [Accepted: 12/01/2015] [Indexed: 11/21/2022] Open
Abstract
The chemotherapeutic agent paclitaxel (PTX) causes peripheral neuropathy as a major dose-limiting side effect, and this peripheral neuropathy is difficult to control. Our previous report showed that prophylactic repetitive administration of goshajinkigan ( niú chē shèn qì wán), but not hachimijiogan ( bā wèi dì huáng wán), which lacks two of the constituents of goshajinkigan, inhibited PTX-induced mechanical allodynia in mice. Thus, the herbal medicines Plantaginis Semen ( chē qián zǐ) or Achyranthis Radix ( niú xī) may contribute to the inhibitory action of goshajinkigan on the exacerbation of PTX-induced mechanical allodynia [Andoh et al, J. Tradit. Complement. Med. 2014; 4: 293-297]. Therefore, in this study, we examined whether an extract of Plantaginis Semen (EPS) or Achyranthis Radix (EAR) would relieve PTX-induced mechanical allodynia in mice. A single intraperitoneal injection of PTX caused mechanical allodynia, which peaked on day 14 after injection. Repetitive oral administration of EPS, but not EAR, starting from the day after PTX injection significantly inhibited the exacerbation of PTX-induced mechanical allodynia. Repetitive intraperitoneal injection of aucubin, one of the main components of EPS, starting from the day after PTX injection also significantly reduced PTX-induced mechanical allodynia. However, repetitive intraperitoneal injection of geniposide acid (a precursor of aucubin) or catalpol (a metabolite of aucubin) did not prevent the exacerbation of mechanical allodynia. These results suggest that prophylactic administration of EPS is effective for preventing the exacerbation of PTX-induced allodynia. Aucubin may contribute to the inhibitory action of EPS on the exacerbation of PTX-induced allodynia.
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Affiliation(s)
- Tsugunobu Andoh
- Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Mitsuru Kato
- Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Ryo Kitamura
- Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Shizuka Mizoguchi
- Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Daisuke Uta
- Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Kazufumi Toume
- Division of Pharmacognosy, Institutes of Natural Medicine, University of Toyama, Toyama, Japan
| | - Katsuko Komatsu
- Division of Pharmacognosy, Institutes of Natural Medicine, University of Toyama, Toyama, Japan
| | - Yasushi Kuraishi
- Research Administration Division, Tokyo Medical and Dental University, Tokyo, Japan
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Structural characterization and biological activities of two α-glucans from radix paeoniae alba. Glycoconj J 2016; 33:147-57. [PMID: 26747055 DOI: 10.1007/s10719-015-9647-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Revised: 12/03/2015] [Accepted: 12/21/2015] [Indexed: 12/21/2022]
Abstract
Radix Paeoniae Alba is widely used in Chinese traditional medicine to treat various diseases such as gastrointestinal disorders, cancer, and other diseases. In this study, two polysaccharides RPAPW1 and RPAPW2 were isolated from Radix Paeoniae Alba by DEAE-52 cellulose chromatography and G-25 sephadex. According to physicochemical methods, NMR and methylation analysis, RPAPW1 and RPAPW2 were established to be α-glucans consisting of predominant 4-linked α- Glc residues branched at O-6 and contained trace amount of protein and uronic acid. Immunological tests indicated that RPAPW1, RPAPW2 and could promote splenocyte proliferation and RAW264.7 phagocytic activity. In vitro, RPAPW1 and RPAPW2 elicited a week reducing power, DPPH scavenging activity and could not protect the PC12 cells from H2O2 damage. These data implied polysaccharides RPAPW1 and RPAPW2 had the potential to be a natural immunopotentiating and antioxidant supplement for preparing functional foods and nutraceuticals.
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Xu P, Wang H, Li Z, Yang Z. Triptolide attenuated injury via inhibiting oxidative stress in Amyloid-Beta25-35-treated differentiated PC12 cells. Life Sci 2015; 145:19-26. [PMID: 26679104 DOI: 10.1016/j.lfs.2015.12.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 11/07/2015] [Accepted: 12/07/2015] [Indexed: 11/15/2022]
Abstract
BACKGROUND Recently, an abnormal deposition of Amyloid-Beta (Aβ) was considered the primary cause of the pathogenesis of Alzheimer's disease (AD). And how to inhibit the cytotoxicity is considered an important target for the treatment of AD. Triptolide (TP), a purified diterpenoid from the herb Tripterygium wilfordii Hook.f. (TWHF), has potential neuroprotective effects pertinent to disease of the nervous system. However, whether triptolide and its specific mechanisms have protective functions in differentiated PC12 cells treated with Aβ25-35 remain unclear. AIMS The purpose is to investigate the protective functions of triptolide in Aβ25-35-stimulated differentiated PC12 cells. MAIN METHODS In the study, we use 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) assay, flow cytometry assay, immunohistochemical staining and Western blot to observe the effects of triptolide on cytotoxicity induced by Aβ25-35 and its mechanism of oxidative stress. KEY FINDINGS The result of MTT and LDH assay indicates that triptolide protected PC12 cells against Aβ25-35-induced cytotoxicity. The flow cytometry assay shows that triptolide attenuated Aβ25-35-induced apoptosis in differentiated PC12 cells. Meanwhile, the results give a clear indication that triptolide could downregulate generation of reactive oxygen species (ROS), hydrogen peroxide (H2O2) and malondialdehyde (MDA) induced by Aβ25-35. The apoptotic process triggered by triptolide involved the up-regulation of the activity of superoxide dismutase (SOD). SIGNIFICANCE The results suggest that triptolide may serve as an important role in the inhibition of the cell apoptosis induced by Aβ and the decreased oxidative stress is a key mechanism in the protective effect of triptolide in AD.
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Affiliation(s)
- Pengjuan Xu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
| | - Hui Wang
- College of Life Science, Nankai University, Tianjin 300071, China
| | - Zhigui Li
- College of Medicine, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
| | - Zhuo Yang
- College of Medicine, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
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Characterization of polysaccharides with antioxidant and immunological activities from Rhizoma Acori Tatarinowii. Carbohydr Polym 2015; 133:154-62. [DOI: 10.1016/j.carbpol.2015.07.018] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 06/18/2015] [Accepted: 07/07/2015] [Indexed: 11/21/2022]
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Zhang L, Zhang W, Wang Q, Wang D, Dong D, Mu H, Ye XS, Duan J. Purification, antioxidant and immunological activities of polysaccharides from Actinidia Chinensis roots. Int J Biol Macromol 2015; 72:975-83. [DOI: 10.1016/j.ijbiomac.2014.09.056] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/08/2014] [Accepted: 09/26/2014] [Indexed: 11/30/2022]
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Kim YM, Sim UC, Shin Y, Kim Kwon Y. Aucubin promotes neurite outgrowth in neural stem cells and axonal regeneration in sciatic nerves. Exp Neurobiol 2014; 23:238-45. [PMID: 25258571 PMCID: PMC4174615 DOI: 10.5607/en.2014.23.3.238] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 03/06/2014] [Accepted: 03/06/2014] [Indexed: 11/23/2022] Open
Abstract
Aucubin is an iridoid glycoside with a wide range of biological activities, including anti-inflammatory, anti-microbial, anti-algesic as well as anti-tumor activities. Recently, it has been shown that aucubin prevents neuronal death in the hippocampal CA1 region in rats with diabetic encephalopathy. In addition, it has protective effects on H2O2-induced apoptosis in PC12 cells. We have shown here that aucubin promotes neuronal differentiation and neurite outgrowth in neural stem cells cultured primarily from the rat embryonic hippocampus. We also investigated whether aucubin facilitates axonal elongation in the injured peripheral nervous system. Aucubin promoted lengthening and thickness of axons and re-myelination at 3 weeks after sciatic nerve injury. These results indicate that administration of aucubin improved nerve regeneration in the rat model of sciatic nerve injury, suggesting that aucubin may be a useful therapeutic compound for the human peripheral nervous system after various nerve injuries.
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Affiliation(s)
- Yong Min Kim
- Department of Biology, Kyunghee University, Seoul 130-701, Korea
| | - U-Cheol Sim
- Department of Biology, Kyunghee University, Seoul 130-701, Korea
| | - Yongsung Shin
- Department of Biology, Kyunghee University, Seoul 130-701, Korea. ; Department of Life and Nanopharmaceutical Science, Kyunghee University, Seoul 130-701, Korea
| | - Yunhee Kim Kwon
- Department of Biology, Kyunghee University, Seoul 130-701, Korea. ; Department of Life and Nanopharmaceutical Science, Kyunghee University, Seoul 130-701, Korea
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Han Y, Xu J, Li Z, Yang Z. Neuroprotective effect of leukemia inhibitory factor on antimycin A-induced oxidative injury in differentiated PC12 cells. J Mol Neurosci 2013; 50:577-85. [PMID: 23636893 DOI: 10.1007/s12031-013-0004-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Accepted: 03/11/2013] [Indexed: 12/25/2022]
Abstract
As a neurotrophic cytokine, leukemia inhibitory factor (LIF) has neuroendocrine effects and exerts neuroprotective effects on various neuron injuries both in vitro and in vivo. The aim of the present study was to investigate whether LIF can protect PC12 cells from antimycin A (AMA)-induced oxidative stress. LIF (0.5 and 1 ng/ml) increased PC12 cell viability and significantly attenuated AMA-induced cell death as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results from Hoechst 33342 staining and flow cytometry assay showed that AMA induced apoptosis significantly in PC12 cells, while pretreatment with LIF (0.5 and 1 ng/ml) can attenuate this injury. The presence of LIF partly prevented AMA-induced elevated reactive oxygen species level and decreased superoxide dismutase level, which indicated the antioxidative effects of LIF on the neuron oxidative injury. In conclusion, LIF might protect PC12 cells from the injury induced by AMA through the downregulation of oxidative stress, which may provide basic information of using LIF as a potential targeted therapy for oxidative injury in neurons.
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Affiliation(s)
- Yangguang Han
- College of Medicine, Nankai University, Tianjin, 300071, China
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Mu H, Zhang A, Zhang W, Cui G, Wang S, Duan J. Antioxidative properties of crude polysaccharides from Inonotus obliquus. Int J Mol Sci 2012; 13:9194-9206. [PMID: 22942760 PMCID: PMC3430291 DOI: 10.3390/ijms13079194] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 07/04/2012] [Accepted: 07/16/2012] [Indexed: 12/22/2022] Open
Abstract
The mushroom Inonotus obliquus has been widely used as a folk medicine in Russia, Poland and most of the Baltic countries. In this study, water-soluble and alkali-soluble crude polysaccharides (IOW and IOA) were isolated from I. obliquus, and the carbohydrate-rich fractions IOW-1 and IOA-1 were obtained respectively after deproteination and depigmentation. Their contents, such as neutral carbohydrate, uronic acid and protein, were measured. Their antioxidant properties against chemicals-induced reactive species (ROS) including 1,1'-Diphenyl-2-picrylhydrazyl (DPPH) radical, hydroxyl radical and superoxide anion radical, as well as their protective effects on H(2)O(2)-induced PC12 cell death were investigated. Results showed that I. obliquus polysaccharides can scavenge all ROS tested above in a dose-dependent manner. IOA and its product IOA-1 could rescue PC12 cell viability from 38.6% to 79.8% and 83.0% at a concentration of 20μg/mL. Similarly, IOW and its product IOW-1 at the same dose, can also increase cell viability to 84.9% and 88.6% respectively. The antioxidative activities of water-soluble and alkali-soluble polysaccharide constituents from I. obliquus might contribute to diverse medicinal and nutritional values of this mushroom.
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Affiliation(s)
- Haibo Mu
- College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China; E-Mails: (H.M.); (A.Z.); (W.Z.); (G.C.)
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Amin Zhang
- College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China; E-Mails: (H.M.); (A.Z.); (W.Z.); (G.C.)
| | - Wuxia Zhang
- College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China; E-Mails: (H.M.); (A.Z.); (W.Z.); (G.C.)
| | - Guoting Cui
- College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China; E-Mails: (H.M.); (A.Z.); (W.Z.); (G.C.)
| | - Shunchun Wang
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Authors to whom correspondence should be addressed; E-Mails: (S.W.); (J.D.); Tel.: +86-21-51322511 (S.W.); +86-29-87092226 (J.D.); Fax: +86-21-51322519 (S.W.); +86-29-87092226 (J.D.)
| | - Jinyou Duan
- College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China; E-Mails: (H.M.); (A.Z.); (W.Z.); (G.C.)
- Authors to whom correspondence should be addressed; E-Mails: (S.W.); (J.D.); Tel.: +86-21-51322511 (S.W.); +86-29-87092226 (J.D.); Fax: +86-21-51322519 (S.W.); +86-29-87092226 (J.D.)
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Xue HY, Lu YN, Fang XM, Xu YP, Gao GZ, Jin LJ. Neuroprotective properties of aucubin in diabetic rats and diabetic encephalopathy rats. Mol Biol Rep 2012; 39:9311-8. [PMID: 22810648 DOI: 10.1007/s11033-012-1730-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 06/06/2012] [Indexed: 12/26/2022]
Abstract
In this study, we determined the neuroprotective effect of aucubin on diabetes and diabetic encephalopathy. With the exception of the control group, all rats received intraperitoneal injections of streptozotocin (STZ; 60 mg/kg) to induce type 1 diabetes mellitus (DM). Aucubin (1, 5, 10 mg/kg ip) was used after induction of DM (immediately) and diabetic encephalopathy (65 days after the induction of diabetes). The diabetic encephalopathy treatment groups were divided into short-term and long-term treatment groups. Treatment responses to all parameters were examined (body weight, plasma glucose, Y-maze error rates and proportion of apoptotic cells). In diabetic rats, aucubin controlled blood glucose levels effectively, prevented complications, and improved the quality of life of diabetic rats. In diabetic encephalopathy, aucubin significantly rescued neurons in the hippocampal CA1 subfield and reduced working errors during behavioral testing. The significant neuroprotective effect of aucubin could be seen not only in the short term (15 days) but also in the long term (45 days), which was a highly encouraging finding. These data suggest that aucubin may be a potential neuroprotective agent.
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MESH Headings
- Animals
- Blood Glucose
- Body Weight/drug effects
- Brain Diseases, Metabolic/drug therapy
- Brain Diseases, Metabolic/etiology
- Brain Diseases, Metabolic/prevention & control
- CA1 Region, Hippocampal/drug effects
- CA1 Region, Hippocampal/pathology
- Cell Survival/drug effects
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Type 1/blood
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/drug therapy
- Iridoid Glucosides/administration & dosage
- Iridoid Glucosides/pharmacology
- Male
- Neuroprotective Agents/administration & dosage
- Neuroprotective Agents/pharmacology
- Pyramidal Cells/drug effects
- Pyramidal Cells/pathology
- Rats
- Rats, Wistar
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Affiliation(s)
- Hong Yu Xue
- Department of Chemistry and Life Science, Suzhou University, No. 49 Middle Bianhe Road, Yongqiao District, Suzhou, 234000 Anhui, People's Republic of China
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Kim MJ, Lee YH, Kwak J, Na Y, Yoon HG. Protective effects of a chalcone derivative against Aβ-induced oxidative stress and neuronal damage. BMB Rep 2012; 44:730-4. [PMID: 22118539 DOI: 10.5483/bmbrep.2011.44.11.730] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Amyloid Β-peptide (AΒ-peptide)-induced oxidative stress is thought to be a critical component of the pathophysiology of Alzheimer's disease (AD). New chalcone derivatives, the Chana series, were recently synthesized from the retrochalcones of licorice. In this study, we investigated the protective effects of the Chana series against neurodegenerative changes in vitro and in vivo. Among the Chana series, Chana 30 showed the highest free radical scavenging activity (90.7%) in the 1,1-diphenyl-2- picrylhydrazyl assay. Chana 30 also protected against AΒ-induced neural cell injury in vitro. Furthermore, Chana 30 reduced the learning and memory deficits of AΒ(1-42)-peptide injected mice. Taken together, these results suggest that Chana 30 may be a promising candidate as a potent therapeutic agent against neurodegenerative diseases. [BMB reports 2011; 44(11): 730-734].
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Affiliation(s)
- Mi-Jeong Kim
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Sciences,Yonsei University College of Medicine, Seoul
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