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Cheng K, Zhou Y, Hao Y, Wu S, Wang N, Zhang P, Wang Y. Magnolol inhibits appetite and causes visceral fat loss through Growth/differentiation factor-15 (GDF-15) by activating transcription factor 4-CCAAT enhancer binding protein γ-mediated endoplasmic reticulum stress responses. Chin J Nat Med 2025; 23:334-345. [PMID: 40122663 DOI: 10.1016/s1875-5364(25)60835-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 03/11/2024] [Accepted: 05/07/2024] [Indexed: 03/25/2025]
Abstract
Magnolol, a compound extracted from Magnolia officinalis, demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases. Its biological activities encompass anti-inflammatory, antioxidant, anticoagulant, and anti-diabetic effects. Growth/differentiation factor-15 (GDF-15), a member of the transforming growth factor β superfamily, is considered a potential therapeutic target for metabolic disorders. This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism. The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo, and determined the involvement of endoplasmic reticulum (ER) stress signaling in this process. Luciferase reporter assays, chromatin immunoprecipitation, and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4 (ATF4), CCAAT enhancer binding protein γ (CEBPG), and CCCTC-binding factor (CTCF). The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene, as well as the influence of single nucleotide polymorphisms (SNPs) on magnolol and ATF4-induced transcription activity. Results demonstrated that magnolol triggers GDF-15 production in endothelial cells (ECs), hepatoma cell line G2 (HepG2) and hepatoma cell line 3B (Hep3B) cell lines, and primary mouse hepatocytes. The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene. SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15. In high-fat diet ApoE-/- mice, administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15. These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity, indicating its potential as a drug for the treatment of metabolic disorders.
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Affiliation(s)
- Keru Cheng
- School of Basic Medicine, Anhui Medical University, Hefei 230032, China; Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Yanyun Zhou
- Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Yilong Hao
- Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Shengyun Wu
- Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Nanping Wang
- Health Science Center, East China Normal University, Shanghai 200241, China
| | - Peng Zhang
- School of Basic Medicine, Anhui Medical University, Hefei 230032, China; Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
| | - Yinfang Wang
- School of Basic Medicine, Anhui Medical University, Hefei 230032, China; Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
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Fu K, Chen H, Mei L, Wang J, Gong B, Li Y, Cao R. Berberine enhances autophagic flux by activating the Nrf2 signaling pathway in bovine endometrial epithelial cells to resist LPS-induced apoptosis. Anim Sci J 2023; 94:e13847. [PMID: 37427761 DOI: 10.1111/asj.13847] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 03/20/2023] [Accepted: 04/18/2023] [Indexed: 07/11/2023]
Abstract
Berberine exerts many beneficial effects on lipopolysaccharide (LPS)-induced bovine endometrial epithelial cells (BEECs). Recently, we also found that berberine shows significant antiapoptotic and autophagy-promoting activities, but the underlying mechanism has not been elucidated. This research explored the association between the antiapoptotic and autophagy-promoting activities of berberine in LPS-treated BEECs. BEECs were first preconditioned with an inhibitor of autophagic flux (chloroquine [CQ]) for 1 h, treated with berberine for 2 h, and then incubated with LPS for 3 h. Cell apoptosis was assessed by flow cytometry, and autophagy activities were assessed by immunoblot analysis of LC3II and p62. The results indicated that the antiapoptotic activity of berberine was notably inhibited in LPS-treated BEECs after preconditioning with CQ for 1 h. Furthermore, to determine whether berberine promoted autophagy by activating the nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway, we assessed autophagy in LPS-treated BEECs after preconditioning with a signaling pathway inhibitor of Nrf2 (ML385). The results indicated that the enhanced autophagy activity induced by berberine was partially reversed in LPS-treated BEECs after the Nrf2 signaling pathway was disturbed by ML385. In conclusion, berberine enhances autophagic flux to allow resistance to LPS-induced apoptosis by activating the Nrf2 signaling pathway in BEECs. The present study may provide new insight into the antiapoptotic mechanism of berberine in LPS-induced BEECs.
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Affiliation(s)
- Kaiqiang Fu
- College of Veterinary Medicine, Qingdao Agricultural University, Shandong, Qingdao, China
| | - Han Chen
- College of Veterinary Medicine, Qingdao Agricultural University, Shandong, Qingdao, China
| | - Lian Mei
- College of Veterinary Medicine, Qingdao Agricultural University, Shandong, Qingdao, China
| | - Jifang Wang
- College of Veterinary Medicine, Qingdao Agricultural University, Shandong, Qingdao, China
| | - Benzhi Gong
- Academy of Agricultural Sciences, Shandong, Jining, China
| | - Yan Li
- Animal Disease Prevention and Control Center, Shandong, Junan, China
| | - Rongfeng Cao
- College of Veterinary Medicine, Qingdao Agricultural University, Shandong, Qingdao, China
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Heckmann M, Sadova N, Drotarova I, Atzmüller S, Schwarzinger B, Guedes RMC, Correia PA, Hirtenlehner S, Potthast C, Klanert G, Weghuber J. Extracts Prepared from Feed Supplements Containing Wood Lignans Improve Intestinal Health by Strengthening Barrier Integrity and Reducing Inflammation. Molecules 2022; 27:molecules27196327. [PMID: 36234864 PMCID: PMC9572150 DOI: 10.3390/molecules27196327] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 09/21/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
Lignans are known to exhibit a broad spectrum of biological activities, indicating their potential as constituents of feed supplements. This study investigated two extracts derived from the feed supplements ‘ROI’ and ‘Protect’—which contain the wood lignans magnolol and honokiol (‘ROI’), or soluble tannins additional to the aforementioned lignans (‘Protect’)—and their impact on selected parameters of intestinal functionality. The antioxidant and anti-inflammatory properties of the extracts were determined by measuring their effects on reactive oxygen species (ROS) and pro-inflammatory cytokine production in vitro. The impact on intestinal barrier integrity was evaluated in Caco-2 cells and Drosophila melanogaster by examining leaky gut formation. Furthermore, a feeding trial using infected piglets was conducted to study the impact on the levels of superoxide dismutase, glutathione and lipid peroxidation. The Protect extract lowered ROS production in Caco-2 cells and reversed the stress-induced weakening of barrier integrity. The ROI extract inhibited the expression or secretion of interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα). Moreover, the ROI extract decreased leaky gut formation and mortality rates in Drosophila melanogaster. Dietary supplementation with Protect improved the antioxidant status and barrier integrity of the intestines of infected piglets. In conclusion, wood lignan-enriched feed supplements are valuable tools that support intestinal health by exerting antioxidant, anti-inflammatory and barrier-strengthening effects.
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Affiliation(s)
- Mara Heckmann
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Stelzhamerstraße 23, 4600 Wels, Austria
- FFoQSI GmbH–Austrian Competence Centre for Feed and Food Quality, Safety and Innovation, Technopark 1D, 3430 Tulln, Austria
| | - Nadiia Sadova
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Stelzhamerstraße 23, 4600 Wels, Austria
| | - Ivana Drotarova
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Stelzhamerstraße 23, 4600 Wels, Austria
- FFoQSI GmbH–Austrian Competence Centre for Feed and Food Quality, Safety and Innovation, Technopark 1D, 3430 Tulln, Austria
| | - Stefanie Atzmüller
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Stelzhamerstraße 23, 4600 Wels, Austria
- FFoQSI GmbH–Austrian Competence Centre for Feed and Food Quality, Safety and Innovation, Technopark 1D, 3430 Tulln, Austria
| | - Bettina Schwarzinger
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Stelzhamerstraße 23, 4600 Wels, Austria
- FFoQSI GmbH–Austrian Competence Centre for Feed and Food Quality, Safety and Innovation, Technopark 1D, 3430 Tulln, Austria
| | - Roberto Mauricio Carvalho Guedes
- Department of Veterinary Clinic and Surgery, Veterinary School, Universidade Federal de Minas Gerais, Belo Horizonte 130161-970, Brazil
| | - Paula Angelica Correia
- Department of Veterinary Clinic and Surgery, Veterinary School, Universidade Federal de Minas Gerais, Belo Horizonte 130161-970, Brazil
| | | | | | - Gerald Klanert
- FFoQSI GmbH–Austrian Competence Centre for Feed and Food Quality, Safety and Innovation, Technopark 1D, 3430 Tulln, Austria
| | - Julian Weghuber
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Stelzhamerstraße 23, 4600 Wels, Austria
- FFoQSI GmbH–Austrian Competence Centre for Feed and Food Quality, Safety and Innovation, Technopark 1D, 3430 Tulln, Austria
- Correspondence:
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Fan XX, Sun WY, Li Y, Tang Q, Li LN, Yu X, Wang SY, Fan AR, Xu XQ, Chang HS. Honokiol improves depression-like behaviors in rats by HIF-1α- VEGF signaling pathway activation. Front Pharmacol 2022; 13:968124. [PMID: 36091747 PMCID: PMC9453876 DOI: 10.3389/fphar.2022.968124] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Increasing evidence indicates that the pathogenesis of depression is closely linked to impairments in neuronal synaptic plasticity. Honokiol, a biologically active substance extracted from Magnolia Officinalis, has been proven to exert significant antidepressant effects. However, the specific mechanism of action remains unclear. In this study, PC12 cells and chronic unpredictable mild stress (CUMS) model rats were used to explore the antidepressant effects and potential mechanisms of honokiol in vitro and in rats. In vitro experiment, a cell viability detection kit was used to screen the concentration and time of honokiol administration. PC12 cells were administered with hypoxia-inducible factor-1α (HIF-1α) blocker, 2-methoxyestradiol (2-ME), and vascular endothelial growth factor receptor 2 (VEGFR-2) blocker, SU5416, to detect the expression of HIF-1α, VEGF, synaptic protein 1 (SYN 1), and postsynaptic density protein 95 (PSD 95) by western blotting. In effect, we investigated whether the synaptic plasticity action of honokiol was dependent on the HIF-1α-VEGF pathway. In vivo, behavioral tests were used to evaluate the reproducibility of the CUMS depression model and depression-like behaviors. Molecular biology techniques were used to examine mRNA and protein expression of the HIF-1α-VEGF signaling pathway and synaptic plasticity-related regulators. Additionally, molecular docking techniques were used to study the interaction between honokiol and target proteins, and predict their binding patterns and affinities. Experimental results showed that honokiol significantly reversed CUMS-induced depression-like behaviors. Mechanically, honokiol exerted a significant antidepressant effect by enhancing synaptic plasticity. At the molecular level, honokiol can activate the HIF-1α-VEGF signaling pathway in vitro and in vivo, as well as promote the protein expression levels of SYN 1 and PSD 95. Taken together, the results do not only provide an experimental basis for honokiol in the clinical treatment of depression but also suggest that the HIF-1α-VEGF pathway may be a potential target for the treatment of depression.
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Affiliation(s)
- Xiao-Xu Fan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Wen-Yan Sun
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yu Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Qin Tang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Li-Na Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xue Yu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Shu-Yan Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Ang-Ran Fan
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xiang-Qing Xu
- Experiment Center, Encephalopathy Department, Affiliated Hospital of Shandong University of Chinese Medicine, Jinan, China
- *Correspondence: Hong-Sheng Chang, ; Xiang-Qing Xu,
| | - Hong-Sheng Chang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Hong-Sheng Chang, ; Xiang-Qing Xu,
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