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Li X, Yuan Z, Wang Y, Wang W, Shi J. Recent advances of honokiol：pharmacological activities, manmade derivatives and structure-activity relationship. Eur J Med Chem 2024; 272:116471. [PMID: 38704945 DOI: 10.1016/j.ejmech.2024.116471] [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: 03/13/2024] [Revised: 04/28/2024] [Accepted: 04/29/2024] [Indexed: 05/07/2024]
Abstract
Honokiol (HNK) is a typical natural biphenyl polyphenol compound. It has been proven to have a wide range of biological activities, including pharmacological effects such as anti-cancer, anti-inflammatory, neuroprotective, and antimicrobial. However, due to the poor stability, water solubility, and bioavailability of HNK, HNK has not been used in clinical treatment. This article reviews the latest research on the pharmacological activity of HNK and summarizes the HNK derivatives designed and improved by several researchers. Reviewing these contents could promote the research process of HNK and guide the design of better HNK derivatives for clinical application in the future.
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Affiliation(s)
- Xiuxia Li
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Zhuo Yuan
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yuxia Wang
- Geriatric Intensive Care Unit, Sichuan Geriatric Medical Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan Province, China
| | - Wenjing Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; West China Medical Publishers, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Jianyou Shi
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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Lin CF, Lin MH, Hung CF, Alshetaili A, Tsai YF, Jhong CL, Fang JY. The anti-inflammatory activity of flavonoids and alkaloids from Sophora flavescens alleviates psoriasiform lesions: Prenylation and methoxylation beneficially enhance bioactivity and skin targeting. Phytother Res 2024; 38:1951-1970. [PMID: 38358770 DOI: 10.1002/ptr.8140] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 01/03/2024] [Accepted: 01/21/2024] [Indexed: 02/16/2024]
Abstract
The herb Sophora flavescens displays anti-inflammatory activity and can provide a source of antipsoriatic medications. We aimed to evaluate whether S. flavescens extracts and compounds can relieve psoriasiform inflammation. The ability of flavonoids (maackiain, sophoraflavanone G, leachianone A) and alkaloids (matrine, oxymatrine) isolated from S. flavescens to inhibit production of cytokine/chemokines was examined in keratinocytes and macrophages. Physicochemical properties and skin absorption were determined by in silico molecular modeling and the in vitro permeation test (IVPT) to establish the structure-permeation relationship (SPR). The ethyl acetate extract exhibited higher inhibition of interleukin (IL)-6, IL-8, and CXCL1 production in tumor necrosis factor-α-stimulated keratinocytes compared to the ethanol and water extracts. The flavonoids demonstrated higher cytokine/chemokine inhibition than alkaloids, with the prenylated flavanones (sophoraflavanone G, leachianone A) led to the highest suppression. Flavonoids exerted anti-inflammatory effects via the extracellular signal-regulated kinase, p38, activator protein-1, and nuclear factor-κB signaling pathways. In the IVPT, prenylation of the flavanone skeleton significantly promoted skin absorption from 0.01 to 0.22 nmol/mg (sophoraflavanone G vs. eriodictyol). Further methoxylation of a prenylated flavanone (leachianone A) elevated skin absorption to 2.65 nmol/mg. Topical leachianone A reduced the epidermal thickness in IMQ-treated mice by 47%, and inhibited cutaneous scaling and cytokine/chemokine overexpression at comparable levels to a commercial betamethasone product. Thus, prenylation and methoxylation of S. flavescens flavanones may enable the design of novel antipsoriatic agents.
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Affiliation(s)
- Chwan-Fwu Lin
- Department of Cosmetic Science, Chang Gung University of Science and Technology, Taoyuan, Taiwan
- Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ming-Hsien Lin
- Department of Dermatology, Chi Mei Medical Center, Tainan, Taiwan
| | - Chi-Feng Hung
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
- PhD Program in Pharmaceutical Biotechnology, Fu Jen Catholic University, New Taipei City, Taiwan
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Abdullah Alshetaili
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia
| | - Yung-Fong Tsai
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cai-Ling Jhong
- Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan
| | - Jia-You Fang
- Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan
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Ming-Xin Guo MM, Wu X, Feng YF, Hu ZQ. Research Progress on the Structural Modification of Magnolol and Honokiol and the Biological Activities of Their Derivatives. Chem Biodivers 2023; 20:e202300754. [PMID: 37401658 DOI: 10.1002/cbdv.202300754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/04/2023] [Accepted: 07/04/2023] [Indexed: 07/05/2023]
Abstract
Magnolol and Honokiol are the primary active components that have been identified and extracted from Magnolia officinalis, and several investigations have demonstrated that they have significant pharmacological effects. Despite their therapeutic benefits for a wide range of illnesses, research on and the implementation of these compounds have been hindered by their poor water solubility and low bioavailability. Researchers are continually using chemical methods to alter their structures to make them more effective in treating and preventing diseases. Researchers are also continuously developing derivative drugs with high efficacy and few adverse effects. This article summarizes and analyzes derivatives with significant biological activities reported in recent research obtained by structural modification. The modification sites have mainly focused on the phenolic hydroxy groups, benzene rings, and diene bonds. Changes to the allyl bisphenol structure will result in unexpected benefits, including high activity, low toxicity, and good bioavailability. Furthermore, alongside earlier experimental research in our laboratory, the structure-activity relationships of magnolol and honokiol were preliminarily summarized, providing experimental evidence for improving their development and utilization.
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Affiliation(s)
- M M Ming-Xin Guo
- Department of pharmacy, the Affiliated Yixing Hospital of Jiangsu University, Wuxi, Yixing, 214200, China
- New Drug Research and Development Center, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Xia Wu
- New Drug Research and Development Center, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Yi-Fan Feng
- New Drug Research and Development Center, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Zhi-Qiang Hu
- Department of pharmacy, the Affiliated Yixing Hospital of Jiangsu University, Wuxi, Yixing, 214200, China
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Liu HM, Cheng MY, Xun MH, Zhao ZW, Zhang Y, Tang W, Cheng J, Ni J, Wang W. Possible Mechanisms of Oxidative Stress-Induced Skin Cellular Senescence, Inflammation, and Cancer and the Therapeutic Potential of Plant Polyphenols. Int J Mol Sci 2023; 24:ijms24043755. [PMID: 36835162 PMCID: PMC9962998 DOI: 10.3390/ijms24043755] [Citation(s) in RCA: 62] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023] Open
Abstract
As the greatest defense organ of the body, the skin is exposed to endogenous and external stressors that produce reactive oxygen species (ROS). When the antioxidant system of the body fails to eliminate ROS, oxidative stress is initiated, which results in skin cellular senescence, inflammation, and cancer. Two main possible mechanisms underlie oxidative stress-induced skin cellular senescence, inflammation, and cancer. One mechanism is that ROS directly degrade biological macromolecules, including proteins, DNA, and lipids, that are essential for cell metabolism, survival, and genetics. Another one is that ROS mediate signaling pathways, such as MAPK, JAK/STAT, PI3K/AKT/mTOR, NF-κB, Nrf2, and SIRT1/FOXO, affecting cytokine release and enzyme expression. As natural antioxidants, plant polyphenols are safe and exhibit a therapeutic potential. We here discuss in detail the therapeutic potential of selected polyphenolic compounds and outline relevant molecular targets. Polyphenols selected here for study according to their structural classification include curcumin, catechins, resveratrol, quercetin, ellagic acid, and procyanidins. Finally, the latest delivery of plant polyphenols to the skin (taking curcumin as an example) and the current status of clinical research are summarized, providing a theoretical foundation for future clinical research and the generation of new pharmaceuticals and cosmetics.
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Affiliation(s)
- Hui-Min Liu
- School of Perfume & Aroma and Cosmetics, Shanghai Institute of Technology, Shanghai 201418, China
- Engineering Research Center of Perfume & Aroma and Cosmetics, Ministry of Education, Shanghai 201418, China
| | - Ming-Yan Cheng
- School of Perfume & Aroma and Cosmetics, Shanghai Institute of Technology, Shanghai 201418, China
| | - Meng-Han Xun
- School of Perfume & Aroma and Cosmetics, Shanghai Institute of Technology, Shanghai 201418, China
| | - Zhi-Wei Zhao
- School of Perfume & Aroma and Cosmetics, Shanghai Institute of Technology, Shanghai 201418, China
| | - Yun Zhang
- School of Perfume & Aroma and Cosmetics, Shanghai Institute of Technology, Shanghai 201418, China
| | - Wei Tang
- School of Perfume & Aroma and Cosmetics, Shanghai Institute of Technology, Shanghai 201418, China
| | - Jun Cheng
- School of Perfume & Aroma and Cosmetics, Shanghai Institute of Technology, Shanghai 201418, China
| | - Jia Ni
- School of Perfume & Aroma and Cosmetics, Shanghai Institute of Technology, Shanghai 201418, China
| | - Wei Wang
- School of Perfume & Aroma and Cosmetics, Shanghai Institute of Technology, Shanghai 201418, China
- Engineering Research Center of Perfume & Aroma and Cosmetics, Ministry of Education, Shanghai 201418, China
- Correspondence: ; Tel.: +86-18918830550
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Li Y, Liang C, Zhou X. The application prospects of honokiol in dermatology. Dermatol Ther 2022; 35:e15658. [PMID: 35726011 PMCID: PMC9541939 DOI: 10.1111/dth.15658] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 06/16/2022] [Indexed: 11/27/2022]
Abstract
Honokiol is one of the natural extracts of Magnolia officinalis. It is a small molecule, lipophilic compound with extensive biological effects. It has been used in the treatment of multisystem diseases, including digestive diseases, endocrine diseases, nervous system diseases, and various tumors. This paper reviews the biological effects of honokiol on the treatment of skin diseases in recent years, including anti-microbial, anti-oxidant, anti-inflammatory, anti-tumor, anti-fibrosis, anti-allergy, photo-protection, and immunomodulation. Most current researches are focused on the effects of anti-melanoma and photo-protection. Therefore, we summarized the specific mechanisms about these two effects. On the other side of treating skin diseases, the advantages of topical drugs cannot be replaced. As a small molecule fat-soluble compound, honokiol is suitable for external use. We reviewed the advantages and disadvantages of the topical mixed cream and various improved methods. These improvements include physical and chemical penetration enhancers, drug carriers, and chemical derivatives. In conclusion, honokiol has a wide range of effects, and its topical preparation provides a safe and effective way for treating skin diseases.
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Affiliation(s)
- Yao Li
- Institute of Dermatology and Venereology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu, China
| | - Chenglin Liang
- Institute of Dermatology and Venereology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu, China
| | - Xiyuan Zhou
- Institute of Dermatology and Venereology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu, China
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Zhao J, Gao P, Mu C, Ning J, Deng W, Ji D, Sun H, Zhang X, Yang X. Preparation and Evaluation of Novel Supersaturated Solid Dispersion of Magnolol : Theme: Advancements in Amorphous Solid Dispersions to Improve Bioavailability. AAPS PharmSciTech 2022; 23:97. [PMID: 35332440 DOI: 10.1208/s12249-022-02251-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 03/10/2022] [Indexed: 11/30/2022] Open
Abstract
This article aimed to design a new type of supersaturated solid dispersion (NS-SD) loaded with Magnolol (Mag) to raise the oral bioavailability in rats. In the light of the solubility parameters, phase solubility experiments, inhibition precipitation experiment, and in vitro release experiment, Plasdone-630 (PS-630) was selected as the optimum carrier. In addition, Mag-NS-SD was prepared by adding Monoglyceride (MG) and Lecithin High Potency (LHP) into the Mag-S-SD (Mag:PS-630 = 1:3), so as to reduce the dosage of carrier and improve the release rate. Using central composite design of response surface method, the prescription was further optimized. As the optimized condition was Mag:PS-630: MG: LHP = 1:3:0.8:0.266, the drug release rate was the fastest. Besides, after 45 min, the release rate was nearly 100%. The constructed Mag-S-SD and Mag-NS-SD were characterized by powder X-ray diffraction and infrared absorption spectrum. The XRD patterns of Mag-S-SD and Mag-NS-SD indicated that all APIs were amorphous. The IR spectra of Mag-S-SD and Mag-NS-SD demonstrated the existence of hydrogen bonding in the systems. Furthermore, in vivo pharmacokinetic study in rats revealed that compared with Mag and Mag-S-SD, Mag-NS-SD significantly increased the bioavailability (the relative bioavailability was 213.69% and 142.37%, separately). In this study, Mag-NS-SD was successfully prepared, which could improve the oral bioavailability and may increase the clinical application.
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Tseng CH, Lin CF, Aljuffali IA, Huang JR, Yang SH, Fang JY. The effectiveness of synthetic methoxylated isoflavones in delivering to the skin and alleviating psoriasiform lesions via topical absorption. Int J Pharm 2022; 617:121629. [PMID: 35245633 DOI: 10.1016/j.ijpharm.2022.121629] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 02/22/2022] [Accepted: 02/27/2022] [Indexed: 11/28/2022]
Abstract
This study was conducted to appraise the possible potential of synthetic isoflavones (SIFs) on psoriasis treatment. A practical and easy-to-operate approach was employed in synthesizing a series of SIFs, considering that acquiring flavonoids from natural resources is usually expensive, time-consuming, and non-eco-friendly. Seven SIFs derived from daidzein were produced with differences in the location of the hydroxyl groups and degree of methoxylation. The in vitro and in vivo skin absorption of topically applied SIFs was estimated. Further, keratinocytes (HaCaT) were employed as the model to investigate the anti-inflammatory activity of the isoflavones. The lipophilicity was increased from SIF-1 to -7. Noteworthily, there was a parabolic relationship between lipophilicity and skin absorption, with SIF-5 (4',7-dihydroxyisoflavone, daidzein) and SIF-6 (7-hydroxy-3',4'-dimethoxyisoflavone, cladrin) demonstrating the highest retention in pig skin. The methoxylated isoflavone SIF-5 showed the greatest permeation into barrier-deficient skin among the compounds tested, with a 6- and 8-fold increase after lipid and protein removal. The cell-based study exhibited the capability of SIFs to restrain the overexpressed IL-6, IL-8, and CXCL1 in stimulated HaCaT. The therapeutic index (TI) predicted the potential candidates of SIF-5 and SIF-6 for topical application to treat psoriatic inflammation. The imiquimod (IMQ)-driven psoriasiform murine model manifested the inhibition of hyperplasia and immune cell infiltration by topically administered SIF-5 and SIF-6. The epidermal thickness of IMQ-treated skin was decreased from 172 to 40 μm by both isoflavones. This effect was comparable with that of betamethasone, the positive control. The topical treatment of SIF-6 significantly reduced cytokine/chemokine upregulation by IMQ. The methoxylated isoflavone with dramatic anti-inflammatory activity is promising for the development of an antipsoriatic agent.
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Affiliation(s)
- Chih-Hua Tseng
- Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Pharmacy, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Chwan-Fwu Lin
- Department of Cosmetic Science, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan
| | - Ibrahim A Aljuffali
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Jhao-Rong Huang
- Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan
| | - Sien-Hung Yang
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
| | - Jia-You Fang
- Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan; Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan.
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Ezzeldeen Y, Swidan S, ElMeshad A, Sebak A. Green Synthesized Honokiol Transfersomes Relieve the Immunosuppressive and Stem-Like Cell Characteristics of the Aggressive B16F10 Melanoma. Int J Nanomedicine 2021; 16:5693-5712. [PMID: 34465990 PMCID: PMC8402984 DOI: 10.2147/ijn.s314472] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/17/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Honokiol (HK) is a natural bioactive compound with proven antineoplastic properties against melanoma. However, it shows very low bioavailability when administered orally. Alternatively, topical administration may offer a promising route. The objective of the current study was to fabricate HK transfersomes (HKTs) for topical treatment of melanoma. As an ultradeformable carrier system, transfersomes can overcome the physiological barriers to topical treatment of melanoma: the stratum corneum and the anomalous tumor microenvironment. Moreover, the immunomodulatory and stemness-regulation roles of HKTs were the main interest of this study. METHODS TFs were prepared using the modified scalable heating method. A three-factor, three-level Box-Behnken design was utilized for the optimization of the process and formulation variables. Intracellular uptake and cytotoxicity of HKTs were evaluated in nonactivated and stromal cell-activated B16F10 melanoma cells to investigate the influence of the complex tumor microenvironment on the efficacy of HK. Finally, ELISA and Western blot were performed to evaluate the expression levels of TGF-β and clusters of differentiation (CD47 and CD133, respectively). RESULTS The optimized formula exhibited a mean size of 190 nm, highly negative surface charge, high entrapment efficiency, and sustained release profile. HKTs showed potential to alleviate the immunosuppressive characteristics of B16F10 melanoma in vitro via downregulation of TGF-β signaling. In addition, HKTs reduced expression of the "do not eat me" signal - CD47. Moreover, HKTs possessed additional interesting potential to reduce the expression of the stem-like cell marker CD133. These outcomes were boosted upon combination with metformin, an antihyperglycemic drug recently reported to possess different functions in cancer, while combination with collagenase, an extracellular matrix-depleting enzyme, produced detrimental effects. CONCLUSION HKTs represent a promising scalable formulation for treatment of the aggressive B16F10 melanoma, which is jam-packed with immunosuppressive and stem-like cell markers.
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Affiliation(s)
- Yasmeen Ezzeldeen
- Department of Pharmaceutics, Faculty of Pharmacy, The British University in Egypt (BUE), El-Sherouk City, Cairo, 11837, Egypt
| | - Shady Swidan
- Department of Pharmaceutics, Faculty of Pharmacy, The British University in Egypt (BUE), El-Sherouk City, Cairo, 11837, Egypt
- The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt
| | - Aliaa ElMeshad
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
- Department of Bio Nano, Faculty of Nanotechnology for Postgraduate Studies, Cairo University, El-Sheikh Zayed, Giza, 12588, Egypt
| | - Aya Sebak
- Department of Pharmaceutical Technology, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo, Egypt
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Guo JW, Cheng YP, Liu CY, Thong HY, Lo Y, Wu CY, Jee SH. Magnolol may contribute to barrier function improvement on imiquimod-induced psoriasis-like dermatitis animal model via the downregulation of interleukin-23. Exp Ther Med 2021; 21:448. [PMID: 33747183 PMCID: PMC7967813 DOI: 10.3892/etm.2021.9876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 09/16/2020] [Indexed: 12/12/2022] Open
Abstract
Psoriasis is a chronic, recurrent, immune-mediated disease involving the skin and joints. Epidermal hyperproliferation, abnormal keratinocyte differentiation, angiogenesis with blood vessel dilatation, and excess T helper type-1 (Th-1) and Th-17 cell infiltration are the main histopathological features of psoriasis. Magnolol is a polyphenolic compound that exerts its biological properties through a variety of mechanisms such as the NF-κB/MAPK, Nrf2/HO-1 and PI3K/Akt pathways. Magnolol has been demonstrated to exert a number of therapeutic effects on dermatological processes, including acting as an anti-inflammation, antiproliferation and antioxidation agent. However, few studies have been published on the effect of magnolol on psoriasis. Therefore, the present study aimed to elucidate the mechanism of action of magnolol on psoriasis. BALB/c mice were treated topically with imiquimod (IMQ) to induce psoriasis-like dermatitis, and were randomly assigned to the control, vehicle control, low- and high-dose magnolol, and 0.25% desoximetasone ointment treatment groups in order to investigate skin barrier function, any changes in the levels of cytokines and for the histological assessment. High doses of magnolol were indicated to be able to improve the barrier function following IMQ-induced barrier disruption. Magnolol activated peroxisome proliferator-activated receptor-γ, and also significantly inhibited the protein expression of interleukin (IL)-23, IL-1β, IL-6, tumor necrosis factor-α and interferon-γ. However, administering a high dose of magnolol did not lead to any improvement in the clinical and pathological features of the psoriasis severity Taken together, these results demonstrated that downregulation of IL-23 may contribute to barrier function improvement in a psoriatic skin model.
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Affiliation(s)
- Jiun-Wen Guo
- Department of Medical Research, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C.,College of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan, R.O.C
| | - Yu-Pin Cheng
- Department of Dermatology, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C
| | - Chih-Yi Liu
- Division of Pathology, Sijhih Cathay General Hospital, New Taipei City 22174, Taiwan, R.O.C
| | - Haw-Yueh Thong
- Department of Dermatology, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan, R.O.C
| | - Yang Lo
- Department of Dermatology, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C
| | - Chen-Yu Wu
- Department of Dermatology, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C
| | - Shiou-Hwa Jee
- Department of Dermatology, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C
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Chen CY, Fang JY, Chen CC, Chuang WY, Leu YL, Ueng SH, Wei LS, Cheng SF, Hsueh C, Wang TH. 2-O-Methylmagnolol, a Magnolol Derivative, Suppresses Hepatocellular Carcinoma Progression via Inhibiting Class I Histone Deacetylase Expression. Front Oncol 2020; 10:1319. [PMID: 32850418 PMCID: PMC7431949 DOI: 10.3389/fonc.2020.01319] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 06/24/2020] [Indexed: 12/24/2022] Open
Abstract
Magnolia officinalis is widely used in Southeast Asian countries for the treatment of fever, headache, diarrhea, and stroke. Magnolol is a phenolic compound extracted from M. officinalis, with proven antibacterial, antioxidant, anti-inflammatory, and anticancer activities. In this study, we modified magnolol to synthesize a methoxylated derivative, 2-O-methylmagnolol (MM1), and investigated the use of MM1, and magnolol in the treatment of liver cancer. We found that both magnolol and MM1 exhibited inhibitory effects on the growth, migration, and invasion of hepatocellular carcinoma (HCC) cell lines and halted the cell cycle at the G1 phase. MM1 also demonstrated a substantially better tumor-suppressive effect than magnolol. Further analysis suggested that by inhibiting class I histone deacetylase expression in HCC cell lines, magnolol and MM1 induced p21 expression and p53 activation, thereby causing cell cycle arrest and inhibiting HCC cell growth, migration, and invasion. Subsequently, we verified the significant tumor-suppressive effects of magnolol and MM1 in an animal model. Collectively, these findings demonstrate the anti-HCC activities of magnolol and MM1 and their potential for clinical use.
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Affiliation(s)
- Chi-Yuan Chen
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.,Graduate Institute of Health Industry Technology, Research Center for Food and Cosmetic Safety, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan City, Taiwan
| | - Jia-You Fang
- Graduate Institute of Natural Products, Chang Gung University, Taoyuan City, Taiwan.,Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
| | - Chin-Chuan Chen
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.,Graduate Institute of Natural Products, Chang Gung University, Taoyuan City, Taiwan
| | - Wen-Yu Chuang
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Taoyuan City, Taiwan
| | - Yann-Lii Leu
- Graduate Institute of Natural Products, Chang Gung University, Taoyuan City, Taiwan.,Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan City, Taiwan.,Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
| | - Shir-Hwa Ueng
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Taoyuan City, Taiwan
| | - Li-Shan Wei
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
| | - Shu-Fang Cheng
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.,Graduate Institute of Natural Products, Chang Gung University, Taoyuan City, Taiwan
| | - Chuen Hsueh
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.,Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Taoyuan City, Taiwan
| | - Tong-Hong Wang
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.,Graduate Institute of Health Industry Technology, Research Center for Food and Cosmetic Safety, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan City, Taiwan.,Department of Hepato-Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
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11
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Singha SK, Muhammad I, Ibrahim MA, Wang M, Ashpole NM, Shariat-Madar Z. 4- O-Methylhonokiol Influences Normal Cardiovascular Development in Medaka Embryo. Molecules 2019; 24:molecules24030475. [PMID: 30699965 PMCID: PMC6384692 DOI: 10.3390/molecules24030475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 01/24/2019] [Accepted: 01/27/2019] [Indexed: 11/21/2022] Open
Abstract
Although 4-O-Methylhonokiol (MH) effects on neuronal and immune cells have been established, it is still unclear whether MH can cause a change in the structure and function of the cardiovascular system. The overarching goal of this study was to evaluate the effects of MH, isolated from Magnolia grandiflora, on the development of the heart and vasculature in a Japanese medaka model in vivo to predict human health risks. We analyzed the toxicity of MH in different life-stages of medaka embryos. MH uptake into medaka embryos was quantified. The LC50 of two different exposure windows (stages 9–36 (0–6 days post fertilization (dpf)) and 25–36 (2–6 dpf)) were 5.3 ± 0.1 μM and 9.9 ± 0.2 μM. Survival, deformities, days to hatch, and larval locomotor response were quantified. Wnt 1 was overexpressed in MH-treated embryos indicating deregulation of the Wnt signaling pathway, which was associated with spinal and cardiac ventricle deformities. Overexpression of major proinflammatory mediators and biomarkers of the heart were detected. Our results indicated that the differential sensitivity of MH in the embryos was developmental stage-specific. Furthermore, this study demonstrated that certain molecules can serve as promising markers at the transcriptional and phenotypical levels, responding to absorption of MH in the developing embryo.
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Affiliation(s)
- Santu K Singha
- Department of Biomolecular Sciences, Division of Pharmacology, University of Mississippi, University, MS 38677, USA.
| | - Ilias Muhammad
- The National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677, USA.
| | - Mohamed Ali Ibrahim
- The National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677, USA.
- Chemistry of Natural Compounds Department, National Research Centre, Dokki-Giza 12622, Egypt.
| | - Mei Wang
- The National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677, USA.
| | - Nicole M Ashpole
- Department of Biomolecular Sciences, Division of Pharmacology, University of Mississippi, University, MS 38677, USA.
- The National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677, USA.
| | - Zia Shariat-Madar
- Department of Biomolecular Sciences, Division of Pharmacology, University of Mississippi, University, MS 38677, USA.
- The National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677, USA.
- Light Microscopy Core, University of Mississippi, University, MS 38677, USA.
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12
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Fang JY, Huang TH, Hung CF, Huang YL, Aljuffali IA, Liao WC, Lin CF. Derivatization of honokiol by integrated acetylation and methylation for improved cutaneous delivery and anti-inflammatory potency. Eur J Pharm Sci 2018; 114:189-198. [PMID: 29241737 DOI: 10.1016/j.ejps.2017.12.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 12/01/2017] [Accepted: 12/08/2017] [Indexed: 01/17/2023]
Abstract
A set of honokiol derivatives was synthesized to evaluate skin permeation and bioactivity. The reaction for derivatization included acetylation and methylation. The anti-inflammatory activity against neutrophils and macrophages was examined. The experimental setup for the assessment of cutaneous absorption was the in vitro Franz diffusion assembly. Honokiol and its derivatives significantly downregulated superoxide anion and elastase production in neutrophils, with honokiol showing the greatest inhibition. All derivatives could be completely hydrolyzed to the parent compounds after passing into the skin. The skin deposition of honokiol at an infinite dose (3mM) was 0.33nmol/mg 4'-O-acetylhonokiol (AH), and 2,4'-diacetylhonokiol (DAH) exhibited comparable or less absorption than honokiol. The integrated acetylation and methylation (2-O-acetyl-4'-O-methylhonokiol, AMH) led to a 10.5-fold improvement of absorption compared to honokiol. AMH was advantageous for the targeted cutaneous treatment due to the high skin deposition and minimal penetration across the skin (8.40nmol/cm2 compared to 93.49nmol/cm2 for honokiol). The predicted therapeutic index for superoxide and interleukin (IL)-6 inhibition was much higher for topically applied AMH than for the other penetrants tested. The total polarity surface and hydrogen bond acceptor number calculated by molecular modeling were the parameters used to anticipate the cutaneous absorption. Our data suggest that AMH is a potent and safe candidate for cutaneous inflammation therapy.
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Affiliation(s)
- Jia-You Fang
- Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| | - Tse-Hung Huang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan; School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan; School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
| | - Chi-Feng Hung
- School of Medicine, Fu Jen Catholic University, Hsinchuang, New Taipei City, Taiwan
| | - Yu-Ling Huang
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan; Department of Cosmetic Science, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan
| | - Ibrahim A Aljuffali
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Wei-Chun Liao
- Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan
| | - Chwan-Fwu Lin
- Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; Department of Cosmetic Science, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.
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13
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Zhang YM, Zhu L, Zhao XL, Chen H, Kang HX, Zhao JL, Wan MH, Li J, Zhu L, Tang WF. Optimal timing for the oral administration of Da-Cheng-Qi decoction based on the pharmacokinetic and pharmacodynamic targeting of the pancreas in rats with acute pancreatitis. World J Gastroenterol 2017; 23:7098-7109. [PMID: 29093618 PMCID: PMC5656457 DOI: 10.3748/wjg.v23.i39.7098] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 08/27/2017] [Accepted: 09/13/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To identify the optimal oral dosing time of Da-Cheng-Qi decoction (DCQD) in rats with acute pancreatitis (AP) based on the pharmacokinetic and pharmacodynamic parameters.
METHODS First, 24 male Sprague-Dawley rats were divided into a sham-operated group [NG(a)] and three model groups [4hG(a), 12hG(a) and 24hG(a)]. The NG(a) and model groups were administered DCQD (10 g/kg.BW) intragastrically at 4 h, 4 h, 12 h and 24 h, respectively, after AP models induced by 3% sodium taurocholate. Plasma samples were collected from the tails at 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after a single dosing with DCQD. Plasma and pancreatic tissue concentrations of the major components of DCQD were determined by high-performance liquid chromatography tandem mass spectroscopy. The pharmacokinetic parameters and serum amylase were detected and compared. Second, rats were divided into a sham-operated group [NG(b)] and three treatment groups [4hG(b), 12hG(b) and 24hG(b)] with three corresponding control groups [MG(b)s]. Blood and pancreatic tissues were collected 24 h after a single dosing with DCQD. Serum amylase, inflammatory cytokines and pathological scores of pancreatic tissues were detected and compared.
RESULTS The concentrations of emodin, naringin, honokiol, naringenin, aloe-emodin, chrysophanol and rheochrysidin in the 12hG(a) group were higher than those in the 4hG(a) group in the pancreatic tissues (P < 0.05). The area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration values (AUC0→t) for rhein, chrysophanol, magnolol and naringin in the 12hG(a) group were larger than those in the 4hG(a) or 24hG(a) groups. The 12hG(a) group had a higher Cmax than the other two model groups. The IL-10 levels in the 12hG(b) and 24hG(b) groups were higher than in the MG(b)s (96.55 ± 7.84 vs 77.46 ± 7.42, 251.22 ± 16.15 vs 99.72 ± 4.7 respectively, P < 0.05), while in the 24hG(b) group, the IL-10 level was higher than in the other two treatment groups (251.22 ± 16.15 vs 154.41 ± 12.09/96.55 ± 7.84, P < 0.05). The IL-6 levels displayed a decrease in the 4hG(b) and 12hG(b) groups compared to the MG(b)s (89.99 ± 4.61 vs 147.91 ± 4.36, 90.82 ± 5.34 vs 171.44 ± 13.43, P < 0.05).
CONCLUSION Late-time dosing may have higher concentrations of the most major components of DCQD, with better pharmacokinetics and pharmacodynamics of anti-inflammation than early-time dosing, which showed the late time to be the optimal dosing time of DCQD for AP.
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Affiliation(s)
- Yu-Mei Zhang
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lin Zhu
- Digestive System Department, Sichuan Integrative Medicine Hospital, Chengdu 610041, Sichuan Province, China
| | - Xian-Lin Zhao
- Department of Integrative Medicine, Chengdu Integrated TCM and Western Medicine Hospital, Chengdu 610016, Sichuan Province, China
| | - Huan Chen
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hong-Xin Kang
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jian-Lei Zhao
- Department of Pharmacology, School of Preclinical and Forensic Medicine, West China Medical Center, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Mei-Hua Wan
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Juan Li
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lv Zhu
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wen-Fu Tang
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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14
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Honokiol suppresses formyl peptide-induced human neutrophil activation by blocking formyl peptide receptor 1. Sci Rep 2017; 7:6718. [PMID: 28751674 PMCID: PMC5532207 DOI: 10.1038/s41598-017-07131-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 06/23/2017] [Indexed: 11/24/2022] Open
Abstract
Formyl peptide receptor 1 (FPR1) mediates bacterial and mitochondrial N-formyl peptides-induced neutrophil activation. Therefore, FPR1 is an important therapeutic target for drugs to treat septic or sterile inflammatory diseases. Honokiol, a major bioactive compound of Magnoliaceae plants, possesses several anti-inflammatory activities. Here, we show that honokiol exhibits an inhibitory effect on FPR1 binding in human neutrophils. Honokiol inhibited superoxide anion generation, reactive oxygen species formation, and elastase release in bacterial or mitochondrial N-formyl peptides (FPR1 agonists)-activated human neutrophils. Adhesion of FPR1-induced human neutrophils to cerebral endothelial cells was also reduced by honokiol. The receptor-binding results revealed that honokiol repressed FPR1-specific ligand N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein binding to FPR1 in human neutrophils, neutrophil-like THP-1 cells, and hFPR1-transfected HEK293 cells. However, honokiol did not inhibit FPR2-specific ligand binding to FPR2 in human neutrophils. Furthermore, honokiol inhibited FPR1 agonist-induced calcium mobilization as well as phosphorylation of p38 MAPK, ERK, and JNK in human neutrophils. In conclusion, our data demonstrate that honokiol may have therapeutic potential for treating FPR1-mediated inflammatory diseases.
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15
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Liu KS, Huang TH, Aljuffali IA, Chen EL, Wang JJ, Fang JY. Exploring the structure-permeation relationship of topical tricyclic antidepressants used for skin analgesia. Int J Pharm 2017; 523:386-397. [DOI: 10.1016/j.ijpharm.2017.03.048] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 03/06/2017] [Accepted: 03/19/2017] [Indexed: 12/17/2022]
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16
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Wang TH, Chan CW, Fang JY, Shih YM, Liu YW, Wang TCV, Chen CY. 2-O-Methylmagnolol upregulates the long non-coding RNA, GAS5, and enhances apoptosis in skin cancer cells. Cell Death Dis 2017; 8:e2638. [PMID: 28252643 PMCID: PMC5386561 DOI: 10.1038/cddis.2017.66] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 01/21/2017] [Accepted: 01/24/2017] [Indexed: 12/11/2022]
Abstract
Magnolol, a hydroxylated biphenol compound isolated from the bark of Magnolia officinalis, has been shown to exhibit anti-proliferative effect in various cancer cells, including skin cancer cells. Methoxylation of magnolol appears to improve its anti-inflammatory activity, yet the effect of this modification on the agent's antitumor activity remains unknown. In this work, we report that 2-O-methylmagnolol (MM1) displays improved antitumor activity against skin cancer cells compared to magnolol both in vitro and in vivo. The increased antitumor activity of MM1 appears to correlate with its increased ability to induce apoptosis. DNA microarray and network pathway analyses suggest that MM1 affects certain key factors involved in regulating apoptosis and programmed cell death. Interestingly, the level of the long non-coding (lnc) RNA of growth arrest-specific 5 (GAS5) was increased in MM1-treated cells, and inhibition of lncRNA GAS5 inhibited MM1-induced apoptosis. Conversely, overexpression of lncRNA GAS5 inhibited cell proliferation and promoted cell apoptosis in skin cancer cells. The expression of lncRNA GAS5 in the skin cancer tissues was found to be lower than that in the adjacent normal tissues in a majority of patients. Taken together, our findings suggest that MM1 has improved antitumor activity in skin cancer cells, and that this is due, at least in part, to the upregulation of lncRNA GAS5 and the enhancement of apoptosis.
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Affiliation(s)
- Tong-Hong Wang
- Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Kwei-Shan, Tao-Yuan 333, Taiwan.,Tissue Bank, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan
| | - Chieh-Wen Chan
- Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Kwei-Shan, Tao-Yuan 333, Taiwan
| | - Jia-You Fang
- Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan.,Department of Anesthesiology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan
| | - Ya-Min Shih
- Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Kwei-Shan, Tao-Yuan 333, Taiwan
| | - Yi-Wen Liu
- Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Kwei-Shan, Tao-Yuan 333, Taiwan
| | - Tzu-Chien V Wang
- Tissue Bank, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan.,Department of Molecular and Cellular Biology, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan
| | - Chi-Yuan Chen
- Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Kwei-Shan, Tao-Yuan 333, Taiwan.,Tissue Bank, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan
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17
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Topically applied mesoridazine exhibits the strongest cutaneous analgesia and minimized skin disruption among tricyclic antidepressants: The skin absorption assessment. Eur J Pharm Biopharm 2016; 105:59-68. [DOI: 10.1016/j.ejpb.2016.05.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 05/29/2016] [Accepted: 05/30/2016] [Indexed: 01/16/2023]
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18
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Lin CF, Hung CF, Aljuffali IA, Huang YL, Liao WC, Fang JY. Methylation and Esterification of Magnolol for Ameliorating Cutaneous Targeting and Therapeutic Index by Topical Application. Pharm Res 2016; 33:2152-67. [PMID: 27233503 DOI: 10.1007/s11095-016-1953-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 05/23/2016] [Indexed: 12/16/2022]
Abstract
PURPOSE As a continuing effort to elucidate the impact of structure modification upon cutaneous absorption behavior, we attempted to assess the skin permeation of magnolol by methylation and acetylation. METHODS Diacetylmagnolol and 2-O-acetyl-2'-O-methylmagnolol (AMM) were designed and synthesized in this study. The anti-inflammatory activity against stimulated neutrophils and keratinocytes was evaluated to check the bioactivity of the analogues. In vitro skin absorption was investigated using nude mouse and pig skin models at both equimolar and saturated doses. RESULTS Magnolol generally showed the strongest anti-inflammatory potential, followed by diacetylmagnolol and AMM. The antibacterial activity was observed for magnolol and diacetylmagnolol but not AMM. Diacetylmagnolol and AMM could be partly hydrolyzed to magnolol and 2-O-methylmagnolol after entering the skin. The hydrolysis rate of diacetylmagnolol was faster than that of AMM. The lipophilicity played a crucial role in cutaneous absorption, with AMM exhibiting the highest skin deposition. AMM accumulation within nude mouse skin was about 2.5-fold greater than that of magnolol and diacetylmagnolol. On the other hand, the transdermal penetration across the skin was lessened by methylation and esterification. This led to a superior skin targeting of AMM. Although the pharmacological activity of AMM was low, the high skin uptake and bioconversion into 2-O-methylmagnolol in the skin contributed to a greater therapeutic index (TI, skin deposition x inflammatory inhibition percentage) compared to the others. The accumulation of AMM in the hair follicles was 77.12 nmol/cm(2), which was significantly greater than that with magnolol (44.84 nmol/cm(2)) and diacetylmagnolol (26.96 nmol/cm(2)). The synthetic analogues were tolerable to the nude mouse skin. CONCLUSIONS Based on the experimental results, we may suggest topically applied AMM as a potent and safe candidate for the treatment of cutaneous inflammation.
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Affiliation(s)
- Chwan-Fwu Lin
- Department of Cosmetic Science, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan
| | - Chi-Feng Hung
- School of Medicine, Fu Jen Catholic University, Hsinchuang, New Taipei City, Taiwan
| | - Ibrahim A Aljuffali
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Yu-Ling Huang
- Department of Cosmetic Science, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan
- National Research Institute of Chinese Medicine, Taipei, Taiwan
| | - Wei-Chun Liao
- Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan
| | - Jia-You Fang
- Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.
- Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan, Taoyuan, 333, Taiwan.
- Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan.
- Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
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19
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Chen PJ, Wang YL, Kuo LM, Lin CF, Chen CY, Tsai YF, Shen JJ, Hwang TL. Honokiol suppresses TNF-α-induced neutrophil adhesion on cerebral endothelial cells by disrupting polyubiquitination and degradation of IκBα. Sci Rep 2016; 6:26554. [PMID: 27212040 PMCID: PMC4876378 DOI: 10.1038/srep26554] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 05/05/2016] [Indexed: 11/09/2022] Open
Abstract
Adhesion molecules expressed on cerebral endothelial cells (ECs) mediate leukocyte recruitment and play a significant role in cerebral inflammation. Increased levels of adhesion molecules on the EC surface induce leukocyte infiltration into inflammatory areas and are thus hallmarkers of inflammation. Honokiol, isolated from the Chinese medicinal herb Magnolia officinalis, has various pharmacological activities, including anti-inflammatory effects, yet the nature of honokiol targeting molecules remains to be revealed. Here, we investigated the inhibitory effect of honokiol on neutrophil adhesion and vascular cell adhesion molecule-1 (VCAM-1) expression, which underlie its molecular target, and mechanisms for inactivating nuclear factor κ enhancer binding protein (NF-κB) in mouse cerebral ECs. Honokiol inhibited tumour necrosis factor-α (TNF-α)-induced neutrophil adhesion and VCAM-1 gene expression in cerebral ECs. The inflammatory transcription factor NF-κB was downregulated by honokiol. Honokiol significantly blocked TNF-α-induced NF-κB p65 nuclear translocation and degradation of the proteasome-dependent inhibitor of NF-κB α (IκBα). From docking model prediction, honokiol directly targeted the ubiquitin-ubiquitin interface of Lys48-linked polychains. Moreover, honokiol prevented the TNF-α-induced Lys48-linked polyubiquitination, including IκBα-polyubiquitin interaction. Honokiol has protective anti-inflammatory effects on TNF-α-induced neutrophil adhesion and VCAM-1 gene expression in cerebral ECs, at least in part by directly inhibiting ubiquitination-mediated IκBα degradation and then preventing NF-κB nuclear translocation.
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Affiliation(s)
- Po-Jen Chen
- Graduate Institute of Natural Products, School of Traditional Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.,Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan
| | - Yu-Ling Wang
- Graduate Institute of Natural Products, School of Traditional Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.,Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan
| | - Liang-Mou Kuo
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.,Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
| | - Chwan-Fwu Lin
- Research Center for Industry of Human Ecology and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
| | - Chun-Yu Chen
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.,Department of Anaesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Yung-Fong Tsai
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.,Department of Anaesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Jiann-Jong Shen
- Graduate Institute of Natural Products, School of Traditional Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.,Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan
| | - Tsong-Long Hwang
- Graduate Institute of Natural Products, School of Traditional Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.,Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan.,Research Center for Industry of Human Ecology and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan.,Department of Anaesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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20
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Sheng YL, Xu JH, Shi CH, Li W, Xu HY, Li N, Zhao YQ, Zhang XR. UPLC-MS/MS-ESI assay for simultaneous determination of magnolol and honokiol in rat plasma: application to pharmacokinetic study after administration emulsion of the isomer. JOURNAL OF ETHNOPHARMACOLOGY 2014; 155:1568-1574. [PMID: 25102243 DOI: 10.1016/j.jep.2014.07.052] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 07/13/2014] [Accepted: 07/25/2014] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Magnolia officinalis is one of the commonly used in traditional Chinese medicine for the treatment of fever, chronic bronchitis and stomach ailments. Magnolol and honokiol are isomers with hydroxylated biphenol compound in the extract of Magnolia officinalis. This study aims to determine the isomers in rat plasma and evaluate their pharmacokinetic pattern after administration emulsion. MATERIALS AND METHODS Sprague Dawley male rats received either an intravenous (i.v.25, mg/kg) or oral (50mg/kg) dose of the emulsion of the isomer. A sensitive and specific ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed for the investigation of the pharmacokinetics of magnolol and honokiol in rats. Kaempferol was employed as an internal standard. RESULTS The plasma samples were deproteinized with acetonitrile, the post-treatment samples were analyzed on an Agela C18 column interfaced with a triple quadrupole tandem mass spectrometer in negative electrospray ionization mode. Acetonitrile and 5 mmol/L ammonium acetate buffer solution (65: 35, v/v) was used as the mobile phase at a flow rate of 0.2 mL/min. Following oral administration of emulsion to rats, magnolol attained mean peak plasma concentrations of 426.4 ± 273.8 ng/mL at 1.20 h, whereas honokiol reached peak plasma concentrations of 40.3 ± 30.8 ng/mL at 0.45 h. The absolute bioavailability of magnolol and honokiol is 17.5 ± 9.7% and 5.3 ± 11.7%. By comparison, the AUC0-∞ of magnolol was 5.4 times higher than that of honokiol after intravenous administration, but AUC0-∞ of magnolol was about 18-fold higher than honokiol after oral administration.
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Affiliation(s)
- Yi-Ling Sheng
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Box 51, 103 Wenhua Road, Shenyang 110016, China
| | - Jing-Hua Xu
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Cai-Hong Shi
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Box 51, 103 Wenhua Road, Shenyang 110016, China
| | - Wei Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Box 51, 103 Wenhua Road, Shenyang 110016, China
| | - Hai-Yan Xu
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
| | - Ning Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Box 51, 103 Wenhua Road, Shenyang 110016, China; Key Laboratory of Research and Design of "drug targets based on the Ministry of Education", Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yu-Qing Zhao
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Box 51, 103 Wenhua Road, Shenyang 110016, China; Key Laboratory of Research and Design of "drug targets based on the Ministry of Education", Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xiang-Rong Zhang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Box 51, 103 Wenhua Road, Shenyang 110016, China; Key Laboratory of Research and Design of "drug targets based on the Ministry of Education", Shenyang Pharmaceutical University, Shenyang 110016, China.
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Hung CF, Chen WY, Aljuffali IA, Shih HC, Fang JY. The risk of hydroquinone and sunscreen over-absorption via photodamaged skin is not greater in senescent skin as compared to young skin: nude mouse as an animal model. Int J Pharm 2014; 471:135-45. [PMID: 24858384 DOI: 10.1016/j.ijpharm.2014.05.034] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Revised: 04/14/2014] [Accepted: 05/18/2014] [Indexed: 01/13/2023]
Abstract
Intrinsic aging and photoaging modify skin structure and components, which subsequently change percutaneous absorption of topically applied permeants. The purpose of this study was to systematically evaluate drug/sunscreen permeation via young and senescent skin irradiated by ultraviolet (UV) light. Both young and senescent nude mice were subjected to UVA (10 J/cm(2)) and/or UVB radiation (175 mJ/cm(2)). Physiological parameters, immunohistology, and immunoblotting were employed to examine the aged skin. Hydroquinone and sunscreen permeation was determined by in vitro Franz cell. In vivo skin absorption was documented using a hydrophilic dye, rhodamine 123 (log P=-0.4), as a permeant. UVA exposure induced cyclooxygenase (COX)-2 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) upregulation. Epidermal tight junction (TJ) were degraded by UVA. UVB increased transepidermal water loss (TEWL) from 13 to 24 g/m(2)/h. Hyperplasia and inflammation, but not loss of TJ, were also observed in UVB-treated skin. UVA+UVB- and UVA-irradiated skin demonstrated similar changes in histology and biomarkers. UVA+UVB or UVA exposure increased hydroquinone flux five-fold. A negligible alteration of hydroquinone permeation was shown with UVB exposure. Hydroquinone exhibited a lower penetration through senescent skin than young skin. Both UVA and UVB produced enhancement of oxybenzone flux and skin uptake. However, the amount of increase was less than that of hydroquinone delivery. Photoaging did not augment skin absorption of sunscreens with higher lipophilicity, including avobenzone and ZnO. Exposure to UVA generally increased follicular entrance of these permeants, which showed two- to three-fold greater follicular uptake compared to the untreated group. Photoaging had less impact on drug/sunscreen absorption with more lipophilic permeants. Percutaneous absorption did not increase in skin subjected to both intrinsic and extrinsic aging.
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Affiliation(s)
- Chi-Feng Hung
- School of Medicine, Fu Jen Catholic University, Hsinchuang, New Taipei City, Taiwan
| | - Wei-Yu Chen
- Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Ibrahim A Aljuffali
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hui-Chi Shih
- Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan
| | - Jia-You Fang
- Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.
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22
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Pan TL, Wang PW, Aljuffali IA, Leu YL, Hung YY, Fang JY. Coumarin derivatives, but not coumarin itself, cause skin irritation via topical delivery. Toxicol Lett 2014; 226:173-81. [PMID: 24561300 DOI: 10.1016/j.toxlet.2014.02.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2013] [Revised: 02/09/2014] [Accepted: 02/11/2014] [Indexed: 11/19/2022]
Abstract
Coumarin and its derivatives are widely employed as a fragrance in cosmetics and skin care products. The skin absorption level and possible disruption to the skin by topical application of coumarins were evaluated in this study. Percutaneous absorption of osthole, daphnoretin, coumarin, byakangelicin, and 7-hydroxycoumarin was assessed in vitro and in vivo. Skin physiology measurements and immunoblotting were utilized as methodologies for validating toxicity. The relationship between structures and permeation/toxicity of coumarins was elucidated. Both equimolar concentration and saturated solubility in 30% ethanol were used as the applied dose. Osthole with the most lipophilic characteristic demonstrated the greatest skin accumulation, followed by coumarin and 7-hydroxycoumarin. Coumarin was the permeant with the highest flux across the skin. The trend of in vivo deposition was consistent with that of the in vitro profiles. Skin uptake of osthole was 8-fold higher than that of coumarin. Hair follicles played a significant role as a pathway for transport of coumarin according to the examination of follicular accumulation. Osthole and 7-hydroxycoumarin slightly, but significantly, enhanced transepidermal water loss after a consecutive 5-day administration. The immunoblotting profiling verified the role of proliferation in skin damage induced by osthole, byakangelicin, and 7-hydroxycoumarin. The proliferation-related proteins examined in this work included glucose-regulated proteins, cytokeratin, and C-myc. Daphnoretin and coumarin showed a negligible alteration on protein biomarkers. The experimental results suggested that skin irritation caused by coumarins was mainly derived from the analogs but not from coumarin itself.
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Affiliation(s)
- Tai-Long Pan
- School of Traditional Chinese Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan
| | - Pei-Wen Wang
- School of Traditional Chinese Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan
| | - Ibrahim A Aljuffali
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Yann-Lii Leu
- Natural Products Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan
| | - Yi-Yun Hung
- Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan
| | - Jia-You Fang
- Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan; Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.
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