Honokiol

Last updated
Honokiol
Honokiol.png
Names
Preferred IUPAC name
3′,5-Di(prop-2-en-1-yl)[1,1′-biphenyl]-2,4′-diol
Other names
houpa, hnk
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.122.079 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C18H18O2/c1-3-5-13-7-9-18(20)16(11-13)14-8-10-17(19)15(12-14)6-4-2/h3-4,7-12,19-20H,1-2,5-6H2 Yes check.svgY
    Key: FVYXIJYOAGAUQK-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C18H18O2/c1-3-5-13-7-9-18(20)16(11-13)14-8-10-17(19)15(12-14)6-4-2/h3-4,7-12,19-20H,1-2,5-6H2
    Key: FVYXIJYOAGAUQK-UHFFFAOYAL
  • Oc1ccc(cc1C/C=C)c2cc(ccc2O)C\C=C
Properties
C18H18O2
Molar mass 266.334 g/mol
AppearanceWhite solid
sparingly (25 °C)
Related compounds
Related biphenols
diethylstilbestrol,
dihydroxyeugenol
Related compounds
 magnolol.
4-O-Methylhonokiol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Honokiol is a lignan isolated from the bark, seed cones, and leaves of trees belonging to the genus Magnolia . It has been identified as one of the chemical compounds in some traditional eastern herbal medicines along with magnolol, 4-O-methylhonokiol, and obovatol.

Contents

Biology

Honokiol has been extracted from a number of species of Magnolia native to many regions of the globe. Magnolia grandiflora , which is native to the American South, as well as Mexican species like Magnolia dealbata have been found to be sources of honokiol. [1] Traditionally in Asian medicine, the Magnolia biondii , Magnolia obovata , and Magnolia officinalis are commonly used. [2] The compound itself has a spicy odor.

Because of its physical properties, honokiol can readily cross the blood brain barrier and the blood-cerebrospinal fluid barrier. [1] [3] As a result, honokiol is a potentially potent therapy with high bioavailability.

Chemistry

Structure

Honokiol belongs to a class of neolignan biphenols. As a polyphenol it is relatively small and can interact with cell membrane proteins through intermolecular interactions like hydrogen bonding, hydrophobic interactions, or aromatic pi orbital co-valency. [1] It is hydrophobic and readily dissolved in lipids. It is structurally similar to propofol. [1]

Purification

There are several methods for purifying and isolating honokiol. In nature, honokiol exists with its structural isomer magnolol, which differs from honokiol only by the position of one hydroxyl group. Because of the very similar properties of magnolol and honokiol, purification has often been limited to a HPLC or electromigration. However, methods developed in 2006 by workers in the lab of Jack L. Arbiser, took advantage of the proximity of the phenolic hydroxyl groups in magnolol, which form a protectable diol, to generate a magnolol acetonide (Figure 1), with a subsequent simple purification via flash chromatography over silica. [4]

Figure 1

Magnolol and Honokiol are normally inseparable. Honokiol is easily separable from the protected magnolol acetonide Magnolol purification.svg
Magnolol and Honokiol are normally inseparable. Honokiol is easily separable from the protected magnolol acetonide

Additionally a rapid separation approach was published in the Journal of Chromatography A in 2007. The process uses high-capacity high-speed countercurrent chromatography (high-capacity HSCCC). [5] Through this method honokiol can be separated and purified to above 98% purity with a high yield in under an hour.

History

Traditional medicine

Seed Cone Magnolia-grandiflora-fruto.jpg
Seed Cone

Extracts from the bark or seed cones of the Magnolia tree have been widely used in traditional medicine in China, Korea, and Japan. [2]

Magnolia bark has traditionally been used in Eastern medicine as analgesic and to treat anxiety and mood disorders. [2] [6] In traditional Chinese medicine, magnolia bark is called Houpu and is most commonly taken from two species, Magnolia obovata and Magnolia officinalis . [7] Some Chinese traditional formulas containing Houpu include Banxia Houpu Tang (半夏厚朴丸), Xiao Zhengai Tang, Ping Wei San(平胃散) and Shenmi Tang. [2] Japanese Kampo formulas include, Hange-koboku-to (半夏厚朴湯) and Sai-boku-to (柴朴湯). [2] [6]

Seeds Image-Magnolia hypoleuca 6.JPG
Seeds

Western medical research

Honokiol is a pleiotropic compound, meaning it is able to act on the body through a number of pathways. This diversity of interaction makes it a viable therapy for a number of conditions in the central nervous system, cardiovascular system, and gastrointestinal system. It has been shown to have antitumorigenic, anti-inflammatory, and antioxidant effects as well. [1] [8] [9]

Side effects and contraindications

Research has shown a limited side effect profile for honokiol, and it appears to be well tolerated. However, its antithrombotic effects could cause hemorrhage especially in patients with conditions that would put them at a higher risk like hemophilia or Von Willebrand disease. [1] Additionally, patients already taking anticoagulants should talk to their doctor before taking honokiol supplements. In a 2002 study, researchers induced cell death in fetal rat cortical neurons by directly applying 100μM in vitro. [10]

Pharmacology

Antitumorigenic activities

Honokiol has shown pro-apoptotic effects in melanoma, sarcoma, myeloma, leukemia, bladder, lung, prostate, oral squamous cell carcinoma, [11] in glioblastome multiforme cells [12] and colon cancer cell lines. [13] [14] [15] [16] Honokiol inhibits phosphorylation of Akt, p44/42 mitogen-activated protein kinase (MAPK), and src. Additionally, honokiol regulates the nuclear factor kappa B (NF-κB) activation pathway, an upstream effector of vascular endothelial growth factor (VEGF), MCL1, and cyclooxygenase 2 (COX-2), all significant pro-angiogenic and survival factors. Honokiol induces caspase-dependent apoptosis in a TRAIL-mediated manner, and potentiates the pro-apoptotic effects of doxorubicin and other etoposides. So potent is honokiol's pro-apoptotic effects that it overcomes even notoriously drug resistant neoplasms such as multiple myeloma and chronic B-cell leukemia. Honokiol also acts on the PI3K/mTOR pathway in tumor cells while maintaining pathway activity in T cells. [17]

Neurotrophic activity

Honokiol [ quantify ] has been shown to promote neurite outgrowth and have neuroprotective effects in rat cortical neurons. Additionally, honokiol increases free cytoplasmic reforforason Ca2+ in rat cortical neurons. [10] Honokiol is a weak CB2 receptor ligand but the naturally occurring derivative 4-O-methylhonokiol was shown to be a potent and selective cannabinoid CB2 receptor inverse agonist and to possess antiosteoclastic effects. [18]

Antithrombotic activity

Honokiol inhibits platelet aggregation in rabbits in a dose-dependent manner, and protects cultured RAEC against oxidized low density lipoprotein injury. Honokiol significantly increases the prostacyclin metabolite 6-keto-PGF1alpha, potentially the key factor in honokiol's antithrombotic activity. [19]

Anti-inflammatory activity

Studies examining honokiol as a protective therapy against focal cerebral ischemia-reperfusion injury have identified a number of anti-inflammatory pathways. Neutrophil infiltration of injured tissues can cause further damage and issues with healing. In in vitro studies, honokiol reduced fMLP (N-formyl-methionyl-leucyl-phenylalanine) and PMA (phorbol-12-myristate-13-acetate) induced neutrophil firm adhesion which is an integral step for infiltration. [1] [20] Honokiol inhibits ROS production in neutrophils. [20] Honokiol also blocks inflammatory factor production in glial cells through the inhibition on NF-κB activation. [21] [22] This mechanism is believed to suppress production of NO, tumor necrosis factor-α (TNF-α), and RANTES/CCL5. [21]

Antioxidant activity

Honokiol has also been proposed as an antioxidant. The compound protects against lipid peroxidation by interfering with ROS production and migration. [20] Accumulation of ROS extracellularly causes macromolecular damage while intracellular accumulation may induce cytokine activation.

Cytotoxicity inhibition

One way that honokiol acts as a neuroprotective is through cellular regulation and subsequent inhibition of cytotoxicity. Two mechanisms used to achieve this inhibition are GABAA Modulation and Ca2+ Inhibition. Cytotoxicity inhibition may be the neuroprotective mechanism of honokiol. Honokiol has also been shown to inhibit repetitive firing by blocking glutamate. [23]

GABAA modulation
GABAA receptor binding sites GABAA receptor binding sites.jpg
GABAA receptor binding sites

It is believed that honokiol acts on GABAA receptors similarly to benzodiazepines and Z-drugs. However, honokiol has been shown to achieve anxiolysis with fewer motor or cognitive side effects than GABAA receptor agonists such as flurazepam and diazepam. It has been shown that honokiol likely has a higher selectivity for different GABAA receptor subtypes and both magnolol and honokiol showed higher efficacy when acting on receptors containing δ subunits. [1] GABAA receptors control ligand-gated Cl− channels that can help increase seizure thresholds through the influx of chloride anions. Honokiol may also affect the synthesis of GABA. In a study where mice received seven daily injections of honokiol, researchers observed a mild increase in hippocampal levels of glutamate decarboxylase (GAD67) an enzyme that catalyzes the synthesis of GABA. However, the increase was within the margin of error for the method used to quantify the protein. [24]

Ca2+ inhibition

A high concentration of Ca2+ induces excitotoxicity which is believed to be the main mechanism behind movement disorders such as ALS, Parkinson's disease, and convulsive disorders like epilepsy. Honokiol disrupts the interfaces post synaptic density protein (PSD95) and neuronal nitric oxide synthase (nNOS). [1] PSD95 and nNOS coupling to the NMDA receptor causes a conformational change responsible for the intracellular influx of Ca2+ which could in turn be a pathway for neurotoxicity. Calcium overloading can also cause damage by over-activation of calcium-stimulated enzymes. Honokiol can reduce calcium influx through inhibition of the fMLP, AlF4−, and thapsigargin G-protein pathways. [20]

Antiviral activity

Honokiol has been shown to inhibit hepatitis C virus (HCV) infection in vitro. [25] It has weak in vitro activity against human immunodeficiency virus (HIV-1). [4]

Metabolic activity

Honokiol was shown to normalize blood glucose levels and prevent body weight gain in diabetic mice by acting as agonist of PPARgamma. [26]

Pharmacokinetics

The pharmacokinetics of honokiol have been explored in rats and mice; however, further research must be done in humans. [27] Intravenous delivery of 5–10 mg/kg in rodent models has shown a plasma half-life of around 40–60 minutes while intraperitoneal injections of 250 mg/kg had a plasma half-life around 4–6 hours with maximum plasma concentration occurring between 20 and 30 minutes. [1] [28]

Delivery methods

Honokiol is most commonly taken orally. There are a number of supplements available containing honokiol. Magnolia tea made from the bark of the tree is also a common delivery method of honokiol.[ citation needed ] Both Native Americans and Japanese medicine use tea gargles to treat toothaches and sore throats. [29] Because honokiol is highly hydrophobic it must be dissolved in a lipid for many delivery methods. In many current animal studies the compound is dissolved in a lipid emollient and delivered through intraperitoneal injection. There is ongoing[ when? ] work developing liposomal emulsions for IV delivery. [27]

Related Research Articles

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl−) and, to a lesser extent, bicarbonate ions (HCO3−).

Neuropharmacology is the study of how drugs affect function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.

<span class="mw-page-title-main">Neuroprotection</span> Relative preservation of neuronal structure and/or function

Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation. It is a widely explored treatment option for many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxin consumption. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation. Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own. Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are glutamate antagonists and antioxidants, which aim to limit excitotoxicity and oxidative stress respectively.

<span class="mw-page-title-main">Metabotropic glutamate receptor</span> Type of glutamate receptor

The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.

<span class="mw-page-title-main">Endocannabinoid system</span> Biological system of neurotransmitters

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system and peripheral nervous system. The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

<span class="mw-page-title-main">TRPV1</span> Human protein for regulating body temperature

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. Fatty acid metabolites with affinity for this receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA). The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception). In primary afferent sensory neurons, it cooperates with TRPA1 to mediate the detection of noxious environmental stimuli.

<span class="mw-page-title-main">Nociceptin receptor</span> Protein-coding gene in the species Homo sapiens

The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors. Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.

<i>N</i>-Acetylserotonin Chemical compound

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<span class="mw-page-title-main">Magnolol</span> Chemical compound

Magnolol is an organic compound that is classified as lignan. It is a bioactive compound found in the bark of the Houpu magnolia and in M. grandiflora. The compound exists at the level of a few percent in the bark of species of magnolia, the extracts of which have been used in traditional Chinese and Japanese medicine. In addition to magnolol, related lignans occur in the extracts including honokiol, which is an isomer of magnolol.

<span class="mw-page-title-main">Cannabinoid receptor 2</span> Mammalian protein found in Homo sapiens

The cannabinoid receptor 2(CB2), is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. It is closely related to the cannabinoid receptor 1 (CB1), which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol (THC), the active agent in cannabis, and other phytocannabinoids. The principal endogenous ligand for the CB2 receptor is 2-Arachidonoylglycerol (2-AG).

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References

  1. 1 2 3 4 5 6 7 8 9 10 Woodbury, Anna; Yu, Shan Ping; Wei, Ling; García, Paul (2013). "Neuro-Modulating Effects of Honokiol: A Review". Frontiers in Neurology. 265 (7): 4111–5. doi: 10.3389/fneur.2013.00130 . PMC   3769637 . PMID   2406271.
  2. 1 2 3 4 5 Lee, Young-Jung; Lee, Yoot Mo; Lee, Chong-Kil; Jung, Jae Kyung; Han, Sang Bae; Hong, Jin Tae (2011). "Therapeutic applications of compounds in the Magnolia family". Pharmacology & Therapeutics. 130 (2): 157–76. doi:10.1016/j.pharmthera.2011.01.010. PMID   21277893.
  3. ↑ Wang, Xianhuo; Duan, Xingmei; Yang, Guangli; Zhang, Hao; Deng, Chongyang; Wen, Jiaolin; Wang, Ning; Peng, Cheng; Zhao, Xia; Wei, Yuquan; Chen, Lijuan; Wei, Yuquan; Chen, Lijuan (2011). "Honokiol Crosses BBB and BCSFB, and Inhibits Brain Tumor Growth in Rat 9L Intracerebral Gliosarcoma Model and Human U251 Xenograft Glioma Model". PLOS ONE. 6 (4): e18490. Bibcode:2011PLoSO...618490W. doi: 10.1371/journal.pone.0018490 . PMC   3084695 . PMID   21559510.
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  5. ↑ Chen, Lijuan; Zhang, Qiang; Yang, Guangli; Fan, Linyu; Tang, James; Garrard, Ian; Ignatova, Svetlana; Fisher, Derek; Sutherland, Ian A. (2007). "Rapid purification and scale-up of honokiol and magnolol using high-capacity high-speed counter-current chromatography". Journal of Chromatography A. 1142 (2): 115–22. doi:10.1016/j.chroma.2006.09.098. PMID   17222860.
  6. 1 2 Sarris, Jerome; McIntyre, Erica; Camfield, David A. (2013). "Plant-Based Medicines for Anxiety Disorders, Part 1". CNS Drugs. 27 (3): 207–19. doi:10.1007/s40263-013-0044-3. hdl: 11343/216777 . PMID   23436255. S2CID   207485984.
  7. ↑ Maruyama, Yuji; Kuribara, H.; Morita, M.; Yuzurihara, M.; Weintraub, S. (1998). "Identification of Magnolol and Honokiol as Anxiolytic Agents in Extracts of Saiboku-to, an Oriental Herbal Medicine". Journal of Natural Products. 61 (1): 135–138. doi:10.1021/np9702446. PMID   9461663.
  8. ↑ Fried, Levi E.; Arbiser, Jack L. (2009). "Honokiol, a Multifunctional Antiangiogenic and Antitumor Agent". Antioxidants & Redox Signaling. 11 (5): 1139–48. doi:10.1089/ars.2009.2440. PMC   2842137 . PMID   19203212.
  9. ↑ Guerra-Araiza, Christian; Álvarez-Mejía, Ana Laura; Sánchez-Torres, Stephanie; Farfan-García, Eunice; Mondragón-Lozano, Rodrigo; Pinto-Almazán, Rodolfo; Salgado-Ceballos, Hermelinda (2013). "Effect of natural exogenous antioxidants on aging and on neurodegenerative diseases". Free Radical Research. 47 (6–7): 451–62. doi:10.3109/10715762.2013.795649. PMID   23594291. S2CID   30716241.
  10. 1 2 Fukuyama, Yoshiyasu; Nakade, Kousuke; Minoshima, Yuka; Yokoyama, Ritsuko; Zhai, Haifeng; Mitsumoto, Yasuhide (2002). "Neurotrophic activity of honokiol on the cultures of fetal rat cortical neurons". Bioorganic & Medicinal Chemistry Letters. 12 (8): 1163–1166. doi:10.1016/S0960-894X(02)00112-9. PMID   11934579.
  11. ↑ Chen, Xi‐rui; Lu, Rui; Dan, Hong‐xia; Liao, Ga; Zhou, Min; Li, Xiao‐yu; Ji, Ning (2011). "Honokiol: A promising small molecular weight natural agent for the growth inhibition of oral squamous cell carcinoma cells". International Journal of Oral Science. 3 (1): 34–42. doi:10.4248/IJOS11014. PMC   3469873 . PMID   21449214.
  12. ↑ Chang, K. H.; Yan, M. D. (Nov 2013). "Honokiol-induced apoptosis and autophagy in glioblastoma multiforme cells". Oncology Letters. 6 (5): 1435–1438. doi:10.3892/ol.2013.1548. PMC   3813738 . PMID   24179537.
  13. ↑ Shigemura, Katsumi; Arbiser, Jack L.; Sun, Shi-Yong; Zayzafoon, Majd; Johnstone, Peter A.S.; Fujisawa, Masato; Gotoh, Akinobu; Weksler, Babette; Zhau, Haiyen E.; Chung, Leland W.K. (2007). "Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells". Cancer. 109 (7): 1279–89. doi: 10.1002/cncr.22551 . PMID   17326044. S2CID   22184445.
  14. ↑ Ishitsuka, K.; Hideshima, T; Hamasaki, M; Raje, N; Kumar, S; Hideshima, H; Shiraishi, N; Yasui, H; Roccaro, AM; Richardson, P; Podar, K; Le Gouill, S; Chauhan, D; Tamura, K; Arbiser, J; Anderson, KC (2005). "Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis". Blood. 106 (5): 1794–800. doi:10.1182/blood-2005-01-0346. PMC   1895215 . PMID   15870175.
  15. ↑ Battle, T. E.; Arbiser, J; Frank, DA (2005). "The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells". Blood. 106 (2): 690–7. doi: 10.1182/blood-2004-11-4273 . PMID   15802533.
  16. ↑ Bai, X.; Cerimele, F; Ushio-Fukai, M; Waqas, M; Campbell, PM; Govindarajan, B; Der, CJ; Battle, T; Frank, DA; Ye, K; Murad, E; Dubiel, W; Soff, G; Arbiser, JL (2003). "Honokiol, a Small Molecular Weight Natural Product, Inhibits Angiogenesis in Vitro and Tumor Growth in Vivo". Journal of Biological Chemistry. 278 (37): 35501–7. doi: 10.1074/jbc.M302967200 . PMID   12816951.
  17. ↑ Crane, Courtney; Panner, Amith; Pieper, Russell; Arbiser, Jack; Parsa, Andrew (2009). "Honokiol-mediated inhibition of PI3K/mTOR pathway: a potential strategy to overcome immunoresistance in glioma, breast, and prostate carcinoma without impacting T cell function". Journal of Immunotherapy. 32 (6): 585–592. doi:10.1097/CJI.0b013e3181a8efe6. PMC   3795513 . PMID   19483651.
  18. ↑ Schuehly, Wolfgang; Paredes, Juan Manuel Viveros; Kleyer, Jonas; Huefner, Antje; Anavi-Goffer, Sharon; Raduner, Stefan; Altmann, Karl-Heinz; Gertsch, Jürg (2011). "Mechanisms of Osteoclastogenesis Inhibition by a Novel Class of Biphenyl-Type Cannabinoid CB2 Receptor Inverse Agonists". Chemistry & Biology. 18 (8): 1053–64. doi:10.1016/j.chembiol.2011.05.012. PMID   21867920.
  19. ↑ Hu, He; Zhang, Xiao-xue; Wang, Yin-ye; Chen, Shi-Zhong (2005). "Honokiol inhibits arterial thrombosis through endothelial cell protection and stimulation of prostacyclin". Acta Pharmacologica Sinica. 26 (9): 1063–8. doi: 10.1111/j.1745-7254.2005.00164.x . PMID   16115372.
  20. 1 2 3 4 Liou, Kuo-Tong; Shen, Yuh-Chiang; Chen, Chieh-Fu; Tsao, Cheng-Ming; Tsai, Shen-Kou (2003). "Honokiol protects rat brain from focal cerebral ischemia-reperfusion injury by inhibiting neutrophil infiltration and reactive oxygen species production" (PDF). Brain Research. 992 (2): 159–166. doi:10.1016/j.brainres.2003.08.026. PMID   14625055. S2CID   44974515.
  21. 1 2 Zhang, Peng; Liu, Xiaoyan; Zhu, Yanjun; Chen, Shizhong; Zhou, Demin; Wang, Yinye (2012). "Honokiol inhibits the inflammatory reaction during cerebral ischemia reperfusion by suppressing NF-κB activation and cytokine production of glial cells". Neuroscience Letters. 534: 123–7. doi:10.1016/j.neulet.2012.11.052. PMID   23262090. S2CID   10051483.
  22. ↑ Chao, Louis Kuoping; Liao, Pei-Chun; Ho, Chen-Lung; Wang, Eugene I-Chen; Chuang, Chao-Chin; Chiu, Huan-Wen; Hung, Lang-Bang; Hua, Kuo-Feng (2010). "Anti-Inflammatory Bioactives of Honokiol through Inhibition of Protein Kinase C, Mitogen-Activated Protein Kinase, and the NF-κB Pathway To Reduce LPS-Induced TNFα and NO Expression". Journal of Agricultural and Food Chemistry. 58 (6): 3472–8. doi:10.1021/jf904207m. PMID   20192217.
  23. ↑ Lin, Yi-Ruu; Chen, Hwei-Hsien; Ko, Chien-Hsin; Chan, Ming-Huan (2006). "Neuroprotective activity of honokiol and magnolol in cerebellar granule cell damage". European Journal of Pharmacology. 537 (1–3): 64–9. doi:10.1016/j.ejphar.2006.03.035. PMID   16631734.
  24. ↑ Ku, Tien-Hsiung; Lee, Yih-Jing; Wang, Su-Jane; Fan, Chen-Hua; Tien, Lu-Tai (2011). "Effect of honokiol on activity of GAD(65) and GAD(67) in the cortex and hippocampus of mice". Phytomedicine. 18 (13): 1126–9. doi:10.1016/j.phymed.2011.03.007. PMID   21561750.
  25. ↑ Lan, KH; Wang, Ying-Wen; Lee, Wei-Ping; Lan, Keng-Li; Tseng, Szu-Han; Hung, Li-Rong; Yen, Sang-Hue; Lin, Han-Chieh; Lee, Shou-Dong (2012). "Multiple effects of Honokiol on the life cycle of hepatitis C virus". Liver International. 32 (6): 989–97. doi:10.1111/j.1478-3231.2011.02621.x. PMID   22098176. S2CID   22428079.
  26. ↑ Atanasov, Atanas G.; Wang, Jian N.; Gu, Shi P.; Bu, Jing; Kramer, Matthias P.; Baumgartner, Lisa; Fakhrudin, Nanang; Ladurner, Angela; Malainer, Clemens; Vuorinen, Anna; Noha, Stefan M.; Schwaiger, Stefan; Rollinger, Judith M.; Schuster, Daniela; Stuppner, Hermann; Dirsch, Verena M.; Heiss, Elke H. (2013). "Honokiol: A non-adipogenic PPARγ agonist from nature". Biochimica et Biophysica Acta (BBA) - General Subjects. 1830 (10): 4813–4819. doi:10.1016/j.bbagen.2013.06.021. PMC   3790966 . PMID   23811337.
  27. 1 2 Zheng, J; Tang, Y; Sun, M; Zhao, Y; Li, Q; Zhou, J; Wang, Y (2013). "Characterization, pharmacokinetics, tissue distribution and antitumor activity of honokiol submicron lipid emulsions in tumor-burdened mice". Die Pharmazie. 68 (1): 41–6. PMID   23444779.
  28. ↑ Tsai, Tung-Hu; Chou, Cheng-Jen; Cheng, Fu-Chou; Chen, Chieh-Fu (1994). "Pharmacokinetics of honokiol after intravenous administration in rats assessed using high performance liquid chromatography". Journal of Chromatography B. 655 (1): 41–5. doi:10.1016/0378-4347(94)00031-x. PMID   8061832.
  29. ↑ Shimer, Porter (2004). Healing Secrets of the Native Americans: Herbs, Remedies, and Practices That Rebuild the Spirit . Black Dog & Leventhal Publishers, Incorporated. pp.  83–4. ISBN   978-1-57912-392-5.
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