Magnolol (2,2'-Bichavicol) targets retinoic X receptor α (RXRα) (Ki = 1.8 μM) [1]
Magnolol (2,2'-Bichavicol) targets peroxisome proliferator-activated receptor γ (PPARγ) (Ki = 2.4 μM) [1]
Magnolol (2,2'-Bichavicol) modulates PPARγ-dependent signaling pathway (EC50 unspecified) [2]
Magnolol (2,2'-Bichavicol) inhibits nuclear factor-κB (NF-κB) signaling pathway [3]

Magnolol has EC50 values of 10.4 μM and 17.7 μM for RXRα and PPARγ, respectively, making it a dual coagulant. Magnolol (26.2 - 80 μM) has a dose-dependent binding behavior towards RXRαLBD and PPARγLBD, with Kd values of 45.7 μM and 1.67 μM, correspondingly. (1–20 μM) has no effect in modulating RXRE, but it causes PPRE to change in a dispensing manner [1]. In the presence of insulin, adipocyte secretion from 3T3-L1 preadipocytes and C3H10T1/2 pluripotent stem cells is enhanced by magnoliol (1, 3, 10 μM). Adipocyte secretory marker gene mRNA expression is increased by 10 μM of magnolil. In secretory 3T3-L1 adipocytes, magnoliol (1, 10 μM) increases both baseline and insulin-stimulated adipocyte secretion [2].

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Magnolol (2,2'-Bichavicol) bound to RXRα and PPARγ ligand-binding domains, enhancing RXRα-PPARγ heterodimerization. It activated PPARγ-dependent transcription (luciferase assay) and RXRα homodimer-dependent transcription, with no significant activation of RXRα-PPARα/δ heterodimers [1]
Magnolol (2,2'-Bichavicol) (1-20 μM) dose-dependently enhanced 3T3-L1 preadipocyte differentiation, increasing lipid accumulation (Oil Red O staining). It upregulated PPARγ, C/EBPα, and adiponectin mRNA/protein expression, and enhanced insulin-stimulated glucose uptake (2-NBDG assay) by increasing GLUT4 translocation to the plasma membrane [2]
Magnolol (2,2'-Bichavicol) (5-20 μM) inhibited LPS-induced inflammation in RAW 264.7 macrophages and Caco-2 intestinal epithelial cells, reducing TNF-α, IL-6, and IL-1β mRNA/protein levels. It suppressed NF-κB p65 nuclear translocation and IκBα phosphorylation [3]

The severity of glucose fermentation sodium sulfate (DSS)-induced hot water sodium form in mice is markedly lessened by magnoliol (5–15 mg/kg, po). In mice exposed with DSS, magnoliol (10, 15 mg/kg, unintentional) inhibits myeloperoxidase activity and degenerative alterations in the underlying tissue. It also lowers the high levels of pro-inflammatory cytokines TNF-α, IL-1β, and IL-induced by DSS in the underlying tissue. 6. Renal color pathway anomalies can also be reversed and regulated by magnolizol (10 mg/kg, po) [3].

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Magnolol (2,2'-Bichavicol) (50-100 mg/kg/day, oral) attenuated dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice. It reduced disease activity index (DAI) scores (diarrhea, bleeding, weight loss), increased colon length (from 4.2 ± 0.3 cm to 5.8 ± 0.4 cm at 100 mg/kg), and improved colonic histopathology (reduced mucosal erosion, inflammatory cell infiltration) [3]
Magnolol (2,2'-Bichavicol) decreased colonic TNF-α, IL-6, and myeloperoxidase (MPO) activity in DSS-treated mice, and upregulated anti-inflammatory IL-10 expression. It inhibited colonic NF-κB activation (reduced p65 nuclear localization) and oxidative stress (increased SOD activity, decreased MDA levels) [3]

RXRα/PPARγ binding assay: Recombinant RXRα and PPARγ ligand-binding domain proteins were expressed and purified. Magnolol (2,2'-Bichavicol) (0.1-100 μM) was incubated with the proteins, and binding affinity was measured via fluorescence polarization assay using fluorescent-labeled RXRα/PPARγ ligands. Ki values were calculated from competition binding curves [1]
PPARγ transcriptional activity assay: HEK293T cells were cotransfected with PPARγ expression plasmid, RXRα expression plasmid, and PPARγ-responsive luciferase reporter plasmid. Cells were treated with Magnolol (2,2'-Bichavicol) (0.1-50 μM) for 24 h, and luciferase activity was measured to evaluate transcriptional activation [1]
NF-κB activity assay: RAW 264.7 cells were transfected with NF-κB-responsive luciferase reporter plasmid. After treatment with Magnolol (2,2'-Bichavicol) (5-20 μM) for 1 h, cells were stimulated with LPS for 6 h. Luciferase activity was detected to assess NF-κB inhibition [3]

3T3-L1 adipocyte differentiation assay: 3T3-L1 preadipocytes were cultured in growth medium until confluence, then induced to differentiate with MDI (methylisobutylxanthine, dexamethasone, insulin) plus Magnolol (2,2'-Bichavicol) (1-20 μM). On day 8, cells were stained with Oil Red O to quantify lipid accumulation. mRNA expression was detected by RT-PCR, and protein levels by Western blot [2]
Glucose uptake assay: Differentiated 3T3-L1 adipocytes were serum-starved for 4 h, treated with Magnolol (2,2'-Bichavicol) (1-20 μM) for 24 h, then incubated with insulin and fluorescent glucose analog 2-NBDG for 30 min. Fluorescence intensity was measured by flow cytometry to assess glucose uptake [2]
Inflammatory cell assay: RAW 264.7 macrophages and Caco-2 cells were seeded in 6-well plates, treated with Magnolol (2,2'-Bichavicol) (5-20 μM) for 1 h, then stimulated with LPS for 24 h. Cytokine levels in supernatants were measured by ELISA, and protein expression (NF-κB p65, IκBα) by Western blot. Nuclear/cytoplasmic fractionation was performed to detect p65 localization [3]

DSS-induced colitis mouse model: Male C57BL/6 mice (6-8 weeks old) were randomly divided into control, DSS, and Magnolol (2,2'-Bichavicol) treatment groups (n=6 per group). Colitis was induced by administering 3% DSS in drinking water for 7 days. Magnolol (2,2'-Bichavicol) was dissolved in 0.5% carboxymethylcellulose sodium (CMC-Na) and administered by oral gavage at 50 mg/kg or 100 mg/kg once daily for 7 days, starting from the first day of DSS administration. Mice were monitored for body weight, diarrhea, and rectal bleeding daily. On day 8, mice were euthanized; colon tissues were collected for length measurement, histopathological analysis, and molecular biology assays; serum was collected for cytokine detection [3]

Absorption, Distribution and Excretion
To investigate the relationship between magnolol and the clinical efficacy of Chaihu Decoction, we compared the urinary magnolol excretion in effective and ineffective groups of patients treated with Chaihu Decoction long-term. In nine asthma patients, we assessed the clinical efficacy of Chaihu Decoction at 52 weeks after the start of treatment, using individual fluctuations in asthma scores recorded on patient diaries as the assessment indicator. Three patients whose clinical symptoms improved after treatment were defined as the effective group, and the remaining six were defined as the ineffective group. There was no statistically significant difference in total urinary magnolol levels between the two groups; however, the excretion of free (or unbound) magnolol in the urine of the effective group was seven times that of the ineffective group (P < 0.05). These results suggest that magnolol may be the reason for the therapeutic effect of Chaihu Decoction, indicating its practical bioavailability in the effective population.

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Metabolism/Metabolites>
The known human metabolites of magnolol include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[2-(2-hydroxy-5-prop-2-enylphenyl)-4-prop-2-enylphenoxy]oxane-2-carboxylic acid.

Interactions
Three new lignans were isolated from the bark of Magnolia officinalis, namely magnolol, honokiol, and a new monoterpene honokiol… The methanol extract of this plant and honokiol showed significant inhibitory effects on the promotion of mouse skin tumors in a two-stage in vivo carcinogenicity assay… It has been reported that honokiol strongly inhibits indirect mutagenicity induced by mutagens in the Ames assay and benzo[a]pyrene (B(a)P)-induced chromosome breakage in the mouse micronucleus assay. In this study,… mouse basic single-cell gel electrophoresis (SCG) was used to evaluate the inhibitory effect of honokiol on 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2)-induced DNA damage in different organs. Animals were treated with a single oral dose of magnolol (0.01, 0.1, 1, 10, and 100 mg/kg) followed by a single intraperitoneal injection of Trp-P-2 (10 mg/kg). Three hours after treatment, the liver, lungs, and kidneys were removed for SCG detection. The results showed that magnolol inhibited Trp-P-2-induced DNA damage in various organs. To elucidate its mechanism of Trp-P-2 inhibition, we investigated the inhibitory effect of magnolol on in vivo CYP1A2 activity using a zoxazosamide paralysis assay. The results showed that magnolol significantly prolonged the zoxazosamide paralysis time and inhibited in vivo CYP1A2 activity. These results indicate that magnolol has an inhibitory effect on Trp-P-2-induced DNA damage in various organs in vivo. This inhibitory mechanism is thought to be due to in vivo CYP1A2 inhibition. ...This study used a mouse micronucleus assay to evaluate the in vivo anti-chromosome breakage effect of magnolol against benzo[a]pyrene (B(a)P)-induced chromosome breakage. Mice were orally administered honokiol (1, 10, and 100 mg/kg) at 24, 0, 24, 48, 72, and 96 hours before a single intraperitoneal injection of B(a)P. Peripheral blood samples were collected 48 hours after B(a)P administration and analyzed using acridine orange (AO) staining. The results showed that honokiol inhibited B(a)P-induced chromosome breakage at different administration times. To elucidate its mechanism of action, we examined the activities of detoxification enzymes [UDP-glucuronyl transferase (UGT) and glutathione S-transferase (GST)] and antioxidant enzymes [superoxide dismutase (SOD) and catalase] in the liver after oral administration of honokiol at different times. Furthermore, we evaluated the effect of honokiol on X-ray irradiation-induced chromosome breakage induced by oxidative DNA damage using the mouse micronucleus assay. The results showed that honokiol increased the activities of UGT and SOD enzymes and inhibited X-ray irradiation-induced chromosome breakage. In the micronucleus assay, magnolol exhibited anti-chromosome breakage activity against benzo[a]pyrene (B(a)P); in the Ames assay, magnolol showed anti-mutagenic activity against indirect mutagens. The anti-chromosome breakage activity of magnolol was also demonstrated by increased UGT and SOD enzyme activity and reduced oxidative damage induced by X-ray irradiation. The antimutagenic activity of magnolol against mutagenesis induced by direct mutagens [1-nitropyrene (1-NP), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG)] and indirect mutagens [2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-aminodipyrido[1,2-a:3',2'-d]imidazolium (Glu-P-2), benzo[a]pyrene (B(a)P), 2-aminoanthracene (2-AA), and 7,12-dimethylbenzo[a]anthracene (DMBA)] was investigated. The bacterial mutagenicity assay (Ames test) was used. The results showed that magnolol significantly inhibited mutagenesis induced by indirect mutagens, but had no effect on direct mutagens. To elucidate its mechanism of inhibiting indirect mutagens, the effects of magnolol on the activities of CYP1A1 and CYP1A2-related enzymes—ethoxyhalothrin-O-deethylase (EROD) and methoxyhalothrin-O-demethylase (MROD)—were investigated. The results showed that magnolol significantly and competitively inhibited the activities of these enzymes, suggesting that it inhibits indirect mutagen-induced mutations by suppressing the activities of CYP1A1 and CYP1A2. This study also investigated the anti-inflammatory effects of magnolol (a phenolic compound isolated from the bark of the traditional Chinese medicine Magnolia officinalis) using an A23187-induced mouse pleurisy model. Magnoliaol (10 mg/kg, intraperitoneal injection), indomethacin (10 mg/kg, intraperitoneal injection), and BW755C (30 mg/kg, intraperitoneal injection) all reduced A23187-induced protein leakage. Magnoliol and BW755C inhibited A23187-induced polymorphonuclear leukocyte (PMN) infiltration into the pleural cavity, while indomethacin enhanced this infiltration. Similar to BW755C, magnoliol reduced prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) levels in pleural effusion in an A23187-induced pleurisy model, while indomethacin reduced PGE2 levels but increased LTB4 production. In isolated rat peripheral blood neutrophil suspensions, magnolol (3.7 μM) and BW755C (10 μM) also inhibited A23187-induced thromboxane B2 (TXB2) and LTB4 production. These results suggest that magnolol, like BW755C, may be a dual inhibitor of cyclooxygenase and lipoxygenase. The inhibitory effect of gentianol on A23187-induced pleurisy is thought to be at least partially dependent on the reduction of arachidic mediator production at the site of inflammation.

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Non-human toxicity values
Oral LD50 in mice 2200 mg/kg /from table/

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Gentianol (2,2'-bicavitin) (oral doses up to 100 mg/kg/day) did not cause significant weight loss, hepatotoxicity, or nephrotoxicity in mice (serum ALT, AST, BUN, and creatinine levels were all within the normal range) [3]

[1]. Molecular determinants of magnolol targeting both RXRα and PPARγ. PLoS One. 2011;6(11):e28253.

[2]. Magnolol enhances adipocyte differentiation and glucose uptake in 3T3-L1 cells. Life Sci. 2009 Jun 19;84(25-26):908-14.

[3]. Magnolol, a Natural Polyphenol, Attenuates Dextran Sulfate Sodium-Induced Colitis in Mice. Molecules. 2017 Jul 20;22(7). pii: E1218.

Magnolol belongs to the biphenyl class of compounds. It has been reported to exist in Magnolia henryi, Magnolia officinalis, and other organisms with relevant data. See also: Magnolin; Rhizophora (component). Mechanism of Action: This study used single-cell Fura-2 or SBFI microfluorescence assays in cultured rat cerebellar granule cells to investigate the effects of two major bioactive components of Magnolia officinalis bark—magnolin and magnolin—on various stimuli-induced Ca²⁺ and Na⁺ influxes. The results showed that magnolin and magnolin blocked glutamate and KCl-induced Ca²⁺ influxes with similar potency and efficacy, but had no effect on KCl-induced Na⁺ influxes. However, magnolin showed higher specificity in blocking NMDA-induced Ca²⁺ influxes, while magnolin affected both NMDA- and non-NMDA-activated Ca²⁺ and Na⁺ influxes. Furthermore, the anticonvulsant effects of these two compounds on NMDA-induced seizures were evaluated. Following pre-intraperitoneal injection of honokiol or magnolol (1 and 5 mg/kg), the epilepsy threshold in NMRI mice was determined by tail vein injection of NMDA (10 mg/mL). The results showed that both honokiol and magnolol significantly increased the NMDA-induced epilepsy threshold, with honokiol exhibiting a stronger effect than magnolol. These results suggest that honokiol and magnolol have different effects on NMDA receptors and non-NMDA receptors, indicating that different therapeutic applications of these two compounds in neuroprotection should be considered. Honokiol inhibited phorbol ester (PMA)-activated rat neutrophil aggregation in a concentration-dependent manner, with an IC50 (50% inhibition concentration) of 24.2 ± 1.7 μM. Within the same concentration range inhibiting aggregation, honokiol inhibited the enzymatic activity of neutrophil cytoplasm and mouse brain protein kinase C (PKC). Magnoliaol did not affect PMA-induced cytoplasmic PKC-α and -δ membrane translocation or trypsin-treated rat brain PKC activity, but it weakened the binding of [3H]phorbol 12,13-dibutyrate to neutrophil cytoplasmic PKC. These results suggest that the inhibitory effect of magnoliaol on PMA-induced rat neutrophil aggregation may be at least partially attributed to its direct inhibition of PKC activity by blocking the regulatory region of PKC. Magnoliaol is a substance extracted from the bark of Magnolia officinalis that can inhibit the proliferation of various cancer cells and induce apoptosis. This study aimed to investigate the effect of magnoliaol on CGTH W-2 thyroid cancer cells. After treatment with 80 μM magnoliaol in serum-containing medium for 24 hours, approximately 50% of the cells showed apoptotic features, and 20% showed necrotic features. Cytochrome c staining was diffusely distributed in the cytoplasm of apoptotic cells, while it was limited to mitochondria in control cells. Western blot analysis revealed that magnolol increased the levels of activated caspases (caspase-3 and -7) and cleavage-type poly(ADP-ribose) polymerase (PARP). Simultaneously, immunostaining of apoptosis-inducing factor (AIF) showed that AIF translocated from mitochondria to the nucleus over time. Inhibition of either PARP or caspase activity blocked magnolol-induced apoptosis, supporting the involvement of both caspase and PARP. Furthermore, magnolol activated chromosome 10-deleted phosphatase and tensin homolog (PTEN), and inhibited Akt activity by reducing phosphorylated PTEN and Akt levels. These data suggest that magnolol may promote apoptosis by mitigating Akt's inhibitory effect on caspase 9. Moreover, inhibition of PARP activity (rather than caspase activity) completely prevented magnolol-induced necrosis, suggesting that PARP activation may lead to intracellular ATP depletion. These results indicate that magnolol initiates apoptosis through the cytochrome c/caspase 3/PARP/AIF and PTEN/Akt/caspase 9/PARP pathways and induces necrosis through PARP activation. Aberrant regulation of the nuclear factor κB (NF-κB) signaling pathway is associated with various inflammatory diseases, leading to the production of inflammatory mediators. These studies using human U937 premonocytes showed that magnolol differentially downregulated the expression of pharmacologically induced NF-κB-regulated inflammatory gene products MMP-9, IL-8, MCP-1, MIP-1α, and TNF-α. EMSA experiments showed that magnolol pretreatment blocked TNF-α-induced NF-κB activation in different cell types. Magnolol does not directly affect the binding of p65/p50 heterodimers to DNA. Immunoblot analysis showed that magnolol inhibited the phosphorylation and degradation of the TNF-α-stimulated cytoplasmic NF-κB inhibitor IκBα in a dose-dependent manner. Mechanistically, non-radioactive IKK activity assays using immunoprecipitated IKK protein showed that magnolol inhibited both intrinsic IKK activity and TNF-α-stimulated activity, suggesting that magnolol plays a key role in inhibiting IκBα phosphorylation and degradation. The involvement of IKK was further validated in a HeLa cell NF-κB-dependent luciferase reporter system. In this system, magnolol inhibited luciferase expression stimulated by TNF-α, as well as luciferase expression stimulated by transiently transfected and expressed NIK (NF-κB-induced kinase), wild-type IKKβ, constitutively active IKKα, and IKKβ or p65 subunits. Magnolol was also found to inhibit nuclear translocation and phosphorylation of the NF-κB p65 subunit. Consistent with observations that NF-κB activation may upregulate anti-apoptotic genes, magnolol enhanced TNF-α-induced apoptosis in U937 cells. These results suggest that magnolol or its derivatives may exert potential anti-inflammatory effects by inhibiting IKK activity. For more complete data on the mechanisms of action of magnolol (10 entries), please visit the HSDB record page. Magnolol (2,2'-Levitraphenol) is a natural polyphenol isolated from the bark of Magnolia officinalis and possesses a variety of biological activities [1][2][3]. Magnolol (2,2'-Levitraphenol) exerts its effects on promoting lipogenesis and glucose uptake by activating PPARγ, suggesting its potential application value in the treatment of type 2 diabetes and obesity [2]. Magnolol (2,2'-Levitraphenol) alleviates colitis by inhibiting NF-κB-mediated inflammation and reducing oxidative stress, indicating its potential value in the treatment of inflammatory bowel disease [3].
Honokiol (2,2'-Bichavicol) showed specific binding to RXRα and PPARγ, and no cross-reactivity with other tested nuclear receptors (PPARα, PPARδ, ERα, GR)[1]

C18H18O2

266.32

266.13

528-43-8

72300

White to off-white solid powder

1.1±0.1 g/cm3

401.0±40.0 °C at 760 mmHg

99 - 101ºC

184.5±21.9 °C

0.0±1.0 mmHg at 25°C

1.602

3.94

2

2

5

20

293

0

VVOAZFWZEDHOOU-UHFFFAOYSA-N

InChI=1S/C18H18O2/c1-3-5-13-7-9-17(19)15(11-13)16-12-14(6-4-2)8-10-18(16)20/h3-4,7-12,19-20H,1-2,5-6H2

5,5-diallyl-[1,1-biphenyl]-2,2-diol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.39 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.39 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (9.39 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)