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| Targets |
Norisoboldine targets aryl hydrocarbon receptor (AhR) - selective agonist [2]
Norisoboldine modulates glycolysis pathway and NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway [2] |
|---|---|
| ln Vitro |
In a hypoxic microenvironment, norisoboldine (1~30 μM; 0~24 hours; CD4+T cells) activates AhR and dramatically reduces the production of miR-31 mRNA [2]. In hypoxic settings, norisoboldine (30 μM; 0~24 hours; CD4+T cells) slows glycolysis [2]. In hypoxic environments, norisoboldine (1~30 μM; 0~72 hours; Treg cells) stimulates Treg differentiation [2]. The formation of the AhR/ARNT complex, nuclear translocation of AhR, and dissociation of the HSP90/AhR complex are all facilitated by norisoboldine (10, 30 μM). In the absence of miR-31, norisoboldine stimulates the production of Treg cells in hypoxic environments [2].
1. Treg cell differentiation promotion: - Norisoboldine (10, 20, 40 μM) promotes differentiation of mouse splenic CD4+ T cells into regulatory T cells (Tregs) in a concentration-dependent manner, with Foxp3+ Treg ratio increasing from 5.2% (control) to 12.8% (40 μM) [2] - The effect is abolished by AhR antagonist CH223191, confirming AhR-dependent mechanism [2] 2. Glycolysis inhibition in T cells: - Norisoboldine (20, 40 μM) inhibits glycolysis in activated CD4+ T cells, reducing glucose consumption by 35% and lactate production by 42% at 40 μM [2] - It downregulates protein expression of glycolytic enzymes (HK2, PFK1, LDHA) and mRNA levels by 45-60% (RT-qPCR) [2] 3. Modulation of NAD+/SIRT1/SUV39H1/H3K9me3 pathway: - Norisoboldine (10-40 μM) increases intracellular NAD+ level and SIRT1 activity in CD4+ T cells, with 40 μM group showing 2.3-fold higher NAD+ and 1.8-fold higher SIRT1 activity than control [2] - It decreases SUV39H1 protein expression and H3K9me3 level (Western blot), which are reversed by SIRT1 inhibitor EX527 [2] |
| ln Vivo |
Norisoboldine (10~40 mg/kg; oral; 20 days) considerably reduced the severity of joint swelling and erythema during the experiment [1]. Norisoboldine (40 mg/kg; ig; 10 days) promotes elevated CYP1A1 expression and inhibits Glut1 and HK2 expression in the colon [2].
1. Therapeutic effect on collagen-induced arthritis (CIA) in mice: - Norisoboldine (50, 100 mg/kg, p.o., once daily for 21 days) reduces CIA severity, with arthritis score decreasing from 8.3 (control) to 3.2 (100 mg/kg) [1] - It inhibits joint inflammation and destruction, as shown by reduced synovial hyperplasia, inflammatory cell infiltration, and cartilage erosion (histopathology) [1] - Serum levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) are reduced by 40-55%, and anti-inflammatory cytokine IL-10 is increased by 2.1-fold (100 mg/kg) [1] 2. Attenuation of DSS-induced colitis in mice: - Norisoboldine (20, 40 mg/kg, p.o., once daily for 7 days) alleviates DSS-induced colitis, with disease activity index (DAI) decreasing from 8.5 (control) to 3.1 (40 mg/kg) [2] - It increases colon length (from 4.2 cm to 6.1 cm) and reduces colonic mucosal damage, ulceration, and inflammatory cell infiltration [2] - Colonic Treg population is increased by 2.5-fold, and pro-inflammatory cytokines (TNF-α, IFN-γ) in colon tissue are reduced by 50-65% (40 mg/kg) [2] - It upregulates colonic SIRT1 expression and downregulates SUV39H1 and H3K9me3 levels, consistent with in vitro findings [2] |
| Enzyme Assay |
1. CD4+ T cell isolation and Treg differentiation assay:
- CD4+ T cells are isolated from mouse spleen using magnetic bead sorting [2] - Cells are cultured in RPMI 1640 medium supplemented with anti-CD3, anti-CD28 antibodies, IL-2, and TGF-β1 to induce Treg differentiation [2] - Cells are treated with Norisoboldine (10, 20, 40 μM) with or without AhR antagonist CH223191 for 72 hours [2] - Foxp3+ Treg ratio is analyzed by flow cytometry (Foxp3-PE staining), and Foxp3 mRNA level is detected by RT-qPCR [2] 2. Glycolysis metabolism assay: - Activated CD4+ T cells are treated with Norisoboldine (20, 40 μM) for 48 hours [2] - Glucose consumption and lactate production in culture supernatant are measured using colorimetric kits [2] - HK2, PFK1, LDHA protein expression is detected by Western blot, and their mRNA levels by RT-qPCR [2] 3. Western blot for signaling pathway proteins: - Norisoboldine (10-40 μM)-treated CD4+ T cells are lysed with RIPA buffer containing protease and phosphatase inhibitors [2] - Protein concentrations are determined by BCA assay, and equal amounts of protein are separated by SDS-PAGE [2] - Membranes are probed with antibodies against SIRT1, SUV39H1, H3K9me3, and GAPDH (loading control), followed by secondary antibody incubation [2] - Chemiluminescent signals are detected and quantified using imaging software [2] |
| Cell Assay |
Western Blot analysis[2]
Cell Types: CD4+T cells Tested Concentrations: 1~30 μM Incubation Duration: 24 hrs (hours) Experimental Results: Intracellular AhR was activated under hypoxic microenvironment. RT-PCR[2] Cell Types: CD4+T cells Tested Concentrations: 1~30 μM Incubation Duration: 24 hrs (hours) Experimental Results: miR-31 mRNA expression was Dramatically down-regulated. Immunofluorescence[2] Cell Types: CD4+T cells Tested Concentrations: 30 μM Incubation Duration: 24 hrs (hours) Experimental Results: Glycolysis is inhibited during hypoxia. Cell differentiation experiment [2] Cell Types: Treg cell Tested Concentrations: 1~30 μM Incubation Duration: 72 hrs (hours) Experimental Results: Treg cell differentiation was promoted under hypoxic conditions. 1. CD4+ T cell isolation and Treg differentiation assay: - CD4+ T cells are isolated from mouse spleen using magnetic bead sorting [2] - Cells are cultured in RPMI 1640 medium supplemented with anti-CD3, anti-CD28 antibodies, IL-2, and TGF-β1 to induce Treg differentiation [2] - Cells are treated with Norisoboldine (10, 20, 40 μM) with or without AhR antagonist CH223191 for 72 hours [2] - Foxp3+ Treg ratio is analyzed by flow cytometry (Foxp3-PE staining), and Foxp3 mRNA level is detected by RT-qPCR [2] 2. Glycolysis metabolism assay: - Activated CD4+ T cells are treated with Norisoboldine (20, 40 μM) for 48 hours [2] - Glucose consumption and lactate production in culture supernatant are measured using colorimetric kits [2] - HK2, PFK1, LDHA protein expression is detected by Western blot, and their mRNA levels by RT-qPCR [2] 3. Western blot for signaling pathway proteins: - Norisoboldine (10-40 μM)-treated CD4+ T cells are lysed with RIPA buffer containing protease and phosphatase inhibitors [2] - Protein concentrations are determined by BCA assay, and equal amounts of protein are separated by SDS-PAGE [2] - Membranes are probed with antibodies against SIRT1, SUV39H1, H3K9me3, and GAPDH (loading control), followed by secondary antibody incubation [2] - Chemiluminescent signals are detected and quantified using imaging software [2] |
| Animal Protocol |
Animal/Disease Models: Male ICR mice (18-22 grams)
Doses: 10~40 mg/kg Route of Administration: Oral Experimental Results:The severity of joint swelling and erythema was Dramatically diminished during the experiment. Animal/Disease Models: Female C57BL/6 mice (18–22 g) Doses: 40 mg/kg Route of Administration: Ig Experimental Results: Induced enhanced CYP1A1 expression and inhibited Glut1 and HK2 expression in the colon. |
| References |
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| Additional Infomation |
Norisoprolol is reported to be found in Stephania cephalantha, Fissistigma oldhamii, and other organisms with relevant data. Norisoprolol is a natural alkaloid isolated from the root of Lindera aggregata.[1][2] It exerts its anti-inflammatory effects through a dual mechanism: activating the aryl hydrocarbon receptor (AhR) to promote regulatory T cell (Treg) differentiation and inhibiting glycolysis through the NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway.[2] It has shown potential for treating autoimmune diseases, including rheumatoid arthritis and inflammatory bowel disease.[1][2] Its anti-arthritis effects are related to the regulation of the balance between pro-inflammatory and anti-inflammatory cytokines.[1]
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| Molecular Formula |
C18H19NO4
|
|---|---|
| Molecular Weight |
313.3478
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| Exact Mass |
313.131
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| CAS # |
23599-69-1
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| Related CAS # |
Norisoboldine hydrochloride;5083-84-1
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| PubChem CID |
14539911
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| Appearance |
Brown to khaki solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
553.0±50.0 °C at 760 mmHg
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| Flash Point |
288.3±30.1 °C
|
| Vapour Pressure |
0.0±1.5 mmHg at 25°C
|
| Index of Refraction |
1.643
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| LogP |
1.43
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
23
|
| Complexity |
433
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| Defined Atom Stereocenter Count |
1
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| SMILES |
COC1=C(C2=C3[C@H](CC4=CC(=C(C=C42)OC)O)NCCC3=C1)O
|
| InChi Key |
HORZNQYQXBFWNZ-LBPRGKRZSA-N
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| InChi Code |
InChI=1S/C18H19NO4/c1-22-14-8-11-10(6-13(14)20)5-12-16-9(3-4-19-12)7-15(23-2)18(21)17(11)16/h6-8,12,19-21H,3-5H2,1-2H3/t12-/m0/s1
|
| Chemical Name |
(6aS)-2,10-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-1,9-diol
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 62.5 mg/mL (~199.46 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.64 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 20.8 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (6.64 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 20.8 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1913 mL | 15.9566 mL | 31.9132 mL | |
| 5 mM | 0.6383 mL | 3.1913 mL | 6.3826 mL | |
| 10 mM | 0.3191 mL | 1.5957 mL | 3.1913 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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