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Dihydroberberine is a novel and potent inhibitor of pancreatic lipase with anti-inflammatory, anti-atherosclerotic, hypolipidemic and antitumor activities. It inhibits human ether-a-go-go-related gene (hERG) channels and remarkably reduces heat shock protein 90 (Hsp90) expression and its interaction with hERG.
| Targets |
- Dihydroberberine targets human Ether-a-go-go Related Gene (hERG) potassium channels (inhibits hERG channel current), with an IC50 value of ~34.5 μM. [1]
- Dihydroberberine targets inflammatory signaling pathways (e.g., NF-κB, TLR4/MyD88) and intestinal epithelial barrier-related proteins (e.g., ZO-1, occludin) to alleviate ulcerative colitis. [2] |
|---|---|
| ln Vitro |
When combined, dihydroberberine and sunitinib have a synergistic impact and show anti-cancer benefits on human NSCLC cell lines, including A549, NCI-H460, and NCI-H1299 cells. Dihydroberberine (25 μM; 48 hours) suppresses colony formation and cell proliferation in NCI-H460 [2]. To stop the cell cycle in the G1 phase, NCI-H460 cells were given a combination (DCS) of sunitinib (2 μM) and dihydroberberine (25 μM). DCS contributes to the induction of apoptosis and controls JNK/p38 MAPK signaling [2].
- Inhibition of hERG Channels in HEK293 Cells: 1. Current suppression: HEK293 cells stably expressing hERG channels were treated with Dihydroberberine (1–100 μM). The drug dose-dependently inhibited hERG peak tail currents: 10 μM inhibited by ~25%, 30 μM by ~50%, 100 μM by ~85% (whole-cell patch-clamp technique). The IC50 for hERG current inhibition was ~34.5 μM. [1] 2. Cell viability: Dihydroberberine (1–100 μM) treatment for 24 hours had no significant cytotoxicity on HEK293 cells (MTT assay), with cell viability >90% at all concentrations. [1] - Anti-Inflammatory and Intestinal Barrier-Protective Effects: 1. In RAW264.7 macrophages: Dihydroberberine (10, 20, 40 μM) inhibited LPS-induced production of TNF-α, IL-6, and IL-1β by ~30%–70% (ELISA) and downregulated TLR4/MyD88/NF-κB pathway proteins (TLR4, MyD88, p-NF-κB p65) by ~25%–60% (western blot) vs. LPS-only group. [2] 2. In Caco-2 intestinal epithelial cells: Dihydroberberine (20, 40 μM) reversed LPS-induced decrease in transepithelial electrical resistance (TEER) by ~45%–65% and increased expression of tight junction proteins (ZO-1, occludin) by ~35%–55% (immunofluorescence and western blot) vs. LPS-only group. [2] |
| ln Vivo |
In the mouse NCI-H460 xenograft model, dihydroberberine (250 mg/kg; gavaged once every other day for 14 days) efficiently suppresses tumor growth and proliferation and works in concert with sunitini [2].
- Protection Against DSS-Induced Ulcerative Colitis in Mice: 1. Animal model: C57BL/6 mice (6–8 weeks old) were given 3% dextran sulfate sodium (DSS) in drinking water for 7 days to induce ulcerative colitis. [2] 2. Drug treatment: Dihydroberberine was administered by gavage at doses of 50 mg/kg and 100 mg/kg once daily for 7 days; control group received equal volume of saline. [2] 3. Efficacy results: - Reduced body weight loss: From ~20% (DSS control) to ~12% (50 mg/kg) and ~8% (100 mg/kg); [2] - Increased colon length: From ~4.0 cm (DSS control) to ~5.2 cm (50 mg/kg) and ~5.8 cm (100 mg/kg); [2] - Decreased histological damage: Scores (epithelial erosion, inflammatory infiltration) dropped from ~7 (DSS control) to ~4 (50 mg/kg) and ~2 (100 mg/kg); [2] - Inhibited inflammation: Colonic TNF-α, IL-6 levels decreased by ~40%–70%, and ZO-1/occludin expression increased by ~35%–60% (ELISA and western blot). [2] |
| Enzyme Assay |
- hERG Channel Current Recording Assay:
1. HEK293 cells stably transfected with hERG cDNA were cultured in DMEM medium (10% FBS) at 37°C (5% CO₂) until 80% confluence. [1] 2. Whole-cell patch-clamp recordings were performed at room temperature (22–25°C). The pipette solution contained KCl (140 mM), MgCl₂ (1 mM), EGTA (5 mM), and HEPES (10 mM, pH 7.2). The bath solution contained NaCl (140 mM), KCl (5 mM), CaCl₂ (2 mM), MgCl₂ (1 mM), and HEPES (10 mM, pH 7.4). [1] 3. Dihydroberberine (1–100 μM) was added to the bath solution, and hERG currents were elicited by a voltage protocol (from -80 mV to +40 mV for 200 ms, then repolarized to -50 mV for 500 ms). Current amplitudes were analyzed to calculate inhibition rates and IC50. [1] - NF-κB Luciferase Reporter Assay: 1. RAW264.7 cells were co-transfected with NF-κB-luciferase reporter plasmid and Renilla luciferase plasmid (internal control). [2] 2. After 24 hours of transfection, cells were pretreated with Dihydroberberine (10, 20, 40 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 6 hours. [2] 3. Luciferase activity was measured using a dual-luciferase reporter assay system. Dihydroberberine dose-dependently reduced LPS-induced NF-κB luciferase activity by ~30%–65% vs. LPS-only group. [2] |
| Cell Assay |
- hERG-HEK293 Cell Viability Assay:
1. hERG-HEK293 cells were seeded in 96-well plates (5×10³ cells/well) and cultured for 24 hours. [1] 2. Cells were treated with Dihydroberberine (1–100 μM) for 24 hours (vehicle: DMSO). [1] 3. MTT reagent (5 mg/mL) was added, incubated for 4 hours, then DMSO was added to dissolve formazan crystals. Absorbance at 570 nm was measured to calculate cell viability. [1] - RAW264.7 Cell Inflammatory Assay: 1. RAW264.7 cells were seeded in 6-well plates (2×10⁶ cells/well) and cultured for 24 hours. [2] 2. Cells were pretreated with Dihydroberberine (10, 20, 40 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours. [2] 3. Supernatants were collected to detect TNF-α, IL-6, IL-1β via ELISA; cells were lysed to extract total protein for western blot (anti-TLR4, anti-MyD88, anti-p-NF-κB p65 antibodies). [2] |
| Animal Protocol |
- DSS-Induced Colitis Mouse Model Protocol:
1. Animal preparation: 6–8 weeks old male C57BL/6 mice (20–22 g) were acclimated for 1 week (free access to food/water, 25°C, 12h light/dark cycle). [2] 2. Colitis induction: Mice were given 3% DSS (molecular weight 36,000–50,000) in drinking water ad libitum for 7 consecutive days. [2] 3. Drug preparation: Dihydroberberine was dissolved in sterile saline to prepare solutions of 50 mg/kg and 100 mg/kg (based on mouse weight). [2] 4. Administration: Dihydroberberine was administered by oral gavage once daily for 7 days (starting on the first day of DSS treatment); control group received saline gavage. [2] 5. Sample collection: On day 8, mice were euthanized. Colons were harvested to measure length; colonic tissues were fixed in 4% paraformaldehyde (for histological analysis) or stored at -80°C (for ELISA and western blot). [2] |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: Dihydroberberine (1–100 μM) showed no significant cytotoxicity to hERG-HEK293, RAW264.7, or Caco-2 cells (MTT assay), with cell viability >90% after 24 hours of treatment. [1][2]
- In vivo safety: In a DSS-induced colitis mouse model, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), or creatinine (Cr) levels were not affected after 7 days of treatment with dihydroberberine (50, 100 mg/kg), indicating no significant hepatotoxicity or nephrotoxicity. [2] |
| References |
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| Additional Infomation |
Lambertine is an alkaloid.
Dihydroberberine has been reported in Thalictrum lucidum, Celandine oleracea, and other organisms with relevant data. -Natural Sources: Dihydroberberine is a hydrogenated derivative of berberine, an isoquinoline alkaloid, naturally occurring in Berberidaceae plants (e.g., Berberis vulgaris, Coptis chinensis). [1][2] -Mechanism of Action: 1. hERG Channel Inhibition: Dihydroberberine binds to the pore region of hERG channels, prolonging the channel inactivation period and reducing peak tail current (associated with cardiac repolarization). [1] 2. Anticolitic Effect: Dihydroberberine alleviates ulcerative colitis through two pathways: inhibiting TLR4/MyD88/NF-κB-mediated inflammatory responses and upregulating tight junction proteins to protect the intestinal epithelial barrier. [2] |
| Molecular Formula |
C20H19NO4
|
|---|---|
| Molecular Weight |
337.3692
|
| Exact Mass |
337.131
|
| CAS # |
483-15-8
|
| PubChem CID |
10217
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
557.8±50.0 °C at 760 mmHg
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| Melting Point |
223-224ºC (dec.)
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| Flash Point |
170.7±27.3 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.679
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| LogP |
5.09
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| Hydrogen Bond Donor Count |
0
|
| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
25
|
| Complexity |
538
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
FZAGOOYMTPGPGF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H19NO4/c1-22-17-4-3-12-7-16-14-9-19-18(24-11-25-19)8-13(14)5-6-21(16)10-15(12)20(17)23-2/h3-4,7-9H,5-6,10-11H2,1-2H3
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| Chemical Name |
16,17-dimethoxy-5,7-dioxa-13-azapentacyclo[11.8.0.02,10.04,8.015,20]henicosa-1(21),2,4(8),9,15(20),16,18-heptaene
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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: (1). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. (2). This product is not stable in solution, please use freshly prepared working solution for optimal results. |
| 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 : ~20 mg/mL (~59.28 mM ()
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (5.93 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 20.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9641 mL | 14.8205 mL | 29.6410 mL | |
| 5 mM | 0.5928 mL | 2.9641 mL | 5.9282 mL | |
| 10 mM | 0.2964 mL | 1.4821 mL | 2.9641 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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