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Bilobetin is a naturally occurring biflavonoid isolated from G. biloba with diverse biological activities. It can reduce blood lipids and improve the effects of insulin.
| Targets |
Natural biflavonoid; PPARα; PKA
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|---|---|
| ln Vitro |
HepG2 and Huh7 cell growth is inhibited by bilobetin (0–40 μM, 24/48/72 hours) [4]. In Huh7 and HepG2 cells, bilobetin (0–20 μM, 24 and 48 hours) causes ROS buildup, DNA damage, and an increase in G1 cells [4]. In sebaceous gland cells, bilobetin (1-2 μM, 1 day) suppresses AKT phosphorylation [4].
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| ln Vivo |
Through PKA-mediated phosphorylation of PPARα, Bilobetin (intraperitoneal injection, 12 mg/kg/day, 4 or 14 days) improves high-fat warning, lipotoxicity, and insulin resistance of high-fat diet [1]. injection (50 mg/kg for seven days) has the potential to cause renal damage and encourage the transport of AQP-2 to the transport plasma membrane [2]. Testicular toxicity caused by cisplatin (7 mg/kg, intraperitoneal injection, single dosage on the third day) is mitigated by Bilobetin (6 and 12 mg/kg, once daily for 10 days) [3].
Cisplatin (CP) is a productive anti-tumor used to treat numerous tumors. However, multiple toxicities discourage prolonged use, especially toxicity on the reproductive system. This experiment was mapped out to determine the potential therapeutic impact of Bilobetin on CP-induced testicular damage. Herein, Bilobetin was isolated from Cycas thouarsii leaves R. Br ethyl acetate fractions for the first time. A single dose of CP (7 mg/kg, IP) was used to evoke testicular toxicity on the third day. Rats were classified into five groups; Normal control, Bilobetin 12 mg/kg, Untreated CP, and CP treated with Bilobetin (6 and 12 mg/kg, respectively) orally daily for ten days. Bilobetin treatment ameliorated testicular injury. In addition, it boosted serum testosterone levels considerably and restored relative testicular weight. Nevertheless, apoptosis biomarkers such as P53, Cytochrome-C, and caspase-3 decreased significantly. Additionally, it enhanced the testes' antioxidant status via the activation of Nrf-2, inhibition of Keap-1, and significant elevation of SOD activity in addition to a reduction in lipid peroxidation. Histopathologically, Bilobetin preserved testicular architecture and improved testicular immunostaining of Ki67 substantially, showing evidence of testicular regeneration. Bilobetin's beneficial effects on CP-induced testicular damage are associated with enhanced antioxidant effects, lowered apoptotic signals, and the restoration of testes' regenerative capability. In addition, Bilobetin may be used in combination with CP in treatment protocols to mitigate CP-induced testicular injury.[3] |
| Enzyme Assay |
Enzyme activity and palmitate oxidation rate[1]
Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were measured spectroscopically using diagnostic kits from Wako. The extraction of cAMP and PKA from liver, RQ and mWAT was accomplished using the method described by Woo et al. (2006). The cAMP level and the PKA activity in tissues and primary hepatocytes were measured by use of commercial kits. The preparation of LPL from liver, RQ and mWAT was as described by Iverius and Lindqvist (1986). LPL activity in tissues was determined by use of a commercial kit. CPT-1 activity in mitochondria from liver and skeletal muscle was measured using a u.v. spectrophotometry method as described by Bieber et al. (1972). To measure the in vitro palmitate oxidation rate in homogenates of liver and muscle, 14C-metabolites and 14CO2 produced from [14C]-palmitate were quantified according to the method ofDoha et al. (2005). The hepatic levels of ATP, ADP and AMP were measured by HPLC. The concentrations of these nucleotides were calculated from the computer-integrated areas of the peaks in the sample chromatogram in relation to the areas obtained for standard solutions, as previously described by Maessen et al. (1988). Acyl-CoA dehydrogenase activity was measured in an isolated mitochondrial fraction according to the method described by Dommes et al. (1981). Acyl-CoA oxidase activity was measured in the 500× g supernatant fraction of liver homogenates as described previously (Ide et al., 1987). 16:0-CoA was used as a substrate for the acyl-CoA dehydrogenase and acyl-CoA oxidase assays. PDE activity in the cytosolic fraction and adenylate cyclase (AC) activity in the membrane fraction extracted from cultured hepatocytes were measured after the different treatments. Ligand binding assays[1] The binding affinities of Bilobetin to the ligand-binding domain (LBD) of PPARα and PPARγ were measured using the LanthaScreen PPARα and PolarScreen PPARγ Competitor Assay Kits according to the manufacturer's instructions. Fenofibrate acid and pioglitazone were used as positive control compounds. |
| Cell Assay |
Cell viability assay [4]
Cell Types: Huh7 and HepG2 cells Tested Concentrations: 0, 2.5, 5, 10, 20 and 40 μM Incubation Duration: 24/48/72 h Experimental Results: Inhibited cell proliferation in a dose-dependent manner. 5]. , the IC50 in Huh7 cells was 18.28 μM at 48 hrs (hours), and the IC50 in HepG2 cells at 72 hrs (hours) was 19 μM. Apoptosis analysis [4] Cell Types: Huh7 and HepG2 Cell Tested Concentrations: 0, 2.5, 5, 10, 20 μM Incubation Duration: 24/48 h Experimental Results: demonstrated total apoptotic cell rates of 2.2, 2.2, 1.9 and 10.6% 0, 5, 10 and 20 μM for 24 h (Huh7 cells) and 0, 5, 10 and 20 μM for 48 h (Huh7 cells) at 1.7, 1.5, 7.5 and 22.5%. Showing total apoptotic cell rates of 1.1, 1.2, 1.6 and 3.0% at 24 hrs (hours) (Huh7 cells) and 1.5, 1.1, 3.2 at 48 hrs (hours) (Huh7 cells) at 0, 5, 10 and 20 μM and 14.2%) at 0, 5, 10 and 20 μM, respectively. |
| Animal Protocol |
Animal/Disease Models: High-fat diet rats [1] Usage and
Doses: 12 mg/kg/day Route of Administration: intraperitoneal (ip) injection, 4 or 14 days after feeding mice HFD for 8 weeks. Experimental Results: Glucose infusion rate increased (GIR, P < 0.05) and EGP diminished (P < 0.05) during basal and clamp conditions. Total TG (P < 0.01) and VLDL-TG (P < 0.01) were diminished. Enhance liver absorption of Intralipid-TG. Reduces total lipid content in liver and muscle. Promotes the phosphorylation of PPARα and the translocation of PPARα from the cytoplasm to the nucleus in rat liver. Rats fed a high-fat diet were treated with bilobetin for either 4 or 14 days before applying a hyperinsulinaemic-euglycaemic clamp. Triglyceride and fatty acids labelled with radioactive isotopes were used to track the transportation and the fate of lipids in tissues. The activity of lipid metabolism-related enzymes and β-oxidation rate were measured. Western blot was used to investigate the phosphorylation, translocation and expression of PPARα in several tissues and cultured cells. The location of amino acid residues subjected to phosphorylation in PPARα was also studied.[1] In this study, rats were injected with 50 mg/kg of bilobetin, a biflavone isolated from Gb, for 7 days and aristolochic acid was used as positive controls. The results showed that the body weight and urine output of the rats were dramatically decreased, and urinary protein increased after the intraperitoneal injection of bilobetin compared with the control group. Bilobetin treatment showed vacuolar degeneration in the renal tubular epithelium, glomerular atrophy by histostaining, and podocyte fusion by electron microscopy. This study further showed that bilobetin promoted the trafficking of aquaporin 2 (AQP-2) onto the plasma membrane to achieve the function of urine concentration by in vivo study in rats and in vitro study in IMCD-3 cells. The redistribution of AQP-2 is due to increased expression of cGMP in IMCD-3 cells, which in turn promoted the phosphorylation of AQP-2 at site Ser-256. The proteinuria caused by bilobetin may be attributed to podocyte cell cycle arrest at G2/M transition, which is may associated with AKT and MAPK signaling.[2] |
| References |
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| Additional Infomation |
Bilobetin is a flavonoid oligomer.
Bilobetin has been reported in Austrocedrus chilensis, Thujopsis dolabrata, and other organisms with data available. |
| Molecular Formula |
C₃₁H₂₀O₁₀
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|---|---|
| Molecular Weight |
552.48
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| Exact Mass |
552.105
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| Elemental Analysis |
C, 67.39; H, 3.65; O, 28.96
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| CAS # |
521-32-4
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| PubChem CID |
5315459
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.6±0.1 g/cm3
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| Boiling Point |
869.9±65.0 °C at 760 mmHg
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| Melting Point |
296-298ºC
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| Flash Point |
291.9±27.8 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.750
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| LogP |
4.2
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
41
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| Complexity |
1060
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
IWEIJEPIYMAGTH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C31H20O10/c1-39-24-7-4-15(26-12-22(37)29-19(34)9-17(33)10-27(29)40-26)8-18(24)28-20(35)11-21(36)30-23(38)13-25(41-31(28)30)14-2-5-16(32)6-3-14/h2-13,32-36H,1H3
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| Chemical Name |
8-[5-(5,7-dihydroxy-4-oxochromen-2-yl)-2-methoxyphenyl]-5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one
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| Synonyms |
Bilobetin; 521-32-4; 4'-Monomethylamentoflavone; 8-[5-(5,7-dihydroxy-4-oxochromen-2-yl)-2-methoxyphenyl]-5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one; AJ4UE8X6JZ; 3''',8-Biflavone, 4',5,5'',7,7''-pentahydroxy-4'''-methoxy-; 8-[5-(5,7-dihydroxy-4-oxo-4H-1-benzopyran-2-yl)-2-methoxyphenyl]-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one; 8-(5-(5,7-DIHYDROXY-4-OXO-4H-1-BENZOPYRAN-2-YL)-2-METHOXYPHENYL)-5,7-DIHYDROXY-2-(4-HYDROXYPHENYL)-4H-1-BENZOPYRAN-4-ONE;
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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 : ~250 mg/mL (~452.51 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (3.76 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 | 1.8100 mL | 9.0501 mL | 18.1002 mL | |
| 5 mM | 0.3620 mL | 1.8100 mL | 3.6200 mL | |
| 10 mM | 0.1810 mL | 0.9050 mL | 1.8100 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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