Imperatorin is a secondary metabolite found in plants that is a member of the coumarin family, namely the furanocoumarins. Imperatorin acts through α1β2η2S receptors to increase GABA-induced chloride currents (IGABA). At 100 μmol and 300 μmol, respectively, imperatorin increased IGABA by 50.5±16.3% and 109.8±37.7%. In vitro, [3H]diazepam's binding to the benzodiazepine site of the GABAA receptor in rat brain is inhibited by both Phellopterin and Imperatorin, which are both present in resveratrol root. Imperatorin's IC50 is 12.3 μmol, while Phellopterin's is There is a 400 nmol IC50. By permanently attaching to the GABA-T active site, imperatorin strongly and irreversibly inhibits GABA-T at concentrations ranging from 3.5 to 14 mmol in a way that is dependent on time and concentration. Imperatorin functions as a dose-dependent reversible inhibitor of acetylcholinesterase (AChE). Utilizing spectrophotometry, the AChE and BChE inhibitory properties of imperatorin and crude extract from Angelica sinensis fruit were examined at doses of 12.5, 25, 50, and 100 μg/mL. The inhibitory impact of imperatorin on AChE is low (13.75-46.11%), while it is significant (37.46-83.98%) on BChE. The IC50 of 31.4 μmol for BChE indicated that imperatorin was selective for BChE but not AChE. The most effective BACE-1 inhibitors were discovered to be imperatorin and (+)-Byakangelicol, with IC50 values of 91.8 and 104.9 μmol, respectively. Strong NO synthesis inhibition is also exhibited by imperatorin (IC50=9.2 μmol) [1]. Imperatorin, whose EC50 is 12.6±3.2 μM, is a mild agonist of TRPV1, a channel that is implicated in sensing a range of unpleasant stimuli [2].

Imperatorin had anxiolytic effects and enhanced memory at dosages of 10 and 20 mg/kg and 30 minutes post-injection. It also increased learning at two distinct stages: acquisition and consolidation. It has also been demonstrated that acute administration of imperatorin at doses of 10 and 20 mg/kg reduces the anxiogenic effects of nicotine (subcutaneous injection, 0.1 mg/kg). The anticonvulsant effectiveness of carbamazepine against maximal shock-induced seizures was dramatically increased by intraperitoneal injection of imperatorin at doses of 30 and 40 mg/kg. This resulted in a lowering of the ED50 from 10.8 to 6.8 mg/kg (34% reduction) and 6 mg/kg (42% reduction), respectively. Additionally, the total brain concentration of carbamazepine increased by 85% (from 1.260 μg/mL to 2.328 μg/mL) when imperatorin at 30 mg/kg and carbamazepine at 6.8 mg/kg were administered. This increase may have resulted from altered blood barrier permeability or from effects akin to those of multidrug resistance protein inhibitors [1]. A naturally occurring furanocoumarin called imperatorin inhibits the action of acetylcholinesterase and inactivates gamma-aminobutyric acid transaminase. Scopolamine-impaired memory consolidation and acquisition are improved when imperatorin, at doses of 5 and 10 mg/kg, is administered acutely prior to scopolamine injection (1 mg/kg). Additionally, the effects of scopolamine on memory acquisition were greatly reduced by the maximum dose of imperatorin (10 mg/kg), which was given twice a day for seven days. In contrast, doses of 5 and 10 mg/kg of furanocoumarins had the same effect. efficient when memory is improved. Measurement is consolidation [3].

Mouse Memory Study:** 10-month-old mice received imperatorin (0.79 mg/kg) or A. archangelica extract orally for 14 days or longer. Memory was assessed using the step-down passive avoidance test. [1]
- **Mouse Anxiolytic/Cognitive Study:** Swiss male mice received imperatorin (1, 5, 10, 20 mg/kg, i.p.) 30 min before testing in the elevated plus maze, modified elevated plus maze, and passive avoidance tests. [1]
- **Mouse Oxidative Stress Study:** Mice received imperatorin (1 mg/kg, i.p., twice daily for 6 days) and nicotine (0.1 mg/kg, s.c.). Brain tissues were analyzed for MDA, GPx, SOD, and GR levels. [1]
- **Mouse Scopolamine Study:** Mice received imperatorin (5 or 10 mg/kg, i.p.) before scopolamine (1 mg/kg). Memory was assessed in passive avoidance test, and oxidative stress markers were measured. [1]
- **Mouse Anticonvulsant Study:** Mice received imperatorin (10-100 mg/kg, i.p.) at various times before the maximal electroshock seizure (MES) test. Seizure threshold was determined. ED50 and TD50 values were calculated. [1]
- **Rat Antihypertensive Study:** Renal hypertensive rats received imperatorin (6.25, 12.5, or 25 mg/kg/day, intragastric). Blood pressure was measured, and kidney tissue was analyzed for NADPH oxidase expression and antioxidant markers. [1]
- **Rat Cardiac Hypertrophy Study:** Hypertensive rats received imperatorin (25 mg/kg/day, intragastric). Heart tissue was examined for myocyte diameter, fibrosis, and hemodynamic parameters. [1]
- **Mouse Xenograft Study:** Nude mice bearing HepG2 tumors received imperatorin (50 or 100 mg/kg/day, oral) for 14 days. Tumor volume, body weight, and signs of toxicity were monitored. [1]
- **Mouse Hepatitis Study:** Mice with concanavalin A-induced or anti-Fas antibody-induced hepatitis received imperatorin (100 mg/kg). Plasma ALT activity was measured. [1]

Absorption, Distribution and Excretion
We developed a rapid and sensitive detection method for the quantitative determination of isoprenone in plasma and tissues. Gas chromatography/mass spectrometry (GC/MS) was used for analysis in selected ion monitoring mode. The main pharmacokinetic parameters obtained were: Tmax = 1.23 ± 0.26 h, Cmax = 0.95 ± 0.38 μg/mL, AUC = 3.42 ± 0.52 h·μg/mL, and Ka = 1.34 ± 0.18 h. The results showed that isoprenone was readily absorbed, but its elimination was slow within 3 to 12 hours after oral administration. The concentrations of isoprenone in the liver, kidney, lung, and heart of rats were higher than in other organs. To determine the free fraction in serum, samples were filtered using an ultrafiltration membrane with a molecular weight cutoff of 10 kDa, and extracted using liquid-liquid extraction. The protein binding rates in rat plasma, spontaneously hypertensive rat plasma, human plasma, and human serum albumin were 84±3%, 69±7%, 81±7%, and 75±3%, respectively. This study established a simple and sensitive gas chromatography-mass spectrometry (GC-MS) method to investigate the bioavailability, protein binding rate, and metabolism of isoflavones in rats. The results showed that the pharmacokinetics of isoflavones were linear after intravenous and oral administration in rats. The absolute bioavailability of isoflavones at doses of 6.25, 12.5, and 25 mg/kg were approximately 3.85%, 33.51%, and 34.76%, respectively. The low bioavailability of imperatorin may be attributed to its poor absorption or extensive metabolism. This study investigated the phase I metabolites of imperatorin metabolized in rat liver microsomes, isolating and identifying two metabolites: flavovirin and heraclinin. Following oral administration of imperatorin, one metabolite (heracin) was detected in rat plasma, and two potential metabolites (heraclinin and flavovirol) were detected in rat urine. However, no potential metabolites were detected in rat feces or bile. These results indicate that imperatorin metabolites are primarily excreted via the kidneys, and heraclinin is associated with the active ingredient. Demethylation and oxidation are the main metabolic pathways. In in vitro experiments, when the concentrations of imperatorin in rat plasma were 1.0 μg/mL and 50.0 μg/mL, the plasma protein binding rates were 90.1% and 92.6%, respectively, indicating that the distribution of imperatorin in both intracellular and extracellular spaces is relatively slow. Imperatorin (IMP) is a major component of many traditional Chinese medicines and possesses anti-osteoporosis activity. This study aimed to investigate the biotransformation process of IMP and evaluate the anti-osteoporosis activity of its metabolites. Among 18 screened filamentous fungi, Penicillium AS 3.510 exhibited good IMP metabolism, generating novel derivatives. Ten transformation products were isolated and purified, and their structures were precisely identified based on spectral data. Eight metabolites (2-8 and 10) were newly discovered and had not been previously reported. The main biotransformation reactions included hydroxylation of the isopentenyl side chain and lactone ring-opening of the furanocoumarin backbone. Furthermore, the anti-osteoporosis activity of all products (1-10) was evaluated using MC3T3-E1 cells. The results showed that products 5 and 8 had the best bioactivity in promoting MC3T3-E1 cell growth. These products could be used in future treatments for osteoporosis. This study established a simple and sensitive gas chromatography-mass spectrometry method to investigate the bioavailability, protein binding, and metabolism of isopentenone in rats. The results showed that the pharmacokinetics of isopentenone were linear after intravenous and oral administration in rats. The absolute bioavailability of isoprenone at doses of 6.25, 12.5, and 25 mg/kg was approximately 3.85%, 33.51%, and 34.76%, respectively. The low bioavailability of imperatorin may be attributed to poor absorption or extensive metabolism. This study investigated the phase I metabolites of imperatorin metabolized in rat liver microsomes, isolating and identifying two metabolites, flavovirol and heracrine. Following oral administration of imperatorin, one metabolite (heracrine) was detected in rat plasma, and two potential metabolites (flavovirol and heracrine) were detected in rat urine. However, no potential metabolites were detected in rat feces or bile. These results indicate that imperatorin metabolites are primarily excreted via the kidneys, and heracrine is associated with the active ingredient. Demethylation and oxidation are the main metabolic pathways. In in vitro experiments, when the concentrations of imperatorin in rat plasma were 1.0 μg/mL and 50.0 μg/mL, the plasma protein binding rates were 90.1% and 92.6%, respectively, indicating that the distribution of imperatorin in both intracellular and extracellular spaces was relatively slow. Paraoxygenase 1 (PON1) is a key enzyme in organophosphate metabolism. PON1 can inactivate certain organophosphates through hydrolysis. PON1 can hydrolyze the active metabolites of various organophosphate pesticides and nerve agents (such as soman, sarin, and VX). The existence of PON1 gene polymorphism leads to differences in the enzyme activity level and catalytic efficiency of this esterase, suggesting that different individuals may be more sensitive to the toxic effects of organophosphates.

Toxicity Summary
Identification and Uses: Imperatorin is a furanocoumarin compound isolated from the fruit of Imperatorinus arvense. It has been used as an experimental drug in testing. Human Studies: Imperatorin exhibits phototoxicity and photomutability in human lymphocytes. In vitro experiments showed that imperatorin can induce chromosomal structural aberrations and sister chromatid exchange in human lymphocytes. Animal Studies: Imperatorin has anticonvulsant effects in mice. No lesions were observed in the livers of rats treated with imperatorin. Imperatorin can induce mutations in the ouabain locus in Chinese hamster V79 cells and mouse C3H/1OT1/2 cells. In Chlamydomonas reinhardtii, imperatorin exhibits phototoxicity and photomutability. The isoflavones are mutagenic in the Ames test strains (TA92, TA97, TA98, TA100), but not in the TA94 and TA102 strains. The TA98 and TA100 strains showed the highest mutagenicity. Microsomal activation is not essential for mutagenicity. In vivo and in vitro studies have demonstrated that isoflavones possess anti-inflammatory and antioxidant activities. Isoflavones are inhibitors of cholinesterase, or acetylcholinesterase (AChE). Cholinesterase inhibitors (or "anticholinesterases") inhibit the activity of acetylcholinesterase. Because acetylcholinesterase plays a vital physiological role, chemicals that interfere with its activity are potent neurotoxins; even low doses can cause excessive salivation and lacrimation, followed by muscle spasms and ultimately death. Neurotoxins and substances in many pesticides have been shown to exert their effects by binding to serine residues at the active site of acetylcholinesterase, thereby completely inhibiting the enzyme's activity. Acetylcholinesterase is responsible for breaking down the neurotransmitter acetylcholine, which is released at the neuromuscular junction, causing muscle or organ relaxation. Inhibition of acetylcholinesterase results in the accumulation and sustained action of acetylcholine, leading to continuous nerve impulse transmission and unstoppable muscle contractions. The most common acetylcholinesterase inhibitors are phosphorus-containing compounds designed to bind to the enzyme's active site. Its structural requirements include a phosphorus atom with two lipophilic groups, a leaving group (e.g., a halide or thiocyanate), and a terminal oxygen atom. Many furanocoumarins' mechanisms of action are based on their ability to form photoadducts with DNA and other cellular components such as RNA, proteins, and membrane proteins, including phospholipases A2 and C, calcium-dependent and cAMP-dependent protein kinases, and epidermal growth factor. Furanocoumarins can intercalate between DNA base pairs and form cycloadducts upon UVA irradiation (L579).

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Interactions
This study investigated the effects of isoprenone (IMP) on the anticonvulsant activity and acute adverse reactions of lamotrigine (LTG, a second-generation antiepileptic drug) in a mouse maximal electroshock-induced epilepsy (MES) model and chimney assay. To assess the nature of the interaction between IMP and LTG in the MES assay, the total concentration of LTG in brain tissue was determined using high-performance liquid chromatography (HPLC). The results showed that intraperitoneal injection of 50 mg/kg IMP 30 minutes prior to the maximal electroconvulsive shock (MES) test significantly enhanced the anticonvulsant effect of LTG, reducing the half-maximal effective dose (ED50) of LTG from 6.11 mg/kg to 2.47 mg/kg (p < 0.05). Conversely, intraperitoneal injection of 30 mg/kg and 40 mg/kg IMP did not significantly enhance the anticonvulsant activity of LTG against MES-induced seizures, although the ED50 values of LTG were observed to decrease from 6.11 mg/kg to 5.77 mg/kg and 4.28 mg/kg, respectively. On the other hand, intraperitoneal injection of IMP (at doses of 30, 40, and 50 mg/kg, respectively) had no effect on the acute adverse reactions of LTG, and the half-maximal toxic dose (TD₅₀) of LTG remained almost unchanged in the chimney test, ranging from 22.13 to 30.04 mg/kg. The protective index (TD50 to ED50 ratio) of LTG alone was 4.90, while the protective index increased to 5.21, 6.77, and 8.96 when LTG was used in combination with IMP at doses of 30, 40, and 50 mg/kg, respectively. Pharmacokinetic evaluation of the total intracranial LTG concentration using high-performance liquid chromatography (HPLC) showed that a dose of 50 mg/kg IMP did not affect the total intracranial LTG concentration in experimental animals. Therefore, the interaction between IMP and LTG observed in the maximal electroshock test was essentially pharmacodynamic. This study demonstrates that, in preclinical animal studies, IMP can improve the pharmacological properties of LTG, including its antiepileptic effect and acute adverse reactions. If these results can be generalized to clinical applications, the combination of LTG and IMP may be of significant importance for patients with epilepsy, representing a potentially effective combination.
Background and Objective: Herbal remedies are widely used as food and medicine and participate in various physiological and pathological processes. Melatonin is a human hormone synthesized and secreted by the pineal gland, possessing a variety of biological functions. This study evaluated the potential effects of components extracted from common herbs on human melatonin metabolism. Methods: This study employed in vivo pharmacokinetic studies (including 12 healthy subjects), in vitro human liver microsome (HLM) and recombinant human cytochrome P450 (CYP) isoenzyme incubation experiments, and computer-aided quantitative structure-activity relationship (QSAR) model analysis based on comparative molecular field analysis and comparative molecular similarity index analysis to explore these interactions. Main Results: After systematic screening of 66 commonly used herbs, Angelica dahurica was found to have the strongest inhibitory effect on melatonin metabolism in vitro. In vivo pharmacokinetic studies showed that Angelica dahurica inhibited melatonin metabolism, increasing the AUC and Cmax of melatonin in human subjects by approximately 12-fold and 4-fold, respectively. Coumarins from Hedyotis diffusa (including isohexenoside, isohexenoside, chlorophyll, 5-methoxypsoralen, and 8-methoxypsoralen) significantly inhibited melatonin metabolism by suppressing CYP 1A2, 1A1, and 1B1 in human liver microsomes (HLM), with Ki values of 14.5 nM, 38.8 nM, 6.34 nM, 5.34 nM, and 18 nM, respectively. We established a QSAR model, which can effectively predict the potential risk of coumarins inhibiting melatonin metabolism in vivo. Conclusion and Significance: Coumarins from Hedyotis diffusa can inhibit melatonin metabolism both in vitro and in vivo. Our findings provide important guidance for the clinical application of melatonin. Naturally occurring coumarins (NOCs) have anticancer effects in a mouse skin model. To characterize the chemopreventive potential of NOC compounds against breast cancer, we first examined their effects on the formation of 7,12-dimethylbenzo[a]anthracene (DMBA)-DNA adducts in mouse mammary glands. We hypothesized that NOC compounds that both inhibit cytochrome P450 1A1/1B1 and induce hepatic glutathione S-transferases (GSTs) would be most effective in blocking DMBA-DNA adduct formation in mouse mammary glands. To test this hypothesis, we compared simple coumarin compounds (e.g., coumarin and limonene, which induce mouse hepatic GSTs but have little effect on P450 1A1/1B1) with linear furanocoumarins (e.g., isoimperatorin and isoimperatorin, which induce hepatic GSTs and are potent inhibitors of P450 1A1/1B1). Mice were pretreated with NOCs (150 mg/kg body weight, by gavage) before receiving a single dose of DMBA (50 μg) or multiple doses of DMBA (20 μg daily for 3 and 6 weeks, respectively). The formation of DMBA-DNA adducts in mammary tissue was quantified using a nuclease P1-enhanced 32P labeling assay. After a single DMBA dose, coumarin, limonene, isoimperatorin, and isoimperatorin inhibited DMBA-DNA adduct formation by 50%, 41%, 79%, and 88%, respectively. After 3 weeks of continuous administration, coumarin, limonene, and isoimperatorin inhibited DMBA-DNA adduct formation by 36%, 60%, and 66%, respectively; after 6 weeks of continuous administration, they inhibited DMBA-DNA adduct formation by 0%, 49%, and 55%, respectively. In a 6-week dose-response study, researchers tested selected NOCs and 7,8-benzoflavonoids (a potent P4501 inhibitor with minimal effect on GST). Results showed that at doses of 35, 70, and 150 mg/kg, DMBA-DNA adduct formation was inhibited by 0%, 43%, and 24%, respectively; DMBA-DNA adduct formation was inhibited by 26%, 26%, and 69%, respectively, in the isomaltose group; and DMBA-DNA adduct formation was inhibited by 80%, 96%, and 97%, respectively, in the 7,8-benzoflavonoid group. In summary, these results indicate that linear furanocoumarins have a stronger inhibitory effect on DMBA-DNA adduct formation in mouse mammary glands compared to simple coumarins, and their primary role is likely the inhibition of P4501. We investigated several natural coumarins previously identified as potent inhibitors of ethoxyhalogen-O-deethylase (EROD) and/or pentohalogen-O-dealkylase (PROD) in mouse liver to examine their effects on the formation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenzo[a]anthracene (DMBA) DNA adducts in mouse epidermis, and their influence on the development of skin tumors induced by these polycyclic aromatic hydrocarbons (PAHs). Bergamotin, a potent hepatic EROD inhibitor, significantly reduced the total valent binding of B[a]P to DNA in a dose-dependent manner when applied topically 5 minutes before the initial dose of benzo[a]pyrene (B[a]P), 24 hours after treatment. 400 nmol of bergamotin reduced the covalent binding of B[a]P by 72%. 400 nmol of bergamotin also significantly reduced the total valent binding of B[a]P by 59%. Furthermore, both coumarins selectively reduced the formation of major (+) anti-B[a]P-diol epoxide-N2-dGuo adducts. Conversely, bergamotin and corianderin did not significantly reduce the covalent binding of DMBA to epidermal DNA at doses of 400 nmol or 800 nmol. Isoimperatorin and isoimperatorin are potent inhibitors of hepatic PROD activity, significantly reducing the overall binding of DMBA to epidermal DNA by 67% and 52%, respectively, at a dose of 400 nmol. Both coumarins also inhibited the formation of B[a]P-DNA adducts at similar doses, but to a lesser extent. A dose of 400 nmol of isoimperatorin significantly reduced the formation of DMBA trans- and cis-diol epoxide-derived covalent DNA adducts. Bergamotin is a potent inhibitor of B[a]P-induced tumorigenesis, while corianderin is less effective in this regard. Isohexanterin is a potent inhibitor of DMBA-induced skin tumorigenesis and can completely inhibit the carcinogenic effects of this polycyclic aromatic hydrocarbon. At doses higher than those inhibiting DMBA, isohexanterin also inhibits B[a]P-induced tumorigenesis. These findings suggest that several naturally occurring coumarins can block DNA adduct formation and tumor initiation induced by polycyclic aromatic hydrocarbons (such as benzo[a]pyrene and dimethylbenzo[dMBA]). The mechanism by which they inhibit DNA adduct formation and tumor initiation appears to be related to the inhibition of P450 enzymes involved in the metabolic activation of these hydrocarbons. Finally, the varying effects of certain coumarins on B[a]pyrene and DMBA-induced DNA adduct formation and tumor initiation may help elucidate the role of specific cytochrome P450 enzymes in their metabolic activation. For more complete data on interactions of isoprenones (11 in total), please visit the HSDB record page.

[1]. Imperatorin-pharmacological meaning and analytical clues: profound investigation. Phytochem Rev. 2016;15:627-649.

[2]. Furanocoumarins are a novel class of modulators for the transient receptor potential vanilloid type 1 (TRPV1) channel. J Biol Chem. 2014 Apr 4;289(14):9600-10.

[3]. Effects of imperatorin on scopolamine-induced cognitive impairment and oxidative stress in mice. Psychopharmacology (Berl). 2015 Mar;232(5):931-42.

Therapeutic Uses
Previous studies have found that humans ingest various naturally occurring coumarins in their daily diet. These coumarins can inhibit the P450-mediated metabolism of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenzo[a]anthracene (DMBA) in vitro, block the formation of DNA adducts in mouse epidermis, and inhibit B[a]P and/or DMBA-induced skin tumors when applied topically to mice. This study aims to investigate the effects of two linear furanocoumarin compounds (70 mg/kg, orally administered for four consecutive days) on P450 and glutathione S-transferase (GST) activities in different mouse tissues, as well as the formation of B[a]P and DMBA-induced DNA adducts. One hour and 24 hours after oral administration of isoprenone, the activities of ethoxyhalogen O-deethylase (EROD) and pentylohalogen O-dealkylase (PROD) in the epidermis were significantly reduced. One hour after oral administration of isoprenone, EROD activity in the lungs and forestomach was slightly inhibited, while PROD activity was significantly reduced one hour after the last oral administration. Twenty-four hours after the last oral administration of isoprenone or isoprenone, EROD and PROD activities in the epidermis and lungs remained inhibited. However, forestomach P450 activity had recovered to control levels. Interestingly, one hour after treatment with isoprenone or isoprenone, EROD activity in the liver was inhibited, but PROD activity was unaffected at this time; however, at 24 hours, the activities of both enzymes increased. The increase in EROD and PROD activities was consistent with the increase in hepatic P450 content. Compared with the corn oil control group, treatment with imperatorin and isoimperatorin resulted in a 1.6-fold increase in hepatic cytoplasmic GST activity at 1 hour and 24 hours after the last oral administration. Oral administration of imperatorin and isoimperatorin also protected against DNA adduct formation induced by benzo[a]pyrene (B[a]P) and dimethylbenzo[a]pyrene (DMBA). Imperatorin pretreatment reduced DMBA-induced DNA adduct formation in the forestomach. Isoimperatorin pretreatment reduced DNA adduct levels in liver (B[a]P), lung (B[a]P), and mammary epithelial cells (DMBA). These results suggest that dietary supplementation with isopentenone and isoimperatorin may have potential chemopreventive effects.
/EXPL THER/ Enhanced endothelial nitric oxide synthase (eNOS) signaling has been reported to be associated with improved cardiac remodeling, while nitric oxide (NO) levels are associated with cardiac hypertrophy and heart failure. Isopentenone, a dietary furanocoumarin, has been shown to prevent cardiac hypertrophy in spontaneously hypertensive rats (SHR). Therefore, we aimed to elucidate whether isopentenone alleviates cardiac hypertrophy and heart failure through the NO signaling pathway. In neonatal mouse cardiomyocytes, isopentenone inhibited protein synthesis stimulated by isoproterenol or phenylephrine, while NG-nitro-L-arginine methyl ester (L-NAME) had no effect. Four weeks after transverse aortic coarctation (TAC) in male Kunming (KM) mice, compared with the control group, isoprenone treatment significantly reduced the heart weight/body weight ratio (6.60 ± 0.35 mg/g in the TAC group and 4.54 ± 0.29 mg/g in the isoprenone 15 mg kg⁻¹ d⁻¹ gavage group, P<0.01); similar changes were observed in the lung weight/body weight ratio (7.30 ± 0.85 mg/g in the TAC group and 5.42 ± 0.51 mg/g in the isoprenone 15 mg kg⁻¹ d⁻¹ gavage group) and the degree of myocardial fibrosis. L-NAME inhibited all of the above improvements. Isoprenone treatment significantly activated eNOS phosphorylation. The elevated levels of myocardial mRNA of natriuretic peptide precursor B and NO synthase protein inhibitors in TAC mice were reduced in mice treated with isoprenone. Isoprenone can reduce cardiac hypertrophy in vivo and in vitro, and prevent the progression of hypertrophy to heart failure via a NO-mediated pathway. This study investigated the effects of isoprenone (IMP) on the anticonvulsant activity and acute adverse reactions of lamotrigine (LTG, a second-generation antiepileptic drug) in a mouse maximal electroshock-induced epilepsy (MES) model and chimney test. To assess the interaction between IMP and LTG in the MES test, the total concentration of LTG in the mouse brain was determined by high-performance liquid chromatography (HPLC). The results showed that intraperitoneal injection of 50 mg/kg IMP 30 minutes before the maximal electroshock (MES) test significantly enhanced the anticonvulsant effect of LTG, reducing the half-maximal effective dose (ED50) of LTG from 6.11 mg/kg to 2.47 mg/kg (p < 0.05). Conversely, intraperitoneal administration of IMP at doses of 30 mg/kg and 40 mg/kg did not significantly enhance the anticonvulsant activity of LTG against MES-induced seizures, although the ED50 values of LTG were observed to decrease from 6.11 mg/kg to 5.77 mg/kg and 4.28 mg/kg, respectively. On the other hand, intraperitoneal administration of IMP (at doses of 30, 40, and 50 mg/kg, respectively) had no effect on the acute adverse reactions of LTG, and the median toxic dose (TD₅₀) of LTG remained almost unchanged in the chimney assay, ranging from 22.13 to 30.04 mg/kg. The protection index (the ratio of TD₅₀ to ED₅₀) of LTG alone was 4.90, while the protection index increased to 5.21, 6.77, and 8.96, respectively, when LTG was used in combination with IMP at doses of 30, 40, and 50 mg/kg. Pharmacokinetic evaluation of the total intracranial LTG concentration was performed using high-performance liquid chromatography (HPLC). Results showed that a 50 mg/kg dose of IMP did not affect the total intracranial LTG concentration in experimental animals. Therefore, the interaction between IMP and LTG observed in the maximal electroshock test was essentially pharmacodynamic. This study indicates that in preclinical animal studies, IMP can improve the pharmacological properties of LTG when considering both antiepileptic effects and acute adverse drug reactions. If these results can be generalized to clinical applications, the combined use of LTG and IMP may have significant clinical implications for epilepsy patients, representing a potentially advantageous combination.
/EXPL THER/ Background: Isoprenylcoumarin (IM) is a furanocoumarin isolated from the root of Angelica dahurica and has been reported to have anticonvulsant and anticancer effects. This study examined the antiproliferative effects of IM on nine human cancer cell lines and selected human hepatocellular carcinoma HepG2 cells as the preferential target cells for IM killing. Furthermore, this study explored the mechanism of IM-induced apoptosis and its role in animals. Methods: Cell viability was detected by the MTT assay, and apoptosis was detected by Hoechst staining, Annexin V-PI double staining, and DNA fragmentation assay. Mitochondrial membrane potential was detected by JC-1 staining. The expression of apoptosis-related proteins was detected by Western blot analysis. Furthermore, the in vivo anticancer effect of imatinib (IM) was detected in a nude mouse model bearing HepG2 cells. Results: IM inhibited HepG2 cell proliferation in a time- and dose-dependent manner by inducing apoptosis, specifically through changes in nuclear morphology, DNA fragmentation, phosphatidylserine eversion, loss of mitochondrial membrane potential, release of cytochrome c into the cytoplasm, and activation of caspase-3, caspase-8, and caspase-9, as well as poly(ADP-ribose) polymerase (PARP) cleavage. Since caspase-8 or caspase-9 inhibitors can partially prevent cell death, and this was confirmed by Western blot analysis, our results also indicate that imatinib-induced apoptosis is mediated by both death receptors and the mitochondrial pathway. In animal models, imatinib at doses of 50 mg/kg and 100 mg/kg for 14 days effectively inhibited tumor growth by 31.93% and 63.18%, respectively. No significant weight loss or host toxicity was observed. Conclusion: Imatinib exerts its anti-tumor effect by inducing apoptosis in HepG2 cells through death receptors and mitochondrial pathways. Furthermore, IM exhibits significant in vivo antitumor activity with negligible weight loss and host damage.
For more complete data on the therapeutic uses of imperatorins (9 in total), please visit the HSDB record page.

C16H14O4

270.284

270.089

482-44-0

10212

White to off-white solid powder

1.2±0.1 g/cm3

448.3±45.0 °C at 760 mmHg

98-100ºC

224.9±28.7 °C

0.0±1.1 mmHg at 25°C

1.606

3.81

0

4

3

20

436

0

O(C([H])([H])/C(/[H])=C(\C([H])([H])[H])/C([H])([H])[H])C1=C2C(C([H])=C([H])C(=O)O2)=C([H])C2C([H])=C([H])OC1=2

OLOOJGVNMBJLLR-UHFFFAOYSA-N

InChI=1S/C16H14O4/c1-10(2)5-7-19-16-14-12(6-8-18-14)9-11-3-4-13(17)20-15(11)16/h3-6,8-9H,7H2,1-2H3

9-(3-methylbut-2-enoxy)furo[3,2-g]chromen-7-one

Ammidin MarmelosinImperatorin Pentosalen

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)

DMSO : ~50 mg/mL (~184.99 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.25 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 (9.25 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.)