Osthol

244.29

244.29

610-421-7

XH1TI1759C

31868

DTXSID20197507

Colorless needle like crystals|Prisms from ether|White powder

2932209090

35.5

3.8

white

1.1±0.1 g/cm3

83.5 °C

396.7°C at 760 mmHg

167.6±22.5 °C

1.557

methanol: soluble 10mg/mL, clear, colorless

room temp

6.9X10-6 mm Hg at 25 °C (est)

Henry's Law constant = 1.46X10-6 atm-cu m/mol at 25 °C (est)

Hydroxyl radical reaction rate constant = 1.26X10-1- cu cm/molec-sec at 25 °C (est)

NONH for all modes of transport

3

R36/37/38:Irritating to eyes, respiratory system and skin . R20/21/22:Harmful by inhalation, in contact with skin and if swallowed .

S26-S36/37-S36/37/39

GN7700000

Xi,Xn

Stable under recommended storage conditions.

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place.|Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.|ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Avoid breathing dust. Environmental precautions: Do not let product enter drains.|Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

IDENTIFICATION AND USE: Osthole is a natural product found in several medicinal plants such as Cnidium monnieri and Angelica pubescens. It has been tested as an experimental therapy. HUMAN STUDIES: Osthole has been reported to have antitumor activities via the induction of apoptosis and inhibition of cancer cell growth and metastasis. Studies in human colon cancer cell lines demonstrated that p53 was activated followed by generation of reactive oxygen species and activation of c-Jun N-terminal kinase. ANIMAL STUDIES: In vitro and in vivo experimental results have revealed that osthole demonstrates multiple pharmacological actions including neuroprotective, osteogenic, immunomodulatory, anticancer, hepatoprotective, cardiovascular protective, and antimicrobial activities. Osthole and other coumarins showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene. ECOTOXICITY STUDIES: There was an increase in the morphological abnormalities in D. rerio embryo due to osthol over time. Coagulation, delayed hatching, yolk sac edema, pericardial edema, and pigmentation were observed in embryos at 24-48 hours. Symptoms of scoliosis and head edema occurred after 72 hours. In addition, bent tails, ocular defects, and symptoms of collapse were observed in fertilized embryo tissue within 96 hours. Ocular defects and pigmentation were the additional symptoms observed in this study.

Acetaminophen (APAP) overdose leads to severe hepatotoxicity. Osthole, a natural coumarin found in traditional Chinese medicinal herbs, has therapeutic potential in the treatment of various diseases. In this study, we investigated the effects of osthole against APAP-induced hepatotoxicity in mice. Mice were administered osthole (100 mg/kg per day, ip) for 3 d, then on the fourth day APAP (300 mg/kg, ip) was co-administered with osthole. The mice were euthanized post-APAP, their serum and livers were collected for analysis. Pretreatment with osthole significantly attenuated APAP-induced hepatocyte necrosis and the increases in ALT and AST activities. Compared with the mice treated with APAP alone, osthole pretreatment significantly reduced serum MDA levels and hepatic H2O2 levels, and improved liver GSH levels and the GSSG-to-GSH ratio. Meanwhile, osthole pretreatment markedly alleviated the APAP-induced up-regulation of inflammatory cytokines in the livers, and inhibited the expression of hepatic cytochrome P450 enzymes, but it increased the expression of hepatic UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs). Furthermore, osthole pretreatment reversed APAP-induced reduction of hepatic cAMP levels, but pretreatment with H89, a potent selective PKA inhibitor, failed to abolish the beneficial effect of osthole, whereas pretreatment with L-buthionine sulfoximine, a GSH synthesis inhibitor, abrogated the protective effects of osthole on APAP-induced liver injury, and abolished osthole-caused alterations in APAP-metabolizing enzymes. In cultured murine primary hepatocytes and Raw264.7 cells, however, osthole (40 umol/L) did not alleviate APAP-induced cell death, but it significantly suppressed APAP-caused elevation of inflammatory cytokines. Collectively, we have demonstrated that osthole exerts a preventive effect against APAP-induced hepatotoxicity by inhibiting the metabolic activation of APAP and enhancing its clearance through an antioxidation mechanism.|Inflammation and oxidative stress are implicated in the development of neurodegenerative diseases. Osthole is a compound that is extracted from She Chuang Zi, which is a type of traditional Chinese medicine. Osthole has previously been demonstrated to exhibit anticancer activities and has a low toxicity. However, to the best of our knowledge, the anti-inflammatory effects of osthole in microglial cells have not been investigated extensively. The aim of the present study was to investigate the potential protective effects of osthole against inflammation induced by lipopolysaccharide (LPS) in microglial cells. The present study employed LPS-stimulated BV2 mouse microglia to establish an inflammatory cell model and to investigate the anti-inflammatory effects of osthole. Cells were pretreated with osthole for 1 hr prior to LPS (10 ug/mL) stimulation. At 6 hr after the addition of LPS, alterations in the levels of inflammatory factors, including tumor necrosis factor (TNF)-a, interleukin (IL)-6 and IL-1beta, were determined by ELISA. Furthermore, at 24 hr after the addition of LPS, western blot analysis was performed to analyze the alterations in the protein expression of nuclear factor-kappaB (NF-kappaB) p65, phosphorylated-NF-kappaB p65, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase (HO)-1. The results demonstrated that the secretion of the inflammatory cytokines TNF-a, IL-6 and IL-1beta by LPS-stimulated BV2 cells was significantly reduced by osthole treatment. Simultaneously, osthole treatment inhibited the LPS-induced activation of the NF-kappaB signaling pathway. In addition, osthole upregulated the expression of Nrf2 and HO-1 in a dose-dependent manner. Based on these results, osthole may exhibit anti-inflammatory effects via the NF-kappaB and Nrf2 pathways, indicating that osthole has the potential to be developed into an effective anti-inflammatory drug.|Pulmonary arterial hypertension (PAH) is an insidious and progressive disease that is triggered by various cardiopulmonary diseases. Inflammation has an important role in the progression of PAH. Osthole (Ost) is a coumarin that has clear anti-inflammatory properties. The present study aimed to investigate the effects of Ost on PAH, and to explore the mechanism underlying this effect. Using the monocrotaline (MCT)-induced PAH rat model, the effects of Ost on PAH were investigated. Rats were subcutaneously administered a single dose of MCT (50 mg/kg) to establish the PAH model, followed by daily treatment with Ost (10 or 20 mg/kg) by gavage for 28 days. The mean pulmonary arterial pressure (mPAP) was measured and histological analysis was performed. The results demonstrated that Ost significantly decreased mPAP, and reduced thickening of the pulmonary artery, compared with in rats in the MCT group. To further determine whether the effects of Ost on MCT-induced PAH were associated with inflammatory responses, the nuclear factor-kappaB (NF-kappaB) p65 signaling pathway was investigated by western blot analysis. The results demonstrated that Ost increased inhibition of the NF-kappaB p65 signaling pathway. In conclusion, the results of the present study demonstrate that Ost may suppress the progression of MCT-induced PAH in rats, which may be, at least partially, mediated through modulation of the NF-kappaB p65 signaling pathway.|Osthole, a natural coumarin found in traditional Chinese medicinal plants, has shown multiple biological activities. In the present study, we investigated the preventive effects of osthole on inflammatory bowel disease (IBD). Colitis was induced in mice by infusing TNBS into the colonic lumen. Before TNBS treatment, the mice received osthole (100 mg/kg par day, ip) for 3 d. Pretreatment with osthole significantly ameliorated the clinical scores, colon length shortening, colonic histopathological changes and the expression of inflammatory mediators in TNBS-induced colitis. Pretreatment with osthole elevated serum cAMP levels; but treatment with the PKA inhibitor H89 (10 mg/kg per d, ip) did not abolish the beneficial effects of osthole on TNBS-induced colitis. In mouse peritoneal macrophages, pretreatment with osthole (50 umol/L) significantly attenuated the LPS-induced elevation of cytokines at the mRNA level; inhibition of PKA completely reversed the inhibitory effects of osthole on IL-1beta, IL-6, COX2, and MCP-1 but not on TNFa. In Raw264.7 cells, the p38 inhibitor SB203580 markedly suppressed LPS-induced upregulation of the cytokines, whereas the PKA inhibitors H89 or KT5720 did not abolish the inhibitory effects of SB203580. Moreover, in LPS-stimulated mouse peritoneal macrophages, SB203580 strongly inhibited the restored expression of IL-1beta, IL-6, COX2, and MCP-1, which was achieved by abolishing the suppressive effects of osthole with the PKA inhibitors. Western blot analysis showed that osthole significantly suppressed the phosphorylation of p38, which was induced by TNBS in mice or by LPS in Raw264.7 cells. Inhibition of PKA partially reversed the suppressive effects of osthole on p38 phosphorylation in LPS-stimulated cells. Collectively, our results suggest that osthole is effective in the prevention of TNBS-induced colitis by reducing the expression of inflammatory mediators and attenuating p38 phosphorylation via both cAMP/PKA-dependent and independent pathways, among which the cAMP/PKA-independent pathway plays a major role.|For more Interactions (Complete) data for Osthole (9 total), please visit the HSDB record page.

/AQUATIC SPECIES/ This study focused on the assessment of acute toxicity caused by Osthol, a major component of environment-friendly biological pesticides, by using two aquatic organisms. The assessment of acute toxicity caused by Osthol was conducted in Daphnia magna and by examining the morphological abnormalities in Danio rerio embryos. The median effective concentration value of Osthol in D. magna 48 hours after inoculation was 19.3 uM. The median lethal concentration of D. rerio embryo at 96 hours was 30.6 uM. No observed effect concentration and predicted no effect concentration values of Osthol in D. magna and D. rerio were calculated as 5.4 and 0.19 uM, respectively. There was an increase in the morphological abnormalities in D. rerio embryo due to Osthol over time. Coagulation, delayed hatching, yolk sac edema, pericardial edema, and pigmentation were observed in embryos at 24-48 hours. Symptoms of scoliosis and head edema occurred after 72 hours. In addition, bent tails, ocular defects, and symptoms of collapse were observed in fertilized embryo tissue within 96 hours. Ocular defects and pigmentation were the additional symptoms observed in this study. Because Osthol showed considerable toxicity levels continuous toxicity evaluation in agro-ecosystems is necessary when bio-pesticides containing Osthol are used.

Osthole is a compound found in many plants(1).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1300(SRC), determined from a structure estimation method(2), indicates that osthole is expected to have low mobility in soil(SRC). Volatilization of osthole from moist soil surfaces is expected(SRC) given an estimated Henry's Law constant of 1.5X10-6 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Osthole is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.9X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2019).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1300(SRC), determined from a structure estimation method(2), indicates that osthole is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 1.5X10-6 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 40 and 290 days, respectively(SRC). Osthole is expected to undergo hydrolysis in the environment due to the presence of functional groups that hydrolyze under environmental conditions(3). According to a classification scheme(4), an estimated BCF of 190(SRC), from an estimated log Kow of 3.95(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is high. Biodegradation data in water were not available(SRC, 2019).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), osthole, which has an estimated vapor pressure of 6.9X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase osthole is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 3 hours(SRC), calculated from its rate constant of 1.3X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). The rate constant for the vapor-phase reaction of osthole with ozone has been estimated as 4.5X10-16 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). This corresponds to an atmospheric half-life of about 37 minutes at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3). Particulate-phase osthole may be removed from the air by wet and dry deposition(SRC). Osthole has a light absorption peak at 322 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of osthole with photochemically-produced hydroxyl radicals has been estimated as 1.3X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 3 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of osthole with ozone has been estimated as 4.5X10-16 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(1). This corresponds to an atmospheric half-life of about 37 minutes at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(2). The lactone ring in analogous psoralen is susceptible to alkaline hydrolysis(3); therefore, osthole may undergo hydrolysis under alkaline environmental conditions(SRC). Osthole has a light absorption peak at 322 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 190 was calculated in fish for osthole(SRC), using an estimated log Kow of 3.95(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of osthole can be estimated to be 1300(SRC). According to a classification scheme(2), this estimated Koc value suggests that osthole is expected to have low mobility in soil(SRC).

The Henry's Law constant for osthole is estimated as 1.5X10-6 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that osthole is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 40 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 290 days(SRC). Osthole's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). Osthole is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.9X10-6 mm Hg(SRC), determined from a fragment constant method(1).

Osthole was not detected (detection limit not reported) in lemon, lime, bergamot or mandarin oils(1). Osthole was detected at 3.18 and 1.12 mg/kg fresh weight in grapefruit and pummelo peel extract, respectively, at a trace in orange, lemon and bergamot peel extracts, but not detected (detection limit 0.03 mg/kg fresh weight) in clementine peel extract(2).

Occupational exposure may be limited to dermal exposure where plants that contain osthole are harvested and processed. Monitoring data indicate that the general population may be exposed to osthole via dermal application or ingestion of herbal remedies containing osthole. (SRC)

/EXPL THER/ Osthole, an active coumarin extracted from the dried fruits of Cnidium monnieri (L.) Cusson, is known to possess a variety of pharmacological activities. In the present study, we investigated and illuminated the mechanisms underlying the protective effects of osthole in an experimental model of allergic asthma. Our results show that osthole treatment significantly reduced the OVA-induced increase in serum IgE and inflammatory cytokines (IL-4, IL-5, IL-13) in bronchoalveolar lavage fluid (BALF), and decreased the recruitment of inflammatory cells in BALF and the lung. It also effectively attenuated goblet cell hyperplasia and mucus overproduction in lung tissue. In addition, western blot analysis demonstrated that osthole blocked NF-kappaB activation, which may be associated with a reduction in inflammatory cytokine production. These data suggest that osthole attenuated OVA-induced allergic asthma inflammation by inhibiting NF-kappaB activation. The present study identified the molecular mechanisms of action of osthole, which support the potential pharmaceutical application of osthole treatment for asthma and other airway inflammation disorders.|/EXPL THER/ Hepatocellular carcinoma (HCC) accounts for approximately 90% of all cases of primary liver cancer, and the majority of patients with HCC are deprived of effective curative methods. Osthole is a Chinese herbal medicine which has been reported to possess various pharmacological functions, including hepatocellular protection. In the present study, we investigated the anticancer activity of osthole using HCC cell lines. We found that osthole inhibited HCC cell proliferation, induced cell cycle arrest, triggered DNA damage and suppressed migration in HCC cell lines. Furthermore, we demonstrated that osthole not only contributed to cell cycle G2/M phase arrest via downregulation of Cdc2 and cyclin B1 levels, but also induced DNA damage via an increase in ERCC1 expression. In addition, osthole inhibited the migration of HCC cell lines by significantly downregulating MMP-2 and MMP-9 levels. Finally, we demonstrated that osthole inhibited epithelial-mesenchymal transition (EMT) via increasing the expression of epithelial biomarkers E-cadherin and beta-catenin, and significantly decreasing mesenchymal N-cadherin and vimentin protein expression. These results suggest that osthole may have potential chemotherapeutic activity against HCC.|/EXPL THER/ Osthole (7-methoxy-8-isopentenoxy-coumarin), a compound extracted from Cnidiummonnieri (L.) Cusson seeds, has been found to exhibit potent therapeutic effects in cancer due to its ability to inhibit inflammation and cell proliferation. However, its effects on arterial wall hypertrophy-related diseases remain unclear. Therefore, in this study, we aimed to investigate the effects of Osthole on intimal hyperplasia in a rat model of carotid artery balloon injury. We established the balloon-induced carotid artery injury rat model in male Sprague-Dawley rats, after which we administered Osthole (20 mg/kg/day or 40 mg/kg/day) or volume-matched normal saline orally by gavage for 14 consecutive days. Intimal hyperplasia and the degree of vascular smooth muscle cell proliferation were then evaluated by histopathological examination of the changes in the carotid artery, as well as by examination of proliferating cell nuclear antigen (PCNA) expression. Tumor necrosis factor-alpha (TNF-a), interleukin-1beta (IL-1beta), transforming growth factor-beta (TGF-beta1) and PCNA mRNA expression levels were examined by real-time RT-PCR, while nuclear factor-kappaB (NF-kappaB (p65)), IkappaB-a, TGF-beta1 and phospho-Smad2 (p-Smad2) protein expression levels were analyzed by immunohistochemistry or western blot analysis. We found that Osthole significantly attenuated neointimal thickness and decreased the elevations in PCNA protein expression induced by balloon injury. Moreover, Osthole down-regulated the pro-inflammatory factors TNF-a and IL-1beta and NF-kappaB (p65), whose expression had been upregulated after balloon injury. Moreover, IkappaB-a protein expression levels increased following Osthole treatment. In addition, the elevations in TGF-beta1 and p-Smad2 protein expression induced by balloon injury were both significantly attenuated by Osthole administration. We concluded that Osthole significantly inhibited neointimal hyperplasia in balloon-induced rat carotid artery injury and that the mechanism by which this occurs may involve NF-kappaB, IL-1beta and TNF-alpha down-regulation, which alleviates the inflammatory response, and TGF-beta1/Smad2 signalling pathway inhibition.|/EXPL THER/ Multiple pharmacological applications of osthole have been previously recognized, including antioxidant, anti-inflammatory, anti-platelet and estrogenic effects, and resistance to pain. The present study investigated the protective effects of osthole against inflammation in a rat model of chronic kidney failure (CRF) and the underlying mechanisms. Osthole treatment with significantly reversed CRF-induced changes in serum creatinine, calcium, phosphorus and blood urea nitrogen levels in CRF rats. Male Sprague-Dawley rats (age, 8 weeks) received 200 mg/kg 2% adenine suspension to induce CRF in the model group. In the osthole-treated group, rats received 200 mg/kg 2% adenine suspension + osthole (40 mg/kg, intravenously). The results revealed that treatment with osthole significantly inhibited CRF-induced tumor necrosis factor-a, interleukin (IL)-8 and IL-6 expression, and suppressed nuclear factor-kappaB (NF-kappaB) protein expression in CRF rats. Osthole treatment significantly attenuated the protein expression of transforming growth factor-beta1 (TGF-beta1), reduced monocyte chemoattractant protein-1 activity and increased the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) ratio in CRF rats. These results suggested that osthole protects against inflammation in a rat model of CRF via suppression of NF-kappaB and TGF-beta1, and activation of PI3K/Akt/nuclear factor (erythroid-derived 2)-like 2 signaling. Therefore, osthole may represent a potential therapeutic agent for the treatment of CRF.|For more Therapeutic Uses (Complete) data for Osthole (18 total), please visit the HSDB record page.

Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (Freund's adjuvant, BCG, Corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. (See all compounds classified as Adjuvants, Immunologic.)|A class of drugs that act by selective inhibition of calcium influx through cellular membranes. (See all compounds classified as Calcium Channel Blockers.)

ETHNOPHARMACOLOGICAL RELEVANCE: Libanotis buchtormensis is the source of an important traditional medicine from Shaanxi province of China used in the treatment of many illnesses. Libanotis buchtormensis supercritical extract (LBSE) has analgesic, sedative and anti-inflammatory qualities. Osthole is one of the major bioactive components of LBSE; it is known for its significant anti-tumor, analgesic, and anti-inflammatory properties, it also alleviates hyperglycemia. AIM OF THE STUDY: The purpose of the present study was to compare the pharmacokinetics and tissue distribution of osthole in Sprague-Dawley (SD) rats after oral administration of pure osthole and LBSE. The two preparations were administered at the same osthole dose (approximately 130 mg/kg). The results should provide some guidance for the clinical applications of Libanotis buchtormensis. MATERIALS AND METHODS: Comparative pharmacokinetics and tissue distribution of osthole in SD rats after oral administration of pure osthole and LBSE were analyzed using reversed-phase high-performance liquid chromatography (RP-HPLC). All pharmacokinetic data were analyzed using 3P97 software. Samples of blood and internal organs (heart, liver, spleen, lungs and kidney) were collected and pretreated according to the experimental schedule. After pretreatment, plasma and tissue samples were extracted using ether-ethyl acetate mixture (3:1, v/v). The concentration of osthole in the plasma and tissues were determined using the RP-HPLC method. RESULTS: The procedure described in this paper shows good precision and stability and is suitable for the osthole assays in biological samples. We found that the average plasma concentration-time profile of osthole after oral administration of osthole and LBSE showed a single peak. There were also clear differences between plasma concentrations of osthole after oral administration of pure osthole and LBSE. Non-osthole ingredients in LBSE showed some pharmacokinetic interactions with osthole and hence decreased its absorption levels (p<0.05). Our results show different tissue distribution of osthole in the single and composite administration regimens. CONCLUSIONS: This study compares the pharmacokinetic characteristics and tissue distribution of osthole in rats after oral administration of pure osthole and LBSE; the results might be useful in clinical application of this traditional Chinese herbal medicine.|ETHNOPHARMACOLOGICAL RELEVANCE: Bushen Yizhi prescription (BSYZ) is a traditional Chinese compound prescription, which is commonly used in China for treating ShenXu and hypophrenia based on traditional Chinese medicine and Alzheimer's Disease according to modern Chinese medicine. Cnidium monnieri (L.) Cusson fruits (CM) is treated as the main herb of BSYZ, and its main active ingredient Osthole (OST) is considered as one of the major active ingredients of BSYZ. Even though OST plays an important role in the BSYZ its bioavailability is poor. In order to investigate whether the bioavailability of OST was influenced by BSYZ and CM extract, the comparative evaluations on pharmacokinetics of OST after oral administration of pure OST at different doses, CM and BSYZ extract were studied. MATERIALS AND METHODS: 30 rats were randomly assigned to five groups and orally administered with pure OST at different doses (15, 75 and 150 mg/kg), CM (15 mg/kg OST) and BSYZ (15 mg/kg OST) extract. At different predetermined time points after administration, the concentrations of OST in rat plasma were determined by using the HPLC-UV method, and main pharmacokinetic parameters were investigated. RESULTS: The results showed that the pharmacokinetic parameters of OST were significantly different (p<0.05) among the groups. The AUC(0 to t), AUC(0 to infinity) and Cmax of OST were significantly increased after oral administration of BSYZ extract, followed by CM extract, in comparison to pure osthole at different doses. CONCLUSIONS: This present study indicated that the bioavailability of pure OST after oral administration was extremely low and it was dramatically enhanced because of the synergistic effect of the traditional Chinese Bushen Yizhi prescription.|A simple high-performance liquid chromatographic method was developed to study the pharmacokinetics of osthole in rat plasma. After addition of an internal standard (paeonol), plasma was deproteinized by acetonitrile for sample clean-up. The drugs were separated on a reversed-phase column and detected by UV absorption at 323 nm. Acetonitrile-water-diethylamine (50:50:0.1, v/v/v) (pH 3.0, adjusted with orthophosphoric acid) was used as the mobile phase. It was applied to the pharmacokinetic study of osthole in rats after a dose of 10 mg/kg by intravenous administration. A biphasic phenomenon with a rapid distribution followed by a slower elimination phase was observed from the plasma concentration-time curve.

Osthole is an active ingredient and one of the major coumarin compounds that were identified in the genus Cnidium moonnieri (L.) Cussion, the fruit of which was used as traditional Chinese medicine to treat male impotence, ringworm infection and blood stasis conventionally. Recent studies revealed that osthole has diverse pharmacological effects, such as improving male sexual dysfunction, anti-diabetes, and anti-hypertentions. The inhibition of thrombosis and platelet aggregation and protection of central nerve were also observed. On the other hand, the metabolism of osthole has not yet been investigated thoroughly. Herein the biotransformation of osthole in rat was investigated after oral administration of osthole by using efficient and sensitive ultra-performance liquid chromatography-tandem quadrupole-time of flight mass spectrometry (UPLC-QTOF/MS). Eighteen osthole metabolites and the parent drug were detected and identified in rat urine. Fourteen metabolites of osthole were identified and characterized for the first time. Structures of metabolites of osthole were elucidated by comparing fragment pattern under MS/MS scan and change of molecular weight with those of osthole. The main phase I metabolic pathways were summed as 7-demethylation, 8-dehydrogenation, hydroxylation on coumarin and 3,4-epoxide. Sulfate conjugates were detected as phase II metabolites of osthole.|The biotransformation of osthole (1) by Alternaria longipes was carried out, and five transformed products were obtained in the present research work. Based on their extensive spectral data, the structures of these metabolites were characterized as 4'-hydroxyl-osthole (2), 4'-hydroxyl-2',3'-dihydroosthole (3), 2',3'-dihydroxylosthole (4), osthole-4'-oic acid methyl ester (5), and osthole-4'-oic acid glucuron-1-yl ester (6), respectively. Among them, products 5 and 6 were new compounds.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/ALTERNATIVE and IN VITRO TESTS/ Glioblastoma multiforme (GBM) is the most common type of primary and malignant tumor occurring in the adult central nervous system. GBM often invades surrounding regions of the brain during its early stages, making successful treatment difficult. Osthole, an active constituent isolated from the dried C. monnieri fruit, has been shown to suppress tumor migration and invasion. However, the effects of osthole in human GBM are largely unknown. Focal adhesion kinase (FAK) is important for the metastasis of cancer cells. Results from this study show that osthole can not only induce cell death but also inhibit phosphorylation of FAK in human GBM cells. Results from this study show that incubating GBM cells with osthole reduces matrix metalloproteinase (MMP)-13 expression and cell motility, as assessed by cell transwell and wound healing assays. This study also provides evidence supporting the potential of osthole in reducing FAK activation, MMP-13 expression, and cell motility in human GBM cells.|/ALTERNATIVE and IN VITRO TESTS/ Osthole has been reported to have antitumor activities via the induction of apoptosis and inhibition of cancer cell growth and metastasis. However, the detailed molecular mechanisms underlying the anticancer effects of osthole in human colon cancer remain unclear. In the present study, we have assessed osthole-induced cell death in two different human colon cancer cell lines, HCT116 and SW480. Our results also showed that osthole activated proapoptotic signaling pathways in human colon cancer cells. By using cell culture insert system, osthole reduced cell motility in both human colon cancer cell lines. This study also provides evidence supporting the potential of osthole in p53 activation. Expression of p53, an apoptotic protein, was remarkably upregulated in cells treated with osthole. Importantly, the levels of phosphorylation of p53 on Ser15 (p-p53) and acetylation of p53 on Lys379 (acetyl-p53) were increased under osthole treatment. Our results also demonstrated that p53 was activated followed by generation of reactive oxygen species (ROS) and activation of c-Jun N-terminal kinase (JNK). Our study provides novel insights of p53-mediated responses under osthole treatment. Taken together, we concluded that osthole induces cancer cell death and inhibits migratory activity in a controlled manner and is a promising candidate for antitumor drug development.|/ALTERNATIVE and IN VITRO TESTS/ Osthole, an active constituent isolated from the fruit of Cnidium monnieri (L.) Cusson, has been shown to induce various beneficial biochemical effects such as anti-inflammatory and antitumor. In the present study, we examined whether osthole could sensitize TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma Caki cells. We found that osthole and TRAIL alone, had no effect on apoptosis, but combined treatment with osthole and TRAIL markedly induced apoptosis in Caki (renal carcinoma), U251MG (glioma) and MDA-MB-231 (breast carcinoma) cells. In contrast, combined treatment with osthole and TRAIL did not induce apoptosis in normal human skin fibroblast cells. Osthole induced downregulation of cellular FLICE-like inhibitory protein (c-FLIP) expression, and overexpression of c-FLIP markedly blocked apoptosis induced by the combined treatment with osthole and TRAIL. In addition, osthole markedly reduced mitochondrial membrane potential levels, and increased cytosolic cytochrome c release in combined treatment with osthole and TRAIL. Therefore, these data suggest that osthole may be an efficient TRAIL sensitizer.|/ALTERNATIVE and IN VITRO TESTS/ Osthole is an active compound isolated from Chinese herb Cnidium monnieri (L.) Cusson, and had been reported to possess antitumor effect. However, the effect of osthole on the gastric cancer cells has not been investigated. In this study, the effects of osthole on the proliferation of human gastric cancer cells were tested. The data showed that osthole treatment significantly inhibited the proliferation of gastric cancer cells and resulted in the cell cycle arrest at G2/M phase in a dose-dependent manner. Western-blot study showed that the expression of cyclin B1 and cdc2 was markedly reduced by osthole. Moreover, expression of PI3K and pAKT was also significantly suppressed, and the results indicated that the inhibition of pAKT, cyclin B1, and cdc2 levels by osthole was notably enhanced by a PI3K inhibitor. These results demonstrate that osthole could inhibit gastric cancer cells proliferation via induction of cell cycle arrest at G2/M phase by the reduction of PI3K/AKT.

7-methoxy-8-(3-methylpent-2-enyl)coumarin

Osthole is a major component of Cnidium monnieri (L) Cuss., an annual plant used as a traditional herbal medication to treat a variety of diseases in China, Vietnam and Japan.|Osthole was found in Yuanhu Zhitong tablet (Chinese medicine)

A simple high-performance liquid chromatographic method was developed to study the pharmacokinetics of osthole in rat plasma. After addition of an internal standard (paeonol), plasma was deproteinized by acetonitrile for sample clean-up. The drugs were separated on a reversed-phase column and detected by UV absorption at 323 nm. Acetonitrile-water-diethylamine (50:50:0.1, v/v/v) (pH 3.0, adjusted with orthophosphoric acid) was used as the mobile phase. It was applied to the pharmacokinetic study of osthole in rats after a dose of 10 mg/kg by intravenous administration. A biphasic phenomenon with a rapid distribution followed by a slower elimination phase was observed from the plasma concentration-time curve.