decursin and Disease-Models--Animal

Topics: Angelica; Angelica sinensis; Animals; Antineoplastic Agents, Phytogenic; Benzopyrans; Butyrates; Disease Models, Animal; Drugs, Chinese Herbal; Humans; Liquid-Liquid Extraction; Medicine, Korean Traditional; Neoplasms; Phytotherapy; Plant Extracts; Plant Roots; Plants, Medicinal; Pyranocoumarins; Rodentia

The herbal plant

Topics: Angelica; Animals; Benzopyrans; Butyrates; Disease Models, Animal; Interleukin-6; Kaplan-Meier Estimate; Lipopolysaccharides; Macrophages; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; NF-kappa B; Proto-Oncogene Proteins c-akt; RAW 264.7 Cells; Reactive Oxygen Species; Sepsis; Signal Transduction; Tumor Necrosis Factor-alpha

Chemotherapy-induced neuropathic pain (CINP) is a severe adverse effect of platinum- and taxane-derived anticancer drugs. The pathophysiology of CINP includes damage to neuronal networks and dysregulation of signal transduction due to abnormal Ca

Topics: Animals; Benzopyrans; Butyrates; Disease Models, Animal; Enzyme Activators; Humans; Hyperalgesia; Mice; Neuralgia; Paclitaxel

Inhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity are emerging as attractive therapeutic strategies for the management of severe vascular inflammatory diseases. Recently, we found that JH-4, a synthesized decursin derivative, exhibited a strong anti-Hutchinson-Gilford progeria syndrome by efficiently blocking progerin-lamin A/C binding. In this study, we examined the effects of JH-4 on HMGB1-mediated septic responses and the survival rate in a mouse sepsis model. The anti-inflammatory activities of JH-4 were monitored based on its effects on lipopolysaccharide- or cecal ligation and puncture (CLP)-mediated release of HMGB1. The antiseptic activities of JH-4 were determined by measuring permeability, leukocyte adhesion, migration, and the activation of proinflammatory proteins in HMGB1-activated human umbilical vein endothelial cells and mice. JH-4 inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. JH-4 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with JH-4 reduced CLP-induced release of HMGB1, sepsis-related mortality, and pulmonary injury in vivo. Our results indicate that JH-4 is a possible therapeutic agent to treat various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.

Topics: Angelica; Animals; Anti-Infective Agents, Local; Anti-Inflammatory Agents; Benzopyrans; Butyrates; Capillary Permeability; Cell Adhesion; Cell Movement; Cell Survival; Cells, Cultured; Disease Models, Animal; HMGB1 Protein; Human Umbilical Vein Endothelial Cells; Humans; Leukocytes; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Plant Extracts; Sepsis; Survival Rate

Angelica gigas Nakai (AGN) is an oriental traditional medicine to treat anemia, dysmenorrhea, and migraine. However, its anti-lymphoma effect is yet to be tested. Here, we demonstrated that AGN and its major component decursin target Myc to suppress lymphomagenesis in vitro and in vivo. AGN inhibited cell viability in multiple B lymphoma cells, while sparing normal splenocytes and bone marrow cells. Increased cleaved PARP level and caspase 3/7 activity and the repression of survival-promoting AKT/mTOR and MAPK pathways downstream of BCR, were responsible for the pro-apoptotic effects of AGN. We found that Myc, a prominent downstream target of these signaling pathways, contributes to AGN-induced cell death. Moreover, co-treatment with AGN and a Myc inhibitor, JQ1 or 10058-F4 yielded synergistic cytotoxic activities against cancer cells with markedly reduced Myc expression. AGN downregulated Myc expression and suppressed tumorigenesis in Eμ-myc transgenic mice. The proapoptotic activities of AGN were recapitulated by decursin, indicating that the anti-tumor effect of AGN was mainly caused by decursin. These findings suggest that AGN and decursin possess potent anti-lymphoma activity, and combination therapies with AGN/decursin and a Myc inhibitor to target Myc more efficiently could be a valuable avenue to explore in the treatment of B-cell lymphoma.

Topics: Angelica; Animals; Apoptosis; Benzopyrans; Butyrates; Carcinogenesis; Cell Line, Tumor; Disease Models, Animal; Down-Regulation; Drug Screening Assays, Antitumor; Female; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, B-Cell; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Plant Extracts; Proto-Oncogene Proteins c-myc

We have previously shown that the ethanol extract of dried Angelica gigas Nakai (AGN) root exerts anticancer activity against androgen receptor (AR)-negative human DU145 and PC-3 prostate cancer xenografts and primary carcinogenesis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The major pyranocoumarin isomers decursin (D) and decursinol angelate (DA), when provided at equi-molar intake to that provided by AGN extract, accounted for the inhibitory efficacy against precancerous epithelial lesions in TRAMP mice. Since we and others have shown in rodents and humans that D and DA rapidly and extensively convert to decursinol, here we tested whether decursinol might be an in vivo active compound for suppressing xenograft growth of human prostate cancer cells expressing AR. In SCID-NSG mice carrying subcutaneously inoculated human LNCaP/AR-Luc cells overexpressing the wild type AR, we compared the efficacy of 4.5[Formula: see text]mg decursinol per mouse with equi-molar dose of 6[Formula: see text]mg D/DA per mouse. The result showed that decursinol decreased xenograft tumor growth by 75% and the lung metastasis, whereas D/DA exerted a much less effect. Measurement of plasma decursinol concentration, at 3[Formula: see text]h after the last dose of respective dosing regimen, showed higher circulating level in the decursinol-treated NSG mice than in the D/DA-treated mice. In a subsequent single-dose pharmacokinetic experiment, decursinol dosing led to 3.7-fold area under curve (AUC) of plasma decursinol over that achieved by equi-molar D/DA dosing. PK advantage notwithstanding, decursinol represents an active compound to exert in vivo prostate cancer growth and metastasis inhibitory activity in the preclinical model.

Topics: Adenocarcinoma; Angelica; Animals; Antineoplastic Agents, Phytogenic; Benzopyrans; Butyrates; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Heterografts; Humans; Male; Mice, SCID; Mice, Transgenic; Neoplasm Transplantation; Phytotherapy; Plant Roots; Prostatic Neoplasms; Pyranocoumarins

1. JHL45, a novel immune modulator against atopic dermatitis (AD), was synthesized from decursin isolated from Angelica gigas. The goal is to evaluate the lead compound using quantitative modeling approaches to novel anti-AD drug development. 2. We tested the anti-inflammatory effect of JHL45 by in vitro screening, characterized its in vitro pharmacokinetic (PK) properties. The dose-dependent efficacy of JHL45 was developed using a pharmacokinetics/pharmacodynamics/disease progression (PK/PD/DIS) model in NC/Nga mice. 3. JHL45 has drug-like properties and pharmacological effects when administered orally to treat atopic dermatitis. The developed PK/PD/DIS model described well the rapid metabolism of JHL45, double-peak phenomenon in the PK of decursinol and inhibition of IgE generation by compounds in NC/Nga mice. Also, a quantitative model was developed and used to elucidate the complex interactions between serum IgE concentration and atopic dermatitis symptoms. 4. Our findings indicate that JHL45 has good physicochemical properties and powerful pharmacological effects when administered orally for treatment of AD in rodents.

Topics: Acrylates; Angelica; Animals; Anti-Inflammatory Agents; Benzopyrans; Butyrates; Caffeic Acids; Cell Line; Chromans; Coumarins; Cytochrome P-450 Enzyme System; Dermatitis, Atopic; Disease Models, Animal; Humans; Immunoglobulin E; Male; Mice; Microsomes, Liver; Rats; Rats, Sprague-Dawley

We studied that a potent antifibrotic effect of decursin on in vivo liver damage model and the mechanism in inhibiting which transforming growth factor (TGF)-β1-induced human hepatic stellate cells (HSCs) activation.. Liver injury was induced in vivo by intraperitoneal injection of carbon tetrachloride (CCl4) with or without decursin for 4weeks in mice. Human hepatic stellate cell line, an immortalized human HSC line, was used in in vitro assay system. The effects of decursin on HSC activation were measured by analyzing the expression of α-smooth muscle actin (α-SMA) and collagen I in liver tissue and human HSCs.. Decursin treatment significantly reduced the ratio of liver/body weight, α-SMA activation, and type I collagen overexpression in CCl4 treated mice liver. The elevated serum levels, including ALT, AST, and ALP, were also decreased by decursin treatment. Treatment of decursin markedly proved the generation of reactive oxygen species, NAD(P)H oxidase (NOX) protein (1, 2, and 4) upregulation, NOX activity, and superoxide anion production in HSCs by TGF-β1. It also significantly reduced TGF-β1-induced Smad 2/3 phosphorylation, nuclear translocation of Smad 4, and association of Smad 2/3-Smad 4 complex. Consistent with in vitro results, decursin treatment effectively blocked the levels of NOX protein, and Smad 2/3 phosphorylation in injured mice liver.. Decursin blocked CCl4-induced liver fibrosis and inhibited TGF-β1-mediated HSC activation in vitro. These data demonstrated that decursin exhibited hepatoprotective effects on experimental fibrosis, potentially by inhibiting the TGF-β1 induced NOX activation and Smad signaling.

Topics: Actins; Animals; Benzopyrans; Butyrates; Carbon Tetrachloride; Cell Line; Collagen Type I; Disease Models, Animal; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; NADPH Oxidases; Phosphorylation; Reactive Oxygen Species; Signal Transduction; Smad Proteins; Transforming Growth Factor beta1; Up-Regulation

Stroke is the second leading cause of death. Experimental animal models of cerebral ischemia are widely used for researching mechanisms of ischemic damage and developing new drugs for the prevention and treatment of stroke. The present study aimed to comparatively investigate neuroprotective effects of aspirin (ASA), decursinol (DA) and new synthetic aspirin-decursinol adduct (ASA-DA) against transient focal and global cerebral ischemic damage. We found that treatment with 20 mg/kg, not 10 mg/kg, ASA-DA protected against ischemia-induced neuronal death after transient focal and global ischemic damage, and its neuroprotective effect was much better than that of ASA or DA alone. In addition, 20 mg/kg ASA-DA treatment reduced the ischemia-induced gliosis and maintained antioxidants levels in the corresponding injury regions. In brief, ASA-DA, a new synthetic drug, dramatically protected neurons from ischemic damage, and neuroprotective effects of ASA-DA may be closely related to the attenuation of ischemia-induced gliosis and maintenance of antioxidants.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Benzopyrans; Butyrates; Disease Models, Animal; Drug Combinations; Fluorescent Antibody Technique; Immunoenzyme Techniques; Ischemic Attack, Transient; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Stroke

Although decursinol, which is one of the coumarins purified from the dried roots of Angelica gigas Nakai, was previously demonstrated to have antinociceptive effects on various mouse pain models such as tail-flick, hot-plate, formalin, writhing, and several cytokine-induced pain tests, the possible involvement of its analgesic effects and non-steroidal anti-inflammatory drugs (NSAIDs) has not been clearly elucidated yet. In this study, we characterized the possible interaction between decursinol and aspirin or acetaminophen in the writhing test. The antinociceptive effects of decursinol were observed at an orally-administered dose of 50 mg/kg but not at 25 or 10 mg/kg. In addition, the analgesic effects of aspirin (ASA) and acetaminophen (APAP) were shown at an orally-administered dose of 200 mg/kg but not at 50 or 100 mg/kg. We examined the effects of decursinol on the ASA or APAP at sub-analgesic doses. Although the co-administration of decursinol and ASA did not show any differences at doses of 10 or 25 mg/kg and 50 or 100 mg/kg, respectively, synergistic effects between decursinol and APAP were observed in the group of decursinol (25 mg/kg) and APAP (100 mg/kg) co-administration. These results indicated that the analgesic effect of decursinol might be involved in supraspinal cyclooxygenase regulation that might be overlapped with APAP-induced analgesic mechanisms rather than systemic or peripheral prostaglandin modulation.

Topics: Acetaminophen; Acetic Acid; Analgesics; Angelica; Animals; Aspirin; Benzopyrans; Butyrates; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Male; Mice; Mice, Inbred ICR; Pain; Plant Extracts

We previously reported that a total methanolic extract of the underground part of Angelica gigas Nakai (Umbelliferae) (here-in-after abbreviated AG) significantly inhibited acetylcholinesterase (AChE) activity. We characterized 12 coumarin derivatives including both decursin and decursinol from extracts of AG. In this study, we evaluated the anti-amnestic activity of decursin, a major coumarin constituent isolated from AG, in vivo using ICR mice with amnesia induced by scopolamine (1 mg/kg body weight, s.c.). Decursin, when administered to mice at 1 and 5 mg/kg body weight i.p., significantly ameliorated scopolamine-induced amnesia as measured in both the passive avoidance test and the Morris water maze test. Moreover, decursin significantly inhibited AChE activity by 34% in the hippocampus of treated mice. These results indicate that decursin may exert anti-amnestic activity in vivo through inhibition of AChE activity in the hippocampus.

Topics: Acetylcholinesterase; Amnesia; Angelica; Animals; Avoidance Learning; Benzopyrans; Brain; Butyrates; Cholinesterase Inhibitors; Disease Models, Animal; Male; Maze Learning; Memory; Mice; Mice, Inbred ICR; Muscarinic Antagonists; Plant Extracts; Scopolamine