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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. Tumour necrosis factor-ɑ (TNF-α), interleukin-1β (IL-1β), transforming growth factor-beta (TGF-β1) and PCNA mRNA expression levels were examined by real-time RT-PCR, while nuclear factor-κB (NF-κB (p65)), IκB-α, TGF-β1 and phospho-Smad2 (p-Smad2) protein expression levels were analysed 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-α and IL-1β and NF-κB (p65), whose expression had been upregulated after balloon injury. Moreover, IκB-α protein expression levels increased following Osthole treatment. In addition, the elevations in TGF-β1 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-κB, IL-1β and TNF-ɑ down-regulation, which alleviates the inflammatory response, and TGF-β1/Smad2 signalling pathway inhibition. [ABSTRACT FROM AUTHOR]

FXF is a third-generation antihistamine drug and osthole is assumed a natural antihistamine alternative. This paper compares peripheral blood mononuclear cell (PBMC) incubation with FXF and osthole, by studying FXF, osthole and histamine cytokine secretion in PBMC in vitro cultures. Mabtech kits determined the interleukins IL-1β, IL-4, IL-10, IL-13 and TNF-α. The influence of the above active substances on cytokine secretion in PBMC's and serum was assessed: cytokines were IL-1β, IL-4, IL-10, IL-13 and TNF-α; and cytokine levels secreted by untreated PBMCs in pure culture medium formed the absolute control (ctrl). We determined that osthole affects PBMC cytokine secretion to almost precisely the same extent as FXF (IL-1β, IL-4, IL-10 and TNF). In addition osthole had greater IL-13 blocking ability than FXF. Moreover, we observed significantly decreased IL-4 level in histamine/osthole theatment compared to histamine alone. Meanwhile, FXF not significantly decrease the level of IL-4 increased by histamine. This data indicates osthole's strong role in allergic inflamation. All results confirm our hypothesis that osthole is a natural histamine antagonist and therefore can be beneficially used in antihistamine treatment of conditions such as allergies. [ABSTRACT FROM AUTHOR]

Esculin, a coumarin compound derived from the traditional Chinese herbs such as Cortex Fraxini , has long been used for treating inflammatory and vascular diseases. In present study, we analyzed the role of esculin against macrophages and endotoxin shock induced by lipopolysaccharide (LPS) in mice. Here, we demonstrated that esculin suppressed inflammatory reactions in macrophages and protected mice from LPS-induced endotoxin shock. We found that esculin significantly inhibited the production of nitric oxide (NO) production via the inhibition of nuclear factor-κB (NF-κB) activation in macrophages. In animal model, esculin pretreatment significantly improved the survival rate of mice. LPS-induced increase of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in serum, lung, liver and kidney were markedly inhibited by esculin. IL-10, an anti-inflammatory cytokine, was up-regulated by esculin. Moreover, the histopathological analyses showed that esculin significantly attenuated the tissues injury of lung, liver, kidney in endotoxic mice. In addition, esculin significantly diminished the protein expression of NF-κB p65 in lung, liver, kidney, which resulted in lower levels of inflammatory mediators. These results suggest that esculin may be a potential drug for treatment of various inflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract: The numerous mediators of pain and inflammation are products of injury-induced gene expression that lead to changes in the nervous system and immune responses. These multiple molecules and mechanisms suggest novel strategies that could be used for analgesic drug development. The present study investigated the possible anti-hyperalgesic effects of anomalin in complete Freund′s adjuvant (CFA)-induced acute and chronic inflammatory pain models. Acute pretreatment of mice with anomalin (10 and 50mg/kg, i.p.) produced a significant anti-nociceptive effect against CFA- and carrageenan-induced mechanical hyperalgesia and allodynia. In a chronic pain model, administration of anomalin inhibited CFA-induced hyperalgesia, and it did not cause any apparent toxicity. Another set of experiments observed that anomalin inhibited CFA- and carrageenan-induced paw edema in acute and chronic models. To elucidate the molecular mechanism underlying the anti-nociceptive effect of anomalin, the various pain signaling pathways [NF-κB, cAMP response element-binding protein (CREB), and mitogen activated protein kinase (MAPKs)/AP-1] that are involved were examined. Intraperitoneal (i.p.) pretreatment of anomalin exhibited potent inhibitory effects on direct mediators of hyperalgesia (iNOS and COX-2). The release of CFA-induced plasma nitrite and paw tissue hyperalgesic cytokine (TNF-α) was reduced remarkably. In addition, the adenosine 5'-triphosphate (ATP) in plasma and substance P (SP) in paw tissue were markedly suppressed by anomalin. These results demonstrate that anomalin exhibits an analgesic effect in a consistent manner and that its mechanisms involve the inhibition of the NF-κB, CREB, and MAPKs/AP-1 signaling pathways. [Copyright &y& Elsevier]

Abstract: Osthole, a natural coumarin, is known to have a variety of pharmacological and biochemical uses and is considered to have potential therapeutic applications. Here we examined the effects of osthole on the central nervous system demyelination in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis and its mechanism(s). C57 BL/6 mice immunized with myelin oligodendrocyte glycoprotein 35–55 amino acid peptide were treated with osthole at day 7 post immunization (7 p.i., subclinical periods, early osthole treatment) and day 13 p.i. (clinical periods, late osthole treatment) respectively and both therapies continued throughout the study. The content of nerve growth factor (NGF) and interferon gamma (IFN-γ) in the sera and brain of mice in vivo as well as the splenocytes culture supernatants in vitro were detected. The results showed that osthole retarded the disease process when the therapy was initiated at subclinical periods, attenuated the clinical severity of EAE mice when the therapy was initiated at both subclinical and clinical periods, ameliorated inflammation and demyelination and improved the outcomes of magnetic resonance imaging. In addition, osthole blocked the reduction of NGF and suppressed IFN-γ increase in EAE mice. These results suggested that osthole might be a new pharmacological approach to treat multiple sclerosis. [Copyright &y& Elsevier]

Abstract: Advanced glycation end products (AGE) have been implicated in the pathogenesis of diabetic complications. The purpose of this study was to examine the novel coumarin–aspirin compound XLF-III-43 in the inhibition of AGE formation in diabetic nephropathy. In vitro analysis showed XLF-III-43 in a dose-dependent manner decreased glucose induced formation of glycation adducts on albumin and inhibited AGE–lysozyme crosslinking. The streptozotocin-induced diabetic rats were used to investigate the beneficial effects of XLF-III-43 treatment on diabetic nephropathy. Administration of XLF-III-43 significantly decreased (P <0.05) blood urea nitrogen and urinary albumin excretion. Moreover, XLF-III-43 ameliorated kidney hypertrophy, mesangial expansion and glomerulosclerosis in diabetic rats relative to untreated model group. These data correlated with decreased both AGE and downstream markers of AGE stress (TGF-β1, CTGF, fibronectin and collagen IV fibrolysis) in kidneys of diabetic rats. These data support further development of XLF-III-43 for prevention of nephropathy via inhibition of AGE formation consequent to chronic hyperglycemia. [Copyright &y& Elsevier]

Abstract: Scopoletin, an alkaloid separated from ethanolic extract of the medicinal plant, Gelsemium sempervirens (Fam: Loganiaceae) has been reported to have anti-cancer potentials. The synthetic coumarin (4-Methyl-7 hydroxy coumarin) derived from resorcinol and ethyl aceto-acetate in presence of concentrated sulphuric acid is structurally close to scopoletin, being a coumarin derivative. Whether this synthetic compound also has anti-cancer potentials has been evaluated in vivo on DMBA (7,12-Dimethylbenz[a]anthracene) induced skin cancer in mice by analyzing results of several cytogenetic endpoints, Comet assay, and fluorescence activated cell sorting (FACS). Further, expressions of signal proteins like Aryl hydrocarbon receptor , p53, PCNA, Akt, Bcl-2, Bcl-xL, Bad, Bax, NF-kB Apaf, IL-6, Cytochrome-c, Caspase-3 and Caspase-9 were studied by immunoblot analysis along with histology of skin and immuno-histochemical localization of Aryl hydrocarbon receptor and PCNA in DMBA treated mice vis-a-vis carcinogen treated synthetic coumarin fed mice. Feeding of this synthetic coumarin induced positive modulations in expression of all biomarkers in DMBA administered mice, giving clues on its possible signaling pathway(s) - primarily through down-regulation of Aryl hydrocarbon receptor and PCNA and up-regulation of apoptotic proteins like Bax, Bad, Cytochrome c, Apaf, Caspase-3 and Caspase-9, resulting in an appreciable reduction in growth of papilloma in mice. Therefore, this synthetic coumarin shows promise for use in cancer therapy, particularly in skin cancer. [Copyright &y& Elsevier]

Abstract: The therapeutic effects of umbelliferone (30, 60 and 90 mg/kg), a coumarin isolated from Typha domingensis (Typhaceae) were investigated in a mouse model of bronchial asthma. BALB/c mice were immunized and challenged by nasal administration of ovalbumin. Treatment with umbelliferone (60 and 90 mg/kg) caused a marked reduction of cellularity and eosinophil numbers in bronchoalveolar lavage fluids from asthmatic mice. In addition, a decrease in mucus production and lung inflammation were observed in mice treated with umbelliferone. A reduction of IL-4, IL-5, and IL-13, but not of IFN-γ, was found in bronchoalveolar lavage fluids of mice treated with umbelliferone, similar to that observed with dexamethasone. The levels of ovalbumin-specific IgE were not significantly altered after treatment with umbelliferone. In conclusion, our results demonstrate that umbelliferone attenuates the alteration characteristics of allergic airway inflammation. The investigation of the mechanisms of action of this molecule may contribute for the development of new drugs for the treatment of asthma. [Copyright &y& Elsevier]

Abstract: The aim of this study was to determine the anticonvulsant effects of osthole {[7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one] – a natural coumarin derivative} in the mouse maximal electroshock-induced seizure model. The antiseizure effects of osthole were determined at 15, 30, 60, and 120 min after its systemic (i.p.) administration. Time course of anticonvulsant action of osthole revealed that the natural coumarin derivative produced a clear-cut antielectroshock activity in mice and the experimentally-derived ED50 values for osthole ranged from 259 to 631 mg/kg. In conclusion, osthole suppresses seizure activity in the mouse maximal electroshock-induced seizure model. It may become a novel treatment option following further investigation in other animal models of epilepsy and preclinical studies. [Copyright &y& Elsevier]