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Cell migration in three-dimensional environment is extremely important for tissue regeneration and other biological processes. In this work, a model system was developed to study how endothelial cells (ECs) migrate into photo-responsive hydrogels under the presence of pro-inflammatory macrophages. The hydrogel was synthesized from hyaluronic acid grafted with coumarin and methacrylate moieties by both carbon–carbon covalent linking and coumarin dimerization under UV irradiation at 365 nm. The structure of the hydrogel was conveniently modulated by UV irradiation at 254 nm to decompose the coumarin dimers, leading to the significant decrease of modulus and increase of swelling ratio and mesh size. Under the presence of M1 macrophages, ECs were induced to migrate into the hydrogels with a different degree. A significant larger net displacement of ECs was found in the softer hydrogel obtained by irradiation with UV at 254 nm than in the stiffer original one at day 7. [ABSTRACT FROM AUTHOR]

The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta‐analysis at the individual patients level to capture the possible effect of ethnicity, gene—gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta‐analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7–10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived. [ABSTRACT FROM AUTHOR]

Abstract Association constants and thermodynamicsparameters on inclusion of four 3-amido coumarins that present trypanocidal activity, into 6-amino-β-cyclodextrin (1:1 stoichimetry) were determined. In addition, pure homopolymeric-α- l -guluronate fraction prepared by partial hydrolysis of sodium alginate from Sub-Antarctic Kelp Durvillaea antarctica was conjugated with 6-amino-β-cyclodextrin (64% yield). To glycoconjugates, 3-amido coumarins were incorporated (73% of encapsulation) and supramolecular hydrogels were prepared by gelation with Ca2+ ions. The trypanocidal activity of the inclusion complexes increased by 10%. Likewise, an increase in diffusion in artificial membrane was observed (13%). It was found that the inclusion complexes increased the variation of the mitochondrial potential of T. cruzi (17%). The lowest release of substituted amidocoumarins (ACS) from supramolecular hydrogels occurred at pH 1.2 whereas the maximum release (34%) was observed at pH 8.0. Encapsulation of lipophilic bioactive compounds in supramolecular hydrogels allows the generation of release systems sensitive to pH with potential application in biomedicine. Highlights • Inclusion complexes increase of passive diffusion of substituted amidocumarins in artificial membrane (PAMPA). • The trypanocidal activity of inclusion complexes increased by 10% in relation to free amidocumarins. • Inclusion complexes increased the variation of the mitochondrial membrane potential of T. cruzi in relation to free amidocumarins. • Supramolecular hydrogels allowed the controlled release by pH of amidocumarins; reaching the maximum release at pH 8. [ABSTRACT FROM AUTHOR]

Abstract Osthole, a naturally-derived coumarin, has been shown to exhibit pharmacological activities including anti-inflammatory, anti-oxidative and cardiovascular protective effects. However, the effect of osthole on oxidized low-density lipoprotein (ox-LDL)-induced endothelial injury and its underlying mechanism remain unknown. We found that osthole did not affect viability of human umbilical vein endothelial cells (HUVECs) but alleviated ox-LDL-induced cytotoxicity in HUVECs. Osthole repressed ox-LDL-induced release of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 in HUVECs. Osthole reversed ox-LDL-induced elevation of reactive oxygen species (ROS) production and malondialdehyde (MDA) level, and reduction of superoxide dismutase (SOD) activity in HUVECs. Meanwhile, osthole attenuated ox-LDL-induced increase of mRNA expression and secretion of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in HUVECs. Osthole increased nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) phosphorylation in ox-LDL-treated HUVECs. Furthermore, osthole inhibited ox-LDL-induced activation of the transforming growth factor-β1 (TGF-β1)/Smad pathway and activation of TGF-β1/Smad pathway by TGF-β1 attenuated the protective effects of osthole on HUVECs injury. These results suggested that osthole attenuated ox-LDL-induced HUVECs injury by inhibiting the TGF-β1/Smad pathway, suggesting that osthole might be a promising therapeutic agent for the treatment of atherosclerosis. Highlights • Osthole alleviated ox-LDL-induced viability inhibition of HUVECs. • Osthole inhibited ox-LDL-induced release of inflammatory cytokines. • Osthole alleviated ox-LDL-induced oxidative stress. • Osthole inhibited ox-LDL-induced expression of adhesion molecules. • Osthole attenuated ox-LDL-induced activation of the TGF-β1/Smad pathway. [ABSTRACT FROM AUTHOR]

Highlights • Antimicrobial activities of plant-derived coumarin compounds were investigated. • Coumarins are major compounds on Ferulago species. • Antimicrobial activity-guided isolation were firstly made from Ferulago trachycarpa. • Crenulatin, suberosin, marmecin senecioate demonstrated antifungal activity. Abstract Ferulago trachycarpa (Apiaceae) is a plant used traditionally for its sedative, digestive, carminative and aphrodisiac properties with distribution in West, Southwest and South Anatolian part of Turkey. In this study the antimicrobial activities of fractionally n-hexane, dichloromethane, methanol and only methanol extracts from rhizomes of F. trachycarpa were screened against Stapylococcus aureus ATCC 6538, S. epidermidis ATCC 12228, Escherichia coli ATCC 8739, Klebsiella pneumoniae ATCC 4352, Pseudomonas aeruginosa ATCC 27853, Proteus mirabilis ATCC 14153, Enterococcus feacalis ATCC 29212 bacterial strains and fungal strains such as Candida albicans ATCC 10231, C. tropicalis ATCC 750 and C. parapsilosis ATCC 22019 by microdilution method. All extracts have been shown to possess antimicrobial activities against bacteria and fungal strains and according to the antimicrobial results, the isolation of the active constituents was made from the most active n-hexane and dichloromethane extracts. So, four pure compounds are known as coumarin derivatives, crenulatin (6-formyl-7-methoxycoumarin), suberosin (7-methoxy-6-prenylcoumarin), marmesin senecioate ((-)-prantschimgin) as dihydrofuranocoumarin derivative and ulopterol [6- (2’, 3’-dihydroxy-3’-methylbutyl)-7-methoxy-coumarin] were isolated. Crenulatin (6-formyl-7-methoxycoumarin), suberosin (7-methoxy-6-prenylcoumarin), marmesin senecioate ((-)-prantschimgin) which are pure compounds demonstrated antifungal activity with 625 mg/L MIC against C. albicans and antibacterial activity with 1250 mg/L MIC against S. aureus (MRSA). These results indicate that extracts and pure compounds obtained from Ferulago trachycarpa could be a potential for pharmaceutical products which have antimicrobial activity. [ABSTRACT FROM AUTHOR]

Psoriasis is an autoimmune and inflammatory skin disease affecting around 2-3% of the world's population. Patients with psoriasis need extensive treatments with global immunosuppressive agents that may cause severe side effects. Esculetin, a type of coumarins, is an active ingredient extracted mainly from the bark of Fraxinus rhynchophylla, which has been used to treat inflammatory and autoimmune diseases in China. However, the antipsoriatic effects of esculetin have not been reported. In this study, we aimed to investigate the effects of esculetin on psoriatic skin inflammation in a mouse model and explored the potential molecular mechanisms underlying its action. We found that esculetin ameliorated the skin lesion and reduced PASI scores as well as weight loss in imiquimod-induced psoriasis-like mice, accompanied with weakened proliferation and differentiation of keratinocytes and T cell infiltration in esculetin-treated psoriatic mice. In addition, esculetin reduced the frequency of CD8+CD44highCD62Llow effector T cells in psoriatic mice. In contrast, it increased the frequency of CD4+Foxp3+ Tregs in both lymph nodes and spleens of the psoriatic mice while promoting the differentiation of CD4+CD25- T cells into CD4+Foxp3+ Tregs in vitro. Interestingly, depleting CD4+Foxp3+ Tregs largely reversed esculetin-mediated reduction in PASI scores, indicating that esculetin attenuates murine psoriasis mainly by inducing CD4+Foxp3+ Tregs. Furthermore, the mRNA levels of proinflammatory cytokines in the psoriatic mouse skin, including IL-6, IL-17A, IL-22, IL-23, TNF-α, and IFN-g, were dramatically decreased by the treatment with esculetin. Finally, we found that esculetin inhibited the phosphorylation of IKKa and P65 in the psoriatic skin, suggesting that it inhibits the activation of NF-κB signaling. Thus, we have demonstrated that esculetin attenuates psoriasis-like skin lesion in mice and may be a potential therapeutic candidate for the treatment of psoriasis in clinic. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD), the most common cause of dementia, is a neurodegenerative disorder characterized by progressive deterioration of memory and cognition. The evidenced multifactorial nature of AD has been considered the main reason for the absence of cure so far. Therefore, the development of novel hybrids to treat the disease is very much essential. Focusing on this, a novel series of coumarin–benzofuran hybrids have been designed and screened as anti‐Alzheimer’s disease agents. The strategy is to obtain an effective mimetic of donepezil, which is acetylcholinesterase inhibitor. Herein, the two main scaffolds namely coumarin and benzofuran are known pharmacophore moieties and we have performed their molecular design, pharmacokinetic descriptor studies for drug‐likeliness. Further, in vitro studies such as antioxidant capacity, acetylcholinesterase (AChE) inhibition and amyloid‐β (Aβ) self‐aggregation inhibition have also been performed. Most importantly, these studies revealed that the newly synthesized hybrids can be versatile and promising drug‐like moieties as efficient anti‐AD agents. [ABSTRACT FROM AUTHOR]

Background: Ferula vesceritensis is an indigenous plant of Algerian Sahara riche in sesquiterpene coumarins. Objective: In this study, we investigated the biological activity of sesquiterpene coumarins; coladin, ferulenol, and lapiferin (10_-acetoxy-6_-angeloyloxy-8_,9_-epoxy-trans-caxotan-4_-ol) isolated for the first time from the crude extract CH2Cl2—MeOH (1:1) of the roots of F. vesceritensis Coss. et Dur. Materials and Methods: Structures of coladin, ferulenol, and lapiferin were determined by extensive nuclear magnetic resonance (NMR) analyses, including 1D-(1H and13C) and 2D-NMR experiments (correlation spectroscopy, heteronuclear single-quantum coherence, heteronuclear multiple bond correlation (HMBC), and nuclear overhauser effect spectroscopy) as well as high-resolution electron ionization mass spectra and mass spectroscopy analyses. Results: Tested on mouse B16F1 melanoma cells, ferulenol, coladin, and lapiferin exhibited a significant decrease in cell proliferation and a decrease of mitochondrial dehydrogenase activity evaluated on living FAO cells and B16F1 melanoma cells with the WST-1 throughout an apoptotic pathway. They displayed pro-apoptotic effects observed by a decrease in mitochondrial membrane potential and the mitochondrial respiratory rate on isolated liver mitochondria in a dose-dependent manner. Conclusion: Our results highlight the importance of the sesquiterpene coumarins extracted from F. vesceritensis as new biologically active natural products against cancer cells. Abbreviations used: FAO: Hepatoma cell line; B16F1: Pulmonary metastasis melanoma cell line. [ABSTRACT FROM AUTHOR]

Coumarin is an important bioactive pharmacophore. It is found in plants as a secondary metabolite and exhibits diverse pharmacological properties including anticancer effects against different malignancies. Therapeutic efficacy of coumarin derivatives depends on the pattern of substitution and conjugation with different moieties. Cancer cells contain elevated copper as compared to normal cells that plays a role in angiogenesis. Thus, targeting copper in malignant cells via copper chelators can serve as an attractive targeted anticancer strategy. Our previous efforts led to the synthesis of di(2-picolyl)amine-3(bromoacetyl)coumarin hybrid molecule (ligand-L) endowed with DNA/Cu(II) binding properties, and ROS generation ability in the presence of copper ions. In the present study, we aimed to validate copper-dependent cytotoxic action of ligand-L against malignant cells. For this, we used a cellular model system of copper (Cu) overloaded lymphocytes (CuOLs) to simulate malignancy-like condition. In CuOLs, lipid peroxidation/protein carbonylation, ROS generation, DNA fragmentation and apoptosis were investigated in the presence of ligand-L. Results showed that ligand-L-Cu(II) interaction leads to ROS generation, lipid peroxidation/protein carbonylation (oxidative stress parameters), DNA damage, up-regulation of p53 and mitochondrial-mediated apoptosis in treated lymphocytes. Further, pre-incubation with neocuproine (membrane permeable copper chelator) and ROS scavengers attenuated the DNA damage and apoptosis. These results suggest that cellular copper acts as molecular target for ligand-L to propagate redox cycling and generation of ROS via Fenton-like reaction leading to DNA damage and apoptosis. Further, we showed that ligand-L targets elevated copper in breast cancer MCF-7 and colon cancer HCT116 cells leading to a pro-oxidant inhibition of proliferation of cancer cells. In conclusion, we propose copper-dependent ROS-mediated mechanism for the cytotoxic action of ligand-L in malignant cells. Thus, targeting elevated copper represents an effective therapeutic strategy for selective cytotoxicity against malignant cells. [ABSTRACT FROM AUTHOR]

Introduction. Bleeding after dental surgery is still a common cause for emergency presentation in patients using anticoagulants. Our aim was to analyze pertinent characteristic features on the one hand and to bare existing problems in handling on the other. Materials and Methods. The study included 76 patients. We documented basic data, anticoagulant medication, type of surgery, and tooth socket sutures in respective patients. Results. The vast majority of patients took a coumarin derivative (41) and acetylsalicylic acid (27). Nine (12%) of the patients had to be hospitalized due to ongoing bleeding despite local haemostyptic steps and/or circulatory dysregulation. Most patients could be successfully treated in outpatient settings. No statistically significant correlation between bleeding, level of INR value, number of extracted teeth, and sewed alveoli could be shown. Sixty-five percent of cases with tooth extractions did not have suture of tooth sockets. Eighty-seven percent of the patients denied being informed about possible self-treatment options by their surgeon/dentist, and none of the patients got presurgical-fabricated bandage plate(s). Conclusions. Patients taking coumarin derivative currently, furthermore, represent the biggest anticoagulant after-bleeding group in dentoalveolar surgery. The major part of after-bleedings (90%) can be handled in an outpatient setting with simplest surgical interventions. Unfortunately, the biggest part of the patient collective got no suture, no prefabricated dental bandage plate(s), and no explanation by their dentist how to handle in case of after-bleeding. Therefore, dental practitioners should furthermore get enlightenment on how to prevent after-bleeding situations. [ABSTRACT FROM AUTHOR]

A novel series of coumarin-lipoic acid conjugates were synthesized via cycloaddition click reaction to find out new multi-target-directed ligands (MTDLs) for treatment of Alzheimer's disease (AD). All of synthesized compounds were screened for neuroprotective and anti-cholinesterase activities. Based on primary screening, two compounds ( 5 and 11 ) were subjected to further biological evaluations. In particular, compound 11 which was the most potent AChE inhibitor showed good inhibitory effect on Aβ-aggregation and intracellular ROS (reactive oxygen species) formation, as well as the ability of selective bio-metal chelation and neuroprotection against H 2 O 2 - and Aβ 1-42 -induced cytotoxicity. In the light of these results, the applied hybridization approach introduced new promising lead compound with desired multifunctional properties, being useful in the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Naturally occurring coumarins 7-isopentenyloxycoumarin, auraptene, and umbelliprenin are able to modulate the biosynthesis of melanin in murine Melan-a cells probably through the interaction with selected biological targets like estrogen receptor β and aryl hydrocarbon receptor. Such a modulation strictly depends on the individual structure of the coumarin: the presence of a 3,3-dimethylallyloxy side chain is a structural determinant for tanning activation whereas a farnesyl one leads to the opposite effect. The parent compound with a free OH group, umbelliferone, did not provide any interaction. Other coumarins assayed, having shorter chains and/or being substituted in other positions, and prenyloxypsoralens, were not active or not further investigated in this context being cytotoxic at low doses. [ABSTRACT FROM AUTHOR]

In this study, we presented rational designing and synthesis of coumarin-dihydroquinazolinone conjugates to evaluate their agonist activity at GPR109a receptor. Among the synthesized small molecule library, compound 10c displayed robust agonist action at GPR109a with EC 50  < 11 nM. Homology model of human GPR109a protein was generated to realize the binding interaction of the active molecule with the active site of GPR109a. Further, the efficacy of active compound 10c was supported by in-vivo experiments which showed reduced body weight in diet induced obese mice model. Interestingly, compound 10c reduced leptin in blood plasma and total serum cholesterol. These results suggest that the coumarin-dihydroquinazolinone conjugate is a suitable scaffold to further expand the chemical diversity and make them potential niacin receptor 1 agonist. [ABSTRACT FROM AUTHOR]

Five new compounds including two phenyldilactones ( 1 , 2 ), two coumarins ( 3 , 4 ) and a dimer of N-E -feruloyl tyramine ( 5 ) together with twenty-three known compounds ( 6 – 28 ) were isolated from a medicinal plant Polygonum chinense. The structures of the new compounds were established by detailed spectral analysis. The absolute configurations of 1 and 5 were elucidated by Mosher’s method, Mo 2 (OAc) 4 -induced electronic circular dichroism (ECD) data, and ECD calculation. All the compounds were found to show potent anticomplement activity with CH 50 and AP 50 values ranging from 0.18 to 1.45 mM, and 0.26 to 2.80 mM, respectively. Phenyldilactones and phenylpropionic tyramines were firstly reported as anticomplement agents. The targets of compounds 1 , 3 , 5 and 10 in complement activation cascade were identified as well. [ABSTRACT FROM AUTHOR]

Coumarin containing pyrazoline derivatives have been synthesized and tested as inhibitors of in vitro development of a chloroquine-sensitive (MRC-02) and chloroquine-resistant (RKL-2) strain of Plasmodium falciparum and in vivo Plasmodium berghei malaria. Docking study was also done on cysteine protease falcipain-2 which showed that the binding pose of C-14 molecule and epoxysuccinate, inhibitor of falcipain-2, binds in the similar pattern. The most active antimalarial compound was 3-(1-benzoyl-5-(4-flurophenyl)-4,5-dihydro-1H-pyrazol-3yl)-7-(diethyamino)-2H-chromen-2-one C-14 , with an IC 50 of 4.21 µg/ml provided complete protection to the infected mice at 24 mg/kg X 4 days respectively. [ABSTRACT FROM AUTHOR]

Several mediators were associated with the pathogenesis of inflammatory bowel disease such as oxidative stress through the production of reactive oxygen metabolites, neutrophils infiltration and release of pro-inflammatory cytokines. This study was designed to investigate the therapeutic efficacy of osthole against dinitrobenzene sulfonic acid (DNBS) induced-colitis in rats through its anti-oxidant and anti-inflammatory properties. Colitis was induced in rats by single intracolonic instillation of (250 μl DNBS-25 mg/rat). Then 4 days later, rats were received oral administration of either (osthole 50 mg/kg), (sulfasalazine 500 mg/kg) or both in combination for 7 consecutive days. Body weight, some hematological parameters, colonic malondialdehyde (MDA) and myeloperoxidase activity (MPO), antioxidant parameters, colon injury and mucosa architectures were assessed. T helper (Th1)-related cytokines [Tumor necrosis factor alpha (TNF-α) and interferon-gamma (INF-γ)], Th2-relarted cytokines (interleukin-4 [IL-4 and IL-10], and Th-17 related cytokines [IL-17] were determined by ELISA. Osthole significantly improved the loss in body weight. That was accompanied with a remarkable amelioration of the disruption of the colonic architecture as well as a significant improvement in the antioxidant defense system. A reduction in MPO and MDA was observed in flamed colon. Treatment with either osthole or combination therapy showed suppressive activities on pro-inflammatory Th2-related cytokines and upregulation of anti-inflammatory Th2-related cytokines The results of this study suggest that osthole exert beneficial therapeutic effect in experimental colitis and improved the efficacy of the synthetized drugs such as sulfasalazine. Therefore, osthole may have a valuable sound in the treatment of inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Auraptene (AUR) is a bioactive antioxidant coumarin with valuable pharmacological properties; however, poor water solubility is a substantial issue for the topical application of AUR. Therefore, we sought to prepare solid lipid nanoparticles (SLNs) containing AUR (AUR-SLNs) to enhance its anti-inflammatory effect. The prepared formulations were optimized by applying the response surface method. Furthermore, AUR-SLNs were compared to conventional cream containing AUR regarding both the permeation rate of the nanoparticles and the anti-inflammatory effect through both in vitro and in vivo studies. Particle size and entrapment efficiency of the optimized formulation were 140.9 ± 3.55 nm and 84.11% ± 3.30, respectively. Transmission electron microscopy revealed that the nanoparticles were spherical. Differential scanning calorimetry (DSC) analysis demonstrated no drug-lipid incompatibility in the formulation. Fourier transform-infrared spectroscopy (FTIR) spectra revealed the amorphous state of AUR and the encapsulation of this agent in SLNs. The in vitro permeation studies exhibited that AUR-SLNs could significantly enhance cutaneous uptake of AUR and skin targeting. The anti-inflammatory and histopathological studies exhibited no significant differences between AUR-SLNs and indomethacin. AUR-SLNs did not induce skin sensitization in guinea pigs. The results suggest that SLNs could be appropriate carriers for the topical application of AUR as a natural anti-inflammatory agent. [ABSTRACT FROM AUTHOR]

Abstract: Hit, Lead & Candidate Discovery Glyoxalase‐I (Glo‐I) enzyme has emerged as a potential target for cancer treatment. Several classes of natural products including coumarins and flavonoids have shown remarkable Glo‐I inhibitory activity. In the present study, computational and experimental approaches were used to explore the structure–activity relationships of a panel of 24 flavonoids as inhibitors of the Glo‐1 enzyme. Scutellarein with an IC50 value of 2.04 μM was identified as the most potent inhibitor among the series studied. Di‐ or tri‐hydroxylation of the benzene rings A and B accompanied with a C2/C3 double bond in ring C were identified as essential structural features for enzyme inhibition. Moreover, the ketol system showed a minor role in the inhibitory power of these compounds. The structure‐activity relationships revealed in this study had deepened our understanding of the Glo‐I inhibitory activities of flavonoids and opened the door for further exploration of this promising compound class. [ABSTRACT FROM AUTHOR]

The present study was to investigate cardioprotective effects of umbelliferone (Umb) on coronary artery ligation-induced myocardial ischemia. The model of myocardial ischemia (MI) was induced by ligatured the left anterior descending coronary artery of SD rats. ST-segment elevation, lactate dehydrogenase (LDH), creatine kinase (CK), catalase (SOD), malondialdehyde (MDA), inflammatory cytokines, Toll-like receptors (TLRs)/nuclear factor (NF)-κBp65 pathway, and apoptosis were evaluated in rats treated with or without Umb. The results showed that Umb treatment could significantly decrease the elevation of the ST segment of electrocardiograph (ECG), the myocardial infarct size of MI significantly. The levels of LDH, CK, and MDA were suppressed, and the content of SOD was enhanced with Umb. The elevated concentration of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 in MI rats was effectively reversed by the Umb administration. Also, TLR/NF-κB and apoptosis-related proteins in MI rats were restored respectively by Umb treatment. The protective effect of Umb against MI injury might be associated with inflammation and apoptosis pathway. [ABSTRACT FROM AUTHOR]

Two series of coumarinyl thiosemicarbazides were synthesized: one, using the coumarin core substituted in position 7 and another, using same core substituted in position 4. All these compounds were obtained in reactions of the corresponding hydrazide and various isothiocyanates. The structures of all products were confirmed by the 1H and 13C NMR and mass spectrometry techniques. The antimicrobial properties of compounds were tested on four bacterial strains: Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. 2-(2-(7-Hydroxy-2-oxo-2H-chromen-4-yl)acetyl)-N-(2,4,6-trichlorophenyl)hydrazine-1-carbothioamide was found to be the most potent agent against B. subtilis. [ABSTRACT FROM AUTHOR]

Biochemical investigations of 3-substituted chromen-2-ones (coumarins) and those condensed with biologically active azaheterocycles assessed their toxic effects and influence on the blood-coagulation system. The studied group of compounds behaved in the initial time period like the well-known anticoagulant warfarin and exhibited insignificant toxic effects. [ABSTRACT FROM AUTHOR]

Many naturally occurring substances, traditionally used in popular medicines around the world, contain the coumarin moiety. Coumarin represents a privileged scaffold for medicinal chemists, because of its peculiar physicochemical features, and the versatile and easy synthetic transformation into a large variety of functionalized coumarins. As a consequence, a huge number of coumarin derivatives have been designed, synthesized, and tested to address many pharmacological targets in a selective way, e.g., selective enzyme inhibitors, and more recently, a number of selected targets (multitarget ligands) involved in multifactorial diseases, such as Alzheimer’s and Parkinson’s diseases. In this review an overview of the most recent synthetic pathways leading to mono- and polyfunctionalized coumarins will be presented, along with the main biological pathways of their biosynthesis and metabolic transformations. The many existing and recent reviews in the field prompted us to make some drastic selections, and therefore, the review is focused on monoamine oxidase, cholinesterase, and aromatase inhibitors, and on multitarget coumarins acting on selected targets of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

A series of 30 compounds were synthetized inspired by active trans-fagaramide structure skeleton. On this synthetic platform, 18 compounds were achieved via Knoevenagel condensation using maleic acid and piperonal, followed by peptide coupling with various amines, giving an average yield of 54%. Subsequently, nine compounds were obtained by palladium-mediated Heck coupling with an average yield of 79%. In addition, cytotoxic activity was evaluated against cardiomyoblast H9c2, breast adenocarcinoma MCF7, hepatocellular carcinoma HepG2, and glioblastoma U-87 cells. The results revealed two aryl halogen-substituted compounds moderately active against H9c2 and MCF7 with IC50 values > 50 μM. One functionalized coumarin showed inhibitory activity against H9c2 (IC50 > 50 μM). In contrast, p-aminophenyl-β-monosubstituted trans-fagaramide was found to inhibit MCF7 (IC50 > 50 μM) without showing toxicity against H9c2 cells. [ABSTRACT FROM AUTHOR]

Colon adenocarcinoma is one of the most common cancers worldwide, and resistance to current therapeutic modalities is a serious drawback in its treatment. Auraptene is a natural coumarin with considerable anticancer effects. The goal of this study was to introduce a novel combinatorial approach for treatment against colon adenocarcinoma cells. To do so, HT29 cells were pretreated with nontoxic auraptene and then hyperthermia was induced. Afterwards, the viability of the cells was assessed, changes induced in the cell cycle were analyzed, and the expression patterns of candidate genes were studied. Results from the MTT assay demonstrated significant ( p < 0.01) decreases in cell viability when 20 μg/mL auraptene was used for 72 h, heat shock was induced, and cells were allowed to recover for 24 h. Flow cytometry analysis also indicated considerable changes in the distribution of cells between the sub-G1/G1 and G2/M phases of cell cycle after the combinatorial treatment. Real-time RT-PCR studies revealed significant ( p < 0.01) up-regulation of P21 in the cells pretreated with auraptene after heat shock, whereas no significant change was observed in HSP27 expression. Our findings not only indicate, for the first time, that the efficacy of hyperthermia was improved by auraptene pretreatment, but also suggest that this coumarin could be used in the future to achieve more effective therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Praeruptorin A (PA) is a pyranocumarin present in the dried root of Peucedanumpraeruptorum Dunn that has anticancer effects against several types of cells. However, the effect of PA on human cervical cancer cells is unknown. Our results indicate that PA significantly inhibited cell proliferation, colony formation, migration, invasion, and wound closure of HeLa and SiHa cells, induced cell cycle arrest at G0/G1 phase, upregulated Rb, p16, p21 and p27 proteins and downregulated cyclin D1 and S-phase kinase-associated protein 2 (Skp2) proteins. PA also significantly reduced expression of matrix metalloproteinase-2 (MMP-2) and increased expression of tissue inhibitor of metalloproteinase-2 (TIMP-2). In addition, PA suppressed ERK1/2 activation and increased the effect of PD98059 (a specific MEK1/2 inhibitor) in downregulation of MMP-2 and upregulation of TIMP-2. PA treatment inhibited the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on upregulation of ERK1/2 activation, MMP-2 expression, cellular migration, and invasion of HeLa cells. Our findings are the first to demonstrate the activity of PA against cervical cancer cells, and suggest this agent has promise as a therapeutic agent in treatment of human cervical cancer. [ABSTRACT FROM AUTHOR]

Coumarins are widely prescribed worldwide, and inMexico acenocumarol is the preferred form. It is well known that despite its efficacy, coumarins show a high variability for dose requirements. We investigated the pharmacogenetic variation of 110 genes in patients receiving acenocumarol using a targeted NGS approach. We report relevant population differentiation for variants on CYP2C8, CYP2C19, CYP4F11, CYP4F2, PROS, and GGCX, VKORC1, CYP2C18, NQO1. A higher proportion of novel-to-known variants for 10 genes was identified on 41 core pharmacogenomics genes related to the PK (29), PD (3), of coumarins, and coagulation proteins (9) including, CYP1A1, CYP3A4, CYP3A5, and F8, and a low proportion of novel-to-known variants on CYP2E1, VKORC1, and SULT1A1/2. Using a Bayesian approach, we identified variants influencing acenocumarol dosing on, VKORC1 (2), SULT1A1 (1), and CYP2D8P (1) explaining 40-55% of dose variability. A collection of pharmacogenetic variation on 110 genes related to the PK/PD of coumarins is also presented. Our results offer an initial insight into the use of a targeted NGS approach in the pharmacogenomics of coumarins in Mexican Mestizos. [ABSTRACT FROM AUTHOR]

Background Coumarins occurs naturally across plant kingdoms exhibits significant pharmacological properties and pharmacokinetic activity. The conventional, therapeutic agents are often associated with poor stability, absorption and increased side effects. Therefore, identification of a drug that has little or no-side effect on humans is consequential. Here, we investigated the antiproliferative activity of styrene substituted biscoumarin against various human breast cancer cell lines, such as MCF-7, (ER-) MDA-MB-231 and (AR+) MDA-MB-453. Styrene substituted biscoumarin induced cell death by apoptosis in MDA-MB-231 cell line was analyzed. Methods Antiproliferative activity of Styrene substituted biscoumarin was performed by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Styrene substituted biscoumarin induced apoptosis was assessed by Hoechst staining, Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) staining and flow cytometric analysis. Migratory and proliferating characteristic of breast cancer cell line MDA-MB-231 was also analyzed by wound healing and colony formation assay. Furthermore, mRNA expression of BAX and BCL-2 were quantified using qRT-PCR and protein expression level analyzed by Western blot. Results The inhibition concentration (IC 50 ) of styrene substituted biscoumarin was assayed against three breast cancer cell lines. The inhibition concentration (IC 50 ) value of styrene substituted biscoumarin toward MDA-MB-231, MDA-MB-453 and MCF-7 cell lines was 5.63, 7.30 and 10.84 μg/ml respectively. Styrene substituted biscoumarin induced apoptosis was detected by Hoechst staining, DAPI/PI analysis and flow-cytometric analysis. The migration and proliferative efficiency of MDA-MB-231 cells were completely arrested upon styrene substituted biscoumarin treatment. Also, mRNA gene expression and protein expression of pro-apoptotic ( BAX ) and anti-apoptotic ( BCL-2 ) genes were analyzed by qRT-PCR and western blot analysis upon styrene substituted biscoumarin treatment to MDA-MB-231 cells. Our results showed that styrene substituted biscoumarin downregulated BCL-2 gene expression and upregulated BAX gene expression to trigger apoptotic process. Conclusion Styrene substituted biscoumarin could induce apoptosis through intrinsic mitochondrial pathway in breast cancer cell lines, particularly in MDA-MB-231. Our data suggest that styrene substituted biscoumarin may act as a potential chemotherapeutic agent against breast cancer. [ABSTRACT FROM AUTHOR]

Coumarin exhibits different hepatotoxicity in rats depending on the administration frequency. To investigate the underlying mechanisms for the differences, we administered coumarin to rats as a single dose or repeatedly for 4 weeks. We found large increases in blood levels of liver enzymes and noticeable centrilobular hepatic necrosis after a single dose of coumarin. After repeated administration, enzyme levels mildly increased, while those of γ-GTP and total bilirubin significantly increased, suggesting bile duct damage. In the control group, cytochrome P450 2E1 (CYP2E1) showed a diffuse subcellular distribution but accumulated within the hepatocyte endoplasmic reticulum after repeated coumarin administration. The maximum blood concentrations of coumarin and its metabolites were significantly lower upon repeated administration. The results suggest that changes in coumarin pharmacokinetics and CYP2E1 subcellular distribution contribute to resistance to coumarin-induced hepatic necrosis, while cytotoxicity of metabolic conjugates shown in vitro may contribute to bile duct damage upon repeated coumarin administration. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is a common urinary malignancy that is resistant to chemotherapy and radiotherapy. Osthole, a monomer compound extracted from a traditional Chinese herb, has potent anti-tumor effects on various types of cancer cells. However, the therapeutic effects of osthole on RCC remain unclear. In our study, osthole could suppress the proliferation and colony formation of two RCC cell lines, ACHN and 786-O cells, in a dose-dependent manner. Treatment with osthole resulted in a significant, dose-dependent increase in the expression of pro-apoptotic proteins (cleaved caspase-3 and Bax) and decreased expression of anti-apoptotic proteins (Bcl-2 and survivin), which were consistent with evidence of apoptotic nuclear morphology revealed by DAPI staining. Pre-treatment with osthole attenuated the migratory and invasive abilities of RCC cells in a dose-dependent manner, as evidenced by a reduction in migrating cells in a Transwell assay and a decreased wound closure ratio in a scratch assay as compared with the control. Additionally, osthole down-regulated the expression of migration/invasion-related proteins matrix metalloproteinase (MMP)-2 and MMP-9. Osthole significantly up-regulated epithelial biomarkers (E-cadherin and beta-catenin) and down-regulated mesenchymal biomarkers (N-cadherin and vimentin). Furthermore, our results suggest that osthole suppressed the expression of epithelial–mesenchymal transition transcriptional factors Smad-3, Snail-1, and Twist-1. Taken together, the results of this study suggest that osthole might be a potential novel herbal agent against RCC. [ABSTRACT FROM AUTHOR]

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]

Angelicae Pubescentis Radix (APR), a well-known traditional Chinese medicine, is widely used for the treatments of rheumatism and headache for centuries. To assess the absorption characteristics of coumarins from APR, a sensitive and reliable UPLC–MS/MS method was established for the simultaneous determination of sixteen coumarins from APR, including psoralen, xanthotoxin, bergapten, bergaptol, isoimperatorin, imperatorin, columbianetin, columbianetin acetate, columbianadin, oxypeucedanin hydrate, angelol B, umbelliferone, scopoletin, osthole, meranzin hydrate and nodakenetin. The specificity, linearity, sensitivity, precision, accuracy, recovery, matrix effect and stability of the method were all validated to be satisfactory. The method was then applied to the in vitro transport of APR extract (APRE) across human intestinal epithelial Caco-2 cell and in vivo pharmacokinetics in rats after oral administration of APRE. All of the tested coumarins were well or moderately absorbed across Caco-2 monolayers, and could be quickly absorbed into rat blood circulation after oral administration. Columbianetin was the most easily absorbed compound across Caco-2 cell, and also had extremely highest plasma concentration in vivo . Excellent correlation between in vitro absorption across Caco-2 cell monolayers and in vivo pharmacokinetics of coumarins from APRE was well verified. The results provided valuable information for the overall absorption characteristics of the coumarins from APR, as well as for its further studies of in vivo active substances in the further. [ABSTRACT FROM AUTHOR]

Due to higher transmembrane potential of tumor cells, enhanced accumulation of cationic drugs in tumor mitochondria has been attributed to a higher (more negative inside) mitochondrial transmembrane potential compared with normal cells, emerging researchers are focus on developing mitochondria-targeted antitumor drugs. Coumarins showed great potential on antitumor, but mitochondria-targeted coumarin derivatives have not been reported. In the present study, we synthesized mitochondria-targeted-methyl coumarin (mito-methyl coumarin) through coupling 6-methyl coumarin to TPP. We confirmed that mito-methyl coumarin inhibited HeLa cells proliferation selectively, induced ROS generation, reduced mitochondrial membrane potential, promoted mitochondria Ca 2+ accumulation, decreased mitochondria mass and induced HeLa cells apoptosis, but methyl coumarin did not. These results demonstrate that we succeed in synthesizing a novel mitochondria-targeted drug, mito-methyl coumarin, which is effective in inhibiting HeLa cells proliferation and inducing HeLa cells apoptosis through promoting ROS generation and mitochondria Ca 2+ accumulation. [ABSTRACT FROM AUTHOR]

Objective: Here, we used various approaches to investigate the suppressive role of daphnetin in LPS-induced inflammatory response, with the goal to understand the underlining molecular mechanism by which daphnetin regulated these processes. Methods: We examined the survival rate and the lung injury in the mice model of LPS-induced endotoxemia. The production of pro-inflammatory factors including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), IL-6, nitric oxide (NO), and prostaglandin E2 (PGE2) was measured by ELISA and nitrite analysis, respectively. The expression of inducible NO synthase (iNOS), cyclooxygenase 2 (COX-2), and the activation of signaling molecules was determined by immunoblotting. The production of reactive oxygen species (ROS) was measured by the ROS assay. Results: In vivo study showed that daphnetin enhanced the survival rate and reduced the lung injury in mice with LPS-induced endotoxemia. Both in vivo and in vitro study showed that daphnetin prevented the production of pro-inflammatory factors including TNF-α, IL-1β, IL-6, NO, and PGE2 after LPS challenge. In Raw264.7 cells, we found that daphnetin reduced LPS-induced expression of iNOS and COX-2, and suppressed LPS-induced ROS production. In addition, we found that daphnetin suppressed the activation of JAK/STATs pathway and inhibited the nucleus import of STAT1 and STAT3. Conclusions: Here, our results indicate that daphnetin shows anti-inflammatory properties, at least in part, through suppressing LPS-induced activation of JAK/STATs cascades and ROS production. [ABSTRACT FROM AUTHOR]

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Aesculin (AES), a coumarin compound derived from Aesculus hippocasanum L, is reported to exert protective role against inflammatory diseases, gastric disease and cancer. However, direct effect of AES in bone metabolism is deficient. In this study, we examined the effects of AES on osteoclast (OC) differentiation in receptor activator of NF-κB ligand (RANKL)-induced RAW264.7 cells. AES inhibits the OC differentiation in both dose- and time-dependent manner within non-toxic concentrations, as analyzed by Tartrate Resistant Acid Phosphatase (TRAP) staining. The actin ring formation manifesting OC function is also decreased by AES. Moreover, expressions of osteoclastogenesis related genes Trap , Atp6v0d2 , Cathepsin K and Mmp-9 are decreased upon AES treatment. Mechanistically, AES attenuates the activation of MAPKs and NF-κB activity upon RANKL induction, thus leading to the reduction of Nfatc1 mRNA expression. Moreover, AES inhibits Rank expression, and RANK overexpression markedly decreases AES's effect on OC differentiation and NF-κB activity. Consistently, AES protects against bone mass loss in the ovariectomized and dexamethasone treated rat osteoporosis model. Taken together, our data demonstrate that AES can modulate bone metabolism by suppressing osteoclastogenesis and related transduction signals. AES therefore could be a promising agent for the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

Aflatoxin contamination of animal diet has adverse effects on animal health and productivity. This study was performed to investigate the effect of using coumarin and/or chlorophyllin in rat diet against aflatoxicosis. Fifty-four rats were assigned into 7 groups (6 rats each). G1 was a negative control. G2 received water with coumarin 0.5%. G3 received water with chlorophyllin 0.5%. G4 received water with coumarin 0.5% and chlorophyllin 0.5%. G5-8 fed aflatoxin B 1 1000 ppb in diet. Group 6–8 were administered similar treatments as G2-4. The experiment ended after 8 weeks. Random glucose, total lipid, total cholesterol, total triglycerides, total protein, serum ALT, AST, creatinine, and urea were measured. Histopathology of liver, kidney and pancreas and immunohistochemical staining of placental glutathione-S-transferase (GST-P) in liver were performed. The glucose serum level, cholesterol, AST, and ALT were elevated in G5 compared to G6-8. The liver and kidney lesions in G5 included vacuolation and necrosis which subsided in G6-8. The necrosis and inflammatory cells infiltration in the pancreas of G5 were absent in G6-8. GST-P positive hepatocytes were abundant in G5, few in G6 and absent in G7 and G8. In conclusion, the chlorophyllin and coumarin possessed protective and anti-carcinogenic effect against aflatoxicosis in rats. [ABSTRACT FROM AUTHOR]

A novel colorimetric and fluorescent sensor 6 for fluoride and cyanide was developed based on BODIPY-coumarin platform and its anions sensing properties were investigated in the mixture of acetonitrile and Tris–HCl buffer (v/v = 95:5, pH = 7.5). Probe 6 could simultaneously detect F – and CN – through colorimetric method over the other competitive anions, such as Cl – , Br – , I – , NO 3 – , ClO 4 – , HSO 4 – , S 2– and H 2 PO 4 – . It exhibited a distinct color change from red to green upon addition of F – through deprotection of tert -butyldiphenylsilyl group of coumarin. Moreover, it displayed an obvious color change from red to yellow through deprotection process firstly, then with a nucleophilic displacement mechanism. Therefore, the sensor 6 provides a novel method to simultaneously detect F − and CN − with different color change in the same solvent environment. The detection limit of sensor 6 toward F – and CN – ion was determined to be 0.43 μM and 1.9 μM respectively, [ABSTRACT FROM AUTHOR]

The percutaneous passage of poorly skin absorbed molecules can be improved using nanocarriers, particularly biodegradable polymeric nanospheres (NSs) or nanocapsules (NCs). However, penetration of the encapsulated molecules may be affected by other factors than the nanocarrier properties. To gain insight information on the skin absorption of two fluorescent cargos, DiIC 18 (5) and coumarin-6 were incorporated in NSs or NCs and topically applied on various human and porcine skin samples. 3D imaging techniques suggest that NSs and NCs enhanced deep dermal penetration of both probes similarly, when applied on excised human skin irrespective of the nature of the cargo. However, when ex vivo pig skin was utilized, the cutaneous absorption of DiIC 18 (5) was more pronounced by means of PLGA NCs than NSs. In contrast, PLGA NSs noticeably improved the porcine skin penetration of coumarin-6, as compared to the NCs. Furthermore, the porcine skin results were reproducible when triplicated whereas from various human skin samples, as expected, the results were not sufficiently reproducible and large deviations were observed. The overall findings from this comprehensive comparison emphasize the potential of PLGA NCs or NSs to promote cutaneous bioavailability of encapsulated drugs, exhibiting different physicochemical properties but depending on the nature of the skin. [ABSTRACT FROM AUTHOR]

Daphnetin (Daph), a natural coumarin derivative isolated from plants of the Genus Daphne , possesses abundant biological activities, such as anti-inflammatory, antioxidant and anticancer properties. In the present study, we focused on investigating the protective effect of Daph against tert -butyl hydroperoxide ( t -BHP)-induced oxidative damage, mitochondrial dysfunction and the involvement of underlying molecular mechanisms. Our findings indicated that Daph effectively inhibited t -BHP-stimulated cytotoxicity, cell apoptosis, and mitochondrial dysfunction, which are associated with suppressed reactive oxygen species (ROS) generation, decreased malondialdehyde (MDA) formation, increased superoxide dismutase (SOD) levels and glutathione (GSH)/GSSG (oxidized GSH) ratio. Further investigation indicated that Daph significantly suppressed cytochrome c release and NLRP3 inflammasome activation and modulated apoptosis-related protein Bcl-2, Bax, and caspase-3 expression. Moreover, Daph dramatically induced the expression of the glutamate-cysteine ligase modifier (GCLM) subunit and the glutamate-cysteine ligase catalytic (GCLC) subunit, heme oxygenase-1 (HO-1), and NAD (P) H: quinone oxidoreductase (NQO1), which is largely dependent on upregulating the nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation, reducing the Keap1 protein expression, and strengthening the antioxidant response element (ARE) promoter activity. Additionally, Daph remarkably activated a c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) phosphorylation, but ERK and JNK inhibitor pretreatment exhibited an evident decrease of the level of Daph-enhanced Nrf2 nuclear translocation. Furthermore, Daph exposure suppressed t -BHP-induced cytotoxicity and ROS overproduction, which are mostly blocked in Nrf2 knockout RAW 264.7 cells and peritoneal macrophages. Accordingly, Daph exhibited protective roles against t -BHP-triggered oxidative damage and mitochondrial dysfunction by the upregulation of Nrf2 antioxidant signaling pathways, which may be involved in the activation of JNK and ERK. [ABSTRACT FROM AUTHOR]

The gastroprotective effect of esculin was investigated in a mouse model of ethanol-induced gastric lesion. Administration of esculin at doses of 5, 10, and 20 mg/kg body weight prior to ethanol ingestion led to significant gastroprotection compared with untreated mice. Gastric mucosal lesions were evaluated by macroscopic and histopathological alterations, lesion index, and myeloperoxidase ( MPO) activity. Pretreatment with esculin significantly reduced macroscopic and histopathological damage, gastric lesion index, and MPO activity in a dose-dependent manner. Moreover, esculin significantly reduced nitric oxide ( NO) production, inducible NO synthase ( iNOS) levels, and nuclear factor-kappa B ( NF-κB) p65 protein expression in gastric tissues after ethanol challenge. Analysis of inflammatory cytokines indicated that esculin pretreatment markedly suppressed the increased expression of tumor necrosis factor-alpha ( TNF-α) and interleukin-6 ( IL-6) in ethanol-treated mice. The results demonstrate a protective effect of esculin against gastric injury and suggest that the underlying mechanism might be associated with inhibition of NF-κB activation, which subsequently reduces expression of iNOS, TNF-α, and IL-6. [ABSTRACT FROM AUTHOR]

Influenza viruses pose a severe threat to human health and a significant increase in antiviral drug-resistant among influenza viruses worldwide has been observed. Therefore, there is an urgent need to develop the new antiviral drugs, specifically from the natural products. In this study, the anti-viral and anti-inflammatory activities of coumarins against influenza A virus in vitro were investigated. One of the derivatives eleutheroside B 1 showed a wide spectrum of anti- human influenza virus effect with the IC 50 value of 64–125 μg/ml in vitro , but it showed no effects against avian influenza virus. The time of addition was done and the results indicated that it had a potent antiviral effect when added at 0–6 h, and also the virus yield was reduced by 60%. The influenza virus ribonucleoprotein was inhibited at 200 μg/ml, and also the NP mRNA expression was inhibited at 50 and 200 μg/ml. The expression level of cytokines and chemokines influenced by eleutheroside B 1 was further demonstrated, the IL-6, CXCL-8, CCL-2 expression were all inhibited by the eleuthe roside B 1 at concentration 200 μg/ml. The findings of study suggest that eleutheroside B 1 can be as potential agent to develop for the prevention and treatment of influenza A virus. [ABSTRACT FROM AUTHOR]

The first occurrences and dissemination of resistant microorganisms led to the inefficacy of many antibiotics, available in the market nowadays, therefore, the search for new substances with antimicrobial activity from natural sources has gained a great importance. The purpose of this work is to evaluate the antibacterial activity and modulation of drug resistance in Staphylococcus aureus by coumarins such as bergapten, xantotoxin, isopimpinellin and imperatorin obtained from two Rutaceae species ( Metrodorea mollis and Pilocarpus spicatus ). The antimicrobial activity was assessed based on the minimum inhibitory concentration (MIC), using the microdilution method. The MIC was >256 g/mL for all coumarins tested. Regarding the modulation of drug resistance assay, the isopimpinellin reducted the MIC of erytromicin by 4 times, whereas imperatorin exhibited the best result, reducing the MIC of tetracycline (2 times), erytomicin (4 times) and norfloxacin (4 times). By reducing the MIC of ethidium bromide, the imperatorin is consider in fact, as a putative efflux pump inhibitor of bacteria. [ABSTRACT FROM AUTHOR]

A series of 7-substituted coumarin derivatives were designed and synthesised to display ChE and MAO-B inhibitory activity. The compounds consisted out of a coumarin structure (MAO-B inhibitor) and benzyl-, piperidine-, N -benzylpiperidine- or p -bromo- N -benzylpiperizine moiety, resembling the N -benzylpiperidine function of donepezil (ChE inhibitor), connected via an alkyl ether linkage at the 7 position. The biological assay results indicated that all the compounds ( 1 – 25 ) displayed selective inhibition to hMAO-B over hMAO-A, with the benzyloxy series ( 1 – 8 , 10 – 13 ) showing nano-molar hMAO-B inhibition (IC 50 : 0.5–73 nM). Limited ChE inhibitory activity was however observed for the benzyloxy series with the exception of 2 and especially 3 showing selective BuChE inhibition. From this series 3 showed the best multifunctional activity (eqBuChE IC 50 = 0.96 μM, hMAO-A IC 50 = 2.13 μM, hMAO-B IC 50 = 0.0021 μM). Within the N -benzylpiperidine ( 16 – 19 ) and p -bromo- N -benzylpiperizine ( 21 – 24 ) series the compounds in general showed moderate ChE and MAO-B inhibitory activity. Of these compounds 19 was the most potent multifunctional agent showing good eeAChE and eqBuChE inhibition (IC 50 = 9.10 μM and 5.90 μM, respectively), and relatively potent and selective hMAO-B inhibition (IC 50 = 0.30 μM, SI = >33). Molecular modeling revealed that 19 was able to bind simultaneously to the CAS, mid-gorge and PAS sites of AChE and BuChE suggesting that it will be able to inhibit AChE induced Aβ aggregation. From this study, compounds that 3 and 19 can be considered as promising multifunctional lead compounds. [ABSTRACT FROM AUTHOR]

Imperatorin and isoimperatorin are 6,7-furocoumarin compounds, which are the major medicinal effective ingredients of Radix Angelicae Dahuricae. Coumarin compounds are widely used in topical formulations because it has many properties, such as anti-bacterial, anti-inflammatory, antipyretic and analgesic effects. At present, the chemical components of traditional Chinese medicine are mainly analyzed by thin layer chromatography (TLC), gas chromatography (GC) and high performance liquid chromatography (HPLC). However, because there are some difficulties in Chinese medicine analysis, such as complex composition, difficulty in separation and low-content, traditional methods (TLC, HPLC, etc.) were difficult to determine and analyze the composition sometimes. HPLC/MS is a comprehensive technique, it has become an important modern separation and analysis technique because of its high separation ability, high sensitivity, wide application range and strong specificity. Tandem mass spectrometry (MS/MS) has higher sensitivity and selectivity than unipolar mass spectrometry and can obtain more structural information. In this study, the in vitro percutaneous permeability of imperatorin and isoimperatorin in Radix Angelicae Dahuricael extracting solution was evaluated by the modified Franz diffusion cell with isolated rat skin. The content of imperatorin and isoimperatorin was determined by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The chromatographic conditions were as follows: Dimonsil C18 column (250 mm×4.6 mm, 5 μm), the temperature of column is 35 ℃, mobile phase was methanol-water (80∶20, V/V) and flow rate was 0.8 mL/min. A tandem mass spectrometer coupled with positive electro-spray ionization (ESI) source was used for detection. The quantitative and qualitative analysis were performed on selective ion chromatograms acquired by a multiple reaction monitoring (MRM) mode of following transitions: m/z 271.1→m/z 203.04, m/z 271.1→m/z 147.05. The results showed that the limits of detection (LODs) of imperatorin and isoimperatorin were 0.01 and 1 μg/L, and the limits of quantification (LOQs) of imperatorin and isoimperatorin were 0.25 and 2 μg/L, respectively. Calibration curves were linear over the range of 0.001-1 mg/L for imperatorin and isoimperatorin. Both the inter-day and intra-day reproducibility (RSDs) were lower than 4%, the precision and stability of the method were lower than 2%, which indicated that the method has good precision, and the test solution could keep steady within 24 h. The mean recoveries of imperatorin and isoimperatorin were 98.09% and 100.60%. The cumulative permeation amounts of imperatorin and isoimperatorin were 116.11 μg/cm2 and 210.06 μg/cm2 and the percentage of cumulative permeation were 37.75% and 71.86%, respectively. The steady state permeation rate of imperatorin was 26.5 μg/h•cm2 and its in vitro percutaneous permeabilities was conformed to Higuchi equation. This study clarified the percutaneous permeation mechanism of imperatorin in vitro and provided a theoretical basis for the development of Radix Angelicae Dahuricae as a topical transdermal preparation. [ABSTRACT FROM AUTHOR]

In this work, naturally occurring esculin (6,7-dihydroxycoumarin-6-glucoside), of great potential in therapy of nephrolithiasis − was successfully encapsulated in sodium alginate/chitosan hydrogel matrix by means of extrusion/external gelation-based and emulsification/internal gelation-based methods and the final microparticles were characterized with regard to structure and morphology, particle size and its distribution, swelling and release kinetics. Considering the fact, that the selected bioactive compound may be partially degradable in the aggressive conditions of the upper gastrointestinal tract, it was essential to develop a suitable carrier in order to provide its functional release directly in the small intestine. Therefore, in vitro release profiles of the microparticles were also investigated in order to provide the most effective encapsulation procedures in terms of operating conditions coupled with functionality of the fabricated particles, especially their ability to encapsulate the studied cargo, protect it under the simulated gastric conditions and promote its release under intestinal ones. The observed distinctions between the results of extensively physico-chemical studies obtained for both types of microparticles were the result of different matrix structures. The esculin cargo was successfully encapsulated with relatively high efficacies into both types of alginate/chitosan particles (ACPs). However, products prepared with an internal gelation/emulsification-based method remained more stable in different media and revealed the desired pH-dependent cargo release ability in vitro. The ACPs protected esculin in the simulated upper gastrointestinal tract, and enabled its release under the simulated intestinal conditions. The hydrogel microparticles thus obtained may be contributed as an effective delivery system for other therapeutic phenolic compounds, when it is necessary to maintain their stability during passage through the upper gastrointestinal tract to deliver them directly to the intestine. [ABSTRACT FROM AUTHOR]

Sulfocoumarins behave as interesting inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Here, we report a new series of 7-substituted derivatives which were obtained by the click chemistry approach from 7-propargyloxy-sulfocoumarin and aryl azides incorporating halogens, hydroxy, methoxy and carboxyl moieties in their molecules. The new compounds were screened for the inhibition on four physiologically relevant human CA (hCA) isoforms, the cytosolic hCA I and II and the transmembrane tumor-associated hCA IX and XII. The new compounds did not inhibit the cytosolic isoforms but were low nanomolar inhibitors of the tumor-associated ones hCA IX and XII. [ABSTRACT FROM PUBLISHER]

Polyphenols are used as phlebotonic drugs, but their mechanism of action remains unknown. Since platelet activity and platelet-endothelial cell interactions are involved in the pathogenesis of cardiovascular disease, this work examines whether different flavonoid and coumarin drugs are able to inhibit platelet aggregation. This specific case of coumarins, the antiplatelet effect is not linked with a possible interaction over blood coagulation since this effect only dicoumarols have it. The antiplatelet capacity of polyphenols was assayed using peripheral blood platelets from healthy controls. The distribution of the different platelets subsets was quantified by flow cytometry, using the calcium ionophore as a pro-aggregant. The number of GPIIb/IIIa receptors occupied by the drugs was assayed by flow cytometry using two CD61 surface fluorescein antibodies. All the polyphenols tested inhibited platelet aggregation. A percentage antiplatelet activity of 88.91 ± 7.98% was recorded for naringin, 48.43 ± 8.84% for naringenin, 53.83 ± 7.87% for esculetin, 54.65 ± 6.91% for fraxetin, and 25.75 ± 4.12% for coumarin. Naringin showed significantly greater percentage occupation of GPIIb/IIIa receptors than did naringenin (14.82 ± 0.81% vs. 3.90 ± 0.55%), and esculetin returned significantly higher values than fraxetin and coumarin (12.47 ± 0.97 vs. 7.53 ± 0.49 and 7.90 ± 0.69 respectively). All drugs show important antiplatelet activity. Naringin was the best antiplatelet compound, showing the greatest antiplatelet activity and the highest percentage binding of GPIIb/IIIa receptors. However, any of the compounds used could be used in the prevention of cardiovascular disease. [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]

In this review, we will present the different aspects of coumarins and derivatives, from natural origins or synthetically prepared, and their action on inflammation. Coumarins and also furo- and pyranocoumarins are found in many different plants. These compounds are very often investigated for antioxidant properties. Other biological properties are also possible and anti-inflammation activity is one of these. As coumarins are also available quite easily via synthesis, natural ones can be prepared this way but derivatives with special substituents are also feasible. A review on the same topic appeared in 2004 and our contribution will take into account everything published since then. [ABSTRACT FROM AUTHOR]