Search

Umbelliferone (UMB), a natural coumarin compound, has been reported to possess anti-rheumatic effects on rheumatoid arthritis (RA) experimental models, but its potential role of UMB in regulating migration, invasion and inflammation of RA fibroblast-like synoviocytes (FLS) remain unclear. Herein, MTT assay was performed to confirm the non-cytotoxic concentrations (10, 20, and 40 μ M) and the treatment time (24 h) of UMB on TNF- α -stimulated RA FLS (MH7A cells) in vitro. Results of wound-healing, transwell and phalloidin staining assays revealed that UMB inhibited TNF- α -induced migration, invasion and F-actin cytoskeletal reorganization in MH7A. Results of ELISA, western blot and gelatin zymography indicated that UMB decreased the productions of pro-inflammatory factors, including IL-1 β , IL-6, IL-8, MMP-2 and MMP-9, and inhibited MMP-2 activity in TNF- α -stimulated MH7A cells. In vivo, UMB (25 mg/kg and 50 mg/kg) relieved the joint damage and synovial inflammation in rats with adjuvant-induced arthritis (AIA). Mechanistically, UMB could suppress Wnt/ β -catenin signaling both in TNF- α -induced MH7A cells and in AIA rat synovium, evidenced by decreasing Wnt1 protein level, activating GSK-3 β kinase by blocking GSK-3 β (Ser9) phosphorylation, and reducing the protein level and nuclear translocation of β -catenin. Importantly, combined use of lithium chloride (a Wnt/ β -catenin signaling agonist) eliminated the inhibitory effects of UMB on migration, invasion and inflammation in vitro and the anti-arthritic effects of UMB in vivo. We concluded that UMB inhibited TNF- α -induced migration, invasion and inflammation of RA FLS and attenuated the severity of rat AIA through its ability to block Wnt/ β -catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVD) are the deadliest noncommunicable disease worldwide. Hypertension is the most prevalent risk factor for the development of CVD. Although there is a wide range of antihypertensive drugs, there still remains a lack of blood pressure control options for hypertensive patients. Additionally, natural products remain crucial to the design of new drugs. The natural product 7-hydroxycoumarin (7-HC) exhibits pharmacological properties linked to antihypertensive mechanisms of action. This study aimed to evaluate the vascular effects of 7-HC in an experimental model of essential hypertension. The isometric tension measurements assessed the relaxant effect induced by 7-HC (0.001 μM–300 μM) in superior mesenteric arteries isolated from hypertensive rats (SHR, 200–300 g). Our results suggest that the relaxant effect induced by 7-HC rely on K+-channels (KATP, BKCa, and, to a lesser extent, Kv) activation and also on Ca2+ influx from sarcolemma and sarcoplasmic reticulum mobilization (inositol 1,4,5-triphosphate (IP3) and ryanodine receptors). Moreover, 7-HC diminishes the mesenteric artery's responsiveness to α1-adrenergic agonist challenge and improves the actions of the muscarinic agonist and NO donor. The present work demonstrated that the relaxant mechanism of 7-HC in SHR involves endothelium-independent vasorelaxant factors. Additionally, 7-HC reduced vasoconstriction of the sympathetic agonist while improving vascular endothelium-dependent and independent relaxation. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVD) are the deadliest noncommunicable disease worldwide. Hypertension is the most prevalent risk factor for the development of CVD. Although there is a wide range of antihypertensive drugs, there still remains a lack of blood pressure control options for hypertensive patients. Additionally, natural products remain crucial to the design of new drugs. The natural product 7-hydroxycoumarin (7-HC) exhibits pharmacological properties linked to antihypertensive mechanisms of action. This study aimed to evaluate the vascular effects of 7-HC in an experimental model of essential hypertension. The isometric tension measurements assessed the relaxant effect induced by 7-HC (0.001 μM–300 μM) in superior mesenteric arteries isolated from hypertensive rats (SHR, 200–300 g). Our results suggest that the relaxant effect induced by 7-HC rely on K+-channels (KATP, BKCa, and, to a lesser extent, Kv) activation and also on Ca2+ influx from sarcolemma and sarcoplasmic reticulum mobilization (inositol 1,4,5-triphosphate (IP3) and ryanodine receptors). Moreover, 7-HC diminishes the mesenteric artery’s responsiveness to α1-adrenergic agonist challenge and improves the actions of the muscarinic agonist and NO donor. The present work demonstrated that the relaxant mechanism of 7-HC in SHR involves endothelium-independent vasorelaxant factors. Additionally, 7-HC reduced vasoconstriction of the sympathetic agonist while improving vascular endothelium-dependent and independent relaxation.

Coumarins are well known secondary metabolites widely found in various plants. However, the degradation of these compounds in the environment has not been studied in detail, and, especially, the initial stages of the catabolic pathways of coumarins are not fully understood. A soil isolate Pseudomonas mandelii 7HK4 is able to degrade 7-hydroxycoumarin (umbelliferone) via the formation of 3-(2,4-dihydroxyphenyl)propionic acid, but the enzymes catalyzing the α-pyrone ring transformations have not been characterized. To elucidate an upper pathway of the catabolism of 7-hydroxycoumarin, 7-hydroxycoumarin-inducible genes hcdD, hcdE, hcdF, and hcdG were identified by RT-qPCR analysis. The DNA fragment encoding a putative alcohol dehydrogenase HcdE was cloned, and the recombinant protein catalyzed the NADPH-dependent reduction of 7-hydroxycoumarin both in vivo and in vitro. The reaction product was isolated and characterized as a 7-hydroxy-3,4-dihydrocoumarin based on HPLC-MS and NMR analyses. In addition, the HcdE was active towards 6,7-dihydroxycoumarin, 6-hydroxycoumarin, 6-methylcoumarin and coumarin. Thus, in contrast to the well-known fact that the ene-reductases usually participate in the reduction of the double bond, an alcohol dehydrogenase catalyzing such reaction has been identified, and, for P. mandelii 7HK4, 7-hydroxycoumarin degradation via a 7-hydroxy-3,4-dihydrocoumarin pathway has been proposed.

Abstract: New diorganotin(IV) derivatives of the general formula R2Sn(Umb)2 (where R= n-Bu, n-Oct and Ph; Umb=umbelliferone anion) have been synthesized either by the reaction of R2SnO with umbelliferone under azeotropic removel of water or by the reaction of R2SnCl2 with sodium salt of umbelliferone. Further, the adducts of the general formula R2Sn(Umb)2·phen (where R= n-Bu and n-Oct; phen=1,10-phenanthroline) have also been synthesized by the interaction of R2Sn(Umb)2 with 1,10-phenanthroline. The bonding and coordination behavior in these derivatives are discussed on the basis of IR and 119Sn Mössbauer spectroscopic studies in solid state. Their coordination behavior in solution is discussed by the multinuclear (1H, 13C and 119Sn) NMR spectral studies. The Mössbauer and IR studies indicate that umbelliferone acts as a monoanionic bidentate ligand in R2Sn(Umb)2 coordinating through O(7) and O(1). A distorted octahedral geometry around tin has been proposed for R2Sn(Umb)2 as well as for R2Sn(Umb)2·phen in solid state. The newly synthesized derivatives have been tested for their anti-inflammatory and cardiovascular activities. The average LD50 value >1000mgkg−1 of these compounds indicates their safety margin. [Copyright &y& Elsevier]

Coumarins are well known secondary metabolites widely found in various plants. However, the degradation of these compounds in the environment has not been studied in detail, and, especially, the initial stages of the catabolic pathways of coumarins are not fully understood. A soil isolate Pseudomonas mandelii 7HK4 is able to degrade 7-hydroxycoumarin (umbelliferone) via the formation of 3-(2,4-dihydroxyphenyl)propionic acid, but the enzymes catalyzing the α-pyrone ring transformations have not been characterized. To elucidate an upper pathway of the catabolism of 7-hydroxycoumarin, 7-hydroxycoumarin-inducible genes hcdD, hcdE, hcdF, and hcdG were identified by RT-qPCR analysis. The DNA fragment encoding a putative alcohol dehydrogenase HcdE was cloned, and the recombinant protein catalyzed the NADPH-dependent reduction of 7-hydroxycoumarin both in vivo and in vitro. The reaction product was isolated and characterized as a 7-hydroxy-3,4-dihydrocoumarin based on HPLC-MS and NMR analyses. In addition, the HcdE was active towards 6,7-dihydroxycoumarin, 6-hydroxycoumarin, 6-methylcoumarin and coumarin. Thus, in contrast to the well-known fact that the ene-reductases usually participate in the reduction of the double bond, an alcohol dehydrogenase catalyzing such reaction has been identified, and, for P. mandelii 7HK4, 7-hydroxycoumarin degradation via a 7-hydroxy-3,4-dihydrocoumarin pathway has been proposed. [ABSTRACT FROM AUTHOR]