benzofurans and Coronary-Artery-Disease

The recently discovered chemokine CXC motif ligand 16 (CXCL16) is highly expressed in atherosclerotic lesions and is a potential pathogenic mediator in coronary artery disease.. The aim of this study was to test the role of CXCL16 on platelet activation and vascular adhesion, as well as the underlying mechanism and signaling pathway.. Reverse-transcriptase polymerase chain reaction, Western blotting, confocal microscopy, and flow cytometry revealed that CXCL16-specific receptor, CXC motif receptor 6, is highly expressed in platelets. According to flow cytometry and confocal microscopy, stimulation of platelets with CXCL16 induced platelet degranulation, integrin α(IIb)β(3) activation, and shape change. CXCL16 increased Akt phosphorylation (Thr(308)/Ser(473)), an effect abrogated by phosphatidylinositide 3-kinase inhibitors wortmannin (100 nmol/L) and LY294002 (25 µmol/L). The phosphatidylinositide 3-kinase inhibitors and Akt inhibitor SH-6 (20 µmol/L) further diminished CXCL16-induced platelet activation. CXCL16-mediated platelet degranulation, integrin α(IIb)β(3) activation, and Akt phosphorylation were blunted in platelets lacking CXCL16-specific receptor CXC motif receptor 6. CXCL16-induced platelet activation was abrogated in Akt1- or Akt2-deficient platelets. CXCL16 enhanced platelet adhesion to endothelium in vitro after high arterial shear stress (2000(-s)) and to injured vascular wall in vivo after carotid ligation. CXCL16-induced stimulation of platelet adhesion again was prevented by phosphatidylinositide 3-kinase and Akt inhibitors. Apyrase and antagonists of platelet purinergic receptors P(2)Y(1) (MRS2179, 100 µmol/L) and especially P(2)Y(12) (Cangrelor, 10 µmol/L) blunted CXCL16-triggered platelet activation as well as CXCL16-induced platelet adhesion under high arterial shear stress in vitro and after carotid ligation in vivo.. The inflammatory chemokine CXCL16 triggers platelet activation and adhesion via CXC motif receptor 6-dependent phosphatidylinositide 3-kinase/Akt signaling and paracrine activation, suggesting a decisive role for CXCL16 in linking vascular inflammation and thrombo-occlusive diseases.

Topics: Animals; Benzofurans; Blood Platelets; Chemokine CXCL16; Chemokine CXCL6; Coronary Artery Disease; Endothelium, Vascular; Female; Humans; Male; Mice; Mice, Mutant Strains; Phosphatidylinositol 3-Kinases; Platelet Activation; Platelet Adhesiveness; Proto-Oncogene Proteins c-akt; Quinolines; Receptors, CXCR; Receptors, CXCR6; Signal Transduction; Thrombosis; Vasculitis

A sensitive LC/MS method was established to investigate the in vivo metabolism of GuanXin II prescription, a five-component Chinese herbal medicine formulation. Rat plasma, bile, urine, and feces were collected and analyzed following oral administration of the water decoction. A total of 50 compounds were identified, including 17 prototypes and 33 metabolites underwent methylation, oxidation, hydrolysis, sulfate conjugation, glucuronide conjugation, and glutathion conjugation. In addition, the component herb of the formulation from which the metabolites were derived was also identified. Among the five component herbs, Rhizoma Chuanxiong, Flos Carthami, and Lignum Dalbergiae Odoriferae were actively metabolized, contributing 26 metabolites and 2 prototypes, while Radix Salviae Miltiorrhizae and Radix Paeoniae Rubra underwent less biotransformation, yielding 7 metabolites and 15 prototypes. This is the first study on the metabolic profile of GuanXin II prescription. The results could be valuable to elucidate the material basis of this formulated Chinese medicine.

Topics: Animals; Benzofurans; Bicyclic Monoterpenes; Bile; Biotransformation; Chromatography, High Pressure Liquid; Coronary Artery Disease; Drugs, Chinese Herbal; Feces; Flavonoids; Male; Molecular Structure; Phenols; Polyphenols; Rats; Rats, Sprague-Dawley; Solid Phase Extraction; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Technology, Pharmaceutical; Terpenes

Topics: Benzofurans; Coronary Artery Disease; Coronary Disease; Furans; Humans; Vasodilator Agents

Topics: Benzofurans; Coronary Artery Disease; Coumarins; Heart Failure; Humans