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Cassaine: mechanism of inhibition of Na+ +K+ -ATPase and relationship of this inhibition to cardiotonic actions.

The erythrophleum alkaloid cassaine shares many of the pharmacological actions of the cardiac glycosides but lacks the structural characteristics typical of cardiac glycosides. To further investigate the relationship between Na+ +K+ -ATPase inhibition and the cardiotonic actions of these drugs we investigated the interaction of cassaine with the Na+ +K+ -ATPase. Cassaine inhibited rat brain Na+ +K+ -ATPase with about one quarter of the apparent affinity of ouabain for this enzyme. This inhibition was non-competitive with respect to K+. Cassaine also inhibited this enzyme in the presence of Mg2+ and this inhibition was enhanced by Pi and antagonized by Na+. In the presence of Na+, Mg2+ and (gamma-32P)-ATP cassaine acted to stabilize the phosphorylated intermediate of Na+ +K+ -ATPase. Cassaine also acted to displace specifically bound (3H)-ouabain from this enzyme. These observations suggested that cassaine inhibited the Na+ +K+ -ATPase by interacting at the cardiotonic steroid binding sites of Na+ +K+ -ATPase. Consistent with this hypothesis, dog, guinea pig and rat heart Na+ +K+ -ATPase showed differing sensitivities to cassaine paralleling their differing sensitivities to ouabain. The principal difference between the interaction of cassaine and ouabain with Na+ +K+ -ATPase appeared to be the more rapid dissociation of cassaine from the cardiotonic steroid binding site(s) of Na+ +K+ -ATPase. In keeping with this the rates of offset of cassaine-induced inotropy in Langendorff perfused dog and guinea pig hearts were several times faster than those of ouabain-induced inotropy.

Abietanes↗
PubMed1976

Studies on the stable inhibition of Na+ + K+-ATPase by cassaine.

Exposure of rat brain Na+ + K+-ATPase (ATP phosphohydrolase E.C. 3.6.1.3) to concentrations of cassaine greater than 1 x 10(-4) M resulted in a poorly reversible inhibition of this enzyme. Inhibition did not require the presence of ATP and developed rapidly, but the final amount of inhibition observed was independent of time. The amount of inhibition observed at a given concentration of cassaine was reduced by increasing the concentration of membranes in the system. The inhibition of Na+ + K+-ATPase activity was associated with equivalent inhibition of the phosphorylation and (3H)-ouabain binding reactions of this enzyme, while the uninhibited enzyme was apparently kinetically normal. Concentrations of cassaine which produced this stable inhibition of Na+ + K+-ATPase had no effect on the Mg2+-activated ATPase or the NADH cytochrome-c-reductase activities of crude rat brain microsomal preparations. Cassaine inhibited the cholinesterase activity of rat brain microsomes with a Ki of about 5 x 10(-5) M, but his inhibition was fully reversible. The poorly reversible inhibitory actions of cassaine, thus, appeared specific for Na+ + K+-ATPase. Because this stable pattern of inhibition of the Na+ + K+-ATPase by cassaine required drug concentrations at least one hundred-fold greater than those which produce positive inotropic effects, it appears unlikely that this pattern of Na+ + K+-ATPase inhibition is involved in the cardiotonic actions of this drug.

Abietanes↗
PubMed2026

Tanshinone IIA impairs platelet function and thrombus formation.

BACKGROUND: Tanshinone IIA (T-IIA) is a fat-soluble active ingredient derived from the traditional Chinese medicine Danshen and possesses cardioprotective property. However, its exact role in platelet function is unknown. OBJECTIVES: This study investigated T-IIA's role in platelet aggregation, granules release, spreading, clot retraction, as well as in vivo hemostasis and thrombus formation. METHODS: Human platelets were treated with different doses of T-IIA (10, 50, and 100 μM) to measure platelet function and activation. In addition, T-IIA was administrated into wild-type mice to evaluate hemostasis and thrombus formation. RESULTS: T-IIA significantly impaired platelet aggregation, adenosine triphosphate secretion, P-selectin expression, and spreading and clot retraction dose dependently without affecting the expression profiles of αIIbβ3 and glycoprotein VI or Ibα. Administration of T-IIA significantly prolonged mice tail bleeding time and inhibited arterial and venous thrombosis. Further analysis showed that T-IIA dose dependently reduced platelet reactive oxygen species generation. Quantitative proteomic and phosphoproteimic assays analyzing T-IIA-treated vs vehicle-treated platelets after stimulation identified dysregulated phosphorylation of several proteins, which were enriched in platelet activation. Among the downregulated phosphoproteins, Rho-associated protein kinase (ROCK)1, integrin β3, and talin1 exhibited the lower fold change of phosphorylation in T-IIA-treated platelets compared with those in vehicle-treated platelets. Consistently, T-IIA treatment inhibited the phosphorylation of ROCK1, p47phox, integrin β3, and talin1 in activated platelets. CONCLUSION: T-IIA impairs platelet function and thrombosis via inhibition of several signaling pathways including ROCK1/p47phox, β3, and talin1, implying that T-IIA may represent a promising therapeutic candidate for treating thrombotic diseases.

Animals↗
PubMed2025

Biosynthesis and regulatory mechanism of tanshinones and phenolic acids in Salvia miltiorrhiza.

Salvia miltiorrhiza, a perennial plant of the genus Salvia in the family Lamiaceae, is one of the most important traditional Chinese medicinal herbs, renowned for its significant economic and medicinal value. Its application in China dates back to 200 BC, where it has been utilized clinically either as a monotherapy or in combination with other herbal medicines for treating cardiovascular and cerebrovascular diseases, as well as various other ailments. The bioactive constituents of S. miltiorrhiza primarily include lipophilic tanshinones and hydrophilic phenolic acids. Over the past decades, the biosynthetic pathways of tanshinones and phenolic acids have been elucidated. Coupled with the sequencing of its genome, substantial progress has been made in deciphering the biosynthesis and regulatory mechanisms of bioactive compounds in S. miltiorrhiza, including tanshinones, phenolic acids, flavonoids, and prenylated quinones. This review summarizes recent advances in the regulatory mechanisms underlying the biosynthesis of phenolic acids and tanshinones in S. miltiorrhiza, focusing on transcriptional regulation, post-translational modifications, and epigenetic regulation. These insights provide a foundation for enhancing the production of bioactive compounds through biotechnological approaches and advancing pharmacological applications.

Salvia miltiorrhiza↗
PubMed2025

DNA methylation controls the expression of tanshinone synthesis genes and the tanshinone accumulation in Salvia miltiorrhiza and Salvia bowleyana.

DNA methylation plays pivotal roles in regulating gene expression and the secondary metabolism in plants. Salvia miltiorrhiza and Salvia bowleyana are traditional Chinese medicinal plants with roots enriched with tanshinone components. However, the regulatory mechanism of DNA methylation on tanshinone production remains elusive. Here, we analyzed 30-day-old hairy roots of S. miltiorrhiza and S. bowleyana using targeted high-performance liquid chromatography analysis and found significantly higher tanshinone content in S. miltiorrhiza. Whole-genome bisulfite sequencing revealed elevated DNA methylation levels in S. miltiorrhiza, potentially due to the upregulation of methylation-related genes, including DOMAINS REARRANGED METHYLTRANSFERASE 1 (DRM1), DECREASE IN DNA METHYLATION 1 (DDM1), CHROMOMETHYLASE 2 (CMT1), and CHROMOMETHYLASE 3 (CMT3), alongside the low expression of the demethylase gene REPRESSOR OF SILENCING 1 (ROS1) in S. miltiorrhiza. Additionally, four genes that are involved in tanshinone biosynthesis, including 1-DEOXY-D-XYLULOSE-5-PHOSPHATE REDUCTASE (DXS1), GERANYLGERANYL DIPHOSPHATE SYNTHASE (GGPPS2), 4-HYDROXY-3-METHYLBUT-2-ENYL PYROPHOSPHATE REDUCTASE (HDR2), and COPALYL PYROPHOSPHATE SYNTHASE (CPS3), showed lower methylation levels in the promoters of DXS1, GGPPS2, and CPS3 and a higher DNA methylation level in the gene body of HDR2 in S. miltiorrhiza, which may lead to their high expression and the accumulation of tanshinones. Consistently, overexpression of the SmCMT3 in S. miltiorrhiza significantly reduced the contents of cryptotanshinone, tanshinone I, and tanshinone IIA. Transcriptomic and methylome analyses confirmed that the expression levels of the tanshinone biosynthesis-related genes, including SmMK, SmCPS1, SmDXS2, and SmAACT1, were correlated with their promoter or gene body DNA methylation levels. Our findings reveal that DNA methylation critically regulates tanshinone biosynthesis in S. miltiorrhiza and S. bowleyana, offering valuable insights for breeding.

Abietanes↗