Pharmacological Effects of Hydrocotyle bonariensis Comm. ex Lam (Araliaceae) Extract on Cardiac Activity

Hydrocotyle bonariensis is one of the medicinal plants used in traditional medicine for the management of hypertension in Africa, Asia, and Latin America. However, the real impact of the traditional use of this plant on arterial hypertension has not yet been the subject of conclusive scientific information in the literature. This study aimed essentially to evaluate the potential cardiomodulatory effect of the hydroethanolic extract of Hydrocotyle bonariensis. In other to do so, the hydroethanolic extract of H. bonariensis was studied in vivo on the Wistar rat ECG and then in vitro on the isolated perfused Wistar rat heart using the Langendorff system. The extract was also tested on isolated guinea pig atria kept alive in the organ-specific vessel under physiological conditions similar to those of a living organism. At the cellular level, the effects of the extract were evaluated on the human cardiac sodium current INav1.5 and on the human cardiac pacemaker current If. We noted that the extract caused a decrease in P wave and T wave amplitudes and heart rate and an increase in the duration of the RR interval on the in vivo rat ECG. On the isolated perfused Langendorff heart as well as on the isolated atria, a decrease in the RR interval and in the heart rate was noted. The extract had no effect on human cardiac sodium current, but it did reduce human cardiac pacemaker current. In conclusion, the present study demonstrated that Hydrocotyle bonariensis, a medicinal plant traditionally used to prevent and treat hypertension, has an overall cardiomoderating effect. This effect would contribute to the reduction of blood pressure

Hydrocotyle bonariensis Comm ex Lamm (Araliaceae) leaves extract inhibits IKs not IKr potassium currents: Potential implications for anti-arrhythmic therapy

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ANO1 contributes to angiotensin-II-activated Ca2+-dependent Cl- current in human atrial fibroblasts.

International audienceCardiac fibroblasts are an integral part of the myocardial tissue and contribute to its remodelling. This study characterises for the first time the calcium-dependent chloride channels (CaCC) in the plasma membrane of primary human atrial cardiac fibroblasts by means of the iodide efflux and the patch clamp methods. The calcium ionophore A23187 and Angiotensin II (Ang II) activate a chloride conductance in cardiac fibroblasts that shares pharmacological similarities with calcium-dependent chloride channels. This chloride conductance is depressed by RNAi-mediated selective Anoctamine 1 (ANO1) but not by Anoctamine 2 (ANO2) which has been revealed as CaCC and is inhibited by the selective ANO1 inhibitor, T16inh-A01. The effect of Ang II on anion efflux is mediated through AT1 receptors (with an EC50 = 13.8 ± 1.3 nM). The decrease of anion efflux by calphostin C and bisindolylmaleimide I (BIM I) suggests that chloride conductance activation is dependent on PKC. We conclude that ANO1 contributes to CaCC current in human cardiac fibroblasts and that this is regulated by Ang II acting via the AT1 receptor pathway

Modulation of the inwardly rectifying potassium channel Kir4.1 by the pro-invasive miR-5096 in glioblastoma cells.

IF 5.168International audienceInwardly rectifying potassium channels (Kir), and especially the barium-sensitive Kir4.1 encoded by KCNJ10, are key regulators of glial functions. A lower expression or mislocation of Kir4.1 is detected in human brain tumors. MicroRNAs participate in the regulation of ionic channels and associated neurologic disorders. Here, we analyze effects of miR-5096 on the Kir4.1 expression and function in two glioblastoma cell lines, U87 and U251. Using whole-cell patch-clamp and western-blot analysis, we show that cell loading with miR-5096 decreases the Kir4.1 protein level and associated K+ current. Cell treatment with barium, a Kir4.1 blocker, or cell loading of miR-5096 both increase the outgrowth of filopodia in glioma cells, as observed by time-lapse microscopy. Knocking-down Kir4.1 expression by siRNA transfection similarly increased both filopodia formation and invasiveness of glioma cells as observed in Boyden chamber assay. MiR-5096 also promotes the release of extracellular vesicles by which it increases its own transfer to surrounding cells, in a Kir4.1-dependent manner in U251 but not in U87. Altogether, our results validate Kir4.1 as a miR-5096 target to promote invasion of glioblastoma cells. Our data highlight the complexity of microRNA effects and the role of K+ channels in cancer

A galactosidase-responsive doxorubicin-folate conjugate for selective targeting of acute myelogenous leukemia blasts

International audienceCytarabine combined with an anthracycline or an anthracenedione represents the usual intensive induction therapy for the treatment of AML. However, this protocol induces severe side effects and treatment-related mortality due to the lack of selectivity of these cytotoxic agents. In this paper, we present the study of the first galactosidase-responsive molecular "Trojan Horse" programmed for the delivery of doxorubicin exclusively inside AML blasts over-expressing the folate receptor (FR). This targeting system allows the selective killing of AML blasts without affecting normal endothelial, cardiac or hematologic cells from healthy donors suggesting that FDC could reduce adverse events usually recorded with anthracyclines