DS2

Induction of the mitochondria-mediated apoptosis in human esophageal cancer cells by DS2, a newly synthetic diterpenoid analog, is regulated by Bax and caused by generation of reactive oxygen species.[Pubmed:27863415]

Oncotarget. 2016 Dec 27;7(52):86211-86224.

Ent-kaurane diterpene compounds have attracted considerable attention in recent years due to its antitumor, antibacterial, and antiviral activities. However, the clinical development of natural kaurane diterpenes, for example, oridonin for cancer therapy has been hampered by its relatively moderate potency, limited bioavailability. Herein, we report a newly synthetic analog of natural ent-kaurane diterpene, DS2, which exhibits significantly improved activity of antiproliferation against various cancer cell lines relative to oridonin. DS2 treatment triggers the mitochondria-mediated apoptosis and cell cycle arrest in human esophageal cancer cell lines (EC9706, EC109). Interestingly, normal human esophageal epithelial cells (HEECs) and normal human liver cells (HL-7702) are both significantly more resistant to the growth inhibition by DS2 compared with esophageal cancer cells. The DS2-induced apoptosis in EC9706 cells correlated with the drop of mitochondrial membrane potential (MMP), release of cytochrome c into the cytosol and activation of caspase-9 and -3. The induction of proapoptotic proteins p21 and Bax were also observed in DS2-treated cells. The DS2-induced apoptosis was significantly attenuated by knockdown of Bax proteins. Meanwhile, the DS2 treatment caused generation of reactive oxygen species (ROS) in human esophageal cancer cells, but not in HEECs, which was attenuated by pretreatment with ROS scavenger N-acetylcysteine (NAC). More interestingly, the antioxidants pretreatment completely attenuated DS2 mediated loss of the MMP and apoptosis, as well as Bax expression and growth inhibition. In conclusion, the present study reveals that the mitochondria-mediated cell death by DS2 is associated with Bax regulation and ROS generation, and understanding the function and mechanism of DS2 will help us to design better anti-cancer drugs.

Correlation between cardiac rhythm, left atrial appendage flow velocity, and CHA2 DS2 -VASc score: Study based on transesophageal echocardiography and 2-dimensional speckle tracking.[Pubmed:28075503]

Clin Cardiol. 2017 Feb;40(2):120-125.

BACKGROUND: The CHA2 DS2 -VASc score is a classic predictor of stroke in patients with atrial fibrillation (AF). Decreased left atrial appendage flow velocity (LAA-FV) reflects the blood stasis, and left atrial (LA) strain is a manifestation of atrial remodeling. This study aimed to explore the effects of AF rhythm and CHA2 DS2 -VASc score in the development of thrombogenesis and their potential correlation with LAA-FV and LA strain. HYPOTHESIS: AF rhythm and high CHA2 DS2 -VASc score correlate independently with decreased LAA-FV, which can be predicted by LA strain. METHODS: In 98 AF patients, LAA-FV was measured by transesophageal echocardiography and LA strain was measured by transthoracic echocardiography. RESULTS: LAA-FV decreased sharply in the AF rhythm group (26.22 vs 61.87 mm/s; P < 0.001), and CHA2 DS2 -VASc score did not differ between the decreased and normal LAA-FV groups in all patients (P = 0.289). However, in sinus rhythm (SR), LAA-FV was associated with CHA2 DS2 -VASc score (coefficient = -0.317, P = 0.013), and the CHA2 DS2 -VASc score differed between the normal and decreased LAA-FV groups (2 [0-7] vs 3 [0-6], respectively; P = 0.038). Moreover, LA strain was a predictor of LAA-FV in both AF rhythm and SR, whereas a peak positive systolic strain divided by LA volume index <0.744 predicted decreased LAA-FV. CONCLUSIONS: AF rhythm caused a sharp decrease in LAA-FV independent of CHA2 DS2 -VASc score. In SR, the CHA2 DS2 -VASc score correlated negatively with LAA-FV. LA strain was a predictor of LAA-FV in both SR and AF rhythm.

CHA2 DS2 VASc score predicts unsuccessful electrical cardioversion in patients with persistent atrial fibrillation.[Pubmed:27860070]

Intern Med J. 2017 Mar;47(3):275-279.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia occurring in 2% of the population. It is known that AF increases morbidity and limits quality of life. The CHA2 DS2 VASc score (congestive heart failure/left ventricular dysfunction, hypertension, age >/=75 (doubled), diabetes, stroke (doubled), vascular disease, age 65-74 and sex category (female)) is widely used to assess thrombotic complications. The CHA2 DS2 VASc score was not used until now in predicting the effectiveness of electrical cardioversion. AIM: To assess the value of CHA2 DS2 VASc score in predicting unsuccessful electrical cardioversion. METHODS: We analysed 258 consecutive patients with persistent AF who underwent electrical cardioversion between January 2012 and April 2016 in a Cardiology University Centre in Poland. RESULTS: Out of 3500 hospitalised patients with AF, 258 (mean age 64 +/- 11 years, 64% men) underwent electrical cardioversion. The CHA2 DS2 VASc score in analysed population (258 patients) was 2.5 +/- 1.7 (range 0-8), and the HAS-BLED (hypertension, abnormal liver or renal function, stroke, bleeding, labile international normalised ratio, elderly, drugs or alcohol) was 1 +/- 0.9 (range 0-4). Electrical cardioversion was unsuccessful in 12%. Factors associated with unsuccessful cardioversion were age (P = 0.0005), history of ischaemic stroke (P = 0.04), male gender (P = 0.01) and CHA2 DS2 VASc score (P = 0.002). The CHA2 DS2 VASc score in patients who had unsuccessful cardioversion was higher compared to patients who had successful cardioversion - 3.5 versus 2.4 (P = 0.001). In the logistic regression model, if the CHA2 DS2 VASc score increases by 1, the odds of unsuccessful cardioversion increase by 39% (odds ratio (OR) 1.39; confidence interval (CI): 1.12-1.71; P = 0.002). The odds of unsuccessful cardioversion are three times higher in patients with a CHA2 DS2 VASc score >/= 2 than in patients with a CHA2 DS2 VASc score of 0 or 1 (OR 3.06; CI: 1.03-9.09; P = 0.044). CONCLUSION: The CHA2 DS2 VASc score routinely used in thromboembolic risk assessment may be a simple, easy and reliable scoring system that can be used to predict unsuccessful electrical cardioversion.

Novel compounds selectively enhance delta subunit containing GABA A receptors and increase tonic currents in thalamus.[Pubmed:18762200]

Neuropharmacology. 2009 Jan;56(1):182-9.

Inhibition in the brain is dominated by the neurotransmitter gamma-aminobutyric acid (GABA); operating through GABA(A) receptors. This form of neural inhibition was presumed to be mediated by synaptic receptors, however recent evidence has highlighted a previously unappreciated role for extrasynaptic GABA(A) receptors in controlling neuronal activity. Synaptic and extrasynaptic GABA(A) receptors exhibit distinct pharmacological and biophysical properties that differentially influence brain physiology and behavior. Here we used a fluorescence-based assay and cell lines expressing recombinant GABA(A) receptors to identify a novel series of benzamide compounds that selectively enhance, or activate alpha4beta3delta GABA(A) receptors (cf. alpha4beta3gamma2 and alpha1beta3gamma2). Utilising electrophysiological methods, we illustrate that one of these compounds, 4-chloro-N-[6,8-dibromo-2-(2-thienyl)imidazo[1,2-a]pyridine-3-yl benzamide (DS1) potently (low nM) enhances GABA-evoked currents mediated by alpha4beta3delta receptors. At similar concentrations DS1 directly activates this receptor and is the most potent known agonist of alpha4beta3delta receptors. 4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridine-3-yl benzamide (DS2) selectively potentiated GABA responses mediated by alpha4beta3delta receptors, but was not an agonist. Recent studies have revealed a tonic form of inhibition in thalamus mediated by the alpha4beta2delta extrasynaptic GABA(A) receptors that may contribute to the regulation of thalamocortical rhythmic activity associated with sleep, wakefulness, vigilance and seizure disorders. In mouse thalamic relay cells DS2 enhanced the tonic current mediated by alpha4beta2delta receptors with no effect on their synaptic GABA(A) receptors. Similarly, in mouse cerebellar granule cells DS2 potentiated the tonic current mediated by alpha6betadelta receptors. DS2 is the first selective positive allosteric modulator of delta-GABA(A) receptors and such compounds potentially offer novel therapeutic opportunities as analgesics and in the treatment of sleep disorders. Furthermore, these drugs may be valuable in elucidating the physiological and pathophysiological roles played by these extrasynaptic GABA(A) receptors.