The synthetic caged garcinia xanthone cluvenone induces cell stress and apoptosis and has immune modulatory activity

Several caged Garcinia xanthone natural products have potent bioactivity and a documented value in traditional Eastern medicine. Previous synthesis and structure activity relationship studies of these natural products resulted in the identification of the pharmacophore represented by the structure of cluvenone. In the current study, we examined the anticancer activity of cluvenone and conducted gene expression profiling and pathway analyses. Cluvenone was found to induce apoptosis in T-cell acute lymphoblastic leukemia cells (EC?? = 0.25 μmol/L) and had potent growth-inhibitory activity against the NCI60 cell panel, including those that are multidrug-resistant, with a GI?? range of 0.1 to 2.7 μmol/L. Importantly, cluvenone was approximately 5-fold more potent against a primary B-cell acute lymphoblastic leukemia compared with peripheral blood mononuclear cells from normal donors, suggesting that it has significant tumor selectivity. Comparison of cluvenone's growth-inhibitory profile to those in the National Cancer Institute database revealed that compounds with a similar profile to cluvenone were mechanistically unlike known agents, but were associated with cell stress and survival signaling. Gene expression profiling studies determined that cluvenone induced the activation of mitogen-activated protein kinase and NrF2 stress response pathways. Furthermore, cluvenone was found to induce intracellular reactive oxygen species formation. Lastly, the modulation in the expression of several genes associated with T cell and natural killer cell activation and function by cluvenone suggests a role as an immune-modulator. The current work highlights the potential of cluvenone as a chemotherapeutic agent and provides support for further investigation of these intriguing molecules with regard to mechanism and targets.     

Cardiac resynchronization therapy response is associated with shorter duration of atrial fibrillation

BACKGROUND: Atrial fibrillation (AF) is commonly associated with heart failure. The benefit of cardiac resynchronization therapy (CRT) on atrial remodeling has been demonstrated. However, biventricular pacing did not reduce the global incidence of AF. We evaluated the relationship between CRT response and AF duration. METHODS: We retrospectively analyzed data from 96 patients (59 +/- 15 years; 78% male) who underwent CRT. All patients had class III-IV New York Heart Association (NYHA) symptoms despite maximal medical therapy, left ventricular ejection fraction (LVEF) < or = 35%, QRS >130 ms, and sinus rhythm before implantation. CRT response in patients who survived at six months of follow-up was defined as: (1) no hospitalization for heart failure and (2) improvement of one or more grades in the NYHA classification. RESULTS: CRT responders (n = 54) and non-responders (n = 42) had similar baseline characteristics, including the incidence of persistent AF within six months before implantation. Six months after implantation, when compared to baseline, CRT responders exhibited a significant decrease in left atrial size (47.5 +/- 7.1 mm vs 44.6 +/- 7.7 mm, P < 0.01) and in the incidence of persistent AF (17% vs 2%, P = 0.02). At six months, CRT responders demonstrated shorter mean AF duration (7.5 +/- 43.3 hours vs 48.8 +/- 129.0 hours, P = 0.03) and lower incidence of persistent AF (2% vs 19%, P = 0.004) compared to nonresponders. CONCLUSION: CRT response is associated with a reversal of atrial remodeling and a shorter AF duration.     

Magnetic resonance enterography in Crohn's disease: techniques, interpretation, and utilization for clinical management

Crohn's disease treatment has improved significantly with the development of immunosuppressive and immunomodulatory agents, while surgery remains an important option in selected patients. However, a relative lag in diagnostics has become apparent with a growing need for the capacity to noninvasively and safely evaluate the tissue changes of Crohn's disease within the bowel wall and deeper tissues. We have noted marked technical improvements in magnetic resonance enterography (MRE) and in our understanding of the different facets of Crohn's disease that can be elucidated by optimized MRE, in contrast to other diagnostics. This review will provide an integrated understanding of MRE related to other available tests and recommendations for the optimal use of MRE for the clinical management of Crohn's disease. We will review the relative strengths and limitations of MRE as applied to clinical evaluation and therapeutic decisions, including the use of the unique capacity to delineate active inflammation and fibrosis in the submucosal and deeper enteric tissues, which is beyond the diagnostic reach of endoscopy and biopsy.     

Influence of exercise order on repetition performance during low-intensity resistance exercise

The purpose of this study was to compare repetition maximum performance and ratings of perceived exertion during resistance exercise sessions conducted at a low intensity (i.e., 20 RM) and in different exercise orders. Twenty-one recreationally trained men performed two total body resistance exercise sessions in opposite orders; each exercise was performed for three sets with 2 minutes passive rest between sets and exercises. The results indicated significantly greater total repetitions for each exercise when performed near the beginning of a sequence and for the first set of each exercise, irrespective of the sequence. The ratings of perceived exertion, however, were not significantly different between sequences. In conclusion, repetition maximum performance for resistance exercise sessions conducted at a low intensity is significantly different based on exercise order. Therefore, when performing high repetitions with relatively low intensity loads, exercises should be prioritized based on individual needs and sports-specific movement patterns for greater volume and potential for the desired neuromuscular adaptations.