Modulation of breast cancer resistance protein (BCRP/ABCG2) by non-basic chalcone analogues

Chalcones are biosynthetic precursors of flavonoids found to possess cytotoxic and chemopreventive activities. In this study, 17 non-basic chalcone analogues were synthesized and evaluated for their ability to modulate the function of either the human wild-type (482R) or mutant (482T) breast cancer resistance protein (BCRP/ABCG2) stably expressed in breast cancer MDA-MB-231 cells. At 5muM, chalcones with 2,4-dimethoxy groups or 2,4-dihydroxyl groups on ring A were found to increase mitoxantrone accumulation to a greater extent than an established BCRP inhibitor, fumitremorgin C. At the same time, these chalcones had negligible effect on calcein accumulation in P-glycoprotein overexpressing MDCKII cells, indicating their potential as selective BCRP inhibitors. Functionally, these compounds were able to increase the sensitivity of BCRP-overexpressing cancer cells to mitoxantrone by 2-5-fold. The effect of chalcone compounds on both wild-type and mutant BCRP ATPase activity was also examined and variable effects were observed. A stimulatory effect was mostly observed with chalcones with 2,4-dimethoxy substitution on ring A which were earmarked as good BCRP inhibitors in the MX accumulation and cytotoxicity assays. These findings underscore the potential of methoxylated and hydroxylated chalcones as selective and potent inhibitors of BCRP whose mode of action may not involve the inhibition of ATPase activity.     

Comparison of oropharyngeal leak pressure between the Ambu® AuraGain™ and the LMA® Supreme™ supraglottic airways: a randomized-controlled trial

Purpose

Studies comparing the recently introduced Ambu® AuraGain? (Auragain) with the LMA® Supreme? (Supreme) supraglottic airway (SGA) have reported conflicting results regarding differences in oropharyngeal leak pressure (OLP). This randomized-controlled trial investigated the OLP of the Auragain compared with the Supreme in patients undergoing ambulatory surgery.

Methods

Adult patients with a body mass index ≤ 40 kg·m^?2 presenting for ambulatory surgery and requiring an SGA were randomized to receive either the Auragain or the Supreme. Anesthesia was induced with lidocaine (1 mg·kg^?1), fentanyl (1-2 μg·kg^?1), and propofol (2-3 mg·kg^?1). The SGA was inserted using a standard technique with the cuff inflated to 60 cmH₂O. The groups were compared for the primary outcome of OLP.

Results

One hundred sixty-five patients (n = 81, Auragain; n = 84, Supreme) completed the study. Demographics were similar between the groups. The mean (standard deviation [SD]) OLP was significantly higher in the Auragain than in the Supreme group [26.4 (2.8) cmH₂O vs 21.6 (3.4) cmH₂O, respectively; difference in means (MD), 4.8 cmH₂O; 95% confidence interval (CI), 3.9 to 5.8; P < 0.001]. The mean (SD) insertion time was longer in the Auragain than in the Supreme group [13 (4) sec vs 11 (3) sec, respectively; MD, 2 sec; 95% CI, 1 to 3 sec; P < 0.001].

Conclusion

In patients undergoing ambulatory anesthesia, the OLP was higher but took longer to insert with the Auragain than with the Supreme. A higher OLP may allow for SGAs to be utilized in a wider range of patients and procedures.

Trial registration

www.clinicaltrials.gov (NCT02816463). Registered 28 June 2016.

     

Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease

Therapies that raise levels of HDL, which is thought to exert atheroprotective effects via effects on endothelium, are being examined for the treatment or prevention of coronary artery disease (CAD). However, the endothelial effects of HDL are highly heterogeneous, and the impact of HDL of patients with CAD on the activation of endothelial eNOS and eNOS-dependent pathways is unknown. Here we have demonstrated that, in contrast to HDL from healthy subjects, HDL from patients with stable CAD or an acute coronary syndrome (HDLCAD) does not have endothelial antiinflammatory effects and does not stimulate endothelial repair because it fails to induce endothelial NO production. Mechanistically, this was because HDLCAD activated endothelial lectin-like oxidized LDL receptor 1 (LOX-1), triggering endothelial PKCβII activation, which in turn inhibited eNOS-activating pathways and eNOS-dependent NO production. We then identified reduced HDL-associated paraoxonase 1 (PON1) activity as one molecular mechanism leading to the generation of HDL with endothelial PKCβII-activating properties, at least in part due to increased formation of malondialdehyde in HDL. Taken together, our data indicate that in patients with CAD, HDL gains endothelial LOX-1- and thereby PKCβII-activating properties due to reduced HDL-associated PON1 activity, and that this leads to inhibition of eNOS-activation and the subsequent loss of the endothelial antiinflammatory and endothelial repair-stimulating effects of HDL.     

Effect of phaleria macrocarpa supplementation on apoptosis and tumor growth of C3H mice with breast cancer under treatment with adriamycin-cyclophosphamide

The objective of this study was to know the response of supplementation of Phaleria macrocarpa (PM) to adriamycin-cyclophosphamide (AC) in the treatment of C3H mice with breast cancer. Twenty-four C3H mice, who were successfully inoculated with breast cancer cells, were randomly allocated into 4 groups: without treatment, treated with AC, treated with AC + PM 0.07 mg/d, and treated with AC + PM 0.14 mg/d. The tumor size was measured using millimeter calipers before and 12 weeks after treatment. The tumor, liver, and kidneys were removed and prepared for pathologic examination using imunohistochemistry staining, and the apoptotic index was counted using the terminal deoxynucleotidyl transferase dUTP nick end labeling method. AC reduce the tumor growth significantly (P < 0.001), whereas supplementation of PM, which significantly reduced the tumor growth compared with AC only, was at the 0.14 mg/d dose (P = 0.007). AC increase the apoptotic index significantly (P < 0.001), and supplementation with PM showed that the higher dose increased the apoptotic index. The correlation between the apoptotic index and the diameter of tumor was significantly negative (r = -0.884; P = 0.020). The apoptotic index of the liver and kidney increased significantly in the AC group (P < 0.001 and P = 0.002, respectively); supplementation with PM decreased significantly the high apoptotic index caused by AC. We conclude that PM supplementation has a synergic effect to AC treatment in reducing the tumor growth, by increasing apoptosis, and protects the liver and kidney from damage caused by AC.     

Myeloperoxidase,paraoxonase-1, and HDL form a functional ternary complex

Myeloperoxidase (MPO) and paraoxonase 1 (PON1) are high-density lipoprotein–associated (HDL-associated) proteins mechanistically linked to inflammation, oxidant stress, and atherosclerosis. MPO is a source of ROS during inflammation and can oxidize apolipoprotein A1 (APOA1) of HDL, impairing its atheroprotective functions. In contrast, PON1 fosters systemic antioxidant effects and promotes some of the atheroprotective properties attributed to HDL. Here, we demonstrate that MPO, PON1, and HDL bind to one another, forming a ternary complex, wherein PON1 partially inhibits MPO activity, while MPO inactivates PON1. MPO oxidizes PON1 on tyrosine 71 (Tyr₇₁), a modified residue found in human atheroma that is critical for HDL binding and PON1 function. Acute inflammation model studies with transgenic and knockout mice for either PON1 or MPO confirmed that MPO and PON1 reciprocally modulate each other’s function in vivo. Further structure and function studies identified critical contact sites between APOA1 within HDL, PON1, and MPO, and proteomics studies of HDL recovered from acute coronary syndrome (ACS) subjects revealed enhanced chlorotyrosine content, site-specific PON1 methionine oxidation, and reduced PON1 activity. HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation, whereupon PON1 binding partially inhibits MPO activity, and MPO promotes site-specific oxidative modification and impairment of PON1 and APOA1 function.     

Interpretation of sleep studies for patients with sleep-disordered breathing: What the anesthesiologist needs to know

There is increased interest in the perioperative management of patients with sleep-disordered breathing (SDB). Anesthesiologists must distill information from clinical reports to make key decisions for optimizing perioperative care. A patient with SDB may present with a sleep study report at the time of surgery. Knowledge of the essential components of such a report can help the anesthesiologist evaluate the patient and optimize the perioperative management. In this narrative review, we describe how level I (i.e., laboratory-based) polysomnography (PSG) data are collected and scored using the recommended scoring guidelines, as well as the basic information and salient features of a typical PSG report relevant to the anesthesiologist. In addition, we briefly review the indications for sleep studies, including the types of laboratory-based studies, as well as the role and limitations of portable monitors (level II-IV studies) and examples of PSG reports in the clinical context.