A novel prenylflavone restricts breast cancer cell growth through AhR-mediated destabilization of ERα protein

There is concern that ingestion of dietary phytoestrogens may increase risk of estrogen receptor alpha (ERα)-positive breast cancer. The prenylflavone icaritin, a phytoestrogen consumed in East Asian societies for its perceived beneficial effects on bone health, stimulated the growth of breast cancer (MCF-7) cells at low concentrations. Although acting like an estrogenic ligand, icaritin exerted an unexpected suppressive effect on estrogen-stimulated breast cancer cell proliferation and gene expression at higher concentrations. Like estradiol, icaritin could dose-dependently destabilize ERα protein. However, destabilization of ERα by the estradiol/icaritin combination was profound and greater than that observed for either compound alone. Microarray gene expression analyses implicated aryl hydrocarbon receptor (AhR) signaling for this suppressive effect of icaritin. Indeed, icaritin was an AhR agonist that competitively reduced specific binding of a potent AhR agonist and increased expression of the AhR-regulated gene CYP1A1. When AhR was knocked down by small interfering RNA, the suppressive effect of icaritin on estradiol-stimulated breast cancer cell growth and gene expression was abolished, and ERα protein stability was partially restored. Similarly in an athymic nude mouse model, icaritin restricted estradiol-stimulated breast cancer xenograft growth and strongly reduced ERα protein levels. Overall, our data support the feasibility for the development of dual agonists like icaritin, which are estrogenic but yet, through activating AhR-signaling, can destabilize ERα protein to restrict ERα-positive breast cancer cell growth.     

Inhibitory effects of cytochrome P450 enzymes CYP2C8, CYP2C9, CYP2C19 and CYP3A4 by Labisia pumila extracts

Ethnopharmacological relevance

Labisa pumila (LP), popularly known with its local name, Kacip Fatimah, is a well known herb grown in Indochina and Southeast Asia and is traditionally used to regain energy after giving birth in women. The propensity of LP to cause drug–herb interaction via cytochrome P450 (CYP) enzyme system has not been investigated.

Aim of the study

To evaluate the in vitro inhibitory effects of various LP extracts (aqueous, ethanol, dichloromethane (DCM) and hexane) on cytochrome P450 2C8 (CYP2C8), CYP2C9, CYP2C19 and CYP3A4 activities.

Materials and methods

Probe substrate-based high performance liquid chromatography (HPLC) methods were established for CYP2C9, CYP2C19 and CYP3A4 whereas a fluorescence-based enzyme assay was established for CYP2C8. The metabolite formations were examined after incubation of probe substrate with respective CYP isoform in the present or absent of LP extracts. The inhibitory effect of LP was characterized with kinetic parameters IC₅₀ and K_i values.

Results

LP extracts showed differential effect of CYP activities with the order of inhibitory potency as follows: dichloromethane>hexane>ethanol>aqueous. This differential effect was only observed in CYP2C isoforms but not CYP3A4. Both the hexane and DCM extracts exhibited moderate to potent inhibition towards CYP2C activities in different modes including non-competitive, competive and mixed-type. The DCM effect was notably strong for CYP2C8 and CYP2C9 showing K_i values of below 1 μg/ml. The selectivity of LP for CYP2C isoforms rather than CYP3A4 may be attributed to the presence of relatively small, lipophilic yet slightly polar compounds within the LP extracts.

Conclusions

The results of our study revealed that phytoconstituents contained in LP, particularly in hexane and dichloromethane extracts, were able to selectively inhibit CYP2C isoforms. The inactivation was characterized by low K_i values, in particular, in CYP2C8 and CYP2C9. These in vitro data indicate that LB preparations contain constituents that can potently inhibit CYP2C activities and suggest that this herb should be examined for potential pharmacokinetic drug interactions in vivo.     

Cost effectiveness of the B type natriuretic peptide, electrocardiography, and portable echocardiography for the assessment of patients from the community with suspected heart failure

To analyze the cost efficiency of guidelines proposed by the European Society of Cardiology for investigation of patients in the community with suspected heart failure (HF). The guidelines recommend electrocardiography (ECG) and/or measurement of N-terminal pro B type natriuretic peptide (NTproBNP) prior to referral for echocardiography. Portable echocardiography is a new but validated technique for the evaluation of HF. Accordingly, 137 suspected HF patients (mean age 71+/-13 years) from the community underwent ECG and NTproBNP estimation prior to portable echocardiography. Cost effective analysis for ECG, NTproBNP, portable echocardiography and a combination of these; to define valvular heart disease, right ventricular dysfunction and left ventricular systolic and diastolic dysfunction were compared. The cost of abnormal NTproBNP followed by portable echocardiography, abnormal ECG followed by portable echocardiography and portable echocardiography alone for the detection per case of left ventricular systolic dysfunction were 313 euro, 310 euro, and 296 euro respectively and that for detection per case of any of the aforementioned cardiac abnormalities were 198 euro, 223 euro, and 170 euro respectively. Portable echocardiography alone for the assessment of suspected HF patients resulted in a cost reduction of up to 1083 euro for the detection per case of cardiac abnormality. While a strategy where initial NTproBNP estimation is cost effective in detecting any causes of heart failure, portable echocardiography remains the most costeffective strategy to assess patients from the community with suspected heart failure.     

Stroke-work loss underestimates hemodynamic significance of aortic stenosis in patients with hypertension

BACKGROUND: Stroke-work loss (SWL) represents the amount of energy the left ventricle dissipates as heat because of outflow obstruction. Recent studies suggest that SWL > 25% was the most clinically efficient Doppler measure for predicting hemodynamic significance, symptomatic status, and outcome in patients with aortic stenosis (AS). However, SWL may be affected by systolic blood pressure (SBP). OBJECTIVE: To determine if SWL reliably predicts hemodynamic significance of AS in patients with hypertension. METHODS: We studied 42 consecutive patients with hemodynamically significant AS requiring aortic valve replacement (AVR). Data on demographics, preoperative hemodynamics, and echocardiographic parameters were obtained. SWL was measured using the formula SWL = 100 x mean PG/ (mean PG + SBP), where PG is transaortic pressure gradient. Patients were considered hypertensive if their BP > 140/90 mmHg or if they are on antihypertensive medications. RESULTS: There were 27 males (64%) and mean age was 68 +/- 11 years. Twenty-four patients (57%) were hypertensive. Mean SBP was 134 +/- 24 mmHg, mean transaortic PG 47 +/- 20 mmHg, effective valve orifice area (EOA) by Doppler estimation 0.74 +/- 0.23 cm(2), and SWL 26 +/- 9%. Patients with hypertension had smaller SWL than normotensives (table I). SWL was >25% in 20 (49%) patients, and fewer patients with hypertension have SWL >25% (33% vs 71%, P = 0.019). Of note, patients with SWL < or =25% had significantly higher SBP (145 +/- 21 mmHg vs 122 +/- 22 mmHg, P = 0.02). CONCLUSION: SWL underestimates the hemodynamic significance of aortic stenosis in the majority of patients with hypertension.     

White matter tract involvement in brain tumors: a diffusion tensor imaging analysis

BackgroundCharacterization of WM alteration using MR imaging is important in the pre- and intraoperative assessment of brain tumors.This study characterizes the extent and severity of WM tract alterations near brain tumors using DTI in an effort to determine preoperative viability or resectability of the adjacent WM tracts. Fractional anisotropy is an important DTI-derived metric of MR imaging.MethodsTwenty-one patients underwent MR DTI. Eighty-six WM tracts composed of 43 WM lesions paired with 43 contralateral WM hemispheric controls were categorized using FA. Neuroradiologists categorized the WM tracts as edematous, displaced, disrupted, or infiltrated with tumor using directionally encoded color maps. A mixed model analysis was used to compare FA.ResultsOf the lesioned tracts, 5 were scored as edema, 9 as infiltration, 18 as displacement, and 11 as disruption. A significant ΔFA_% was found between the lesioned and contralateral hemispheres only in WM disruption (P = .0056). Both edema FA and disruption FA are significantly less than displacement FA (P < .05). The FA change (ΔFA_% = [FA_lesion ? FA_normal]/FA_normal × 100%) on the lesioned side was calculated. A ΔFA% less than ?30% is likely to be associated with WM disruption. A positive ΔFA% is likely to be associated with edema or displacement, and a ΔFA% between 0% and ?30% is likely to be associated with WM displacement or infiltration.ConclusionsQuantitative analysis of DTI data may provide insight as to whether WM tracts are salvageable preoperatively.     

Childhood Dupuytren’s disease of the interphalangeal joint of the thumb

To date, there are only 13 cases of Dupuytren’s disease documented in the English literature in children less than 13 years and only seven cases histologically diagnosed in those under 10 years. We present a rare case of childhood Dupuytren’s contracture involving only the interphalangeal joint of the thumb and review of current literature of the preferred management of Dupuytren’s disease in childhood.