BackgroundQuercetin, the most abundant dietary flavonol, has antioxidant effects in cardiovascular disease, but the evidence regarding its effects on blood pressure (BP) has not been conclusive. We assessed the impact of quercetin on BP through a systematic review and meta‐analysis of available randomized controlled trials.Methods and ResultsWe searched PUBMED, Cochrane Library, Scopus, and EMBASE up to January 31, 2015 to identify placebo‐controlled randomized controlled trials investigating the effect of quercetin on BP. Meta‐analysis was performed using either a fixed‐effects or random‐effect model according to I2 statistic. Effect size was expressed as weighted mean difference (WMD) and 95% CI. Overall, the impact of quercetin on BP was reported in 7 trials comprising 9 treatment arms (587 patients). The results of the meta‐analysis showed significant reductions both in systolic BP (WMD: −3.04 mm Hg, 95% CI: −5.75, −0.33, P=0.028) and diastolic BP (WMD: −2.63 mm Hg, 95% CI: −3.26, −2.01, P<0.001) following supplementation with quercetin. When the studies were categorized according to the quercetin dose, there was a significant systolic BP and diastolic BP‐reducing effect in randomized controlled trials with doses ≥500 mg/day (WMD: −4.45 mm Hg, 95% CI: −7.70, −1.21, P=0.007 and −2.98 mm Hg, 95% CI: −3.64, −2.31, P<0.001, respectively), and lack of a significant effect for doses <500 mg/day (WMD: −1.59 mm Hg, 95% CI: −4.44, 1.25, P=0.273 and −0.24 mm Hg, 95% CI: −2.00, 1.52, P=0.788, respectively), but indirect comparison tests failed to significant differences between doses.ConclusionsThe results of the meta‐analysis showed a statistically significant effect of quercetin supplementation in the reduction of BP, possibly limited to, or greater with dosages of >500 mg/day. Further studies are necessary to investigate the clinical relevance of these results and the possibility of quercetin application as an add‐on to antihypertensive therapy.

Ovarian cancer is the most lethal gynecological malignancy. Cisplatin and its derivatives are first-line chemotherapeutics, and their resistance is a major hurdle in successful ovarian cancer treatment. Understanding the molecular dysregulation underlying chemoresistance is important for enhancing therapeutic outcome. Here, we review two established pathways in cancer chemoresistance. p53 is a major tumor suppressor regulating proliferation and apoptosis, and its mutation is a frequent event in human malignancies. The PI3K/Akt axis is a key oncogenic pathway regulating survival and tumorigenesis by controlling several tumor suppressors, including p53. The interplay between these pathways is well established, although the oncogenic phosphatase PPM1D adds a new layer to this intricate relationship and provides new insights into the processes determining cell fate. Inhibition of the PI3K/Akt pathway by functional food compounds as an adjunct to chemotherapeutics may tip the balance in favor of apoptosis rather than survival, enhancing therapeutic efficacy, and reducing side effects.

Cisplatin (CDDP: cis-diamminedichloroplatinum) resistance is a major hurdle in the treatment of human ovarian cancer (OVCA). A better understanding of the mechanisms of CDDP resistance can greatly improve therapeutic outcome for patients. A determinant of CDDP sensitivity in OVCA, p53, is activated by checkpoint kinase 1 (Chk1) in response to DNA damage. Although the oncogenic phosphatase protein phosphatase magnesium-dependent 1 (PPM1D) can deactivate both p53 and Chk1 through sitespecific dephosphorylation, whether PPM1D has a role in CDDP resistance is unknown. Here, using pair-matched wild-type p53 CDDP-sensitive (OV2008) and -resistant (C13*) cells, and p53-compromised CDDP-resistant cells (A2780cp, OCC-1, OVCAR-3 and SKOV3), we have demonstrated (i) the existence of site-specific differences in phospho-Ser-Chk1 content between sensitive and resistant cells in response to CDDP; (ii) PPM1D, but not phosphoinositide-3-kinase-related kinase (ataxia telangiectasia and Rad3 related protein (ATR)), is important in the regulation of CDDP-induced Chk1 activation and OVCA cell chemosensitivity; (iii) PPM1D downregulation sensitizes resistant cells to CDDP primarily by activating Chk1 and p53. Our findings establish for the first time that PPM1D confers CDDP resistance in OVCA cells through attenuating CDDP-induced, Chk1-mediated, p53-dependent apoptosis. These findings extend the current knowledge on the molecular and cellular basis of cisplatin resistance and offer the rationale for PPMID as a potential target for treatment of chemoresistant OVCA.

Hyperglycaemia-mediated oxidative stress plays an imperative role in the progression of diabetic nephropathy. NF-kB is an important transcription factor in eukaryotes which regulates a diverse array of cellular process, including inflammation, immunological response, apoptosis, growth and development. Increased expression of NF-kB plays a vital role in the pathogenesis of many inflammatory diseases including diabetic nephropathy. Hence, the present study was designed to explore the nephroprotective nature of diosmin by assessing the various biochemical parameters, markers of oxidative stress and proinflammatory cytokine levels in alloxan-induced diabetic Wistar rats. Type 2 diabetes was induced in Wistar rats by single intraperitoneal injection of alloxan (120 mg/kg body weight). Seventy-two hours after the conformation of diabetes (blood glucose level ≥ 250 mg/dl), the rats were segregated into four groups, each group having six animals. Diabetic rats were treated with diosmin at a dose of 50 mg and 100 mg/kg body weight respectively. After the 28th day of treatment, rats were sacrificed, blood serum, plasma and kidney tissue were collected for various biochemical analysis. Inflammatory cytokine levels were measured through ELISA kit. Diosmin treatment produces significant reduction in the blood glucose and plasma insulin level and increases the body weight when compared with diabetic rats. Elevated level of malondialdehyde (MDA) and decrease levels of superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and nitric oxide (NO) were significantly restored after 28 days of diosmin treatment. Diosmin treatment group also restores the normal architecture of the kidney tissue which was confirmed by histopathological examination. Moreover, oral administration of diosmin shows a significant normalization in the level of NF-kB, proving its pivotal role in maintaining renal function. The above ameliorative effects were more pronounced with diosmin at a dose of 100 mg/kg body weight. The above results permit us to conclude that treatment with diosmin halts hyperglycaemia-mediated oxidative stress and decline in pro-inflammatory cytokines and thus has beneficial anti-diabetic activity.

Ovarian cancer (OVCA) and cervical cancer (CECA) are lethal gynecological malignancies. Cisplatin (CDDP) and platinum derivatives are first line chemotherapeutics and their resistance impedes successful treatment. Understanding the molecular dysregulation underlying chemoresistance is important in developing rational therapeutic strategies. We have established that Protein Phosphatase Magnesium-dependent 1 D (PPM1D) confers CDDP resistance in gynecological cancer cells by deactivating p53. However, whether CDDP regulates intra-cellular PPM1D localization and whether this regulation is different between chemosensitive and chemoresistant cancer cells is unknown. Moreover, whether Akt regulates PPM1D in the context of CDDP resistance has not been studied. To illustrate the role of PPM1D in gynecological cancer cell chemoresistance and its regulation by Akt we have demonstrated that: (a) CDDP induced PPM1D downregulation through proteasomal degradation in sensitive CECA cells; (b) CDDP induced PPM1D nuclear localization in resistant CECA cells, and nuclear exclusion in sensitive CECA cells and OVCA xenografts; (c) Over-expression of active Akt in sensitive CECA cells stabilized PPM1D content through inhibition of CDDP-induced PPM1D down-regulation; (d) Inhibition of Akt activity in resistant OVCA cells leads to decreased PPM1D stability and CDDP-induced down-regulation in resistant CECA cells; and (e) PPM1D is highly expressed in human ovarian tumor subtypes and in a tissue microarray panel of human ovarian tumors. In conclusion, we have established that PPM1D plays an important role in promoting CDDP resistance and as a novel downstream target of Akt, PPM1D mediates its action in conferring CDDP resistance in gynecological cancer cells. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.Key words: cisplatin chemoresistance; ovarian cancer; PPM1D; Akt; apoptosis INTRODUCTIONOvarian cancer (OVCA) and cervical cancer (CECA) are the most lethal gynecological malignancies. Although OVCA ranks first in the number of deaths each year, due primarily to its late diagnosis and the development of chemoresistance [1], CECA is more frequent and less deadly due to early detection. Surgical de-bulking of the tumor mass followed by adjuvant chemotherapy is the conventional course of therapy for OVCA, whereas a combination of radiation and chemotherapy is the preferred treatment regimen for CECA. Platinum derivatives, including Cisplatin (CDDP; cis-diamminedichloroplatinum) in combination with paclitaxel, are first-line chemotherapeutic agents in the treatment of these gynecologic cancers. CDDP induces apoptosis by creating inter-and intra-strand DNA adducts through irreversible intercalation, thereby inducing both the DNA damage and the apoptotic responses [2]. The majority of patients respond to chemotherapy at first, however, recurrence of the disease is a common event and tumors are usually more aggressive, metastasize to secondary target tissues, and acquire resistance to conventional chemotherape...

The PI 3-kinases (PI3K) are essential mediators of chemokine receptor signaling necessary for migration of chronic lymphocytic leukemia (CLL) cells and their interaction with tissue-resident stromal cells. While the PI3Kδ-specific inhibitor idelalisib shows efficacy in treatment of CLL and other B cell malignancies, the function of PI3Kγ has not been extensively studied in B cells. Here, we assess whether PI3Kγ has non-redundant functions in CLL migration and adhesion to stromal cells. We observed that pharmaceutical PI3Kγ inhibition with CZC24832 significantly impaired CLL cell migration, while dual PI3Kδ/γ inhibitor duvelisib had a greater impact than single isoform-selective inhibitors. Knockdown of PI3Kγ reduced migration of CLL cells and cell lines. Expression of the PI3Kγ subunits increased in CLL cells in response to CD40L/IL-4, whereas BCR cross-linking had no effect. Overexpression of PI3Kγ subunits enhanced cell migration in response to SDF1α/CXCL12, with the strongest effect observed within ZAP70 + CLL samples. Microscopic tracking of cell migration within chemokine gradients revealed that PI3Kγ functions in gradient sensing and impacts cell morphology and F-actin polarization. PI3Kγ inhibition also reduced CLL adhesion to stromal cells to a similar extent as idelalisib. These findings provide the first evidence that PI3Kγ has unique functions in malignant B cells.

Diffusive clearance depends on blood (Qb) and dialysate flow (Qd) rates and the overall mass transfer area coefficient (KoA) of the dialyzer. In this article we describe a model to predict an appropriated AutoFlow (AF) factor (AF factor = Ratio Qd/Qb), that is able to provide adequate Kt/V for hemodialysis patients (HDP), while consuming lower amounts of dialysate, water and energy during the treatment. We studied in vivo the effects of three various Qd on the delivered dose of dialysis in 33 stable HDP. Hemodialysis was performed at Qd of 700 mL/mn, 500 mL/mn, and with AF, whereas specific dialysis prescriptions (treatment time, blood flow rate [Qb], and type and size of dialyzer) were kept constant. The results showed that increasing the dialysate flow rate more than the model of AF predicted had a small effect on the delivered dose of dialysis. The Kt/V (mean ± SD) was 1.52 ± 0.16 at Qd 700, 1.50 ± 0.16 at Qd 500, and 1.49 ± 0.15 with AF. The use of the AF function leads to a significant saving of dialysate fluid. The model predicts the appropriate AF factor that automatically adjusts the dialysate flow rate according to the effective blood flow rate of the patient to achieve an appreciable increase in dialysis dose at the lowest additional cost.

BackgroundHepatocyte growth factor (HGF) plays a pivotal role in breast cancer cell motility, invasion and angiogenesis. These pro-metastatic events are triggered through HGF coupling and activation of the c-Met receptor. Reports have demonstrated that HGF/c-Met signalling plays an important part in breast cancer progression and that their expression is linked to poor patient outcome. In the present study, we investigated the anti-metastatic potential of an extract from traditional Somalian frankincense, Boswellia frereana, on human breast cancer cells. In addition, we also examined the effect of this Boswellia frereana extract (BFE) upon HGF-mediated stimulation of the c-Met receptor.MethodsTwo triple negative human breast cancer cell lines, BT549 and MDA-MB-231, were utilised in the study to examine the effect of BFE on tumour cell proliferation, migration, matrix-adhesion, angiogenesis and invasion. Cell migration was investigated using a Cell IQ time-lapsed motion analysis system; while tumour cell–matrix adhesion, angiogenesis and invasion were assessed through Matrigel-based in vitro assays. Breast cancer cell growth and spheroid formation was examined through proliferation assay and 3D non-scaffold cell culture techniques. Western Blotting was employed to determine the phosphorylation status of the c-Met receptor tyrosine kinase following BFE treatment and subsequent HGF stimulation.ResultsFollowing HGF treatment, the breast cancer cells displayed a significant increase in migration, matrix adhesion, vessel/tubule formation, invasion and c-Met activation. HGF did not appear to have any bearing on the proliferation rate or spheroid formation of these breast cancer cells. The addition of the BFE extract quenched the HGF-enhanced migratory, angiogenic and invasive potential of these cells. Further study revealed that BFE inhibited c-Met receptor tyrosine kinase phosphorylation within these breast cancer cells.ConclusionsOur findings reveal that BFE was able to significantly suppress the influence of HGF in breast cancer cell motility and invasion in vitro, through the ability of BFE to reduce HGF/c-Met signalling events. Therefore, these results indicate that BFE could play a novel role in the treatment of breast cancer.