Triple-Band Notched Ultra-Wideband Microstrip MIMO Antenna with Bluetooth Band.

In this paper, a novel ultra-wideband UWB antenna element with triple-band notches is proposed. The proposed UWB radiator element operates from 2.03 GHz up to 15.04 GHz with triple rejected bands at the WiMAX band (3.28-3.8 GHz), WLAN band (5.05-5.9 GHz), and X-band (7.78-8.51 GHz). In addition, the radiator supports the Bluetooth band (2.4-2.483 GHz). Three different techniques were utilized to obtain the triple-band notches. An alpha-shaped coupled line with a stub-loaded resonator (SLR) band stop filter was inserted along the main feeding line before the radiator to obtain a WiMAX band notch characteristic. Two identical U-shaped slots were etched on the proposed UWB radiator to achieve WLAN band notch characteristics with a very high degree of selectivity. Two identical metallic frames of an octagon-shaped electromagnetic band gap structure (EBG) were placed along the main feeding line to achieve the notch characteristic with X-band satellite communication with high sharpness edges. A novel UWB multiple-input multiple-output (MIMO) radiator is proposed. The proposed UWB-MIMO radiator was fabricated on FR-4 substrate material and measured. The isolation between every two adjacent ports was below -20 dB over the FCC-UWB spectrum and the Bluetooth band for the four MIMO antennas. The envelope correlation coefficient (ECC) between the proposed antennas in MIMO does not exceed 0.05. The diversity gains (DG) for all the radiators are greater than 9.98 dB.

Travoprost Liquid Nanocrystals: An Innovative Armamentarium for Effective Glaucoma Therapy.

To date, the ophthalmic application of liquid crystalline nanostructures (LCNs) has not been thoroughly reconnoitered, yet they have been extensively used. LCNs are primarily made up of glyceryl monooleate (GMO) or phytantriol as a lipid, a stabilizing agent, and a penetration enhancer (PE). For optimization, the D-optimal design was exploited. A characterization using TEM and XRPD was conducted. Optimized LCNs were loaded with the anti-glaucoma drug Travoprost (TRAVO). Ex vivo permeation across the cornea, in vivo pharmacokinetics, and pharmacodynamic studies were performed along with ocular tolerability examinations. Optimized LCNs are constituted of GMO, Tween® 80 as a stabilizer, and either oleic acid or Captex® 8000 as PE at 25 mg each. TRAVO-LNCs, F-1-L and F-3-L, showed particle sizes of 216.20 ± 6.12 and 129.40 ± 11.73 nm, with EE% of 85.30 ± 4.29 and 82.54 ± 7.65%, respectively, revealing the highest drug permeation parameters. The bioavailability of both attained 106.1% and 322.82%, respectively, relative to the market product TRAVATAN®. They exhibited respective intraocular pressure reductions lasting for 48 and 72 h, compared to 36 h for TRAVATAN®. All LCNs exhibited no evidence of ocular injury in comparison to the control eye. The findings revealed the competence of TRAVO-tailored LCNs in glaucoma treatment and suggested the potential application of a novel platform in ocular delivery.

Short term effect of spinal mobilization with movement (MWM) on pulmonary functions in nonsmokers with thoracic hyperkyphosis: a randomized single-blinded controlled trial.

OBJECTIVES: To investigate the effect of mobilization with movement (MWM) on pulmonary functions in subjects with thoracic hyperkyphosis. METHODS: This randomized single-blinded controlled trial included a sample of 50 subjects (age 18 - 25 years old) with thoracic hyperkyphosis. Subjects were randomly allocated into two groups; the Real MWM group (n = 25) which received thoracic MWM plus standard postural correction exercises, and the Sham MWM group (n = 25) which received sham MWM plus standard postural correction exercises. Digital X-ray and handheld spirometer were used to measure selected pulmonary function tests (FVC, FEV1/FVC ratio, MVV) respectively. RESULTS: Within-group comparisons demonstrated a statistically significant improvement in all outcome measures in both groups. The between-group comparisons demonstrated significant improvement in the MWM compared to the Sham group regarding the value of FVC, FEV1/FVC ratio, and MVV (P < .05). CONCLUSION: In young adults with thoracic hyperkyphosis, MWM plus postural exercise produces better improvements in FVC, FEV1, FEV1/FVC, and MVV compared to sham MWM plus postural exercise.

Effect of manual physical therapy on sleep quality and jaw mobility in patients with bruxism: A biopsychosocial randomized controlled trial.

This study aimed to investigate the effects of deep-stripping and trigger-point pressure release massage on the Pittsburgh Sleep Quality Index (PSQI), jaw mobility, and pressure pain threshold (PPT) of masticatory muscles in patients with sleep bruxism. A randomized controlled trial was conducted among 45 patients diagnosed with sleep bruxism. The patients were randomly assigned to three groups. Group I was the control group and included five men and 10 women; Group II was the deep-stripping massage group, which included two men and 13 women; and Group III was the pressure release group, which involved four men and 11 women. Patients were tested two times, before and after 6 weeks. Group I received transcutaneous electrical nerve stimulation and passive stretching; Group II received a deep-stripping massage; and Group III received a trigger-point pressure release massage. Findings revealed significant improvements in PSQI (p = 0.0001), jaw opening (p = 0.0001), jaw protrusion (p = 0.0001), jaw left lateral movement (p = 0.004), jaw retraction (p = 0.0001), right temporalis PPT (p = 0.0001), left temporalis PPT (p = 0.0001), right master PPT (p = 0.001), left master PPT (p = 0.001), right lateral pterygoid PPT (p = 0.001), left lateral pterygoid PPT (p = 0.001), right digastric muscle PPT (p = 0.001), and left digastric muscle PPT (p = 0.001) in the post-test condition in Group II compared with Group I and Group III. Deep-stripping massage improved PSQI, jaw mobility, or PPT of the masticatory muscles compared with trigger-point pressure release massage and traditional treatment techniques in patients with sleep bruxism.

A biodegradable film based on cellulose and thiazolidine bearing UV shielding property.

The current rationale is exploring new eco-friendly UV- shielding films based on cellulose and thiazolidine. Cellulose was oxidized to dialdehyde cellulose (DAC) and tricarboxy cellulose (TCC) by periodate and TEMPO/periodate/hypochlorite, respectively. While E-3-amino-5-(phenyldiazenyl)-2-thioxothiazolidin-4-one (TH) was synthesized by coupling diazonium salt with the 5-methylene of 2-thioxo-4-thiazolidinone. DAC was then coupled with TH via Schiff base reaction and incorporated onto TCC with different ratios to get UV-shielding films. 1HNMR, infrared spectroscopy (FTIR), and thermal gravimetric analysis (TGA) were used to investigate the chemical structure of the synthesized materials. In addition, the films' morphology, thermal, mechanical, and UV-shielding properties were investigated. The UV-shielding studies revealed that the film with 10% DAC-TH has 99.88, 99.99, and 96.19% UV-blocking (UVB), UV-absorbance (UVA), and Ultra-violet protection (UPF), respectively. Moreover, the prepared films demonstrated promising antimicrobial activity against Escherichia coli, S. aureus, P. aeruginosa, and Candida albicans. Finally, the prepared films showed no cytotoxic effects on normal human skin fibroblast's HFB-4 cell line.

Hydrazonoyl chlorides possess promising antitumor properties.

AIMS: the main purpose of this study was to identify new selective antitumor agents. MAIN METHODS: several hydrazonoyl chlorides (HCs) were synthesized and human tumor cell line viability was determined using the MTT assay. Tumor development was assessed using Ehrlich ascites carcinoma (EAC)-bearing mice. KEY FINDINGS: our results showed that 2-oxo-N-phenyl-2-(phenylamino)acetohydrazonoyl chloride (compound 4; CPD 4) and 2-oxo-2-(phenylamino)-N-(p-tolyl)acetohydrazonoyl chloride (CPD 5) were the most cytotoxic HCs to human cervical tumor HeLa (IC50: 20 and 25 µM for CPD 4 and 5 respectively), breast MCF7 (IC50: 29 and 34 µM for CPD 4 and 5 respectively) and colon HCT116 cancer cells (IC50: 26 and 25 µM for CPD 4 and 5 respectively) with the least cytotoxicity to human non-tumor CCD-18Co colon fibroblasts as well as murine splenocytes. The active compounds significantly inhibited colony formation as well as tumor development in EAC-bearing mice. We also observed that PTEN-deficient cells displayed greater sensitivity than cells expressing wild type PTEN. At the molecular level, comet and cell cycle analyses indicated that the active compounds generate DNA damage. In light of the PTEN-dependent sensitivity and genomic instability we examined the influence of HCs on the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) and the PI3K/AKT/mTOR pathway, which are each known to be synthetic lethal with PTEN. We found that both PNKP and the PI3K/AKT/mTOR pathway to be adversely affected by the HCs, which may partially account for their toxicity. SIGNIFICANCE: hydrazonoyl chlorides can be considered as hit compounds for the development of new antitumor agents.

Wi-Fi Access Point Design Concept Targeting Indoor Positioning for Smartphones and IoT.

Indoor positioning systems (IPS) have been regarded as essential for many applications, particularly for smartphones, during the past decade. With the internet of things (IoT), and especially device-to-device (D2D) cases, the client is supposed to have a very simple structure and low cost. It is also desirable that the client contains minimal software modules specifically for IPS purposes. This study proposes a new IPS technique that satisfies these conditions. The evaluation of the technique was previously executed based on a manual procedure. This technique utilizes Wi-Fi technology in addition to a new design of two orthogonal phased antenna arrays. This paper provides a complete design of a Wi-Fi access point (AP), considered as the proof of concept of a commercial AP. For the system to be fully automatic, the proposed architecture is based on a Raspberry Pi, external Wi-Fi modules, a powered universal serial bus (USB) hub, and two orthogonal phased antenna arrays. The phases of each antenna array are governed by extra-phase circuits as well as a radio frequency (RF) switch. Extensive design parameters have been chosen through parametric sweeps that satisfy the design conditions. Software testing results for the antenna arrays are included in this paper to show the feasibility and suitability of the proposed antenna array for IPS.

Gold Nanorods are Selective Cytotoxic Agents.

BACKGROUND: Gold nanorods (GNRs) are very promising agents with multiple applications in medicine and biology. However, the cytotoxic effects of GNRs have not been fully explored. OBJECTIVE: Therefore, the main objective of this study was to determine the selective cytotoxic effect of GNRs towards several human tumor cell lines. METHODS: To address this issue, three sizes of GNRs (10-nm, 25-nm, and 50-nm) were tested against two human tumor cell lines, namely, human hepatoma HepG2 and human prostate PC3 cancer cells. As GNRs are usually stored in soft tissues inside living bodies, we also tested the effect of GNRs on murine splenocyte viability. To determine if the GNRs displayed selective cytotoxicity towards cancer cells, active GNRs with the size showing the least cytotoxicity to splenocytes were then tested against a panel of 11 human tumor cell lines and two human non-tumor cell lines. RESULTS: Our results showed that the most cytotoxic size of GNRs is 10-nm, followed by the 25-nm GNRs, while the 50-nm GNRs did not show a significant effect. In addition, the 25-nm GNRs were the least cytotoxic to splenocytes when tested for 24 and 48 h. These GNRs showed a selective cytotoxic effect to prostate cancer PC3 cells with median inhibitory concentration (IC50) = 8.3 ± 0.37 µM, myeloblastic leukemia HL60 cells (IC50 = 19.7 ± 0.89 µM), cervical cancer HeLa cells (IC50 = 24.6 ± 0.37 µM), renal adenocarcinoma 786.0 cells (IC50 = 27.34 ± 0.6 µM), and hepatoma HepG2 cells (IC50 = 27.79 ± 0.03 µM) when compared to the effect on the non-tumor human cells; skin fibroblast BJ cell line (IC50 = 40.13 ± 0.7 µM) or epithelial breast MCF10A cells (IC50 = 33.2 ± 0.89 µM). High selectivity indices (SIs) were observed in GNRs-treated PC3 and HL60 cells with values ranging from 1.69 to 4.83, whereas moderate SIs were observed in GNRs-treated HeLa, 786.0, and HepG2 cells with values ranging from 1.19 to 1.63. Other cells did not show a similar selective effect, including human laryngeal HEp2 cells, colon HCT116, metastatic renal adenocarcinoma ACHN cells, and human breast cancer cells (MCF7, MDA-MB-231, and MDA-MB-468 cells). The effect of GNRs was confirmed using the colony formation assay and the effect was found to be cell cycle-specific. Finally, it was shown that laser treatment could potentiate the cytotoxic effect of the 25-nm GNRs. CONCLUSION: GNRs are selective cytotoxic agents and they have the potential to act as candidate anticancer agents.

Delineating penetration enhancer-enriched liquid crystalline nanostructures as novel platforms for improved ophthalmic delivery.

Liquid crystalline nanostructures (LCNs), for instance cubosomes, have been widely used as a promising carrier for drug delivery through the last few years. To date, the ophthalmic application of these platforms was not well explored, and the effect of integrating penetration enhancers (PEs) into LCNs has not been investigated yet. Hence, the present work aimed coupling novel PEs into glyceryl monooleate-based cubosomes for ocular administration. Various enhancers viz, free fatty acids (oleic and linoleic acids), natural terpenes (D-limonene and cineole), medium-chain triglycerides (Captex® 1000 and Captex® 8000), mono-/di-glycerides (Capmul® MCM, Capmul® PG-8, and Capmul® PG-12) were tested at different amounts. The morphology of the formed LCNs was investigated using transmission electron microscopy (TEM). The crystallinity and thermal behavior studies were also conducted. The ocular safety of optimized formulae was tested via hen's egg test-chorioallantoic membrane (HET-CAM), rabbit eye Draize test, and histopathological examinations of ocular tissues. Confocal laser scanning microscopy (CLSM) was utilized to assess the enhanced permeation of fluorescently-labeled LCNs across corneal layers. The acceptable formulations exhibited relatively homogenous particle nano-sizes ranging from 139.26 ± 3.68 to 590.56 ± 24.86 nm carrying negative surface charges. TEM images, X-ray patterns and DSC thermograms demonstrated the influential effect of PEs in developing altered crystalline structures. The ocular compatibility of optimized LCNs was confirmed. The corneal distribution using CLSM proved the disseminated fluorescence intensity of LCNs enriched with oleic acid, Captex® 8000 and Capmul® MCM. Selected LCNs showed good physical stability upon storage and lyophilization. The results demonstrated the efficiency of tailored PE-modified LCNs in enhancing the ocular transport with no evidence of any irritation potential, and hence suggested their prospective applicability in ophthalmic drug delivery.

A Rapid Lysostaphin Production Approach and a Convenient Novel Lysostaphin Loaded Nano-emulgel; As a Sustainable Low-Cost Methicillin-Resistant Staphylococcus aureus Combating Platform.

Staphylococcus aureus is a Gram-positive pathogen that is capable of infecting almost every organ in the human body. Alarmingly, the rapid emergence of methicillin-resistant S.aureus strains (MRSA) jeopardizes the available treatment options. Herein, we propose sustainable, low-cost production of recombinant lysostaphin (rLST), which is a native bacteriocin destroying the staphylococcal cell wall through its endopeptidase activity. We combined the use of E. coli BL21(DE3)/pET15b, factorial design, and simple Ni-NTA affinity chromatography to optimize rLST production. The enzyme yield was up to 50 mg/L culture, surpassing reported systems. Our rLST demonstrated superlative biofilm combating ability by inhibiting staphylococcal biofilms formation and detachment of already formed biofilms, compared to vancomycin and linezolid. Furthermore, we aimed at developing a novel rLST topical formula targeting staphylococcal skin infections. The phase inversion composition (PIC) method fulfilled this aim with its simple preparatory steps and affordable components. LST nano-emulgel (LNEG) was able to extend active LST release up to 8 h and cure skin infections in a murine skin model. We are introducing a rapid, convenient rLST production platform with an outcome of pure, active rLST incorporated into an effective LNEG formula with scaling-up potential to satisfy the needs of both research and therapeutic purposes.

Differences in Flight Activity of Coleomegilla maculata and Hippodamia convergens (Coleoptera: Coccinellidae) Following Emergence, Mating, and Reproduction.

The flight activity of Coleomegilla maculata DeGeer and Hippodamia convergens Guerin-Meneville (Coleoptera: Coccinellidae) was examined by observing tethered beetles in the laboratory. C. maculata were fed eggs of Ephestia kuehniella Zeller, as were larval H. convergens, whereas adult H. convergens were fed Melanaphis sacchari (Zehntner) to induce egg maturation; adults of both species received water and diluted honey. A spot of magnetic paint was applied to one elytrum of each beetle, which then adhered to a small neodymium magnet attached to a thread. Beetles were permitted 1 h flight opportunities daily for 3-d periods, first as virgins on their fifth day of adult life, secondly after mating, thirdly after females began oviposition, and fourthly after prey were withheld and egg maturation and oviposition ceased. Both species exhibited low flight activity as virgins, and whereas C. maculata females increased their activity after mating, H. convergens females did not. Flight activity in C. maculata did not change with onset of oviposition, whereas it increased in H. convergens males, but not females. In contrast, H. convergens females increased their flight activity after cessation of oviposition, whereas C. maculata females did not. Female flight activity when either virgin or mated correlated weakly with fecundity in C. maculata, but not in H. convergens. Species differences are discussed in the context of nutritional ecology; H. convergens usually enters diapause immediately following emergence, and is more dependent on aphids for reproduction, whereas C. maculata develops and reproduces on a wider range of foods and is not so constrained.

In vitro retention force measurement for three different attachment systems for implant-retained overdenture.

AIM: The aim of this study is to compare the retention force of three different types of overdenture attachment systems used in implant-retained mandibular complete overdentures. MATERIALS AND METHODS: Twenty-one similar acrylic resin blocks were prepared and divided into three study groups: Group A (snap attachment) - 10 specimens, Group B (locator attachment) - 1 specimen, and Group C (syncone attachment) - 10 specimens. A single rectangular heat cure acrylic resin block with two implant analogs 22 mm apart was used with all specimens. Each specimen was subjected to 5500 cycles of insertion and removal in the presence of artificial saliva, representing 5 years of usage. Retention was measured three times for each specimen using universal testing machine. Data were analyzed using one-way and two-way analysis of variance at 95% level of confidence. RESULTS: Locator attachment group (Group B) showed the greatest retention level throughout the study, followed by snap attachment (Group A), and syncone attachment (Group C) showed the lowest retention level. CONCLUSION: Regardless of the initial retention level of overdenture attachment, gradual loss of retention values is inevitable. However, the rate of retention loss in overdenture attachments is higher in types which comprised plastic parts within their components, rather than those totally made up of noble metals.

Design and synthesis of resveratrol-salicylate hybrid derivatives as CYP1A1 inhibitors.

Resveratrol and aspirin are known to exert potential chemopreventive effects through modulation of numerous targets. Considering that the CYP450 system is responsible for the activation of environmental procarcinogens, the aim of this study was to design a new class of hybrid resveratrol-aspirin derivatives possessing the stilbene and the salicylate scaffolds. Using HepG2 cells, we evaluated (a) the inhibition of TCDD-mediated induction of CYP1A1 exerted by resveratrol-aspirin derivatives using the EROD assay, and (b) CYP1A1 mRNA in vitro. We observed significant inhibition (84%) of CYP1A1 activity and a substantial decrease in CYP1A1 mRNA with compound 3, compared to control. Resveratrol did not exert inhibition under the same experimental conditions. This inhibitory profile was supported by docking studies using the crystal structure of human CYP1A1. The potential effect exerted by compound 3 (the most active), provide preliminary evidence supporting the design of hybrid molecules combining the chemical features of resveratrol and aspirin.

Multimodal imaging in persistent placoid maculopathy.

IMPORTANCE: Persistent placoid maculopathy (PPM) is a rare clinical entity with features that superficially resemble acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and macular serpiginous choroidopathy. It is important to differentiate PPM from APMPPE because both conditions may appear similar at presentation. OBJECTIVE: To investigate the short-term and long-term retinal changes in patients with PPM using spectral domain optical coherence tomography (SD-OCT), indocyanine green angiography (ICG-A), fluorescein angiography (FA), and fundus autofluorescence (FAF). DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective medical record review in 5 patients diagnosed as having PPM at tertiary retinal practices. MAIN OUTCOMES AND MEASURES: Findings on SD-OCT, FA, digital FAF, and ICG-A images. RESULTS: Patients presented within 2 weeks of subjective symptoms. Mean best-corrected visual acuity was 20/144 (range, 20/25-20/400). At presentation, all but 1 patient had bilateral macular lesions. Four eyes developed extramacular lesions during follow-up. On SD-OCT, the acute placoid lesions revealed hyperreflectivity of the outer nuclear layer; disruption of the external limiting membrane, ellipsoid layer, and interdigitation zone; and, in some patients, hyporeflective spaces at the level of absent outer segments. On follow-up, lesions revealed either partial or complete restoration of the outer retinal architecture or they progressed to atrophy. On FA, all placoid lesions were hypofluorescent in early frames and hyperfluorescent in late frames. In the acute stage, ICG-A revealed sharply delineated dense hypofluorescent lesions, which persisted on late frames in all patients. Hypofluorescent lesions faded completely or partially after resolution of the placoid lesions on SD-OCT and clinical examination. Variability was seen on the FAF patterns; most lesions were hyperautofluorescent, except in 1 patient, in whom they were hypoautofluorescent. Bilateral choroidal neovascularization developed in only 1 patient. The mean follow-up was 28 weeks (range, 2-92 weeks). On the final follow-up visit, mean best-corrected visual acuity was 20/125 (range, 20/25-20/400). CONCLUSIONS AND RELEVANCE: On SD-OCT, acute retinal changes in PPM involve the outer nuclear layer, external limiting membrane, ellipsoid layer, and interdigitation zone. The retinal pigment epithelium and choroid are involved in severely affected patients. The variable extent of retinal pigment epithelium involvement was reflected in variable FAF findings. We discuss clinical features that differentiate this entity from other white spots, including acute placoid multifocal pigment epitheliopathy. Additional long-term imaging studies are needed to further clarify the exact location and pathogenesis of this rare disease.

Development of cardiac hypertrophy by sunitinib in vivo and in vitro rat cardiomyocytes is influenced by the aryl hydrocarbon receptor signaling pathway.

Sunitinib (SUN) is a new tyrosine kinase inhibitor that possesses both anti-angiogenic and anti-tumor activities. Although SUN has improved survival rate in cancer patients, cardiotoxicity has been reported as a significant side effect. Several studies suggested a role for the aryl hydrocarbon receptor (AhR) and its regulated genes such as cytochrome P4501A1 (CYP1A1) in the pathogenesis of heart failure and cardiac hypertrophy. To test the hypothesis that SUN induces cardiac hypertrophy through the modulation of AhR, Wistar albino rats were treated for 15 and 30 days with increasing doses of SUN (25, 50, and 100 mg/kg), whereas at the in vitro level, rat cardiomyocyte H9c2 cells were incubated with SUN (1, 2.5, and 5 µM). Thereafter, cardiac hypertrophy parameters were determined at the biochemical, histopathology, and gene expression levels. SUN treatment causes increase in cardiac enzymes, changes in histopathology, and induction in several hypertrophic markers. This was associated with proportional increase in the CYP1A1 gene in a concentration- and time-dependent manner. The direct involvement of AhR in the SUN-induced cardiac hypertrophy in H9c2 cells was supported by the ability of resveratrol, an AhR antagonist, to block the SUN-induced hypertrophy and the ability of SB203580, a novel AhR agonist, to potentiate SUN-induced hypertrophic genes. This is the first demonstration that SUN induces hypertrophic genes in vivo and in vitro rat cardiomyocyte through AhR/CYP1A1-mediated mechanism.

WITHDRAWN: Immunogenicity and safety of HCV E1E2 peptide vaccine in chronically HCV-infected patients who did not respond to interferon based therapy.

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Synthetic lethal targeting of PTEN-deficient cancer cells using selective disruption of polynucleotide kinase/phosphatase.

A recent screen of 6,961 siRNAs to discover possible synthetic lethal partners of the DNA repair protein polynucleotide kinase/phosphatase (PNKP) led to the identification of the potent tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Here, we have confirmed the PNKP/PTEN synthetic lethal partnership in a variety of different cell lines including the PC3 prostate cancer cell line, which is naturally deficient in PTEN. We provide evidence that codepletion of PTEN and PNKP induces apoptosis. In HCT116 colon cancer cells, the loss of PTEN is accompanied by an increased background level of DNA double-strand breaks, which accumulate in the presence of an inhibitor of PNKP DNA 3'-phosphatase activity. Complementation of PC3 cells with several well-characterized mutated PTEN cDNAs indicated that the critical function of PTEN required to prevent toxicity induced by an inhibitor of PNKP is most likely associated with its cytoplasmic lipid phosphatase activity. Finally, we show that modest inhibition of PNKP in a PTEN knockout background enhances cellular radiosensitivity, suggesting that such a "synthetic sickness" approach involving the combination of PNKP inhibition with radiotherapy may be applicable to PTEN-deficient tumors.

Harmine and harmaline downregulate TCDD-induced Cyp1a1 in the livers and lungs of C57BL/6 mice.

We previously demonstrated that Peganum harmala L. extract and its main active constituents, harmine and harmaline inhibit the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated induction of the carcinogen-activating enzyme, Cyp1a1, in vitro. However, the effect of both alkaloids on Cyp1a1 in vivo has not been investigated. Therefore, the aim of this study is to examine the effect of harmine and harmaline on TCDD-mediated induction of Cyp1a1 in mice livers and lungs. C57BL/6 male mice were distributed into four groups (n = 6). First group received vehicle, while the second group received TCDD (i.p.). The third and fourth groups received either harmine or harmaline (i.p.) × 3 times along with TCDD one time with the mid dose of harmine and harmaline. All mice were sacrificed after 14 h from TCDD injection, and livers and lungs were isolated. The effect of harmine and harmaline on TCDD-mediated induction of Cyp1a1 mRNA, protein, and activity levels was determined using real-time PCR, Western blot analysis, and 7-ethoxyresurofin as a substrate, respectively. Our results showed that harmine and harmaline significantly decreased the TCDD-mediated induction of Cyp1a1 in both the livers and lungs. We concluded that harmine and harmaline are promising candidate to inhibit TCDD-mediated induction of Cyp1a1 in mice hepatic and extrahepatic tissues.

Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation.

Sunitinib (SUN) is a new multi-targeted oral tyrosine kinase inhibitor that has both anti-angiogenic and anti-tumor activities. However, information reported in the literature on the effects of SUN on the constitutive expression of cytochrome P450 1A1 (CYP1A1) gene in cells from mammalian species remains unclear. Therefore, the main objectives of the current work were to investigate the potentiality of SUN to induce CYP1A1 gene expression in human breast cancer MCF7 cells and to explore the molecular mechanisms involved. Our results showed that SUN induced the CYP1A1 mRNA, protein, and activity levels in a concentration-dependent manner in MCF7 cells. The increase in CYP1A1 mRNA by SUN was completely blocked by the transcriptional inhibitor, actinomycin D; implying that SUN increased de novo RNA synthesis. Furthermore, the ability of SUN to increase luciferase reporter gene expression suggests an aryl hydrocarbon receptor (AhR)-dependent transcriptional control and excludes the possibility of any posttranscriptional mechanisms. In addition, blocking of AhR activation by resveratrol, a well-known AhR antagonist, prevented the SUN-induced CYP1A1 gene expression, further confirms the involvement of AhR. Interestingly, this was associated with the inability of SUN to directly bind to and induce transformation of cytosolic AhR to its DNA-binding form in vitro, suggesting that the effect of SUN does not involve direct binding to AhR. The current manuscript provides the first evidence for the ability of SUN to induce CYP1A1 gene expression in MCF7 cells through AhR ligand-independent mechanisms.