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The objective of the current study was to identify potential drug–drug interactions (DDIs) with the drug candidate fb‐PMT, a novel anticancer thyrointegrin αvß3 antagonist. This was accomplished by using several in vitro assays to study interactions of fb‐PMT with both cytochrome P450 (CYP) enzymes and drug transporters, two common mechanisms leading to adverse drug effects. In vitro experiments showed that fb‐PMT exhibited weak reversible inhibition of CYP2C19 and CYP3A4. In addition, fb‐PMT did not show time‐dependent inhibition with any of the seven CYP isoforms tested, including 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4. Human liver microsomal incubations demonstrated that fb‐PMT is stable. Potential transporter‐mediated DDIs with fb‐PMT were assessed with two ATP binding cassette (ABC) family transporters (P‐glycoprotein and breast cancer resistance protein) using Caco2 cells and seven solute carrier family (SLC) transporters (organic cation transporter OCT2, organic anion transporters OAT1 and OAT3, organic anion transporter peptides OATP1B1 and OATP1B3, and the multidrug and toxic extrusion proteins MATE1 and MATE2‐K using transfected HEK293 cells). Fb‐PMT was not a substrate for any of the nine transporters tested in this study, nor did it inhibit the activity of seven of the transporters tested. However, fb‐PMT inhibited the uptake of rosuvastatin by both OATP1B1 and OATP1B3 with half‐maximal inhibitory concentrations greater than 3 and less than 10 μM. In summary, data suggest that the systemic administration of fb‐PMT is unlikely to lead to DDIs through CYP enzymes or ABC and SLC transporters in humans. [ABSTRACT FROM AUTHOR]

Hyperphosphatemia is present in most patients with end‐stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium‐based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with chronic kidney disease (CKD) treated with sevelamer carbonate (SC) versus calcium acetate (CA). Fifty patients with CKD (stages 3 and 4) were enrolled and assigned to treatment with SC and CA for 12 weeks. At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. A significant increase in HDL‐cholesterol was observed with SC but not with CA in patients with CKD. Treatment with SC reduced serum phosphate, calcium phosphate, and FGF‐23 levels and there was no change with CA treatment. The inflammatory markers IL‐8, IFN‐γ, and TNFα decreased with response to both treatments. The levels of IL‐6 significantly increased with CA treatment and no change was observed in the SC treatment group. SC showed favorable effects on anti‐inflammatory and vascular calcification biomarkers compared to CA treatment in patients with CKD stages 3 and 4 with normal phosphorous values. [ABSTRACT FROM AUTHOR]

Aims: In the pathogenesis of several diseases, neo‐angiogenesis is increased (e.g. tumour growth). The peptide L‐glutamyl‐L‐tryptophan (EW/IM862) has been claimed to exhibit inhibitory effects on tumour growth in vivo. However, the potential role of natural peptides with respect to anti‐angiogenic properties is unsettled. The current study explores anti‐angiogenic effects of the dipeptides WL, EW, IW and WE. Methods and Results: Using a bottom‐up strategy, we first evaluated the effects of the peptides on VEGFR‐2 signalling and quantified their effects in different angiogenesis assays. WL consistently had the strongest effects on phosphorylation of VEGFR‐2 and downstream signalling. Therefore, this peptide was chosen in comparison with EW to further assess anti‐angiogenic properties. However, sprout formation in three‐dimensional (3D) fibrin gel bead assay was significantly inhibited by EW only. Furthermore, vessel sprouting in the mouse aortic ring assay was decreased by the presence of WL and EW compared to control. Results from a chorioallantoic membrane assay showed that under vascular endothelial growth factor (VEGF) stimulation WL and EW decreased the number of blood vessels versus control. These results were in line with those obtained in a matrigel plug assay. The VEGF‐induced increase in the haemoglobin content was nearly abolished when treatment was combined with either WL or EW application. In the murine model of oxygen‐induced retinopathy, WL exhibited a small albeit significant anti‐angiogenic effect. Conclusion: Comprehensive screening of WL suggests an anti‐angiogenic effect, demonstrated in in vitro, ex vivo and in vivo models. Thus, WL is a dipeptide with potential anti‐angiogenic effects and is worthy for further exploration. [ABSTRACT FROM AUTHOR]

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Background Aging is a biological phenomenon that involves an increase of oxidative stress associated with gradual degradation of the structure and function of the retina. Gender differences and subsequent deterioration of retinal cell layers is an interesting topic, especially because there is no published work concerning it. Methods One hundred and twenty male and female Wistar albino rats ages 1, 6, 18, 30 and 42 months ( n = 20 equal for male and female) were used. At the time interval, retinae were investigated by light and transmission electron microscopy, assessments of neurotransmitters, anti-oxidant enzymes (catalase, superoxide dismustase and glutathione S transferase), caspase-3 and -7, malonadialdhyde, and DNA fragmentation. Results Light and transmission electron microscopy observations of the older specimens (30 and 42 months) revealed apparent deterioration of retinal cell layers, especially ganglion and nerve fibres, nuclear, pigmented epithelium and stacked membranes of the photoreceptor's outer segments. Males were highly susceptible to aging processes. Retinal DNA fragmentation was remarked parallel with increase of apoptic markers caspase 3 and 7. Concomitantly, there was a marked reduction of neurotransmitters and anti-oxidant enzymes, and an increase of lipid peroxidation. Conclusions Aging contributed to an increase of oxidative stress resulting from damage of mitochondria in retinal cells, a decrease of the anti-oxidant enzyme system and an increase of markers of retinal cell death. [ABSTRACT FROM AUTHOR]

Thyroid hormone induces tumor cell and blood vessel cell proliferation via a cell surface receptor on heterodimeric integrin αvβ3. We investigated the role of thyroid hormone‐induced internalization of nuclear integrin αv monomer. Physiological concentration of thyroxine (free T4, 10–10 M), but not 3,5,3'‐triiodo‐L‐thyronine (T3), induced cellular internalization and nuclear translocation of integrin αv monomer in human non‐small‐cell lung cancer (H522) and ovarian carcinoma (OVCAR‐3) cells. T4 did not complex with integrin αv monomer during its internalization. The αv monomer was phosphorylated by activated ERK1/2 when it heterodimerized with integrin β3 in vitro. Nuclear αv complexed with transcriptional coactivator proteins, p300 and STAT1, and with corepressor proteins, NCoR and SMRT. Nuclear αv monomer in T4‐exposed cells, but not integrin β3, bound to promoters of specific genes that have important roles in cancer cells, including estrogen receptor‐α, cyclooxygenase‐2, hypoxia‐inducible factor‐1α, and thyroid hormone receptor β1 in chromatin immunoprecipitation assay. In summary, monomeric αv is a novel coactivator regulated from the cell surface by thyroid hormone for the expression of genes involved in tumorigenesis and angiogenesis. This study also offers a mechanism for modulation of gene expression by thyroid hormone that is adjunctive to the nuclear hormone receptor (TR)‐T3 pathway.—Lin, H.‐Y., Su, Y.‐F., Hsieh, M.‐T., Lin, S., Meng, M., London, D., Lin, C., Tang, H.‐Y., Hwang, J., Davis, F. B., Mousa, S. A.and Davis, P. J., Nuclear monomeric integrin αv in cancer cells is a coactivator regulated by thyroid hormone. FASEB J. 27, 3209–3216 (2013). www.fasebj.org [ABSTRACT FROM AUTHOR]

Thyroid hormone induces tumor cell and blood vessel cell proliferation via a cell surface receptor on heterodimeric integrin αvβ3. We investigated the role of thyroid hormone-induced internaliza-tion of nuclear integrin av monomer. Physiological concentration of thyroxine (free T4, 10-10 M), but not 3,5,3'-triiodo-L-thyronine (T3), induced cellular inter-nalization and nuclear translocation of integrin αv monomer in human non-small-cell lung cancer (H522) and ovarian carcinoma (OVCAR-3) cells. T4 did not complex with integrin αv monomer during its internalization. The αv monomer was phosphorylated by activated ERK1/2 when it heterodimerized widi integrin β3 in vitro. Nuclear av complexed with transcriptional coactivator proteins, p300 and STAT1, and with core-pressor proteins, NCoR and SMRT. Nuclear αv monomer in T4-exposed cells, but not integrin β3, bound to promoters of specific genes that have important roles in cancer cells, including estrogen receptor-α, cyclooxygen-ase-2, hypoxia-inducible factor-1α, and thyroid hormone receptor β1 in chromatin immunoprecipitation assay. In summary, monomeric αv is a novel coactivator regulated from the cell surface by thyroid hormone for the expression of genes involved in tumorigenesis and angiogenesis. This study also offers a mechanism for modulation of gene expression by thyroid hormone that is adjunctive to the nuclear hormone receptor (TR)-T3 pathway. [ABSTRACT FROM AUTHOR]

Nicotine, one of the thousands of chemicals in cigarette smoke has a highly debated effect on cell proliferation and tissue healing. Recent studies documented its pro-angiogenesis effects by stimulating endothelial cell α7-non-neronal nicotinic acetyl choline receptors (α7 N-nACHR). It is well known that individuals who smoke or have diabetes experience impaired wound healing although for different reasons. This review evaluates several current studies relating to nicotine’s ability to mediate cellular activation, migration and angiogenesis in attempts to correlate these data with nicotine’s ability to repair wounds in ischaemic tissue. While its beneficial effects are still under investigation, important findings regarding nicotine’s acceleration of atherosclerosis, tumor angiogenesis, cell proliferation e and resistance to apoptosis put its systemic use into question. Based on the good and bad sides of nicotine, it is recommended to restrict its utility to local applications. [ABSTRACT FROM AUTHOR]

Evidence is accumulating that chromatin plays a major role in the control of cellular response to stress. This is best illustrated by the recent findings that chromatin-modifying factors of class III histone deacetylases (sirtuins) are capable of protecting cells from oxidative and genotoxic stress. In particular, Sirt1 has been shown to mimic the action of caloric restriction for the prevention of aging-associated diseases. In the present study, we have investigated the potential role of class I and II histone deacetylases (HDACs) in cellular protection against various stresses, including those caused by nutrient deprivation. For this, we utilized a cellular model in which expression of class I and II HDACs was altered as a result of cellular adaptation to trichostatin A (TSA), a selective inhibitor of these deacetylases. Our results indicated that TSA-resistant cells also developed resistance to H2O2, DNA-damaging agents, and to nutrient deprivation. Interestingly, the insulin signaling pathway mediated by Akt was inhibited in the TSA-resistant cells, mirroring the effect of glucose deprivation on this pathway. Since expression of HDAC4 was consistently enhanced in the TSA-resistant cell lines, we suggest that this enzyme may contribute to their anti-stress response. In agreement with this, siRNA-mediated knockdown of HDAC4 in stress-resistant cells enhanced their sensitivity to the DNA-damaging drug doxorubicin and also to glucose deprivation. Akt phosphorylation was also up-regulated in response to HDC4 knockdown. Together, these findings suggest that cellular conditioning with TSA may represent a useful approach to mimic the effects of caloric restriction. [ABSTRACT FROM AUTHOR]

The present investigation determined the molecular structure and the pharmacokinetic and pharmacodynamic profiles of oral unfractionated heparin containing oral absorption enhancer sodium N-[8-(2-hydroxybenzoyl) amino]caprylate, salcaprozate sodium (SNAG) and assessed the safety and tolerability of the orally dosed heparin solid dosage form versus other routes. Sixteen healthy men were included in this single-dose, 3-way crossover, randomized, open -label study. Disaccharide compositional analysis was performed using capillary high-performance liquid chromatography with electrospray ionization mass spectrometry detection. The ph armacodynamics of heparin were obtained from analysis of plasma anti-factor Xa, anti-factor ha, activated partial thromboplastin time, and total tissue factor pathway inhibitor data. The molecular weight properties and the disaccharide composition of orally administered unfractionated heparin/SNAC and parenterally administered unfractionated heparin are identical and consistent with the starting pharmaceutical standard heparin. Furthermore, the anti-factor Xa, anti-factor IIa ratio achieved is of approximately 1:1 This is the first true pharmacokinetic study to measure the chemical compositions of heparin administered by different routes. [ABSTRACT FROM AUTHOR]

Abstract: Angiogenesis is important for normal growth and wound healing processes. An imbalance of the growth factors involved in this process, however, causes the acceleration of several diseases including malignant, ocular, and inflammatory diseases. Inhibiting angiogenesis through interfering with its pathway is a promising methodology to hinder the progression of these diseases. Herein, we studied the anti-angiogenic effects of various carbon materials such as graphite, multiwalled carbon nanotubes and fullerenes in vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2)-induced angiogenesis evaluated in the chick chorioallantoic membrane (CAM) model. All the carbon materials tested showed substantial anti-angiogenic activity against either FGF2- or VEGF-induced angiogenesis in the CAM model. Those carbon materials did not have any significant effects on basal angiogenesis in the absence of the added growth factors. [Copyright &y& Elsevier]

ABSTRACT The last decade witnessed major advances in the prevention and treatment of venous as well as of arterial thrombosis. Limitations of existing anticoagulants led to the development of novel therapeutic approaches. Ximelagatran is a new direct thrombin inhibitor (DTI) that is given orally, without the need for close monitoring. This compound was tried in the treatment of active venous thromboembolism, and the results were encouraging. Randomized trials suggest that ximelagatran is not inferior to warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Multiple controlled, prospective trials compared ximelagatran with low molecular weight heparin or warfarin in prevention of venous thromboembolism in patients undergoing major orthopedic procedures. The results of these clinical trials are reviewed in this article. Because of certain safety concerns (increased liver enzymes, potential hepatonecrosis, and increased coronary events) ximelagatran has not yet been approved by the FDA. Additional studies may be required to address these concerns. Ximelagatran has been approved, however, by the European regulatory authorities for short-term thromboprophylaxis. The success of ximelagatran or other oral antithrombin agents would provide significant proof of the concept for the long-term use of oral antithrombins in the prevention and treatment of both arterial and venous thrombosis. [ABSTRACT FROM AUTHOR]

ABSTRACT Heparin as well as low-molecular-weight heparins (LMWHs) have polypharmacological actions at various levels. Earlier studies focused on the plasma anti-Xa and anti-IIa pharmacodynamics (PD) for the different LMWHs. Other important PD parameters for heparin and LMWHs might explain the diverse clinical impacts of this class of agents in thrombosis and beyond: the release of the vascular tissue factor pathway inhibitor (TFPI), inhibition of key matrix-degrading enzymes, and other mechanisms. There is much evidence for the key role of LMWHs in hypercoagulation in thrombosis and cancer, angiogenesis, and inflammatory disorders. Many cancer patients reportedly have a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or its low molecular weight fractions interfere with various processes involved in tumor growth and metastasis. Clinical trials have suggested a clinically relevant and improved efficacy of LMWHs, as compared to UFH, on the survival of cancer patients with deep vein thrombosis. Our laboratory has demonstrated a significant role for LMWHs and for LMWH-releasable TFPI on the regulation of angiogenesis, tumor growth, and tumor metastasis; we have also seen potent inhibition of matrix-degrading enzymes by LMWHs but not by TFPI. The antiangiogenesis effect of LMWHs or non-anticoagulant LMWH derivatives was shown to be reversed by anti-TFPI. Thus, modulation of tissue factor/Vila noncoagulant activities by LMWH-releasable TFPI and the inhibitory effects on matrix-degrading enzymes beside the anticoagulant efficacy have provided an expanded clinical utility for LMWHs in angiogenesis-associated disorders, including human tumor growth and metastasis. [ABSTRACT FROM AUTHOR]

Low molecular weight heparins (LMWHs) stimulate the release of endothelial tissue factor pathway inhibitor (TFPI). An inhibitor of tissue factor-induced coagulation, TFPI may contribute to the efficacy of LMWHs. The release of TFPI may be affected by characteristics of LMWHs, such as molecular weight (MW) distribution. The authors measured plasma levels of TFPI after single, subcutaneous injections of tinzaparin (mean MW = 6500 Daltons [Da]; 3.5% of fractions < 2000 Da) or a tinzaparin-like LMWH (mean MW = 5650 Da; 18.3% of fractions < 2000 Da) in 30 healthy subjects. Maximum mean plasma levels of TFPI approached 200 to 230 ng/mL 0.8 hours after administration of either drug. Plasma levels of TFPI remained elevated compared with baseline values for 12 to 16 hours after drug administration. These results suggest that LMWH fractions < 2000 Da do not affect the release of TFPI. [ABSTRACT FROM PUBLISHER]

ABSTRACT Standard unfractionated heparin (UFH) has been in clinical use for over 50 years. The commercial use of low molecular weight heparins (LMWHs) began in the mid 1980s for hemodialysis and the prophylaxis of deep vein thrombosis (DVT). Initially, the clinical development of LMWHs was concentrated on the European continent. Subsequently, LMWHs were introduced in North America as well. In the initial stages of development of these drugs only nadroparin, dalteparin and enoxaparin were used. Subsequently, several other LMWHs such as ardeparin, tinzaparin, reviparin and parnaparin were introduced. LMWHs constitute a group of important medications with total sales reaching nearly 2.5 billion dollars with expanded indications reaching far beyond the initial indications for the prophylaxis of post-surgical DVT. This review highlights the pharmacology of tinzaparin. Unlike other LMWHs, tinzaparin is prepared by enzymatic hydrolysis with heparinase, while various chemical depolymerization methods are used for the synthesis of other LMWHs. As compared with the standard heparin, LMWHs have different pharmacodynamic, and pharmacokinetic properties; they also differ in clinical benefits. [ABSTRACT FROM AUTHOR]

Evidence is accumulating that chromatin plays a major role in the control of cellular response to stress. This is best illustrated by the recent findings that chromatin-modifying factors of class III histone deacetylases (sirtuins) are capable of protecting cells from oxidative and genotoxic stress. In particular, Sirt1 has been shown to mimic the action of caloric restriction for the prevention of aging-associated diseases. In the present study, we have investigated the potential role of class I and II histone deacetylases (HDACs) in cellular protection against various stresses, including those caused by nutrient deprivation. For this, we utilized a cellular model in which expression of class I and II HDACs was altered as a result of cellular adaptation to trichostatin A (TSA), a selective inhibitor of these deacetylases. Our results indicated that TSA-resistant cells also developed resistance to H(2)O(2), DNA-damaging agents, and to nutrient deprivation. Interestingly, the insulin signaling pathway mediated by Akt was inhibited in the TSA-resistant cells, mirroring the effect of glucose deprivation on this pathway. Since expression of HDAC4 was consistently enhanced in the TSA-resistant cell lines, we suggest that this enzyme may contribute to their anti-stress response. In agreement with this, siRNA-mediated knockdown of HDAC4 in stress-resistant cells enhanced their sensitivity to the DNA-damaging drug doxorubicin and also to glucose deprivation. Akt phosphorylation was also up-regulated in response to HDC4 knockdown. Together, these findings suggest that cellular conditioning with TSA may represent a useful approach to mimic the effects of caloric restriction.