Signalling inhibitors against Mycobacterium tuberculosis--early days of a new therapeutic concept in tuberculosis.

Tuberculosis causes nearly two million deaths per year world-wide. In addition multidrug-resistant mycobacterial strains rapidly emerge so novel therapeutic approaches are needed. Recently, several promising mycobacterial target molecules were identified, which are involved in bacterial or host cell signalling e.

Analysis of platelet alpha2-adrenergic receptor activity in stable coronary artery disease patients on dual antiplatelet therapy.

Combined antiplatelet therapy reduces recurrent atherothrombotic events in stable coronary disease patients; however, high residual platelet reactivity measured ex vivo still raises concerns as a condition related to treatment failure. Alpha-2 adrenoceptor enhances platelet reactivity and might contribute to this phenomenon. For the present study, 121 stable angina patients on standard dual antiplatelet therapy (75 mg clopidogrel and 100 mg acetylsalicylic acid) were recruited.

Galectin-1 is implicated in the protein kinase C epsilon/vimentin-controlled trafficking of integrin-beta1 in glioblastoma cells.

Cell motility and resistance to apoptosis characterize glioblastoma (GBM) growth and malignancy. In our current work we report that galectin-1, a homodimeric adhesion molecule and carbohydrate-binding protein with affinity for beta-galactosides, is linked with cell surface expression of integrin beta1 and the process of integrin trafficking. Using immunofluorescence, depletion of galectin-1 through both stable knockdown and transient-targeted small interfering RNA (siRNA) treatment induces an intracellular accumulation of integrin-beta1 coincident with a diminution of integrin-beta1 at points of cellular adhesion at the cell membrane.

Na+/K+-ATPase alpha subunits as new targets in anticancer therapy.

Background: The sodium pump (Na(+)/K(+)-ATPase) could be a target for the development of anticancer drugs as it serves as a signal transducer, it is a player in cell adhesion and its aberrant expression and activity are implicated in the development and progression of different cancers. Cardiotonic steroids (CS) are the natural ligands and inhibitors of the sodium pump and this supports the possibility of their development as anticancer agents targeting overexpressed Na(+)/K(+)-ATPase alpha subunits.

Objectives: To highlight and further develop the concept of using Na(+)/K(+)-ATPase alpha1 and alpha3 subunits as targets in anticancer therapy and to address the question of the actual usefulness of further developing CS as anticancer agents.

[New results in the research of the biomechanics of the venous system].

The upright posture of man had been a major evolutional challenge. The mechanisms responsible for orthostatic tolerance mostly affect the venous system. In this paper, we discuss new results regarding the biomechanics of the venous system highlighting a rather neglected field, the biomechanical properties of the vein wall.

Structure -activity relationships of PDE5 inhibitors.

cGMP has a short-term effect on smooth muscle tone and a longer-term effect on responses to chronic drug treatment or proliferative signals. cGMP-Phosphodiesterase type 5 (PDE5) hydrolizes cGMP, and the result is smooth muscle contraction. PDE5 is a relatively novel therapeutic target of various diseases, such as erectile dysfunction and pulmonary hypertension.

Amaryllidaceae isocarbostyril alkaloids and their derivatives as promising antitumor agents.

This review covers the isolation, total synthesis, biologic activity, and more particularly the in vitro and in vivo antitumor activities of naturally occurring isocarbostyril alkaloids from the Amaryllidaceae family. Starting from these natural products, new derivatives have been synthesized to explore structure-activity relationships within the chemical class and to obtain potential candidates for preclinical development. This approach appears to be capable of providing novel promising anticancer agents.

Videomicroscopic extraction of specific information on cell proliferation and migration in vitro.

In vitro cell imaging is a useful exploratory tool for cell behavior monitoring with a wide range of applications in cell biology and pharmacology. Combined with appropriate image analysis techniques, this approach has been shown to provide useful information on the detection and dynamic analysis of cell events. In this context, numerous efforts have been focused on cell migration analysis.

Activation mechanism of the human histamine H4 receptor--an explicit membrane molecular dynamics simulation study.

Molecular dynamics (MD) simulations in a membrane-embedded environment were carried out on the homology model of the human histamine H4 receptor (hH4R) alone and in complex with its endogenous activator histamine and with the first reported selective hH4R antagonist JNJ7777120. During the simulation of the histamine-hH4R complex, considerable changes occurred in the hH4R structure as well as in the interaction pattern of histamine at the binding site. These changes are in agreement with experimental data published on GPCR activation.

[Pumpless extracorporeal lung assist].

The recently introduced pumpless extracorporeal lung assist (PECLA) is a remarkable alternative to the conventional extracorporeal membrane oxygenation in case of severe lung failure. By establishing a shunt between femoral artery and vein using the arterio-venous pressure gradient as a driving force through a low-resistance membrane oxygenator, PECLA provides highly effective gas-exchange by preserved cardiac function. Due to its closed system, reduced priming volume and low heparin demand, the unfavourable effects of extracorporeal membrane oxygenation can be effectively diminished.

Local structural preferences of calpastatin, the intrinsically unstructured protein inhibitor of calpain.

Calpain, the calcium-activated intracellular cysteine protease, is under the tight control of its intrinsically unstructured inhibitor, calpastatin. Understanding how potent inhibition by calpastatin can be reconciled with its unstructured nature provides deeper insight into calpain function and a more general understanding of how proteins devoid of a well-defined structure carry out their function. To this end, we performed a full NMR assignment of hCSD1 to characterize it in its solution state.

Calcium-induced tripartite binding of intrinsically disordered calpastatin to its cognate enzyme, calpain.

The activity of calpain is controlled by the free intracellular calcium level and by the protein's intrinsically disordered endogenous inhibitor, calpastatin, mediated by short conserved segments: subdomains A-C. The exact binding mode of calpastatin to the enzyme has until now been unclear. Our NMR data of the 141 amino acid long inhibitor, with and without calcium and calpain, have revealed structural changes and a tripartite binding mode, in which the disordered inhibitor wraps around, and contacts, the enzyme at three points, facilitated by flexible linkers.

UNBS5162, a novel naphthalimide that decreases CXCL chemokine expression in experimental prostate cancers.

Several naphthalimides have been evaluated clinically as potential anticancer agents. UNBS3157, a naphthalimide that belongs to the same class as amonafide, was designed to avoid the specific activating metabolism that induces amonafide's hematotoxicity. The current study shows that UNBS3157 rapidly and irreversibly hydrolyzes to UNBS5162 without generating amonafide.

Nucleolus and c-Myc: potential targets of cardenolide-mediated antitumor activity.

The use of cardenolides like ouabain, digitoxin, or oleandrin has been reported previously many times as a means of potentially combating human refractory prostate cancer by inducing apoptosis through an increase in intracellular calcium concentrations. The aims of the current study were to investigate if part of the antitumor effects mediated by cardenolides concerned disorganization of nucleolar structure and whether this was further associated with a marked decrease in c-Myc expression. Accordingly, the antitumor activity of a novel hemisynthetic cardenolide [1R,3aS,3bR,5aS,6aR,7aS,9R,12aR,13aR,15aR]-3a,11a-dihydroxy-13a-(hydroxymethyl)-9,15a-dimethyl-1-(5-oxo-2,5-dihydrofuran-3-yl)icosahydro-1H,4'H-spiro[cyclopenta [7,8]phenanthro[2,3-b]pyrano[3,2-e][1,4]dioxine-11,2'-[1,3]thiazolidin]-4'-one (UNBS1450)] was compared with that of classic cardenolides and reference anticancer agents in prostate cancer cell lines in vitro and in vivo following s.

Discovery of novel human histamine H4 receptor ligands by large-scale structure-based virtual screening.

A structure-based virtual screening (SBVS) was conducted on a ligand-supported homology model of the human histamine H4 receptor (hH4R). More than 8.7 million 3D structures derived from different vendor databases were investigated by docking to the hH4R binding site using FlexX.

Knocking down galectin 1 in human hs683 glioblastoma cells impairs both angiogenesis and endoplasmic reticulum stress responses.

Galectin (Gal) 1 is a hypoxia-regulated proangiogenic factor that also directly participates in glioblastoma cell migration. To determine how Gal-1 exerts its proangiogenic effects, we investigated Gal-1 signaling in the human Hs683 glioblastoma cell line. Galectin 1 signals through the endoplasmic reticulum transmembrane kinase/ribonuclease inositol-requiring 1alpha, which regulates the expression of oxygen-regulated protein 150.

[The sodium pump could constitute a new target to combat glioblastomas].

Malignant gliomas of which glioblastomas represent the ultimate grade of malignancy are characterized by dismal prognoses because malignant glioma cells present both important proliferation and neoangiogenesis processes and can actively migrate through the narrow extra-cellular spaces in the brain, often travelling relatively long distances, making them elusive targets for effective surgical management. Invasive malignant glioma cells show a decrease in their proliferation rates and a relative resistance to apoptosis (type I programmed cell death) as compared to the highly cellular centre of the tumour, and this may contribute to their resistance to conventional proapoptotic chemotherapy and radiotherapy. The multidisciplinary up to date treatment for glioblastoma patients combined maximal surgical removal of the tumor with postoperative radiotherapy and concomitant chemotherapy with temozolomide.

The sodium pump alpha1 subunit as a potential target to combat apoptosis-resistant glioblastomas.

Purpose: To review the involvement of the ion transporter Na+/K+-ATPase (NaK) in the migration and proliferation of glioma cells. Preliminary studies indicate that NaK alpha1 subunits seem to be upregulated in a proportion of glioblastomas but not in normal brain tissues.

Design: The present review focuses on (1) the natural resistance of migrating malignant glioma cells to apoptosis, (2) autophagic cell death as an alternative to combat malignant gliomas, (3) the fact that reducing the levels of malignant glioma cell motility can restore proapoptotic drug sensitivity,and (4) on the observation that inhibiting the NaK activity reduces both glioma cell proliferation and migration.

Evidence of galectin-1 involvement in glioma chemoresistance.

Glioblastomas (GBMs) are resistant to apoptosis but less so to autophagy; a fact that may at least partly explain the therapeutic benefits of the pro-autophagic drug temozolomide in the treatment of GBM patients. Galectin-1 (Gal1) whose expression is stimulated by hypoxia is a potent modulator of GBM cell migration and a pro-angiogenic molecule. Hypoxia is also known to confer cancer cells with resistance to chemotherapy and radiotherapy and to modulate the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress.

Targeting the alpha 1 subunit of the sodium pump to combat glioblastoma cells.

Objective: Ion transporters play pivotal roles in cancer cell migration in general and in glioblastomas (GBMs) in particular. However, the specific role of Na/K-ATPase (the sodium pump) and, in particular, its alpha1 subunit, has remained unexplored in GBMs.

Materials And Methods: The expression of Na+/K+ -ATPase alpha1 in GBM clinical samples, normal brain tissue, and a human GBM cell line has been investigated.

Platinated copper(3-clip-phen) complexes as effective DNA-cleaving and cytotoxic agents.

The synthesis and biological activity of three heteronuclear platinum-copper complexes based on 3-Clip-Phen are reported. These rigid complexes have been designed to alter the intrinsic mechanism of action of both the platinum moiety and the Cu(3-Clip-Phen) unit. The platinum centers of two of these complexes are coordinated to a 3-Clip-Phen moiety, an ammine ligand and two chlorides, which are either cis or trans to each other.

DNA cleavage and binding selectivity of a heterodinuclear Pt-Cu(3-Clip-Phen) complex.

The synthesis and nuclease activity of a new bifunctional heterodinuclear platinum-copper complex are reported. The design of this ditopic coordination compound is based on the specific mode of action of each component, namely, cisplatin and Cu(3-Clip-Phen), where 3-Clip-Phen 1-(1, 10-phenanthrolin-3-yloxy)-3-(1,10-phenanthrolin-8-yloxy)propan-2-amine. Cisplatin is not only able to direct the Cu(3-Clip-Phen) part to the GG or AG site, but also acts as a kinetically inert DNA anchor.

The strengths and limitations of the apoB/apoA-I ratio to predict the risk of vascular disease: a Hegelian analysis.

The levels of pro- and antiatherogenic lipoproteins are the most important risk factors for vascular disease, and there is now compelling evidence that the apolipoprotein (apo) B/apoA-I ratio is a better index of the likelihood of vascular events than any of the corresponding cholesterol indices: the total cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio, non-HDL-C/HDL-C ratio, or low-density lipoprotein cholesterol (LDL-C)/HDL-C ratio. But are there any restrictions on the application of the apoB/apoA-I ratio to clinical practice? This article suggests that the answer is yes. Based on the available biologic and epidemiologic data, the relation between risk and apoB is continuous, whereas at the extremes of HDL concentration in plasma the relation to risk is not certain.

Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas.

The therapeutic goal of cancer treatment has been to trigger tumor-selective cell death. Although cell death can be achieved not only by apoptosis (type I programmed cell death) but also by necrosis, mitotic catastrophe, and autophagy, drugs inducing apoptosis remain the main chemotherapeutic agents in medical oncology. However, cancer cells in their relentless drive to survive, hijack cell processes, resulting in apoptosis resistance, which underlies not only tumorigenesis but also the inherent resistance of certain cancers to radiotherapy and chemotherapy.

Balanitin-6 and -7: diosgenyl saponins isolated from Balanites aegyptiaca Del. display significant anti-tumor activity in vitro and in vivo.

Balanites aegyptiaca is a widely distributed African plant of medicinal interest containing a number of cytotoxic and cytostatic compounds. The studies reported here have attempted to further characterize the anti-cancer activity of a mixture of steroidal saponins: balanitin-6 (28%) and balanitin-7 (72%) isolated from Balanites aegyptiaca kernels. The balanitin-6 and -7 mixture (henceforth referred to as bal6/7) has demonstrated appreciable anti-cancer effects in human cancer cell lines in vitro.