Common Mechanism Of Action Research Articles

Structurally diverse c-Myc inhibitors share a common mechanism of action involving ATP depletion.

The c-Myc (Myc) oncoprotein is deregulated in a large proportion of diverse human cancers. Considerable effort has therefore been directed at identifying pharmacologic inhibitors as potential anti-neoplastic agents. Three such groups of small molecule inhibitors have been described. The first is comprised of so-called "direct" inhibitors, which perturb Myc's ability to form productive DNA-binding heterodimers in association with its partner, Max. The second group is comprised of indirect inhibitors, which largely function by targeting the BET-domain protein BRD4 to prevent the proper formation of transcriptional complexes that assemble in response to Myc-Max DNA binding. Thirdly, synthetic lethal inhibitors cause the selective apoptosis of Myc over-expressing either by promoting mitotic catastrophe or altering Myc protein stability. We report here a common mechanism by which all Myc inhibitors, irrespective of class, lead to eventual cellular demise. This involves the depletion of ATP stores due to mitochondrial dysfunction and the eventual down-regulation of Myc protein. The accompanying metabolic de-regulation causes neutral lipid accumulation, cell cycle arrest, and an attempt to rectify the ATP deficit by up-regulating AMP-activated protein kinase (AMPK). These responses are ultimately futile due to the lack of functional Myc to support the requisite anabolic response. Finally, the effects of Myc depletion on ATP levels, cell cycle arrest, differentiation and AMPK activation can be mimicked by pharmacologic inhibition of the mitochondrial electron transport chain without affecting Myc levels. Thus, all Myc inhibitors promote a global energy collapse that appears to underlie many of their phenotypic consequences.

Decentering as a potential common mechanism across two therapies for generalized anxiety disorder.

The purpose of this study was to examine decentering as a potential mechanism of action across 2 treatments for generalized anxiety disorder: an acceptance-based behavioral therapy (ABBT) and applied relaxation (AR). Sixty-four individuals who completed at least half of the 16 total sessions of either ABBT or AR (65.6% female; 79.7% identified as White; average age = 34.41 years) completed measures of decentering (Experiences Questionnaire) and of symptoms of anxiety (Depression Anxiety Stress Scale-Stress subscale) at 5 time points over the course of therapy, and a measure of worry (Penn State Worry Questionnaire) at pre- and posttreatment. Initial growth curve models showed that decentering increased significantly over therapy (z = 7.09), and this increase was associated with a decrease in worry symptoms (Penn State Worry Questionnaire) at posttreatment (z = -8.51). The rate of change did not significantly vary across treatments, Δχ2/Δdf = 0.16/1, p = .69. Further, a series of bivariate latent difference score models indicated that the best-fitting model was one in which decentering was a leading indicator of change in symptoms (DASS-Stress). Allowing this coupling to vary across treatments did not significantly improve the fit of the model, Δχ2/Δdf = 0.71/1, p = .40. In this sample, results suggest that increased decentering was associated with decreases in anxiety and that changes in decentering appear to precede changes in symptoms within both ABBT and AR, indicating that decentering may be an important common mechanism of action. (PsycINFO Database Record

Toxicity Evaluation of a New Zn-Doped CuO Nanocomposite With Highly Effective Antibacterial Properties.

The increased resistances to conventional antibiotics determine a strong need for new antibacterials, and specific syntheses at the nanoscale promise to be helpful in this field. A novel Zinc-doped Copper oxide nanocomposite (nZn-CuO) has been recently sonochemically synthesized and successfully tested also against multi-drug resistant bacteria. After synthesis and characterization of the physicochemical properties, the new nZn-CuO is here evaluated by the Frog Embyo Teratogenesis Assay-Xenopus test for its toxicological potential and this compared with that of nCuO and nZnO synthesized under the same conditions. No lethal effects are observed, while malformations and growth retardation slightly increase after nZn-CuO exposure. Nevertheless, these effects are smaller than those of nZnO. NP uptake by embryo tissues increase significantly with increasing NP concentrations, while no significant accumulation and adverse effects are seen after exposure to soluble Cu(2+) and Zn(2+) at the concentrations dissolved from the NPs. Key oxidative response genes are upregulated by nZn-CuO, as well as by nCuO and nZnO, suggesting the common mechanism of action. Considering the enhanced biocidal activity shown by the nanocomposite, together with the results presented in this study, we can affirm that the doping of the metal oxide nanoparticles should be considered a useful tool to engineer a safer nano-antibacterial.

Ceftriaxone and cefazolin attenuate the cue-primed reinstatement of alcohol-seeking.

Alcohol consumption and the reinstatement of alcohol-seeking rely on glutamate and GABA transmission. Modulating these neurotransmitters may be a viable treatment strategy to prevent alcohol relapse. N-acetylcysteine (NAC) and the antibiotic ceftriaxone (CEF) alter the glial reuptake and release of glutamate while the antibiotic cefazolin (CEFAZ) modulates GABA signaling without affecting glutamate. Here, we used the extinction-reinstatement model of relapse to test the ability of these compounds to attenuate the reinstatement of alcohol-seeking. Male Sprague-Dawley rats were trained to self-administer 20% (v/v) alcohol in the home cage using an intermittent schedule (24 h on, 24 h off) for 12 sessions. Subsequently, animals self-administered alcohol during daily 45-min operant sessions for 26 sessions, followed by extinction training. We tested whether chronic administration of NAC, CEF, or CEFAZ attenuated the cue-primed reinstatement of alcohol-seeking. CEF and CEFAZ attenuated cue-primed reinstatement of alcohol-seeking while NAC had no effect. We subsequently investigated whether CEF and CEFAZ alter the self-administration of sucrose and chow pellets and if CEFAZ attenuates the reinstatement of cocaine-seeking. The operant self-administration of regular chow and sucrose was not altered by either CEF or CEFAZ. CEFAZ had no effect on cocaine reinstatement, a behavior that has been strongly tied to altered glutamate homeostasis in the nucleus accumbens. Thus the ability of CEFAZ to attenuate alcohol reinstatement likely does not involve the glial modulation of glutamate levels. The dampening of GABA transmission may be a common mechanism of action of cefazolin and ceftriaxone.

Distribution of Herbicide Resistances and Molecular Mechanisms Conferring Resistance in Missouri Waterhemp (Amaranthus rudisSauer) Populations

A survey of soybean fields containing waterhemp was conducted just prior to harvest in 2012 to determine the scope and extent of herbicide resistance and multiple herbicide resistances among a sample of Missouri waterhemp populations. Resistance was confirmed to glyphosate and to acetolactate synthase (ALS), protoporphyrinogen oxidase (PPO), photosystem II (PSII), and 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors, but not to 2,4-D. Of the 187 populations tested, 186 exhibited resistance to chlorimuron. The proportions of populations with atrazine or glyphosate resistance were similar, with 30 and 29% of the populations surviving the 3× rates. Lactofen resistance was observed in 5% of the populations, whereas mesotrione resistance was only found in 1.6% of the populations. All populations tested were susceptible to 2,4-D at the 3× rate. At least 52% of the waterhemp populations tested exhibited resistance to herbicides from two mechanism of action. Resistance to atrazine plus chlorimuron as well as glyphosate plus chlorimuron was present in 29% of the populations. Three-way resistance, primarily comprised of resistance to atrazine plus chlorimuron plus glyphosate, was present in 11% of the populations. Resistance to herbicides from four mechanisms of action was found in 2% of the populations, and one population exhibited resistance to herbicides from five mechanisms of action. DNA analysis of a subsample of plants revealed that previously documented mechanisms of resistance in waterhemp, including the ΔG210 deletion conferring PPO-inhibitor resistance, the Trp574Leu amino acid substitution conferring ALS-inhibitor resistance, and elevated 5-enolypyruvyl-shikimate-3-phosphate synthase copy number and the Pro106Ser amino acid substitution resulting in glyphosate resistance, explained survival in many, but not all, instances. Atrazine resistance was not explained by the Ser264Gly D1 protein substitution. Overall, results from these experiments indicate that Missouri soybean fields contain waterhemp populations with resistance to glyphosate, ALS-, PPO-, PSII-, and HPPD-inhibiting herbicides, which are some of the most common mechanisms of action currently utilized for the control of this species in corn and soybean production systems. Additionally, these results indicate that slightly more than half of the populations tested exhibit resistance to more than one herbicide mechanisms of action. Managing the current resistance levels in existing populations is of utmost importance. The use of multiple, effective herbicide modes of action, both preemergence and postemergence, and the integration of optimum cultural and mechanical control practices will be vital in the management of Missouri waterhemp populations in the future.

Individual respond to stimulation does matter: Combining bi-hemispheric hd tdcs and sep in empathy for pain

s / Brain Stimulation 8 (2015) 343e359 351 while TBS induced localized decrease in the area immediately under the TMS coil. These preliminary data suggest that a common mechanism of action of brain stimulation therapies may involve activation of the NA system. This activation is consistent with the role of NA in antidepressant treatment.

Low intensity rTMS: effects on cerebellar neurons and circuits

s / Brain Stimulation 8 (2015) 343e359 351 while TBS induced localized decrease in the area immediately under the TMS coil. These preliminary data suggest that a common mechanism of action of brain stimulation therapies may involve activation of the NA system. This activation is consistent with the role of NA in antidepressant treatment.

Borderline Personality Disorders

Four different models of Borderline Personality Disorder (BPD), each based on a different psychopathological theory, have produced manualized treatments and on this basis controlled outcome studies that evidenced their efficacy. It can be argued, on the ground of the comparable results of the outcome studies, that these different treatments share a common mechanism of action related to the same psychopathological kernel of BPD . The hypothesis that such a psychopathological kernel can be described as dissociative and caused by chronic psychological traumatization in the developmental years allows for a synthetic description of the basic psychotherapy processes allegedly shared by the four different models of BPD treatment.

Abstract T P417: Remote Ischemic Post Conditioning (RIPostC) Is Effective In A Mouse Model Of Vascular Cognitive Impairment

Background and Purpose: The mouse bilateral common carotid artery stenosis (BCAS) model is regarded as the best animal model for vascular cognitive impairment (VCI). RIPostC is a simple and safe therapy that others and we found protective in ischemic stroke. Other than risk factor control, there are no established treatments for VCI. However observational studies suggest exercise may be effective in patients with leukoaraiosis and cognitive impairment, the major form of VCI. Since RIPostC and exercise share some common mechanisms of action, we hypothesized that RIPostC would be effective in the mouse BCAS model and in VCI. Methods: Adult C57BL/6J male mice of (10-weeks) were subjected to either Sham for BCAS or BCAS surgery using micro coils twined around common carotid arteries. We randomized BCAS mice to daily RIPostC or sham procedure for RIPostC beginning 7 days post-BCAS for 2 weeks until day 21. Cerebral blood flow (CBF) was measured by laser speckle contrast imager. All mice underwent blinded testing for cognitive functions using novel object recognition (NOR). Histopathological examination and beta amyloid contents were investigated in the brain at day 30 post-BCAS. Statistical significance was determined at p <0.05. Results: At 1 hour, CBF was decreased significantly in all animals subjected to BCAS. RIPostC improved CBF in comparison to sham-operated group for RIPostC at day 14 and 28 post-VCI (p<0.05). BCAS impaired the discrimination index of mice in the NOR test but this was improved in the BCAS group treated with RIPostC (p<.05). Histopathological studies revealed that BCAS caused frequent vacuolization, cell death, microglial activation, loss in white matter (WM) and increased accumulation of beta amyloid. This was all attenuated significantly with RIPostC. Conclusions: RIPostC improves CBF, cognition and reduces cell death, WM damage and beta amyloid accumulation in the mouse BCAS model. Chronic RIPostC-therapy might be an effective treatment for VCI and in patients with leukoaraiosis and cognitive impairment Key words: RIPostC, VCI, white matter, beta-amyloid

Tissue kallikrein is required for the cardioprotective effect of Cyclosporin A in myocardial ischemia in the mouse

Clinical and experimental studies suggest that pharmacological postconditioning with Cyclosporin A (CsA) reduces infarct size in cardiac ischemia and reperfusion. CsA interacts with Cyclophilin D (CypD) preventing opening of the mitochondrial permeability transition pore (mPTP). Tissue kallikrein (TK) and its products kinins are involved in cardioprotection in ischemia. CypD knockout mice are resistant to the cardioprotective effects of both CsA and kinins suggesting common mechanisms of action. Using TK gene knockout mice, we investigated whether the kallikrein-kinin system is involved in the cardioprotective effect of CsA.Homozygote and heterozygote TK deficient mice (TK−/−, TK+/−) and wild type littermates (TK+/+) were subjected to cardiac ischemia–reperfusion with and without CsA postconditioning. CsA reduced infarct size in TK+/+ mice but had no effect in TK+/− and TK−/− mice. Cardiac mitochondria isolated from TK−/− mice had indistinguishable basal oxidative phosphorylation and calcium retention capacity compared to TK+/+ mice but were resistant to CsA inhibition of mPTP opening. TK activity was documented in mouse heart and rat cardiomyoblasts mitochondria. By proximity ligation assay TK was found in close proximity to the mitochondrial membrane proteins VDAC and Tom22, and CypD.Thus, partial or total deficiency in TK induces resistance to the infarct size reducing effect of CsA in cardiac ischemia in mice, suggesting that TK level is a critical factor for cardioprotection by CsA. TK is required for the mitochondrial action of CsA and may interact with CypD. Genetic variability in TK activity has been documented in man and may influence the cardioprotective effect of CsA.

Fabrication and evaluation of molecularly imprinted multi-hollow microspheres adsorbents with tunable inner pore structures derived from templating Pickering double emulsions

In this work, lignin was simply tailored by chemical modification with oleic acid, and then surfactant-free water-in-oil-in-water (W1/O/W2) Pickering double emulsions were formed by stabilizing two types of lignins (original and modified) at both interfaces. Based on as-prepared W1/O/W2 emulsions, three kinds of molecularly imprinted multi-hollow microspheres (denoted as MIMMs1, MIMMs2 and MIMMs3) were fabricated and evaluated as adsorbents to selective removal of lambda-cyhalothrin (LC). MIMMs exhibited tunable pore structures (size and number of inner pores) by adjusting the volume ratio of internal water phase to the medium oil phase (W1O), and MIMMs2 showed the larger adsorption capacity than those of MIMMs2 and MIMMs3, resulting from the common action mechanism of more and larger inner pores. Static adsorption experiments showed that equilibrium time was about 3.0h, and the equilibrium adsorption amount was 24.79mgg−1 for MIMMs2. The selective recognition experiments exhibited the obviously selective adsorption effect of the MIMMs2 for target LC, and MIMMs2 could be effectively regenerated and recycled at less seven times without significant loss of adsorption capacity. Overall, batch mode data suggested that MIMMs2 may be useful for the selective removal of LC from aqueous media.

Conservation of Properties of Outer Membranes Protein across Host Genera of Pasteurella multocida Suggests Common Mechanism of Action

A decade before the discovery of non-coding transcripts, approximately 98% of the human genome was known as “transcriptional noise” or “junk DNA”. However, with the recent findings, non-coding transcripts are continuously turning into functional non-coding RNAs (ncRNA). NcRNAs comprise multiple classes of RNA transcripts that are not transcribed into proteins but have shown to regulate the transcription, stability, or translation of protein-coding genes in the mammalian genome. Nowadays the most studied ncRNAs are called miRNAs. They have been involved in the biogenesis and development of cancer. More recently, long non-coding RNAs (lncRNAs) were discovered and they have been shown not only to play a role in transcriptional and translational regulation, but also be involved in several diseases including cancer. LncRNAs are RNA transcripts longer than 200 nucleotides that do not encode proteins. The accumulating body of evidence suggests that lncRNAs play important roles in a variety of biological processes. They have been reported to be altered in many pathological states including cancer. LncRNAs with oncogenic functions (we may call; OncoLncs) were reported to be overexpressed in cancer cells and involved in the hallmarks of cancer including sustained proliferation, invasion, and metastasis. The field of regulatory RNAs is continuously growing especially the lncRNAs. Thus, in this comprehensive review, we discussed the advances on OncoLncs field in the malignant transformation of cancer and the therapeutics opportunities.

Portuguese propolis: Genotoxic, phytotoxic and protective effects against oxidative stress

Propolis is a waxy mixture produced by bees from various plant sources with a diverse chemical composition. Although associated with varied biological activities, like antioxidant, antimicrobial, anti-inflammatory, anti-tumoral using animal and cell models, reports on genotoxicity are very scarce, and on phytotoxicity are absent to our knowledge. In this study Portuguese propolis samples from different apiaries collected in different years were extracted with ethanol (EE) and n-hexane (HE) and tested using yeast (Saccharomyces cerevisiae) and in vitro plants (Linum usitatissimum) as models. Toxicity was assessed by viability assays (drop test) in yeast and by plant growth analysis. Mechanisms of cytotoxicity were investigated by flow cytometry with rhodamine 123 [1] and genotoxicity by the comet assay [2] in the unicellular model. The plant model was used to evaluate effects at the developmental level as well as in the photosynthetic function by pulse amplitude modulated fluorometry [3]. Antioxidant properties were studied in yeast by flow cytometry with the redox-sensitive fluorochrome dichlorofluorescein diacetate [4], and in plants assessing the protective potential against fotooxidative damage induced under highlight conditions. Results showed that some EE exhibit high toxicity in both models, decreasing yeast viability and mitochondrial membrane potential, increasing genotoxicity and affecting significantly early plant growth and photosynthetic competence in a dose-dependent manner. At 200 µg/ml P10 EE caused a DNA damage similar to 10 mM H2O2 treatment. At 50 µg/ml root growth was inhibited up to 20% of the control. Some EE also decrease intracellular oxidation induced by H2O2, and avoid chlorophyll photobleaching under photooxidative conditions. Globally our data support the antioxidant properties revealed by propolis worldwide but also underline the strong toxicity in different cellular models, suggesting common mechanisms of action among eukaryotes.

Antibacterial activity of sulfamethoxazole transformation products (TPs): general relevance for sulfonamide TPs modified at the para position.

Sulfonamide antibiotics undergo transformation in the aquatic environment through biodegradation, photolysis, or hydrolysis. In this study, the residual antibacterial activity of 11 transformation products (TPs) of sulfamethoxazole (SMX) was investigated with regard to their in vitro growth and luminescence inhibition on Vibrio fischeri (30 min and 24 h exposure). Two transformation products, 4-hydroxy-SMX and N(4)-hydroxy-acetyl-SMX, were synthesized in-house and confirmed by nuclear magnetic resonance and high-resolution mass spectrometry. Results of individual compound experiments showed that TPs modified at the para amino group still exhibit clear antibacterial effects, whereas TPs resulting from breakdown of the SMX structure lost this mechanism of action. 4-NO2- and 4-OH-SMX were found to inhibit growth to a clearly greater extent than the parent compound, SMX. In contrast, the N(4)-acetyl- and N(4)-hydroxy-acetyl-derivatives retain less than 10 and 5% of the effect of SMX on growth and luminescence inhibition, respectively. The effect of a mixture of para-modified TPs was observed to be additive. Considering the homologous series of sulfa drugs widely prescribed and their common mechanism of action, the potential environmental impact must consider the total amount of sulfonamide antibiotics and their derivative TPs, which might end up in a water body. Extrapolating the results obtained here for the para TPs of SMX to other sulfa drugs and determining the persistence and occurrence of these compounds in the aquatic environment is required for improved risk assessment.

Exenatida diaria y semanal: perfil clínico de dos formulaciones pioneras en la modulación incretínica

GLP-1 receptors agonists have been a substantial change in treatment of type 2 diabetes mellitus, and its weekly administration has broken pre-established schemes. Daily exenatide is administered every 12 hours (BID) subcutaneously, while weekly exenatide is administered once a week. Both molecules share a common mechanism of action but have differential effects on basal and postprandial glucose. We review the major clinical trials with both exenatide BID and weekly exenatide. It can be concluded that exenatide BID shows a hypoglycemic effect similar to other treatments for type 2 DM but adding significant weight loss with low incidence of hypoglycemia. Weekly exenatide decreases HbA1c similar to liraglutide but larger than exenatide BID, both glargine and biphasic insulin, sitagliptin, and pioglitazone, maintaining weight loss and adding to gastrointestinal intolerance the induration at the injection site as a side effect.

Bacteriophage-derived CHAP domain protein, P128, kills Staphylococcus cells by cleaving interpeptide cross-bridge of peptidoglycan.

P128 is an anti-staphylococcal protein consisting of the Staphylococcus aureus phage-K-derived tail-associated muralytic enzyme (TAME) catalytic domain (Lys16) fused with the cell-wall-binding SH3b domain of lysostaphin. In order to understand the mechanism of action and emergence of resistance to P128, we isolated mutants of Staphylococcus spp., including meticillin-resistant Staphylococcus aureus (MRSA), resistant to P128. In addition to P128, the mutants also showed resistance to Lys16, the catalytic domain of P128. The mutants showed loss of fitness as shown by reduced rate of growth in vitro. One of the mutants tested was found to show reduced virulence in animal models of S. aureus septicaemia suggesting loss of fitness in vivo as well. Analysis of the antibiotic sensitivity pattern showed that the mutants derived from MRSA strains had become sensitive to meticillin and other β-lactams. Interestingly, the mutant cells were resistant to the lytic action of phage K, although the phage was able to adsorb to these cells. Sequencing of the femA gene of three P128-resistant mutants showed either a truncation or deletion in femA, suggesting that improper cross-bridge formation in S. aureus could be causing resistance to P128. Using glutathione S-transferase (GST) fusion peptides as substrates it was found that both P128 and Lys16 were capable of cleaving a pentaglycine sequence, suggesting that P128 might be killing S. aureus by cleaving the pentaglycine cross-bridge of peptidoglycan. Moreover, peptides corresponding to the reported cross-bridge of Staphylococcus haemolyticus (GGSGG, AGSGG), which were not cleaved by lysostaphin, were cleaved efficiently by P128. This was also reflected in high sensitivity of S. haemolyticus to P128. This showed that in spite of sharing a common mechanism of action with lysostaphin, P128 has unique properties, which allow it to act on certain lysostaphin-resistant Staphylococcus strains.

Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anticancer agents.

Reactive oxygen species (ROS)-inducing anticancer agents such as phenethylisothiocyanate (PEITC) activate stress pathways for killing cancer cells. Here we demonstrate that PEITC-induced ROS decreased expression of microRNA 27a (miR-27a)/miR-20a:miR-17-5p and induced miR-regulated ZBTB10/ZBTB4 and ZBTB34 transcriptional repressors, which, in turn, downregulate specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells. Decreased expression of miR-27a/miR-20a:miR-17-5p by PEITC-induced ROS is a key step in triggering the miR-ZBTB Sp cascade leading to downregulation of Sp TFs, and this is due to ROS-dependent epigenetic effects associated with genome-wide shifts in repressor complexes, resulting in decreased expression of Myc and the Myc-regulated miRs. Knockdown of Sp1 alone by RNA interference also induced apoptosis and decreased pancreatic cancer cell growth and invasion, indicating that downregulation of Sp transcription factors is an important common mechanism of action for PEITC and other ROS-inducing anticancer agents.

Structural and functional studies of the modulator NS9283 reveal agonist-like mechanism of action at α4β2 nicotinic acetylcholine receptors.

Modulation of Cys loop receptor ion channels is a proven drug discovery strategy, but many underlying mechanisms of the mode of action are poorly understood. We report the x-ray structure of the acetylcholine-binding protein from Lymnaea stagnalis with NS9283, a stoichiometry selective positive modulator that targets the α4-α4 interface of α4β2 nicotinic acetylcholine receptors (nAChRs). Together with homology modeling, mutational data, quantum mechanical calculations, and pharmacological studies on α4β2 nAChRs, the structure reveals a modulator binding mode that overlaps the α4-α4 interface agonist (acetylcholine)-binding site. Analysis of contacts to residues known to govern agonist binding and function suggests that modulation occurs by an agonist-like mechanism. Selectivity for α4-α4 over α4-β2 interfaces is determined mainly by steric restrictions from Val-136 on the β2-subunit and favorable interactions between NS9283 and His-142 at the complementary side of α4. In the concentration ranges where modulation is observed, its selectivity prevents NS9283 from directly activating nAChRs because activation requires coordinated action from more than one interface. However, we demonstrate that in a mutant receptor with one natural and two engineered α4-α4 interfaces, NS9283 is an agonist. Modulation via extracellular binding sites is well known for benzodiazepines acting at γ-aminobutyric acid type A receptors. Like NS9283, benzodiazepines increase the apparent agonist potency with a minimal effect on efficacy. The shared modulatory profile along with a binding site located in an extracellular subunit interface suggest that modulation via an agonist-like mechanism may be a common mechanism of action that potentially could apply to Cys loop receptors beyond the α4β2 nAChRs.

Clostridial pore-forming toxins: Powerful virulence factors

Pore formation is a common mechanism of action for many bacterial toxins. More than one third of clostridial toxins are pore-forming toxins (PFTs) belonging to the β-PFT class. They are secreted as soluble monomers rich in β-strands, which recognize a specific receptor on target cells and assemble in oligomers. Then, they undergo a conformational change leading to the formation of a β-barrel, which inserts into the lipid bilayer forming functional pore. According to their structure, clostridial β-PFTs are divided into several families. Clostridial cholesterol-dependent cytolysins form large pores, which disrupt the plasma membrane integrity. They are potent virulence factors mainly involved in myonecrosis. Clostridial heptameric β-PFTs (aerolysin family and staphylococcal α-hemolysin family) induce small pores which trigger signaling cascades leading to different cell responses according to the cell types and toxins. They are mainly responsible for intestinal diseases, like necrotic enteritis, or systemic diseases/toxic shock from intestinal origin. Clostridial intracellularly active toxins exploit pore formation through the endosomal membrane to translocate the enzymatic component or domain into the cytosol. Single chain protein toxins, like botulinum and tetanus neurotoxins, use hydrophobic α-helices to form pores, whereas clostridial binary toxins encompass binding components, which are structurally and functionally related to β-PFTs, but which have acquired the specific activity to internalize their corresponding enzymatic components. Structural analysis suggests that β-PFTs and binding components share a common evolutionary origin.

DrugComboRanker: drug combination discovery based on target network analysis.

Motivation: Currently there are no curative anticancer drugs, and drug resistance is often acquired after drug treatment. One of the reasons is that cancers are complex diseases, regulated by multiple signaling pathways and cross talks among the pathways. It is expected that drug combinations can reduce drug resistance and improve patients’ outcomes. In clinical practice, the ideal and feasible drug combinations are combinations of existing Food and Drug Administration-approved drugs or bioactive compounds that are already used on patients or have entered clinical trials and passed safety tests. These drug combinations could directly be used on patients with less concern of toxic effects. However, there is so far no effective computational approach to search effective drug combinations from the enormous number of possibilities.Results: In this study, we propose a novel systematic computational tool DrugComboRanker to prioritize synergistic drug combinations and uncover their mechanisms of action. We first build a drug functional network based on their genomic profiles, and partition the network into numerous drug network communities by using a Bayesian non-negative matrix factorization approach. As drugs within overlapping community share common mechanisms of action, we next uncover potential targets of drugs by applying a recommendation system on drug communities. We meanwhile build disease-specific signaling networks based on patients’ genomic profiles and interactome data. We then identify drug combinations by searching drugs whose targets are enriched in the complementary signaling modules of the disease signaling network. The novel method was evaluated on lung adenocarcinoma and endocrine receptor positive breast cancer, and compared with other drug combination approaches. These case studies discovered a set of effective drug combinations top ranked in our prediction list, and mapped the drug targets on the disease signaling network to highlight the mechanisms of action of the drug combinations.Availability and implementation: The program is available on request.Contact: stwong@tmhs.org