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Mode of action

Raimund Weitgasser, Michaela Ratzinger, Margit Hemetsberger, Peter Siostrzonek
For over 30 years, intensive research efforts investigated the role of LDL cholesterol in the pathogenesis of cardiovascular disease. In various settings, large statin trials showed an association between LDL cholesterol levels and cardiovascular event rates. This association is often referred to as the 'LDL cholesterol hypothesis'. More recent trials on agents with totally different modes of action confirmed this association and indicated a causal relationship between lower LDL cholesterol levels and improved cardiovascular outcomes...
October 21, 2016: Wiener Medizinische Wochenschrift
Lin Li, Kaixiong Yang, Jian Lin, Junxin Liu
An integrated-bioreactor, which consisted of a suspended zone and an immobilized zone, was applied to treat gases containing SO2. The removal of SO2 in suspended zone differed slightly from that in immobilized zone. The influences of operational aspects such as SO2 load, temperature, and pH on integrated-bioreactor performance and bacterial community composition were investigated. The synergistic action of the two zones led to effective reduction of SO2, and the total removal efficiencies with the inlet concentration of 91-117 mg/m(3), were over 85 % in steady state...
October 21, 2016: Bioprocess and Biosystems Engineering
A Didier, R Dietrich, E Märtlbauer
The non-hemolytic enterotoxin complex (Nhe) is supposed to be the main virulence factor of B. cereus causing a diarrheal outcome of food poisoning. This tripartite toxin consists of the single components NheA, -B and -C all of them being necessary for maximum toxicity. In the past, research activities aiming to elucidate the mode-of-action of Nhe were mostly focused on the B- and C-component. In this study the generation of novel monoclonal antibodies (mAb) and their thorough characterization enabled the determination of key features for NheA...
2016: PloS One
Jeffrey Cummings, Philip Scheltens, Ian McKeith, Rafael Blesa, John E Harrison, Paulo H F Bertolucci, Kenneth Rockwood, David Wilkinson, Wouter Wijker, David A Bennett, Raj C Shah
BACKGROUND: Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium), was developed to support the formation and function of neuronal membranes. OBJECTIVE: To determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm. METHODS: Data from all three reported randomized controlled trials of Souvenaid in Alzheimer's disease (AD) dementia (Souvenir I, Souvenir II, and S-Connect) and an open-label extension study were included in analyses of effect size for cognitive, functional, and behavioral outcomes...
October 20, 2016: Journal of Alzheimer's Disease: JAD
Mikyung Lee, Zhichao Liu, Ruili Huang, Weida Tong
BACKGROUND: All biological processes are inherently dynamic. Biological systems evolve transiently or sustainably according to sequential time points after perturbation by environment insults, drugs and chemicals. Investigating the temporal behavior of molecular events has been an important subject to understand the underlying mechanisms governing the biological system in response to, such as, drug treatment. The intrinsic complexity of time series data requires appropriate computational algorithms for data interpretation...
October 6, 2016: BMC Bioinformatics
Rita Meleddu, Simona Distinto, Angela Corona, Enzo Tramontano, Giulia Bianco, Claudia Melis, Filippo Cottiglia, Elias Maccioni
A series of 3-3-{2-[2-3-methyl-4-phenyl-2,3-dihydro-1,3-thiazol-2-ylidene]hydrazin-1-ylidene-2,3-dihydro-1H-indol-2-one derivatives has been designed and synthesized to study their activity on both HIV-1 (Human Immunodeficiency Virus type 1) RT (Reverse Transcriptase) associated functions. These derivatives are analogs of previously reported series whose biological activity and mode of action have been investigated. In this work we investigated the influence of the introduction of a methyl group in the position 3 of the dihydrothiazole ring and of a chlorine atom in the position 5 of the isatin nucleus...
October 21, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Athanasios Tragiannidis, Ioannis Kyriakidis, Ilse Zündorf, Andreas H Groll
Macromolecular immunosuppressive monoclonal antibodies and fusion proteins directed against molecules or cells involved in inflammation and immunity represent a recent and important addition to our therapeutic armamentarium. Tumor necrosis alpha (TNFα) is a cytokine involved in systemic inflammation and clinical utilization of its antagonists has revolutionized treatment of juvenile rheumatoid and psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and plaque psoriasis. Clinical utility has also been demonstrated for use against steroid-refractory graft-vs-host disease and other immune-mediated conditions...
October 21, 2016: Mycoses
Naoaki Morihara, Atsuko Hino
Aged garlic extract (AGE), a garlic preparation rich in water-soluble cysteinyl moieties, has been reported to have multiple beneficial effects on cardiovascular disease including inhibition of platelet aggregation. However, the mode of AGE action on platelets has not been clear. In this study, we examined the effect of AGE on the functional property of platelet by administering AGE to rats and evaluating the platelet aggregation in response to collagen in vitro. We found that AGE treatment significantly reduced the ability of platelet to aggregate and this effect of AGE was manifested on the 14 day, but not 7 day of treatment...
October 20, 2016: Journal of Natural Medicines
Huy X Ngo, Sylvie Garneau-Tsodikova, Keith D Green
Fungal infections directly affect millions of people each year. In addition to the invasive fungal infections of humans, the plants and animals that comprise our primary food source are also susceptible to diseases caused by these eukaryotic microbes. The need for antifungals, not only for our medical needs, but also for use in agriculture and livestock causes a high demand for novel antimycotics. Herein, we provide an overview of the most commonly used antifungals in medicine and agriculture. We also present a summary of the recent progress (from 2010-2016) in the discovery/development of new agents against fungal strains of medical/agricultural relevance, as well as information related to their biological activity, their mode(s) of action, and their mechanism(s) of resistance...
July 1, 2016: MedChemComm
Hui-Ju Tsai, Ching-Ping Tseng
Multiple functions of platelets in various physiological and pathological conditions have prompted considerable attention on understanding how platelets are generated and activated. Of the adaptor proteins that are expressed in megakaryocytes and platelets, Disabled-2 (Dab2) has been demonstrated in the past decades as a key regulator of platelet signaling. Dab2 has two alternative splicing isoforms p82 and p59. However, the mode of Dab2's action remains to be clearly defined. In this review, we highlight the current understanding of Dab2 expression and function in megakaryocytic differentiation, platelet activation and integrin signaling...
2016: Thrombosis Journal
Nada Lallous, Eric Leblanc, Ravi Sn Munuganti, Mohamed D H Hassona, Nader Al Nakouzi, Shannon Awrey, Helene Morin, Mani Roshan-Moniri, Kriti Singh, Sam Lawn, Takeshi Yamazaki, Hans H Adomat, Christophe Andre, Mads Daugaard, Robert N Young, Emma S Tomlinson Guns, Paul S Rennie, Artem Cherkasov
The development of new anti-androgens such as enzalutamide or androgen synthesis inhibitors like abiraterone have improved patient outcomes in the treatment of advanced prostate cancer (PCa). However, due to the development of drug resistance and tumor cell survival, the majority of these patients progress to the refractory state of castration-resistant prostate cancer (CRPC). Thus, newer therapeutic agents and a better understanding of their mode of action are needed for treating these CRPC patients. We demonstrated previously that targeting the Binding Function 3 (BF3) pocket of the androgen receptor (AR) has great potential for treating patients with CRPC...
October 7, 2016: Molecular Cancer Therapeutics
H N Lynch, C T Loftus, J M Cohen, L E Kerper, E M Kennedy, J E Goodman
Research suggests that exposure to ambient particulate matter (PM) may be associated with lung cancer; however, no mode of action (MoA) for this has been established. We applied a weight-of-evidence (WoE) approach to evaluate recent evidence from four realms of research (controlled human exposure, epidemiology, animal, and in vitro) to determine whether the overall evidence supports one or more MoAs by which PM could cause lung cancer. We evaluated three general MoAs: DNA damage and repair; other genotoxic effects, including mutagenicity and clastogenicity; and gene expression, protein expression, and DNA methylation...
October 17, 2016: Regulatory Toxicology and Pharmacology: RTP
John J Guardiola, Juliane I Beier, K Cameron Falkner, Benjamin Wheeler, Craig James McClain, Matt Cave
BACKGROUND: Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures. METHODS: Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS(2) analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed...
October 17, 2016: Toxicology and Applied Pharmacology
A G Dimitrov
The membrane transporters (pumps and co-transporters) are the main players in maintaining the cell homeostasis. Models of various types, each with their own drawbacks, describe transporter behavior. The aim of this study is to find the link between the biophysically based and empirical models to face and solve their specific problems. Instead of decreasing the number of states and using few complex rate constants as is usually done, we use the number of states as great as possible. Then, each transition in the cycle can represent an elementary process and we can apply the mass action law, according to which if rate constants depend on concentrations the dependence is linear...
October 17, 2016: Journal of Theoretical Biology
Francesca Esposito, Ilaria Carli, Claudia Del Vecchio, Lijia Xu, Angela Corona, Nicole Grandi, Dario Piano, Elias Maccioni, Simona Distinto, Cristina Parolin, Enzo Tramontano
BACKGROUND: Despite the availability of effective antiretroviral therapies, drugs for HIV-1 treatment with new mode of action are still needed. An innovative approach is aimed to identify dual HIV-1 inhibitors, small molecules that can inhibit two viral functions at the same time. Rhubarb, originated from Rheum palmatum L. and Rheum officinale Baill., is one of the earliest and most commonly used medicinal plants in Traditional Chinese Medicine (TCM) practice. We wanted to explore TCM for the identification of new chemical scaffolds with dual action abilities against HIV-1...
November 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Si Yeol Song, Kyu-Pyo Kim, Seong-Yun Jeong, Jin Park, Jaesook Park, Joohee Jung, Hye Kyung Chung, Sa-Won Lee, Min Hyo Seo, Jung-Shin Lee, Kyung Hae Jung, Eun Kyung Choi
We assessed the efficacy of the polymeric nanoparticle containing docetaxel (PNP-DTX) in preclinical mouse models and determined the maximum tolerated dose (MTD) through clinical study. Subcutaneous and orthotopic mouse models were dedicated. Tumor growth delay in orthotopic model and quantification of in vivo imaging in orthotopic model were evaluated. Phase I clinical study was a single-center, prospective, open-label trial in advanced solid tumors. PNP-DTX was injected intravenously and the starting dose was 20 mg/m2 escalated to 35 mg/m2, 45 mg/m2, 60 mg/m2 and 75 mg/m2...
October 14, 2016: Oncotarget
G P Adams, M H Ratto, M E Silva, R A Carrasco
The ovulation-inducing effect of seminal plasma was first reported in Bactrian camels over 30 years ago, and the entity responsible was dubbed 'ovulation-inducing factor' (OIF). More recent studies, primarily in llamas and alpacas, characterized the biological and chemical properties of OIF and ultimately identified it as βNGF. This recent discovery has allowed a convergence of knowledge previously separated by discipline and by mechanism; that is, neurobiology and reproductive biology, and autocrine/paracrine vs endocrine...
October 2016: Reproduction in Domestic Animals, Zuchthygiene
Aritreyee Datta, Vikas Yadav, Anirban Ghosh, Jaesun Choi, Dipita Bhattacharyya, Rajiv K Kar, Humaira Ilyas, Arkajyoti Dutta, Eunseol An, Jayanta Mukhopadhyay, Dongkuk Lee, Kaustuv Sanyal, Ayyalusamy Ramamoorthy, Anirban Bhunia
There is a significant need for developing compounds that kill Cryptococcus neoformans, the fungal pathogen that causes meningoencephalitis in immunocompromised individuals. Here, we report the mode of action of a designed antifungal peptide, VG16KRKP (VARGWKRKCPLFGKGG) against C. neoformans. It is shown that VG16KRKP kills fungal cells mainly through membrane compromise leading to efflux of ions and cell metabolites. Intracellular localization, inhibition of in vitro transcription, and DNA binding suggest a secondary mode of action for the peptide, hinting at possible intracellular targets...
October 18, 2016: Biophysical Journal
Scott J Hughes, Leanne Barnard, Katayoun Mottaghi, Wolfram Tempel, Tetyana Antoshchenko, Bum Soo Hong, Abdellah Allali-Hassani, David Smil, Masoud Vedadi, Erick Strauss, Hee-Won Park
The potent antistaphylococcal activity of N-substituted pantothenamides (PanAms) has been shown to at least partially be due to the inhibition of Staphylococcus aureus's atypical type II pantothenate kinase (SaPanKII), the first enzyme of coenzyme A biosynthesis. This mechanism of action follows from SaPanKII having a binding mode for PanAms that is distinct from those of other PanKs. To dissect the molecular interactions responsible for PanAm inhibitory activity, we conducted a mini SAR study in tandem with the cocrystallization of SaPanKII with two classic PanAms (N5-Pan and N7-Pan), culminating in the synthesis and characterization of two new PanAms, N-Pip-PanAm and MeO-N5-PanAm...
September 9, 2016: ACS Infectious Diseases
Jerry M Green
Glyphosate and glyphosate-resistant crops had a revolutionary impact on weed management practices, but the epidemic of glyphosate-resistant (GR) weeds is rapidly decreasing the value of these technologies. In areas that fully adopted glyphosate and GR crops, GR weeds evolved and glyphosate and glyphosate traits now must be combined with other technologies. The chemical company solution is to combine glyphosate with other chemicals, and the seed company solution is to combine glyphosate resistance with other traits...
October 18, 2016: Pest Management Science
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