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https://www.readbyqxmd.com/read/28545481/therapeutic-strategies-to-address-neuronal-nitric-oxide-synthase-deficiency-and-the-loss-of-nitric-oxide-bioavailability-in-duchenne-muscular-dystrophy
#1
REVIEW
Cara A Timpani, Alan Hayes, Emma Rybalka
Duchenne Muscular Dystrophy is a rare and fatal neuromuscular disease in which the absence of dystrophin from the muscle membrane induces a secondary loss of neuronal nitric oxide synthase and the muscles capacity for endogenous nitric oxide synthesis. Since nitric oxide is a potent regulator of skeletal muscle metabolism, mass, function and regeneration, the loss of nitric oxide bioavailability is likely a key contributor to the chronic pathological wasting evident in Duchenne Muscular Dystrophy. As such, various therapeutic interventions to re-establish either the neuronal nitric oxide synthase protein deficit or the consequential loss of nitric oxide synthesis and bioavailability have been investigated in both animal models of Duchenne Muscular Dystrophy and in human clinical trials...
May 25, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28545305/clostridium-difficile-toxins-a-and-b-receptors-pores-and-translocation-into-cells
#2
Kathleen E Orrell, Zhifen Zhang, Seiji N Sugiman-Marangos, Roman A Melnyk
The most potent toxins secreted by pathogenic bacteria contain enzymatic moieties that must reach the cytosol of target cells to exert their full toxicity. Toxins such as anthrax, diphtheria, and botulinum toxin all use three well-defined functional domains to intoxicate cells: a receptor-binding moiety that triggers endocytosis into acidified vesicles by binding to a specific host-cell receptor, a translocation domain that forms pores across the endosomal membrane in response to acidic pH, and an enzyme that translocates through these pores to catalytically inactivate an essential host cytosolic substrate...
May 26, 2017: Critical Reviews in Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28544909/can-human-allergy-drug-fexofenadine-an-antagonist-of-histamine-h1-receptor-be-used-to-treat-dog-and-cat-homology-modeling-docking-and-molecular-dynamic-simulation-of-three-h1-receptors-in-complex-with-fexofenadine
#3
Safaa Sader, Jun Cai, Anna C G Muller, Chun Wu
Fexofenadine, a potent antagonist to human histamine 1 (H1) receptor, is a non-sedative third generation antihistamine that is widely used to treat various human allergic conditions such as allergic rhinitis, conjunctivitis and atopic dermatitis. Encouragingly, it's been successfully used to treat canine atopic dermatitis, this supports the notion that it might have a great potential for treating other canine allergic conditions and other mammal pets such as dog. Regrettably, while there is a myriad of studies conducted on the interactions of antihistamines with human H1 receptor, the similar studies on non-human pet H1 are considerably scarce...
May 17, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28544137/phenotypic-identification-of-a-novel-autophagy-inhibitor-chemotype-targeting-lipid-kinase-vps34
#4
Herbert Waldmann, Lucas Robke, Luca Laraia, Marjorie A Carnero Corrales, Georgios Konstantinidis, Makoto Muroi, André Richters, Michael Winzker, Tobias Engbring, Stefano Tomassi, Nobumoto Watanabe, Hiroyuki Osada, Daniel Rauh, Yaowen Wu, Julian Engel
Autophagy is a critical regulator of cellular homeostasis and metabolism. Interference with this process is considered a new approach for the treatment of disease, in particular cancer and neurological disorders. Therefore, novel small molecule autophagy modulators are in high demand. We describe the discovery of autophinib, a potent autophagy inhibitor with a novel chemotype. Autophinib was identified by means of a phenotypic assay monitoring formation of autophagy-induced puncta indicating accumulation of lipidated cytosolic protein LC3 on the autophagosomal membrane...
May 22, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28537927/wx-132-18b-a-novel-microtubule-inhibitor-exhibits-promising-anti-tumor-effects
#5
Fang Guan, Rui Ding, Qi Zhang, Wei Chen, Feifei Li, Long Long, Wei Li, Linna Li, Dexuan Yang, Lan Xie, Shoujun Yuan, Lili Wang
Cancer drug researchers have been seeking microtubule-inhibiting agents (MIAs) with higher bioactivity and lower toxicity than currently marketed drugs. WX-132-18B, a novel structural compound synthesized at our institute, specifically bound to the colchicine-binding site on tubulin rather than the vinblastine site, and concentration-dependently reduced microtubule content via depolymerization. It exhibited the same cellular phenotypic profiles as the classic MIAs (colchicine, vincristine, and taxol), including inducing cell cycle arrest at the G2/M phase, triggering tumor cell apoptosis, promoting nuclear membrane permeability, reducing mitochondrial membrane potential, and disrupting the redox system balance...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28534905/antimicrobial-peptide-inspired-nh125-analogues-bacterial-and-fungal-biofilm-eradicating-agents-and-rapid-killers-of-mrsa-persisters
#6
Akash Basak, Yasmeen Abouelhassan, Ran Zuo, Hussain Yousaf, Yousong Ding, Robert W Huigens
During microbial infection, antimicrobial peptides are utilized by the immune response to rapidly eradicate microbial pathogens through the destruction of cellular membranes. Inspired by antimicrobial peptides, quaternary ammonium cationic (QAC) compounds have emerged as agents capable of destroying bacterial membranes leading to rapid bacterial death, including the eradication of persistent, surface-attached bacterial biofilms. NH125, an imidazolium cation with a sixteen membered fatty tail, was recently reported to eradicate persister cells and was our starting point for the development of novel antimicrobial agents...
May 23, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28533772/endotoxin-contamination-in-nanomaterials-leads-to-the-misinterpretation-of-immunosafety-results
#7
Yang Li, Mayumi Fujita, Diana Boraschi
Given the presence of engineered nanomaterials in consumers' products and their application in nanomedicine, nanosafety assessment is becoming increasingly important. In particular, immunosafety aspects are being actively investigated. In nanomaterial immunosafety testing strategies, it is important to consider that nanomaterials and nanoparticles are very easy to become contaminated with endotoxin, which is a widespread contaminant coming from the Gram-negative bacterial cell membrane. Because of the potent inflammatory activity of endotoxin, contaminated nanomaterials can show inflammatory/toxic effects due to endotoxin, which may mask or misidentify the real biological effects (or lack thereof) of nanomaterials...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28530615/accumulation-of-primary-and-secondary-metabolites-in-edible-jackfruit-seed-tissues-and-scavenging-of-reactive-nitrogen-species
#8
Fátima Fernandes, Federico Ferreres, Angel Gil-Izquierdo, Andreia P Oliveira, Patrícia Valentão, Paula B Andrade
Studies involving jackfruit tree (Artocarpus heterophyllus Lam.) focus on its fruit. Nevertheless a considerable part of jackfruit weight is represented by its seeds. Despite being consumed in several countries, knowledge about the chemical composition of these seeds is scarce. In this work, the accumulation of primary and secondary metabolites in jackfruit seed kernel and seed coating membrane was studied. Sixty-seven compounds were identified, sixty of them being reported for the first time in jackfruit seed...
October 15, 2017: Food Chemistry
https://www.readbyqxmd.com/read/28528666/role-of-nonneuronal-trpv4-signaling-in-inflammatory-processes
#9
Pradeep Rajasekhar, Daniel P Poole, Nicholas A Veldhuis
Transient receptor potential (TRP) ion channels are important signaling components in nociceptive and inflammatory pathways. This is attributed to their ability to function as polymodal sensors of environmental stimuli (chemical and mechanical) and as effector molecules in receptor signaling pathways. TRP vanilloid 4 (TRPV4) is a nonselective cation channel that is activated by multiple endogenous stimuli including shear stress, membrane stretch, and arachidonic acid metabolites. TRPV4 contributes to many important physiological processes and dysregulation of its activity is associated with chronic conditions of metabolism, inflammation, peripheral neuropathies, musculoskeletal development, and cardiovascular regulation...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28526864/a-broad-spectrum-bactericidal-lipopeptide-with-anti-biofilm-properties
#10
Ohad Meir, Fadia Zaknoon, Uri Cogan, Amram Mor
Previous studies of the oligoacyllysyl (OAK) series acyl-lysyl-lysyl-aminoacyl-lysine-amide, suggested their utility towards generating robust linear lipopeptide-like alternatives to antibiotics, although to date, none exhibited potent broad-spectrum bactericidal activity. To follow up on this premise, we produced a new analog (C14KKc12K) and investigated its properties in various media. Mechanistic studies suggest that C14KKc12K uses a non-specific membrane-disruptive mode of action for rapidly reducing viability of Gram-negative bacteria (GNB) similarly to polymyxin B (PMB), a cyclic lipopeptide used as last resort antibiotic...
May 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28525970/the-immunoregulatory-role-of-alpha-enolase-in-dendritic-cell-function-during-chlamydia-infection
#11
Khamia Ryans, Yusuf Omosun, Danielle N McKeithen, Tankya Simoneaux, Camilla C Mills, Nathan Bowen, Francis O Eko, Carolyn M Black, Joseph U Igietseme, Qing He
BACKGROUND: We have previously reported that interleukin-10 (IL-10) deficient dendritic cells (DCs) are potent antigen presenting cells that induced elevated protective immunity against Chlamydia. To further investigate the molecular and biochemical mechanism underlying the superior immunostimulatory property of IL-10 deficient DCs we performed proteomic analysis on protein profiles from Chlamydia-pulsed wild-type (WT) and IL-10(-/-) DCs to identify differentially expressed proteins with immunomodulatory properties...
May 19, 2017: BMC Immunology
https://www.readbyqxmd.com/read/28525841/ll-37-derived-short-antimicrobial-peptide-kr-12-a5-and-its-d-amino-acid-substituted-analogs-with-cell-selectivity-anti-biofilm-activity-synergistic-effect-with-conventional-antibiotics-and-anti-inflammatory-activity
#12
Eun Young Kim, Ganesan Rajasekaran, Song Yub Shin
KR-12-a5 is a 12-meric α-helical antimicrobial peptide (AMP) with dual antimicrobial and anti-inflammatory activities designed from human cathelicidin LL-37. We designed and synthesized a series of d-amino acid-substituted analogs of KR-12-a5 with the aim of developing novel α-helical AMPs that possess higher cell selectivity than KR-12-a5, while maintaining the anti-inflammatory activity. d-amino acid incorporation into KR-12-a5 induced a significant improvement in the cell selectivity by 2.6- to 13.6-fold as compared to KR-12-a5, while maintaining the anti-inflammatory activity...
May 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28525755/antibodies-from-a-human-survivor-define-sites-of-vulnerability-for-broad-protection-against-ebolaviruses
#13
Anna Z Wec, Andrew S Herbert, Charles D Murin, Elisabeth K Nyakatura, Dafna M Abelson, J Maximilian Fels, Shihua He, Rebekah M James, Marc-Antoine de La Vega, Wenjun Zhu, Russell R Bakken, Eileen Goodwin, Hannah L Turner, Rohit K Jangra, Larry Zeitlin, Xiangguo Qiu, Jonathan R Lai, Laura M Walker, Andrew B Ward, John M Dye, Kartik Chandran, Zachary A Bornholdt
Experimental monoclonal antibody (mAb) therapies have shown promise for treatment of lethal Ebola virus (EBOV) infections, but their species-specific recognition of the viral glycoprotein (GP) has limited their use against other divergent ebolaviruses associated with human disease. Here, we mined the human immune response to natural EBOV infection and identified mAbs with exceptionally potent pan-ebolavirus neutralizing activity and protective efficacy against three virulent ebolaviruses. These mAbs recognize an inter-protomer epitope in the GP fusion loop, a critical and conserved element of the viral membrane fusion machinery, and neutralize viral entry by targeting a proteolytically primed, fusion-competent GP intermediate (GPCL) generated in host cell endosomes...
May 18, 2017: Cell
https://www.readbyqxmd.com/read/28525743/bromodomain-protein-brd4-is-a-transcriptional-repressor-of-autophagy-and-lysosomal-function
#14
Jun-Ichi Sakamaki, Simon Wilkinson, Marcel Hahn, Nilgun Tasdemir, Jim O'Prey, William Clark, Ann Hedley, Colin Nixon, Jaclyn S Long, Maria New, Tim Van Acker, Sharon A Tooze, Scott W Lowe, Ivan Dikic, Kevin M Ryan
Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28524003/targeting-the-programmed-cell-death-1-pathway-in-genitourinary-tumors-current-progress-and-future-perspectives
#15
Rodolfo Montironi, Liang Cheng, Holger Moch, Antonio Lopez-Beltran, Marina Scarpelli, Francesco Massari, Michelangelo Fiorentino, Chiara Ciccarese, Michael Koch, Hristos Z Kaimakliotis, Lisha Wang, Roberto Pili, Steven A Mann
Immune checkpoint inhibitors have revolutionized the treatment many malignancies with over a dozen new United States Food and Drug Administration (FDA) approvals in the past six years. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors, gathering prognostic and predictive information about FDA-indicated tumors is prudent. PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including RCC and urothelial carcinoma...
May 18, 2017: Current Drug Metabolism
https://www.readbyqxmd.com/read/28523432/novel-t-cells-with-improved-in-vivo-anti-tumor-activity-generated-by-rna-electroporation
#16
Xiaojun Liu, Shuguang Jiang, Chongyun Fang, Hua Li, Xuhua Zhang, Fuqin Zhang, Carl H June, Yangbing Zhao
The generation of T cells with maximal anti-tumor activities will significantly impact the field of T-cell-based adoptive immunotherapy. In this report, we found that OKT3/IL-2-stimulated T cells were phenotypically more heterogeneous, with enhanced anti-tumor activity in vitro and when locally administered in a solid tumor mouse model. To further improve the OKT3/IL-2-based T cell manufacturing procedure, we developed a novel T cell stimulation and expansion method in which peripheral blood mononuclear cells were electroporated with mRNA encoding a chimeric membrane protein consisting of a single-chain variable fragment against CD3 and the intracellular domains of CD28 and 4-1BB (OKT3-28BB)...
May 18, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28522994/new-potent-membrane-targeting-antibacterial-peptides-from-viral-capsid-proteins
#17
Susana A Dias, João M Freire, Clara Pérez-Peinado, Marco M Domingues, Diana Gaspar, Nuno Vale, Paula Gomes, David Andreu, Sónia T Henriques, Miguel A R B Castanho, Ana S Veiga
The increasing prevalence of multidrug-resistant bacteria urges the development of new antibacterial agents. With a broad spectrum activity, antimicrobial peptides have been considered potential antibacterial drug leads. Using bioinformatic tools we have previously shown that viral structural proteins are a rich source for new bioactive peptide sequences, namely antimicrobial and cell-penetrating peptides. Here, we test the efficacy and mechanism of action of the most promising peptides among those previously identified against both Gram-positive and Gram-negative bacteria...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28522372/effective-antimicrobial-activity-of-a-peptide-mutant-cbf-14-2-against-penicillin-resistant-bacteria-based-on-its-unnatural-amino-acids
#18
Wei Kang, Hanhan Liu, Lingman Ma, Mengxiao Wang, Shanshan Wei, Pengbo Sun, Meiling Jiang, Min Guo, Changlin Zhou, Jie Dou
Broad spectrum activities, a unique mode of actions and rare resistant variants make antimicrobial peptide (AMP) a potential alternative to antibiotics. However, AMPs still have limitations in clinical development due to their physiological stability, toxicity and manufacturing costs. Cbf-14, derived from cathelicidin-BF has been proven to be effective against drug-resistant bacteria. Herein, a series of Cbf-14 mutants were designed to overcome these limitations. Design strategies included substitutions of lysine (Lys) or leucine (Leu) with similar residues such as ornithine (Orn) and norleucine (Ile), which are unnatural amino acids, to generate AMPs with enhanced therapeutic potential...
May 15, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28521395/marsdenia-tenacissima-extract-suppresses-tumor-growth-and-angiogenesis-in-a20-mouse-lymphoma
#19
Xingbin Dai, Yanhua Ji, Pengjun Jiang, Xuemei Sun
Marsdenia tenacissima (MT), a traditional Chinese medicine, has been utilized in the treatment of a variety of malignant conditions for decades, but the underlying mechanism remains unclear. Angiogenesis, new blood vessel formation by nearby endothelial cells (ECs) from pre-existing vessels, plays a key role in cancer growth. In the present study, the effects of MT extract (MTE) on EC proliferation and apoptosis in vitro, and on A20 mouse lymphoma growth and angiogenesis in vivo were investigated. MTE exhibited an anti-proliferative effect on the ECs, with a half maximal inhibitory concentration of 11...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28515717/the-leaderless-bacteriocin-enterocin-k1-is-highly-potent-against-enterococcus-faecium-a-study-on-structure-target-spectrum-and-receptor
#20
Kirill V Ovchinnikov, Per Eugen Kristiansen, Daniel Straume, Marianne S Jensen, Tamara Aleksandrzak-Piekarczyk, Ingolf F Nes, Dzung B Diep
Enterocin K1 (EntK1), enterocin EJ97 (EntEJ97), and LsbB are three sequence related leaderless bacteriocins. Yet LsbB kills only lactococci while EntK1 and EntEJ97 target wider spectra with EntK1 being particularly active against Enterococcus faecium, including nosocomial multidrug resistant isolates. NMR study of EntK1 showed that it had a structure very similar to LsbB - both having an amphiphilic N-terminal α-helix and an unstructured C-terminus. The α-helix in EntK1 is, however, about 3-4 residues longer than that of LsbB...
2017: Frontiers in Microbiology
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