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Yin Yang, Qian Li, Qi-Hua He, Ji-Sheng Han, Li Su, You Wan
Activation of the cholecystokinin type B receptor (CCKBR) by cholecystokinin octapeptide (CCK-8) inhibits opioid analgesia. Chronic opiate treatment leads to an increase in the CCK-8 concentration and thus enhances the antagonism of CCK-8 against opioid analgesia; the underlying molecular mechanisms remain of great interest. In the present study, we validated the colocalization of the μ-opioid receptor (MOR) and CCKBR in pain signal transmission-related spinal cord dorsal horn and dorsal root ganglion neurons of rats...
May 21, 2018: Experimental & Molecular Medicine
Saki Izumi, Yoshitane Nozaki, Hiroyuki Kusuhara, Koichiro Hotta, Toshiki Mochizuki, Takafumi Komori, Kazuya Maeda, Yuichi Sugiyama
In vitro-in vivo extrapolation based on uptake clearance determined in human hepatocytes has been used to predict in vivo hepatic clearance of organic anion transporting polypeptide (OATP) substrates. This study evaluated the relative activity factor (RAF) approach to extrapolate active uptake clearance in transporter-transfected cell systems (CLuptake ) to that in human hepatocyte suspensions (PSinf,act ). RAF values for OATP1B1 and OATP1B3 were determined in two batches of cryopreserved human hepatocytes using estrone-3-sulfate and cholecystokinin octapeptide as reference substrates, respectively...
May 10, 2018: Molecular Pharmaceutics
Erik Stempel, Robert Franz-Xaver Kaml, Nediljko Budisa, Markus Kalesse
The argyrins are a family of non-ribosomal peptides that exhibits different biological activities through only small structural changes. Ideally, a biologically active molecule can be tracked and observed in a variety of biological and clinical settings in a non-invasive manner. As a step towards this goal, we report here a chemical synthesis of unnatural deep blue amino acid β-(1-azulenyl)-l alanine with different fluorescence and photophysical properties, which allows a spectral separation from the native tryptophan signal...
March 26, 2018: Bioorganic & Medicinal Chemistry
Junji Chida, Hideyuki Hara, Masashi Yano, Keiji Uchiyama, Nandita Rani Das, Etsuhisa Takahashi, Hironori Miyata, Yukiko Tomioka, Toshihiro Ito, Hiroshi Kido, Suehiro Sakaguchi
The cellular prion protein, designated PrPC, is a membrane glycoprotein expressed abundantly in brains and to a lesser extent in other tissues. Conformational conversion of PrPC into the amyloidogenic isoform is a key pathogenic event in prion diseases. However, the physiological functions of PrPC remain largely unknown, particularly in non-neuronal tissues. Here, we show that PrPC is expressed in lung epithelial cells, including alveolar type 1 and 2 cells and bronchiolar Clara cells. Compared with wild-type (WT) mice, PrPC-null mice (Prnp0/0) were highly susceptible to influenza A viruses (IAVs), with higher mortality...
May 3, 2018: PLoS Pathogens
M C Guerrera, F Abbate, G Di Caro, G P Germanà, M Levanti, V Micale, G Montalbano, R Laurà, A Germanà, U Muglia
The peptide hormone cholecistokinin (CCK) plays a key role in the central and peripheral nervous system. It is known to be involved in the digestive physiology and in the regulation of food intake. Moreover, the CCK expression has also been detected in the retina of different vertebrates, including fish, although its biological activity in this tissue remains to be elucidated. In literature no data are yet available about the CCK-immunoreactivity in the zebrafish retina during development. Therefore, the aim of the study was to investigate the distribution of sulfated cholecystokinin octapeptide (CCK8-S) as a well preserved form during evolution in the zebrafish retina from 3days post hatching (dph) until adult stage, using immunohistochemistry in order to elucidate the potential role of this protein in the development and maintenance of normal retinal homeostasis...
April 18, 2018: Annals of Anatomy, Anatomischer Anzeiger: Official Organ of the Anatomische Gesellschaft
Qi Chang, Yu-Lei Li, Xia Zhao
Samoamide A is a cyclic octapeptide rich in proline and phenylalanine residues isolated from an American Samoa marine cyanobacterium, which exhibits potent activity against H460 human non-small-cell lung cancer cells (IC50 of 1.1 μM). The first total synthesis of samoamide A was achieved by employing a strategy of a solid-phase peptide synthesis (SPPS) and a head-to-tail cyclization selecting free steric-hinrance connection sites. Then the final product was purified and identified. This strategy not only provides a basis in producing potent cytotoxic agents for drug discovery, but also provides a reference to the total synthesis of proline-rich peptides...
April 19, 2018: Journal of Asian Natural Products Research
Zhen-Peng Kai, Jing-Jing Zhu, Xi-Le Deng, Xin-Ling Yang, Shan-Shan Chen
Insect G protein coupled receptors (GPCRs) have important roles in modulating biology, physiology and behavior. They have been identified as candidate targets for next-generation insecticides, yet these targets have been relatively poorly exploited for insect control. In this study, we present a pipeline of novel Manduca sexta allatotropin (Manse-AT) antagonist discovery with homology modeling, docking, molecular dynamics simulation and structure-activity relationship. A series of truncated and alanine-replacement analogs of Manse-AT were assayed for the stimulation of juvenile hormone biosynthesis...
April 3, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Heng Zhang, Bo Zhou, Su Qin, Jing Xu, Rachel Harding, Wolfram Tempel, Vinod Nayak, Yanjun Li, Peter Loppnau, Yali Dou, Jinrong Min
The mixed-lineage leukemia (MLL)-AF10 fusion oncoprotein recruits DOT1L to the homeobox A ( HOXA ) gene cluster through its octapeptide motif leucine zipper (OM-LZ), thereby inducing and maintaining the MLL-AF10-associated leukemogenesis. However, the recognition mechanism between DOT1L and MLL-AF10 is unclear. Here, we present the crystal structures of both apo AF10OM-LZ and its complex with the coiled-coil domain of DOT1L. Disruption of the DOT1L-AF10 interface abrogates MLL-AF10-associated leukemic transformation...
March 1, 2018: Genes & Development
Kaveh Matinkhoo, Alla Pryyma, Mihajlo Todorovic, Brian O Patrick, David M Perrin
α-Amanitin is an extremely toxic bicyclic octapeptide isolated from the death-cap mushroom, Amanita phalloides. As a potent inhibitor of RNA polymerase II, α-amanitin is toxic to eukaryotic cells. Recent interest in α-amanitin arises from its promise as a payload for antibody-drug conjugates. For over 60 years, A. phalloides has been the only source of α-amanitin. Here we report a synthesis of α-amanitin, which surmounts the key challenges for installing the 6-hydroxy-tryptathionine sulfoxide bridge, enantioselective synthesis of (2 S,3 R,4 R)-4,5-dihydroxy-isoleucine, and diastereoselective sulfoxidation...
March 21, 2018: Journal of the American Chemical Society
Siew Mei Samantha Ng, Jia Mao Yap, Qiu Ying Lau, Fui Mee Ng, Esther Hong Qian Ong, Timothy Barkham, Jeanette Woon Pei Teo, Mohammad Alfatah, Kiat Whye Kong, Shawn Hoon, Prakash Arumugam, Jeffrey Hill, Cheng San Brian Chia
Vulvovaginal candidiasis (VVC) is a genital fungal infection afflicting approximately 75% of women globally and is primarily caused by the yeast Candida albicans. The extensive use of fluconazole, the first-line antifungal drug of choice, has led to the emergence of fluconazole-resistant C. albicans, creating a global clinical concern. This, coupled to the lack of new antifungal drugs entering the market over the past decade, has made it imperative for the introduction of new antifungal drug classes. Peptides with antifungal properties are deemed potential drug candidates due to their rapid membrane-disrupting mechanism of action...
April 25, 2018: European Journal of Medicinal Chemistry
Irina Velikyan, Örjan Lindhe
Monitoring general disease marker such as angiogenesis may contribute to the development of personalized medicine and improve therapy outcome. Readily availability of positron emitter based imaging agents providing quantification would expand clinical positron emission tomography (PET) applications. Generator produced 68 Ga provides PET images of high resolution and the half-life time frame is compatible with the pharmacokinetics of small peptides comprising arginine-glycine-aspartic acid (RGD) sequence specific to αv β3 integrin receptors...
2018: American Journal of Nuclear Medicine and Molecular Imaging
Chang Seon Lee, Moon-Ki Choi, Ye Young Hwang, Hyunki Kim, Moon Ki Kim, Yun Jung Lee
Water purification by membranes is widely investigated to address concerns related to the scarcity of clean water. Achieving high flux and rejection simultaneously is a difficult challenge using such membranes because these properties are mutually exclusive in common artificial membranes. Nature has developed a method for this task involving water-channel membrane proteins known as aquaporins. Here, the design and fabrication of graphene oxide (GO)-based membranes with a surface-tethered peptide motif designed to mimic the water-selective filter of natural aquaporins is reported...
April 2018: Advanced Materials
Leonel T Takada, Mee-Ohk Kim, Stacy Metcalf, Ignacio Illán Gala, Michael D Geschwind
Genetic prion diseases (gPrDs) are caused by autosomal-dominant mutations in the prion protein gene (PRNP). Although the first PRNP mutations identified, and most since, are PRNP missense, octapeptide repeat insertions, deletion and nonsense mutations have now also been shown to cause gPrD. Based on clinicopathologic features of familial disease, gPrDs historically have been classified into three forms: familial Jakob-Creutzfeldt disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia...
2018: Handbook of Clinical Neurology
Sen Ye, Kejia Shi, Jiefeng Xu, Moli Wang, Chun-Jian Li
Previous studies have demonstrated that cholecystokinin octapeptide (CCK8) induces hypothermia and inhibits the systemic inflammatory response in septic shock in rat and murine models. The present study aimed to ascertain whether CCK8 induced hypothermia and improved the neurological outcomes in a porcine model of cardiopulmonary resuscitation (CPR). Ventricular fibrillation was induced and left untreated for 10 min in 12 male Bama miniature pigs. Defibrillation was attempted after 5 min of CPR. At 5 min following resuscitation, the pigs were randomized and equally assigned into the CCK8 or the control group...
March 2018: Experimental and Therapeutic Medicine
Kota Kasahara, Shun Sakuraba, Ikuo Fukuda
We investigate the problem of artifacts caused by the periodic boundary conditions (PBC) used in molecular simulation studies. Despite the long history of simulations with PBCs, the existence of measurable artifacts originating from PBCs applied to inherently nonperiodic physical systems remains controversial. Specifically, these artifacts appear as differences between simulations of the same system but with different simulation-cell sizes. Earlier studies have implied that, even in the simple case of a small model peptide in water, sampling inefficiency is a major obstacle to understanding these artifacts...
March 8, 2018: Journal of Physical Chemistry. B
Jens J Holst, Nicolai J Wewer Albrechtsen, Maria Buur Nordskov Gabe, Mette Marie Rosenkilde
Oxyntomodulin is a product of the glucagon precursor, proglucagon, produced and released from the endocrine L-cells of the gut after enzymatic processing by the precursor prohormone convertase 1/3. It corresponds to the proglucagon sequence 33-69 and thus contains the entire glucagon sequence plus a C-terminal octapeptide, comprising in total 37 amino acids. As might have been expected, it has glucagon-like bioactivity, but also and more surprisingly also activates the receptor for GLP-1. This has given the molecule an interesting status as a glucagon-GLP-1 co-agonist, which is currently attracting considerable interest for its potential in the treatment of diabetes and obesity...
February 2018: Peptides
Wioleta Kowalczyk, Julie Sanchez, Phillipe Kraaz, Oliver E Hutt, David N Haylock, Peter J Duggan
A 54-member library of boronated octapeptides, with all but the boronated residue being proteinogenic, was tested for affinity to a set of saccharides commonly found on the terminus of mammalian glycans. After experimentation with a high-throughput dye-displacement assay, attention was focused on isothermal titration calorimetry as a tool to provide reliable affinity data, including enthalpy and entropy of binding. A small number of boronated peptides showed higher affinity and significant selectivity for N-acetylneuraminic acid over methyl-α-d-galactopyranoside, methyl-α/β-l-fucopyranoside and N-acetyl-d-glucosamine...
January 30, 2018: Biopolymers
Haijiao Zheng, Xiqian Li, Qiong Jia
β-Cyclodextrin vesicles (CDVs) were first introduced into the polymer monolith to prepare a pH-responsive adsorption material and used for capture and release of a cardiac biomarker, myoglobin (Myo). SH-CDV was decorated with adamantane-modified SH-octapeptide to enhance the encapsulation and release rates of Myo. Afterward, SH-CDV was introduced into the polymer monolith via click reaction to produce a pH-responsive monolith. Combining with the mass spectrometry detection, the CDV-based pH-responsive monolith was used for the enrichment of Myo glycopeptides from the mixture of glycopeptides and nonglycoprotein (bovine serum albumin) tryptsin digests reach up to 1:10 000...
February 14, 2018: ACS Applied Materials & Interfaces
Katlyn A Fleming, Mark D Ericson, Katie T Freeman, Danielle N Adank, Mary M Lunzer, Stacey L Wilber, Carrie Haskell-Luevano
The melanocortin system has five receptors, and antagonists of the central melanocortin receptors (MC3R, MC4R) are postulated to be viable therapeutics for disorders of negative energy balance such as anorexia, cachexia, and failure to thrive. Agouti-related protein (AGRP) is an antagonist of the MC3R and an antagonist/inverse agonist of the MC4R. Biophysical NMR-based structural studies have demonstrated that the active sequence of this hormone, Arg-Phe-Phe, is located on an exposed β-hairpin loop. It has previously been demonstrated that the macrocyclic octapeptide scaffold c[Pro1 -Arg2 -Phe3 -Phe4 -Asn5 -Ala6 -Phe7 -DPro8 ] is 16-fold less potent than AGRP at the mouse MC4R (mMC4R)...
February 13, 2018: ACS Chemical Neuroscience
Subhankar Dolai, Tao Liang, Abrahim I Orabi, Douglas Holmyard, Li Xie, Dafna Greitzer-Antes, Youhou Kang, Huanli Xie, Tanveer A Javed, Patrick P Lam, Deborah C Rubin, Peter Thorn, Herbert Y Gaisano
BACKGROUND & AIMS: Pancreatic acinar cells are polarized epithelial cells that store enzymes required for digestion as inactive zymogens, tightly packed at the cell apex. Stimulation of acinar cells causes the zymogen granules to fuse with the apical membrane, and the cells undergo exocytosis to release proteases into the intestinal lumen. Autophagy maintains homeostasis of pancreatic acini. Syntaxin 2 (STX2), an abundant soluble N-ethyl maleimide sensitive factor attachment protein receptor in pancreatic acini, has been reported to mediate apical exocytosis...
January 31, 2018: Gastroenterology
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