Read by QxMD icon Read


Andrew P Degnan, George O Tora, Hong Huang, David A Conlon, Carl D Davis, Umesh M Hanumegowda, Xiaoping Hou, Yi Hsiao, Joanna Hu, Rudolph Krause, Yu-Wen Li, Amy E Newton, Rick L Pieschl, Joseph Raybon, Thorsten Rosner, Jung-Hui Sun, Matthew T Taber, Sarah J Taylor, Michael K Wong, Huiping Zhang, Nicholas J Lodge, Joanne J Bronson, John E Macor, Kevin W Gillman
Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analog that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model...
October 17, 2016: ACS Chemical Neuroscience
Achire N Mbanwi, Chao Wang, Kaoru Geddes, Dana J Philpott, Tania H Watts
Lymphocytic choriomeningitis virus clone 13 (LCMV13) infection of mice is a widely used model for investigating the mechanisms driving persistent viral infection in humans. LCMV13 disrupts splenic architecture early during infection, but this returns to normal within a few weeks. However, the long-term effects of LCMV13 infection on splenic structure have not been reported. Here we report that persistent infection with LCMV13 results in sustained splenic atrophy that persists for at least 500 days following infection, whereas infection with the acutely infecting LCMV Armstrong is associated with a return to pre-infection spleen weights...
October 11, 2016: European Journal of Immunology
Frances Corrigan, Kimberley A Mander, Anna V Leonard, Robert Vink
BACKGROUND: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. MAIN BODY: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI...
October 11, 2016: Journal of Neuroinflammation
R Navari
Chemotherapy-induced nausea and vomiting (CINV) is a significant clinical issue which affects patients' quality of life as well as treatment decisions. Significant improvements in the control of CINV have occurred in the past 15 years with the introduction of new antiemetic agents: 5-HT3 receptor antagonists, tachykinin NK1 receptor antagonists and olanzapine. Aprepitant was the first NK1 receptor antagonist introduced (2003) for the prevention of CINV in combination with a 5-HT3 receptor antagonist and dexamethasone...
August 2016: Drugs of Today
Vincent Sam Yong Tchang, Michael Stiess, Kerstin Siegmund, Urs Karrer, Jean Pieters
Coronin 1, a member of the evolutionary conserved WD repeat protein family of coronin proteins is expressed in all leukocytes, but a role for coronin 1 in natural killer (NK) cell homeostasis and function remains unclear. Here, we have analyzed the number and functionality of NK cells in the presence and absence of coronin 1. In coronin 1-deficient mice, absolute NK cell numbers and phenotype were comparable to wild type mice in blood, spleen and liver. Following in vitro stimulation of the activating NK cell receptors NK1...
September 20, 2016: Immunobiology
W Teng, H Chen, F Guo, X Du, X Fu, Y Fang, H Zhang, M Fang, M Ding
Neurokinin-1 receptor (NK1R) is a high affinity Substance P (SP) receptor and plays a key role in visceral hypersensitivity in irritable bowel syndrome (IBS). Early life stress is a significant risk factor in IBS. The aim of the present study was to investigate the influence of neonatal maternal separation on the expression and distribution of SP and its receptor along the brain-gut axis in a neonatal maternally separated rat model with visceral hypersensitivity. Male neonatal Sprague-Dawley rats, 2-21-day old, were randomly distributed into maternal separation groups of 3 h daily maternal separation (MS) or non-handling (NH)...
August 30, 2016: Genetics and Molecular Research: GMR
Luhua H Zhang, June Ho Shin, Mikel D Haggadone, John B Sunwoo
A tissue-resident population of natural killer cells (NK cells) in the liver has recently been described to have the unique capacity to confer immunological memory in the form of hapten-specific contact hypersensitivity independent of T and B cells. Factors regulating the development and maintenance of these liver-resident NK cells are poorly understood. The aryl hydrocarbon receptor (AhR) is a transcription factor modulated by exogenous and endogenous ligands that is important in the homeostasis of immune cells at barrier sites, such as the skin and gut...
September 26, 2016: Journal of Experimental Medicine
Zhen-Kui Wang, Li Xue, Tao Wang, Xiu-Jie Wang, Zhi-Qiang Su
Invariant natural killer T (iNKT) cells are a unique subset of T cells that have been implicated in inflammation, atopy, autoimmunity, infections, and cancer. Although iNKT cells have been extensively studied over the past decade, its role in the pathogenesis of ischemic brain injury is still largely unknown. In our study, we determined whether iNKT cells infiltration occur in a mouse model of permanent cerebral ischemia. C57BL6/J male mice were treated with either alpha-galactosylceramide (α-GalCer) or vehicle control before undergoing permanent middle cerebral artery occlusion (pMCAO)...
September 13, 2016: Neuroscience Letters
John A Rudd, Man P Ngan, Zengbing Lu, Guy A Higgins, Claudio Giuliano, Emanuela Lovati, Claudio Pietra
BACKGROUND AND AIMS: Chemotherapy-induced acute and delayed emesis involves the activation of multiple pathways, with 5-hydroxytryptamine (5-HT; serotonin) playing a major role in the initial response. Substance P tachykinin NK1 receptor antagonists can reduce emesis induced by disparate emetic challenges and therefore have a clinical utility as broad inhibitory anti-emetic drugs. In the present studies, we investigate the broad inhibitory anti-emetic profile of a relatively new NK1 receptor antagonist, netupitant, alone or in combination with the long acting 5-HT3 receptor antagonist, palonosetron, for a potential to reduce emesis in ferrets and shrews...
2016: Frontiers in Pharmacology
Éva Borbély, Zsófia Hajna, Liza Nabi, Bálint Scheich, Valéria Tékus, Kristóf László, Tamás Ollmann, Viktória Kormos, Balázs Gaszner, Zoltán Karádi, László Lénárd, Christopher J Paige, John P Quinn, János Szolcsányi, Erika Pintér, Julie Keeble, Alexandra Berger, Zsuzsanna Helyes
The tachykinin NK1 receptor was suggested to be involved in psychiatric disorders, but its antagonists have failed to be effective as antidepressants in clinical trials. Hemokinin-1 (HK-1), the newest tachykinin, is present in several brain regions and activates the NK1 receptor similarly to substance P (SP), but acts also through other mechanisms. Therefore, we investigated the roles of the Tac4 gene-derived HK-1 in comparison with SP and neurokinin A (NKA) encoded by the Tac1 gene, as well as the NK1 receptor in anxiety and depression-like behaviors in mice...
September 9, 2016: Brain, Behavior, and Immunity
James B Lucot
Doses of naloxone far below those which elicit emesis increase the sensitivity to motion sickness. In order to evaluate the possible interaction with broad spectrum antiemetics, low doses of naloxone were tested alone and in combination with 8-hydroxy-2-(di-n-propylamine)tetralin (DPAT), fentanyl and the NK1 antagonist CP-99994. A modified autonomic symptom rating scale was unaffected by any drug and thus considered of little value. Fentanyl and NK1 antagonists decreased the duration of the retch/vomit sequence...
August 30, 2016: Autonomic Neuroscience: Basic & Clinical
M Ikić Matijašević, D Flegar, N Kovačić, V Katavić, T Kelava, A Šućur, S Ivčević, H Cvija, E Lazić Mosler, I Kalajzić, A Marušić, D Grčević
Our study aimed to determine the functional activity of different osteoclast progenitor (OCP) subpopulations and signals important for their migration to bone lesions, causing local and systemic bone resorption during the course of collagen-induced arthritis in C57BL/6 mice. Arthritis was induced with chicken type II collagen (CII), and assessed by clinical scoring and detection of anti-CII antibodies. We observed decreased trabecular bone volume of axial and appendicular skeleton by histomorphometry and micro-computed tomography as well as decreased bone formation and increased bone resorption rate in arthritic mice in vivo...
September 10, 2016: Clinical and Experimental Immunology
Samaneh Bayati, Davood Bashash, Shahin Ahmadian, Ava Safaroghli-Azar, Kamran Alimoghaddam, Ardeshir Ghavamzadeh, Seyed H Ghaffari
Increasing number of genetic and cancer biology studies indicated a prominent role for tachykinin NK1 receptor (NK1R) in cancer cell growth and survival. Considering the fact that neoplastic lymphoid precursors in acute lymphoblastic leukemia (ALL) carry a three- to four-fold NK1R expression as compared to normal lymphocytes, using NK1R antagonist seems to be noteworthy in the treatment of ALL patients. In this study, we found that inhibition of NK1R with aprepitant, a selective high-affinity antagonist of the human NK1R, exerts cytotoxic and anti-proliferative effects against pre-B ALL-derived Nalm-6 cells either as single drug or in combination with doxorubicin...
September 6, 2016: European Journal of Pharmacology
Sunita Timalsena, Panwadee Pluangnooch, Adisak Wongkajornsilp, Kitipong Soontrapa
OBJECTIVE: Cytokine induced killer (CIK) cells are ex-vivo expanded T cells endowed with both T and Natural Killer cell properties. The standard protocol for generation of CIK cells is to culture peripheral blood mononuclear cells (PBMC) in the presence of interferon-gamma (IFN-γ), monoclonal antibody (mAb) against CD3 and interleukin-2 (IL-2). However, this protocol lacks costimulatory signal (CD28), crucial for T cell activation. Herein, the proliferation and functional properties of murine thymocytes derived CIK cells generated with or without costimulatory activation provided by anti-CD28 mAb were examined...
August 16, 2016: Asian Pacific Journal of Allergy and Immunology
Stefano Palea, Véronique Guilloteau, Moéz Rekik, Emanuela Lovati, Marc Guerard, Maria-Alba Guardia, Philippe Lluel, Claudio Pietra, Mitsuharu Yoshiyama
Introduction. Tachykinins potently contract the isolated urinary bladder from a number of animal species and play an important role in the regulation of the micturition reflex. On the guinea-pig isolated urinary bladder we examined the effects of a new potent and selective NK1 receptor antagonist (netupitant) on the contractions induced by a selective NK1 receptor agonist, SP-methylester (SP-OMe). Moreover, the effects of netupitant and another selective NK1 antagonist (L-733,060) were studied in anesthetized guinea-pigs using two experimental models, the isovolumetric bladder contractions and a model of bladder overactivity induced by intravesical administration of acetic acid (AA)...
2016: Frontiers in Pharmacology
Syed Sameer Nasir, Lee S Schwartzberg
Chemotherapy-induced nausea and vomiting (CINV) remains an important adverse effect of cancer therapy. The goal of CINV prophylaxis is to reduce the morbidity associated with nausea and vomiting, as well as to preserve quality of life, while maintaining the desired chemotherapy regimen. The US Food and Drug Administration has recently approved new therapies for prevention of CINV, including the neurokinin-1 (NK1) receptor antagonist rolapitant and the fixed-dose combination of the second-generation 5-hydroxytryptamine type 3 receptor antagonist palonosetron with the novel NK1 receptor antagonist netupitant...
August 2016: Oncology (Williston Park, NY)
Branden L Eggan, Sarah E McCallum
The medial habenula-interpeduncular nucleus (MHb-IPN) pathway has recently been shown to modulate multiple effects nicotine in vivo, however it remains unclear which receptor subtypes in this pathway are critical for mediating these responses. To identify MHb and IPN receptors that play a role in nicotine reward, we studied receptors prevalent in these nuclei, including nicotinic acetylcholine receptors (nAChRs) and the receptor for substance P (neuokinin-1; NK1 receptor) using a model of behavioral and neurochemical sensitization to nicotine...
January 1, 2017: Behavioural Brain Research
Zsófia Hajna, Éva Sághy, Maja Payrits, Aisah A Aubdool, Éva Szőke, Gábor Pozsgai, István Z Bátai, Lívia Nagy, Dániel Filotás, Zsuzsanna Helyes, Susan D Brain, Erika Pintér
It is supposed that TRPA1 receptor can be activated by hydrogen sulphide (H2S). Here, we have investigated the role of TRPA1 receptor in H2S-induced [Ca(2+)]i increase in trigeminal ganglia (TRG) neurons, and the involvement of capsaicin-sensitive sensory nerves in H2S-evoked cutaneous vasodilatation. [Ca(2+)]i was measured with ratiometric technique on TRG neurons of TRPA1(+/+) and TRPA1(-/-) mice after NaHS, Na2S, allylisothiocyanate (AITC) or KCl treatment. Microcirculatory changes in the ear were detected by laser Doppler imaging in response to topical NaHS, AITC, NaOH, NaSO3 or NaCl...
October 2016: Journal of Molecular Neuroscience: MN
Huiling Jiang, Kai Lang, Hongjian Lu, Lukasz Wojtas, X Peter Zhang
Cobalt(II)-based metalloradical catalysis (MRC) has been successfully applied for effective construction of the highly strained 2-sulfonyl-1,3-diazabicyclo[3.1.0]hexane structures in high yields through intramolecular radical aziridination of allylic sulfamoyl azides. The resulting [3.1.0] bicyclic aziridines prove to be versatile synthons for the preparation of a diverse range of 1,2- and 1,3-diamine derivatives by selective ring-opening reactions. As a demonstration of its application for target synthesis, the metalloradical intramolecular aziridination reaction has been incorporated as a key step for efficient synthesis of a potent neurokinin 1 (NK1 ) antagonist in 60 % overall yield...
September 12, 2016: Angewandte Chemie
Fausto Roila, David Warr, Paul J Hesketh, Richard Gralla, Jorn Herrstedt, Karin Jordan, Matti Aapro, Enzo Ballatori, Bernardo Rapoport
PURPOSE: An update of the recommendations for the prophylaxis of acute and delayed emesis induced by moderately emetogenic chemotherapy published after the last MASCC/ESMO antiemetic consensus conference in 2009 has been carried out. METHODS: A systematic literature search using PubMed from January 1, 2009 to January 6, 2015 with a restriction to papers in English was conducted. RESULTS: Overall, two randomized phase II and seven randomized phase III studies plus the results of three subgroup analysis of large phase III trials and those of a pilot study have been included...
August 11, 2016: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"