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https://www.readbyqxmd.com/read/29137411/a-novel-polyamine-blockade-therapy-activates-an-anti-tumor-immune-response
#1
Eric T Alexander, Allyson Minton, Molly C Peters, Otto Phanstiel, Susan K Gilmour
Most tumors maintain elevated levels of polyamines to support their growth and survival. This study explores the anti-tumor effect of polyamine starvation via both inhibiting polyamine biosynthesis and blocking the upregulated import of polyamines into the tumor. We demonstrate that polyamine blockade therapy (PBT) co-treatment with both DFMO and a novel polyamine transport inhibitor, Trimer PTI, significantly inhibits tumor growth more than treatment with DFMO or the Trimer PTI alone. The anti-tumor effect of PBT was lost in mice where CD4(+) and CD8(+) T cells were antibody depleted, implying that PBT stimulates an anti-tumor immune effect that is T-cell dependent...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29113896/neuroinflammation-produced-by-heavy-alcohol-intake-is-due-to-loops-of-interactions-between-toll-like-4-and-tnf-receptors-peroxisome-proliferator-activated-receptors-and-the-central-melanocortin-system-a-novel-hypothesis-and-new-therapeutic-avenues
#2
Osvaldo Flores-Bastías, Eduardo Karahanian
Excessive alcohol intake induces an inflammatory response in the brain, via TNFα, TLR4 and NF-κB signaling pathways. It has been proposed that neuroinflammation would play a very important role in the development of alcohol addiction. In addition to stimulating the synthesis of inflammatory mediators such as IL-6, IL-1β and TNFα, NF-κB is capable of reducing the anti-inflammatory activity of PPARα and PPARγ. Reciprocally, PPARα, PPARγ and melanocortin 4 receptor (MC4R) can decrease the proinflammatory activity of NF-κB, establishing an interplay of inactivations between such nuclear factors and receptors...
November 4, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29077093/why-do-bcl-2-inhibitors-work-and-where-should-we-use-them-in-the-clinic
#3
REVIEW
Joan Montero, Antony Letai
Intrinsic apoptosis is controlled by the BCL-2 family of proteins but the complexity of intra-family interactions makes it challenging to predict cell fate via standard molecular biology techniques. We discuss BCL-2 family regulation and how to determine cells' readiness for apoptosis and anti-apoptotic dependence. Cancer cells often adopt anti-apoptotic defense mechanisms in response to oncogenic stress or anti-cancer therapy. However, by determining their anti-apoptotic addiction, we can use novel BH3 mimetics to overwhelm this apoptotic blockade...
October 27, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29066725/heparan-sulfate-resilience-factor-and-therapeutic-target-for-cocaine-abuse
#4
Jihuan Chen, Tomoya Kawamura, Manveen K Sethi, Joseph Zaia, Vez Repunte-Canonigo, Pietro Paolo Sanna
Substance abuse is a pressing problem with few therapeutic options. The identification of addiction resilience factors is a potential strategy to identify new mechanisms that can be targeted therapeutically. Heparan sulfate (HS) is a linear sulfated polysaccharide that is a component of the cell surface and extracellular matrix. Heparan sulfate modulates the activity and distribution of a set of negatively charged signaling peptides and proteins - known as the HS interactome - by acting as a co-receptor or alternative receptor for growth factors and other signaling peptides and sequestering and localizing them, among other actions...
October 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29059390/cracking-the-betel-nut-cholinergic-activity-of-areca-alkaloids-and-related-compounds
#5
Nicole A Horenstein, Marta Quadri, Clare Stokes, Mohammed Shoaib, Roger L Papke
Introduction: The use of betel quid is the most understudied major addiction in the world. The neuropsychological activity of betel quid has been attributed to alkaloids of Areca catechu. With the goal of developing novel addiction treatments, we evaluate the muscarinic and nicotinic activity of the four major Areca alkaloids: arecoline, arecaidine, guvacoline, and guvacine and four structurally related compounds. Methods: Acetylcholine receptors were expressed in Xenopus oocytes and studied with two-electrode voltage clamp...
October 3, 2017: Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco
https://www.readbyqxmd.com/read/29057665/medications-for-substance-use-disorders-sud-emerging-approaches
#6
Eduardo R Butelman, Mary Jeanne Kreek
Substance use disorders are a group of chronic relapsing disorders of the brain, which have massive public health and societal impact. In some disorders (e.g., heroin/prescription opioid addictions) approved medications have a major long-term benefit. For other substances (e.g., cocaine, amphetamines and cannabis) there are no approved medications, and for alcohol there are approved treatments, which are not in wide usage. Approved treatments for tobacco use disorders are available, and novel medications are also under study...
October 30, 2017: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/29056153/oxytocin-tolerance-and-the-dark-side-of-addiction
#7
Cort A Pedersen
Substance use disorders blight the lives of millions of people and inflict a heavy financial burden on society. There is a compelling need for new pharmacological treatments as current drugs have limited efficacy and other major drawbacks. A substantial number of animal and recent clinical studies indicate that the neuropeptide, oxytocin, is a particularly promising therapeutic agent for human addictions, especially alcohol use disorders. In preliminary trials, we found that oxytocin administered by the intranasal route, which produces some neuropeptide penetration into the CNS, potently blocked withdrawal and reduced alcohol consumption in heavy drinkers...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/29056150/substance-p-and-the-neurokinin-1-receptor-the-new-crf
#8
Jesse R Schank, Markus Heilig
Substance P (SP) is an 11-amino acid neuropeptide of the tachykinin family that preferentially activates the neurokinin-1 receptor (NK1R). First isolated 85 years ago and sequenced 40 years later, SP has been extensively studied. Early studies identified a role for SP and the NK1R in contraction of intestinal smooth muscle, central pain processing, and neurogenic inflammation. An FDA-approved NK1R antagonist, aprepitant, is used clinically for the treatment of chemotherapy-induced nausea, as the NK1R influences the activity of the brain stem emesis centers...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/29054289/cross-talk-between-the-epigenome-and-neural-circuits-in-drug-addiction
#9
Philipp Mews, Erin S Calipari
Drug addiction is a behavioral disorder characterized by dysregulated learning about drugs and associated cues that result in compulsive drug seeking and relapse. Learning about drug rewards and predictive cues is a complex process controlled by a computational network of neural connections interacting with transcriptional and molecular mechanisms within each cell to precisely guide behavior. The interplay between rapid, temporally specific neuronal activation, and longer-term changes in transcription is of critical importance in the expression of appropriate, or in the case of drug addiction, inappropriate behaviors...
2017: Progress in Brain Research
https://www.readbyqxmd.com/read/29024664/the-anterior-insular-cortex%C3%A2-central-amygdala-glutamatergic-pathway-is-critical-to-relapse-after-contingency-management
#10
Marco Venniro, Daniele Caprioli, Michelle Zhang, Leslie R Whitaker, Shiliang Zhang, Brandon L Warren, Carlo Cifani, Nathan J Marchant, Ofer Yizhar, Jennifer M Bossert, Cristiano Chiamulera, Marisela Morales, Yavin Shaham
Despite decades of research on neurobiological mechanisms of psychostimulant addiction, the only effective treatment for many addicts is contingency management, a behavioral treatment that uses alternative non-drug reward to maintain abstinence. However, when contingency management is discontinued, most addicts relapse to drug use. The brain mechanisms underlying relapse after cessation of contingency management are largely unknown, and, until recently, an animal model of this human condition did not exist...
October 11, 2017: Neuron
https://www.readbyqxmd.com/read/29021114/a-police-led-addiction-treatment-referral-program-in-gloucester-ma-implementation-and-participants-experiences
#11
Davida M Schiff, Mari-Lynn Drainoni, Zoe M Weinstein, Lisa Chan, Megan Bair-Merritt, David Rosenbloom
BACKGROUND: The increasing rates of opioid use disorder and resulting overdose deaths are a public health emergency, yet only a fraction of individuals in need receive treatment. OBJECTIVE: To describe the implementation of and participants' experiences with a novel police-led addiction treatment referral program. METHODS: Follow-up telephone calls to participants in the Gloucester Police Department's Angel Program from June 2015-May 2016...
November 2017: Journal of Substance Abuse Treatment
https://www.readbyqxmd.com/read/28971956/tap73-is-a-marker-of-glutamine-addiction-in-medulloblastoma
#12
Maria Victoria Niklison-Chirou, Ida Erngren, Mikael Engskog, Jakob Haglöf, Daniel Picard, Marc Remke, Phelim Hugh Redmond McPolin, Matthew Selby, Daniel Williamson, Steven C Clifford, David Michod, Michalis Hadjiandreou, Torbjörn Arvidsson, Curt Pettersson, Gerry Melino, Silvia Marino
Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma...
September 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28968967/targeting-the-tumor-promoting-microenvironment-in-met-amplified-nsclc-cells-with-a-novel-inhibitor-of-pro-hgf-activation
#13
Benjamin Y Owusu, Shantasia Thomas, Phanindra Venukadasula, Zhenfu Han, James W Janetka, Robert A Galemmo, Lidija Klampfer
Targeted therapeutic agents, such as inhibitors of epithelial growth factor receptor (EGFR), have transformed the management of non-small cell lung cancer (NSCLC) patients. MET-amplified NSCLC cells display resistance to EGFR-targeting agents, but are addicted to MET signaling for survival and proliferation and are sensitive to MET inhibition. However, responsive cancer cells invariably develop resistance to MET-targeted treatment. The tumor microenvironment plays a major role in resistance to anticancer therapy...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28965933/electroacupuncture-suppresses-morphine-reward-seeking-behavior-lateral-hypothalamic-orexin-neurons-implicated
#14
Xueqi Wang, Boyuan Zhang, Longzao Zhang, Sheng Liu
The orexin system specifically located in the lateral hypothalamus (LH) has been shown to play a unique role in reward seeking, drug relapse, and addiction. In this study, we investigated the effects of electroacupuncture (EA) on morphine conditioned place preference (CPP), reinstatement of extinguished CPP, and the expression of orexin in the LH. A two-chamber CPP model was used to measure the rewarding properties of morphine. 2Hz EA at points BL23 and ST36 was carried out for 30min daily before morphine injection on three conditioning days...
November 20, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28958601/ghrelin-receptor-antagonism-of-morphine-induced-conditioned-place-preference-and-behavioral-and-accumbens-dopaminergic-sensitization-in-rats
#15
Pavel Jerabek, Tereza Havlickova, Nina Puskina, Chrysostomos Charalambous, Marek Lapka, Petr Kacer, Magdalena Sustkova-Fiserova
An increasing number of studies over the past few years have demonstrated ghrelin's role in alcohol, cocaine and nicotine abuse. However, the role of ghrelin in opioid effects has rarely been examined. Recently we substantiated in rats that ghrelin growth hormone secretagogue receptors (GHS-R1A) appear to be involved in acute opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing. The aim of the present study was to ascertain whether a ghrelin antagonist (JMV2959) was able to inhibit morphine-induced biased conditioned place preference and challenge-morphine-induced accumbens dopaminergic sensitization and behavioral sensitization in adult male rats...
September 27, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28957777/unseen-scars-cocaine-patients-with-prior-trauma-evidence-heightened-resting-state-functional-connectivity-rsfc-between-the-amygdala-and-limbic-striatal-regions
#16
Michael J Gawrysiak, Kanchana Jagannathan, Paul Regier, Jesse J Suh, Kyle Kampman, Timothy Vickery, Anna Rose Childress
BACKGROUND: Substance use disorder (SUD) patients with a history of trauma exhibit poorer treatment outcome, greater functional impairment and higher risk for relapse. Endorsement of prior trauma has, in several SUD populations, been linked to abnormal functional connectivity (FC) during task-based studies. We examined amygdala FC in the resting state (RS), testing for differences between cocaine patients with and without prior trauma. METHODS: Patients with cocaine use disorder (CUD; n=34) were stabilized in an inpatient setting prior to a BOLD fMRI scan...
November 1, 2017: Drug and Alcohol Dependence
https://www.readbyqxmd.com/read/28951131/targeting-copz1-non-oncogene-addiction-counteracts-the-viability-of-thyroid-tumor-cells
#17
Maria Chiara Anania, Elena Cetti, Daniele Lecis, Katia Todoerti, Alessandro Gulino, Giuseppe Mauro, Tiziana Di Marco, Loredana Cleris, Sonia Pagliardini, Giacomo Manenti, Beatrice Belmonte, Claudio Tripodo, Antonino Neri, Angela Greco
Thyroid carcinoma is generally associated with good prognosis, but no effective treatments are currently available for aggressive forms not cured by standard therapy. To find novel therapeutic targets for this tumor type, we had previously performed a siRNA-based functional screening to identify genes essential for sustaining the oncogenic phenotype of thyroid tumor cells, but not required to the same extent for the viability of normal cells (non-oncogene addiction paradigm). Among those, we found the coatomer protein complex ζ1 (COPZ1) gene, which is involved in intracellular traffic, autophagy and lipid homeostasis...
September 23, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28921760/genome-wide-association-study-of-a-nicotine-metabolism-biomarker-in-african-american-smokers-impact-of-chromosome-19-genetic-influences
#18
Meghan J Chenoweth, Jennifer J Ware, Andy Z X Zhu, Christopher B Cole, Lisa Sanderson Cox, Nikki Nollen, Jasjit S Ahluwalia, Neal L Benowitz, Robert A Schnoll, Larry W Hawk, Paul M Cinciripini, Tony P George, Caryn Lerman, Joanne Knight, Rachel F Tyndale
BACKGROUND AND AIMS: The activity of CYP2A6, the major nicotine-inactivating enzyme, is measurable in smokers using the nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine). Due to its role in nicotine clearance, the NMR is associated with smoking behaviours and response to pharmacotherapies. The NMR is highly heritable (~80%), and on average lower in African Americans (AA) versus Whites. We previously identified several reduce and loss-of-function CYP2A6 variants common in individuals of African descent...
September 16, 2017: Addiction
https://www.readbyqxmd.com/read/28918540/a-mixed-method-assessment-of-a-pilot-peer-advocate-intervention-for-rural-gender-and-sexual-minorities
#19
Cathleen E Willging, Audrey Harkness, Tania Israel, David Ley, Patricia S Hokanson, Catherine DeMaria, Aaron Joplin, Verida Smiley
Mental health disparities affect lesbian, gay, bisexual, transgender, and queer (LGBTQ) people in rural America. There are few empirically-based mental health interventions for this population. This exploratory study uses a mixed-method approach to assess implementation issues related to the feasibility, acceptability, appropriateness, and preliminary impacts of a novel peer-based intervention designed to enhance support and treatment engagement among rural LGBTQ people with mental distress and/or addiction issues...
September 16, 2017: Community Mental Health Journal
https://www.readbyqxmd.com/read/28905937/somcl-085-a-novel-multi-targeted-fgfr-inhibitor-displays-potent-anticancer-activity-in-fgfr-addicted-human-cancer-models
#20
Xi-Fei Jiang, Yang Dai, Xia Peng, Yan-Yan Shen, Yi Su, Man-Man Wei, Wei-Ren Liu, Zhen-Bin Ding, Ao Zhang, Ying-Hong Shi, Jing Ai
Aberrant fibroblast growth factor receptor (FGFR) activation is found across a diverse spectrum of malignancies, especially those lacking effective treatments. SOMCL-085 is a novel FGFR-dominant multi-target kinase inhibitor. Here, we explored the FGFR-targeting anticancer activity of SOMCL-085 both in vitro and in vivo. Among a panel of 20 tyrosine kinases screened, SOMCL-085 potently inhibited FGFR1, FGFR2 and FGFR3 kinase activity, with IC50 values of 1.8, 1.9 and 6.9 nmol/L, respectively. This compound simultaneously inhibited the angiogenesis kinases VEGFR and PDGFR, but without obvious inhibitory effect on other 12 tyrosine kinases...
September 14, 2017: Acta Pharmacologica Sinica
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