Differential Effect of Chronic Morphine on Neuronal Degeneration in Male vs. Female Mice.

Opioid abuse in the United States has been increasing at an alarming rate over the past 20 years. Sex differences are documented for the rates of opioid-related overdoses, abuse patterns, and drug-induced physiological effects. In our previous study, we demonstrated that chronic oxycodone administration in young female rats is associated with neurodegeneration in the brain.

Trends in Drug Tests among Children: A 22-Year Retrospective Analysis.

There are several pathophysiological outcomes associated with substance abuse including metabolic disbalance, neurodegeneration, and disordered redox. Drug use in pregnant women is a topic of great concern due to developmental harm which may occur during gestation and the associated complications in the neonate after delivery. We sought to determine what the trajectory of drug use is like in children aged 0-4 years and mothers of neonates.

SARS-CoV-2 viral protein Nsp2 stimulates translation under normal and hypoxic conditions.

When viruses like SARS-CoV-2 infect cells, they reprogram the repertoire of cellular and viral transcripts that are being translated to optimize their strategy of replication, often targeting host translation initiation factors, particularly eIF4F complex consisting of eIF4E, eIF4G and eIF4A. A proteomic analysis of SARS-CoV-2/human proteins interaction revealed viral Nsp2 and initiation factor eIF4E2, but a role of Nsp2 in regulating translation is still controversial. HEK293T cells stably expressing Nsp2 were tested for protein synthesis rates of synthetic and endogenous mRNAs known to be translated via cap- or IRES-dependent mechanism under normal and hypoxic conditions.

Integrated Stress Response in Neuronal Pathology and in Health.

Neurodegeneration involves progressive pathological loss of a specific population of neurons, glial activation, and dysfunction of myelinating oligodendrocytes leading to cognitive impairment and altered movement, breathing, and senses. Neuronal degeneration is a hallmark of aging, stroke, drug abuse, toxic chemical exposure, viral infection, chronic inflammation, and a variety of neurological diseases. Accumulation of intra- and extracellular protein aggregates is a common characteristic of cell pathologies.

Carbonyl-protein content increases in brain and blood of female rats after chronic oxycodone treatment.

Background: Opioids are the most effective drugs commonly prescribed to treat pain. Due to their addictive nature, opioid pain relievers are now second to marijuana, ahead of cocaine with respect to dependence. Ours and other studies suggest potential toxic effects of chronic opioid administration leading to neuronal degeneration.

GatewayNet: a form of sequential rule mining.

Background: The gateway hypothesis (and particularly the prediction of developmental stages in drug abuse) has been a subject of protracted debate since the 1970s. Extensive research has gone into this subject, but has yielded contradictory findings. We propose an algorithm for detecting both association and causation relationships given a discrete sequence of events, which we believe will be useful in addressing the validity of the gateway hypothesis.

Chronic oxycodone induces axonal degeneration in rat brain.

Background: Chronic opioid therapy for non-malignant pain conditions has significantly increased over the last 15 years. Recently, the correlation between opioid analgesics and alternations in brain structure, such as leukoencephalopathy, axon demyelination, and white matter lesions, has been demonstrated in patients with a history of long-term use of prescription opioids. The exact mechanisms underlying the neurotoxic effect of opioids on the central nervous system are still not fully understood.

Urine Drug Screen Trends from 1998 through 2011 Among Emergency Department Patients Treated in a University Teaching Hospital.

The emergency department (ED) at Louisiana State University-Health Science Center in Shreveport (LSUHSC-S) serves an urban population with a large rural catchment area. This study focuses on demographic variables in substance abuse trends in this region based on urine drug screen (UDS) results. A database of de-identified UDSs ordered in the ED at LSUHSC-S between 1998 and 2011 was analyzed.

Inhibition of Mitogen-activated Protein Kinase (MAPK)-interacting Kinase (MNK) Preferentially Affects Translation of mRNAs Containing Both a 5'-Terminal Cap and Hairpin.

The MAPK-interacting kinases 1 and 2 (MNK1 and MNK2) are activated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) or p38 in response to cellular stress and extracellular stimuli that include growth factors, cytokines, and hormones. Modulation of MNK activity affects translation of mRNAs involved in the cell cycle, cancer progression, and cell survival. However, the mechanism by which MNK selectively affects translation of these mRNAs is not understood.

Chronic oxycodone induces integrated stress response in rat brain.

Background: Oxycodone is an opioid that is prescribed to treat multiple types of pain, especially when other opioids are ineffective. Unfortunately, similar to other opioids, repetitive oxycodone administration has the potential to lead to development of analgesic tolerance, withdrawal, and addiction. Studies demonstrate that chronic opioid exposure, including oxycodone, alters gene expression profiles and that these changes contribute to opioid-induced analgesic effect, tolerance and dependence.

The role of c-Src in integrin (α6β4) dependent translational control.

Background: Integrin α6β4 contributes to cancer progression by stimulating transcription as well as translation of cancer related genes. Our previous study demonstrated that α6β4 stimulates translation initiation of survival factors such as VEGF by activating mTOR pathway. However, the immediate early signaling events that link α6β4 to mTOR activation needs to be defined.

Mnk mediates integrin α6β4-dependent eIF4E phosphorylation and translation of VEGF mRNA.

It was previously shown that integrin α6β4 contributes to translation of cancer-related mRNAs such as VEGF via initiation factor eIF4E. In this study, we found that integrin α6β4 regulates the activity of eIF4E through the Ser/Thr kinase Mnk. Although a role for Mnk in various aspects of cancer progression has been established, a link between integrin and Mnk activity has not.

A C. elegans eIF4E-family member upregulates translation at elevated temperatures of mRNAs encoding MSH-5 and other meiotic crossover proteins.

Caenorhabditis elegans expresses five family members of the translation initiation factor eIF4E whose individual physiological roles are only partially understood. We report a specific role for IFE-2 in a conserved temperature-sensitive meiotic process. ife-2 deletion mutants have severe temperature-sensitive chromosome-segregation defects.

Kinetic mechanism for assembly of the m7GpppG.eIF4E.eIF4G complex.

Interaction of the mRNA cap with the translational machinery is a critical and early step in the initiation of protein synthesis. To better understand this process, we determined kinetic constants for the interaction of m(7)GpppG with human eIF4E by stopped-flow fluorescence quenching in the presence of a 90-amino acid fragment of human eIF4G that contains the eIF4E-binding domain (eIF4G(557-646)). The values obtained, k(on) = 179 x 10(6) m(-1) s(-1) and k(off) = 79 s(-1), were the same as reported previously in the absence of an eIF4G-derived peptide.

Alpha/beta interferon inhibits cap-dependent translation of viral but not cellular mRNA by a PKR-independent mechanism.

The alpha/beta interferon (IFN-alpha/beta) response is critical for host protection against disseminated replication of many viruses, primarily due to the transcriptional upregulation of genes encoding antiviral proteins. Previously, we determined that infection of mice with Sindbis virus (SB) could be converted from asymptomatic to rapidly fatal by elimination of this response (K. D.

Mechanism and regulation of translation in C. elegans.

C. elegans represents a favorable system to study the extraordinarily complicated process of eukaryotic protein synthesis, which involves over 100 RNAs and over 200 polypeptides just for the core machinery. Initial research in protein synthesis relied on fractionated mammalian and plant systems, but in the mid-1970s, the powerful genetics of Saccharomyces cerevisiae began to yield new insights for translation in all eukaryotes.

Translational dysregulation by Pateamine A.

Pateamine A inhibits translation by preventing proper translational initiation complex formation. In the December issue of Chemistry & Biology, Bordeleau et al. demonstrated that the effects of Patemine A on translation are mediated through the interaction between the RNA helicase eIF4A and mRNA .

Translation initiation factor eIF4G-1 binds to eIF3 through the eIF3e subunit.

eIF3 in mammals is the largest translation initiation factor ( approximately 800 kDa) and is composed of 13 nonidentical subunits designated eIF3a-m. The role of mammalian eIF3 in assembly of the 48 S complex occurs through high affinity binding to eIF4G. Interactions of eIF4G with eIF4E, eIF4A, eIF3, poly(A)-binding protein, and Mnk1/2 have been mapped to discrete domains on eIF4G, and conversely, the eIF4G-binding sites on all but one of these ligands have been determined.

Translation of a small subset of Caenorhabditis elegans mRNAs is dependent on a specific eukaryotic translation initiation factor 4E isoform.

The mRNA cap-binding protein eukaryotic translation initiation factor 4E (eIF4E) participates in protein synthesis initiation, translational repression of specific mRNAs, and nucleocytoplasmic shuttling. Multiple isoforms of eIF4E are expressed in a variety of organisms, but their specific roles are poorly understood. We investigated one Caenorhabditis elegans isoform, IFE-4, which has homologues in plants and mammals.

Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk.

The mitogen-activated protein kinase-interacting kinase 1 (Mnk1) is phosphorylated by caspase-cleaved protein kinase Pak2/gamma-PAK but not by Cdc42-activated Pak2. Phosphorylation of Mnk1 is rapid, reaching 1 mol/mol within 15 min of incubation with Pak2. A kinetic analysis of the phosphorylation of Mnk1 by Pak2 yields a K(m) of 0.