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Glutamate, one of the most important excitatory neurotransmitters, acts as a signal transducer in peripheral tissues and endocrine cells. Excessive glutamate secretion has been shown to cause excitotoxicity and neurodegenerative disease. Cerebrolysin is a mixture of enzymatically treated peptides derived from pig brain including neurotrophic factors, like brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and ciliary neurotrophic factor (CNTF). The present study investigated the protective effects of cerebrolysin on glutamate transporters (EAAT 1, EAAT 2) and cytokines (IL-1β and IL-10) activity in glutamate-mediated neurotoxicity. Primary cortex neuron culture was exposed to glutamate and successively treated with various cerebrolysin concentrations for 24 and 48 h. Our data showed that cerebrolysin primarily protects neurons by decreasing glutamate concentration in the synaptic cleft. In addition, Cerebrolysin can decrease oxidative stress and neuron cell damage by increasing antioxidant activity and decreasing inflammation cytokine levels.

This paper describes the synthesis of enamino carbonyl compounds by the copper(i)-catalyzed coupling of acceptor-substituted diazo compounds and tertiary thioamides. We plan to use this method to synthesize indolizidine (-)-237D analogs to find α6-selective antismoking agents. Therefore, we also performed

Humans are exposed to multiple chemicals on a daily basis instead of to just a single chemical, yet the majority of existing toxicity data comes from single-chemical exposure. Multiple factors must be considered such as the route, concentration, duration, and the timing of exposure when determining toxicity to the organism. The need for adequate model systems (in vivo, in vitro, in silico and mathematical) is paramount for better understanding of chemical mixture toxicity. Currently, shortcomings plague each model system as investigators struggle to find the appropriate balance of rigor, reproducibility and appropriateness in mixture toxicity studies. Significant questions exist when comparing single-to mixture-chemical toxicity concerning additivity, synergism, potentiation, or antagonism. Dose/concentration relevance is a major consideration and should be subthreshold for better accuracy in toxicity assessment. Previous work was limited by the technology and methodology of the time, but recent advances have resulted in significant progress in the study of mixture toxicology. Novel technologies have added insight to data obtained from in vivo studies for predictive toxicity testing. These include new in vitro models: omics-related tools, organs-on-a-chip and 3D cell culture, and in silico methods. Taken together, all these modern methodologies improve the understanding of the multiple toxicity pathways associated with adverse outcomes (e.g., adverse outcome pathways), thus allowing investigators to better predict risks linked to exposure to chemical mixtures. As technology and knowledge advance, our ability to harness and integrate separate streams of evidence regarding outcomes associated with chemical mixture exposure improves. As many national and international organizations are currently stressing, studies on chemical mixture toxicity are of primary importance., The research was partly supported by the Ministry of Education, Science and Technological Development of Serbia (Project III 46009), the Special Research Account of University of Crete (ELKE No 3550, No 3963, No 4920) and the University of Crete Spin- Off ToxPlus S.A., the Oklahoma State University Center for Health Science Pilot Grant Program (#1-54333), Ministry of Research and Innovation in Romania: Program 1—The Improvement of the National System of Research and Development, Subprogram 1.2—Institutional Excellence—Projects of Excellence Funding in RDI, Contract No. 7PFE/16.10.2018.

Smoking-cessation drugs bind many off-target nicotinic acetylcholine receptors (nAChRs) and cause severe side effects if they are based on nicotine. New drugs that bind only those receptors, such as α6β2* nAChR, implicated in nicotine addiction would avoid the off-target binding. Indolizidine (-)-237D (IND (-)-237D), a bicyclic alkaloid, has been shown to block α6β2* containing nAChRs and functionally inhibit the nicotine-evoked dopamine release. To improve the affinity of indolizidine (-)-237D for α6β2*, we built a library of 2226 analogs. We screened virtually the library against a homology model of α6β2 nAChR that we derived from the recent crystal structure of α4β2 nAChR. We also screened the crystal structure of α4β2 nAChR as a control on specificity. We ranked the compounds based on their predicted free energy of binding. We selected the top eight compounds bound in their best pose and subjected the complexes to 100 ns molecular dynamics simulations to assess the stability of the complexes. All eight analogs formed stable complexes for the duration of the simulations. The results from this work highlight nine distinct analogs of IND (-)-237D with high affinity towards α6β2* nAChR. These leads can be synthesized and tested in in vitro and in vivo studies as lead candidates for drugs to treat nicotine addiction.

The nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.

We present a 42-year-old male with strictured bilioenteric anastomosis after bile duct injury repair. The patient improved after percutaneous biliary drainage and balloon dilation of the stricture. Persistent bile reflux around the catheter insertion site prompted a cholangiogram that suggested an error in the enteric limb. Surgical exploration revealed that a torsed ileal loop was used for bilioenteric anastomosis. This error was repaired surgically. The patient had immediate and long-term resolution of symptoms.

Maternal cocaine abuse is a societal problem with serious impact on both mother and child. Few studies exist that study the mother/offspring dyad of neurological effects of maternal cocaine abuse. The present study was designed to study alterations in D 2 , D 3 and sigma receptor density in nucleus accumbens and striatum of dams and male and female offspring following gestational cocaine. Long-Evans female rats were implanted with an intravenous (i.v.) access port prior to breeding and were administered saline or 3.0 mg/kg of cocaine from gestational day (GD) GD8–20 (1 injection/day-GD8–14, 2 injections/day-GD15–20). Offspring were raised by maternal dams and allowed to mature until postnatal days 31–35, at which time dams and offspring were sacrificed for assay of radioligand binding. In dams, decreased D 2 (24.6%) and D 3 (36.9%) binding was observed in striatum. Female offspring displayed no differences in receptor binding in either region. Male offspring displayed decreased D 2 receptor binding (27.1%) in nucleus accumbens and increased D 3 (75.2% and 33.5%) and sigma receptor binding (73.4% and 53.1%) in accumbens and striatum, respectively. Collectively, these data clearly demonstrate that male offspring exhibit significant alterations in D 2 , D 3 and sigma receptor binding. These results suggest that dams and offspring display long-lasting alterations (5 weeks) in dopamine receptor binding. These alterations in dopamine and sigma receptor binding in offspring following prenatal cocaine and rearing by maternal dams are sex specific and could have profound effects on the development of behavior.

The regional activity of phosphate-activated glutaminase (PAG) was assessed in 8-month-old and 28-month-old male Fischer-344 (F344) rats from the temporal cortex (TCX), striatum (STR) and hippocampus (HIPP). Basal activity, as represented by activity in the presence of 10 mM phosphate, was decreased 23% in the TCX from aged rats compared to adults while neither the STR or HIPP exhibited age-related changes. In the presence of 100 mM phosphate, which will maximally stimulate PAG activity, none of the regions displayed age-related changes although all groups showed increased PAG activity of 112–169% compared to corresponding values in the presence of 10 mM phosphate.

The ability of structural analogues of glutamate (GLU) to modulate phosphate activated glutaminase (PAG) was assessed in the present series of studies. A number of GLU receptor agonists and antagonists were tested for their ability to inhibit synaptosomal PAG activity. PAG activity was determined by measuring GLU formation from 0.5mM glutamine (GLN) in the presence of 10 mM phosphate. GLU analogues at 5–10 mM were found to significantly inhibit PAG activity. It was determined that PAG inhibition occurred regardless of whether the GLU analogues were receptor agonists or antagonists, however, PAG inhibition was influenced by analogue chain length, isomeric form and substituent substitution. The glutamate uptake blockers, dihydrokainic acid and DL-threo-β-hydroxyaspartic acid were relatively weak inhibitors of PAG (

The regulation of PAG by ammonia in whole brain (Sprague-Dawley) and regional (Fischer-344) synaptosomal preparations from adult and aged animals was assessed. Whole brain synaptosomal preparations from both age groups displayed a significant decrease in PAG activity with increasing ammonium chloride concentrations, however, the aged rats exhibited a significant attenuation in ammonia-induced PAG inhibition. PAG activity measured in synaptosomes prepared from the striatum (STR), temporal cortex (TCX) and hippocampus (HIPP) was also inhibited by ammonium chloride. The STR showed the greatest degree of ammonia-induced PAG inhibition (55%) followed by the HIPP (30-35%) and the TCX (25-30%). This reduction in PAG activity was significantly attenuated in STR from aged rats at ammonium chloride concentrations greater than 50 microM and in the TCX, PAG activity was significantly attenuated in the aged rats at ammonia concentrations of 0.5 and 1.0 mM. Ammonia regulation of PAG activity in the HIPP appeared to be unaffected by age. Ammonium chloride concentrations up to 5 mM had no effect on GLU release from cortical slices, although GLN efflux was significantly enhanced. These findings suggest that isozymes of PAG may exist in different brain regions based on their differential sensitivity to ammonia. The attenuation of ammonia-induced PAG inhibition seen in aged rats may have deleterious effects in the aged brain.

Previous work in our laboratory had shown that serum TAU was lower in aged rats when compared to adult controls. The present study sought to determine if the age-related changes in serum TAU were reflected in tissues where TAU was known to have significant physiological relevance. TAU content was found to be significantly decreased in the atria, kidney and caudal artery of 30-month-old male Fischer 344 rats. Furthermore, glutamine content was also found to be altered by aging in both the heart and kidney. Exogenously administered glutamate was shown to increase renal glutamate content and decrease renal TAU content; however, this response was significantly attenuated in aged rats. Subcellular content and distribution of amino acids were not altered in the cerebral cortex of aged rats. Serum TAU was, however, significantly decreased in aged rats. It was concluded that renal conservation and regulation of TAU appears perturbed in the aged rat. Furthermore, the brain and heart can maintain tissue stores of TAU despite a significant age-related decrease in circulating TAU. Our data also suggests that there is an interrelationship between glutamate and TAU stores in the kidney.

The effects of 3 α2-adrenergic receptor agonists on renal function in vasopressin (AVP)-deficient Brattleboro (DI) rats were evaluated. The aim of this study was to determine the relative c