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Articoli di riviste sul tema "Neurotoxic agents Physiological effect"

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Firdaus, Riyadh, Sandy Theresia, Ryan Austin e Rani Tiara. "Propofol effects in rodent models of traumatic brain injury: a systematic review". Asian Biomedicine 15, n. 6 (1 dicembre 2021): 253–65. http://dx.doi.org/10.2478/abm-2021-0032.

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Abstract Background Traumatic brain injury (TBI) causes high mortality and disability worldwide. Animal models have been developed to explore the complex processes in TBI. Propofol is used to manage head injuries during surgical intervention and mechanical ventilation in patients with TBI. Many studies have investigated the neuroprotective effect of propofol on TBI. However, other studies have shown neurotoxic effects. Objectives To review systematically the literature regarding the neuroprotective and neurotoxic effects of propofol in rodent models of TBI. Methods Data from rodents as models of TBI with propofol as one of the intervention agents, and/or comparing the neuroprotective effects of propofol with the other substances in rodent models of TBI, were obtained from PubMed, EBSCO Host, and ProQuest databases. The PRISMA 2020 statement recommendations were followed and research questions were developed based on PICOS guidelines. Data was extracted from the literature using a standardized Cochrane method. Results We analyzed data from 12 articles on physiological changes of experimental animals before and after trauma, the effects of propofol administration, and the observed neurotoxic effects. The effects of propofol administration were observed in terms of changes in traumatic lesion volume, the release of antioxidants and inflammatory factors, and the neurological function of rodent models of TBI. Conclusion Propofol has neuroprotective and neurotoxic effects via several mechanisms, and various doses have been used in research to determine its effects. The timing of administration, the dose administered, and the duration of administration contribute to determine the effect of propofol in rodent models of TBI. However, the doses that produce neuroprotective and neurotoxic effects are not yet clear and further research is needed to determine them.
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Zengerle, Michael, Florian Brandhuber, Christian Schneider, Franz Worek, Georg Reiter e Stefan Kubik. "Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent". Beilstein Journal of Organic Chemistry 7 (22 novembre 2011): 1543–54. http://dx.doi.org/10.3762/bjoc.7.182.

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The potential of appropriately substituted cyclodextrins to act as scavengers for neurotoxic organophosphonates under physiological conditions was evaluated. To this end, a series of derivatives containing substituents with an aldoxime or a ketoxime moiety along the narrow opening of the β-cyclodextrin cavity was synthesized, and the ability of these compounds to reduce the inhibitory effect of the neurotoxic organophosphonate cyclosarin on its key target, acetylcholinesterase, was assessed in vitro. All compounds exhibited a larger effect than native β-cyclodextrin, and characteristic differences were noted. These differences in activity were correlated with the structural and electronic parameters of the substituents. In addition, the relatively strong effect of the cyclodextrin derivatives on cyclosarin degradation and, in particular, the observed enantioselectivity are good indications that noncovalent interactions between the cyclodextrin ring and the substrate, presumably involving the inclusion of the cyclohexyl moiety of cyclosarin into the cyclodextrin cavity, contribute to the mode of action. Among the nine compounds investigated, one exhibited remarkable activity, completely preventing acetylcholinesterase inhibition by the (−)-enantiomer of cyclosarin within seconds under the conditions of the assay. Thus, these investigations demonstrate that decoration of cyclodextrins with appropriate substituents represents a promising approach for the development of scavengers able to detoxify highly toxic nerve agents.
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Sekeres, Melanie J., Meenakshie Bradley-Garcia, Alonso Martinez-Canabal e Gordon Winocur. "Chemotherapy-Induced Cognitive Impairment and Hippocampal Neurogenesis: A Review of Physiological Mechanisms and Interventions". International Journal of Molecular Sciences 22, n. 23 (24 novembre 2021): 12697. http://dx.doi.org/10.3390/ijms222312697.

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A wide range of cognitive deficits, including memory loss associated with hippocampal dysfunction, have been widely reported in cancer survivors who received chemotherapy. Changes in both white matter and gray matter volume have been observed following chemotherapy treatment, with reduced volume in the medial temporal lobe thought to be due in part to reductions in hippocampal neurogenesis. Pre-clinical rodent models confirm that common chemotherapeutic agents used to treat various forms of non-CNS cancers reduce rates of hippocampal neurogenesis and impair performance on hippocampally-mediated learning and memory tasks. We review the pre-clinical rodent literature to identify how various chemotherapeutic drugs affect hippocampal neurogenesis and induce cognitive impairment. We also review factors such as physical exercise and environmental stimulation that may protect against chemotherapy-induced neurogenic suppression and hippocampal neurotoxicity. Finally, we review pharmacological interventions that target the hippocampus and are designed to prevent or reduce the cognitive and neurotoxic side effects of chemotherapy.
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Sorci, Guglielmo, Roberta Bianchi, Francesca Riuzzi, Claudia Tubaro, Cataldo Arcuri, Ileana Giambanco e Rosario Donato. "S100B Protein, a Damage-Associated Molecular Pattern Protein in the Brain and Heart, and Beyond". Cardiovascular Psychiatry and Neurology 2010 (18 agosto 2010): 1–13. http://dx.doi.org/10.1155/2010/656481.

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S100B belongs to a multigenic family of -binding proteins of the EF-hand type and is expressed in high abundance in the brain. S100B interacts with target proteins within cells thereby altering their functions once secreted/released with the multiligand receptor RAGE. As an intracellular regulator, S100B affects protein phosphorylation, energy metabolism, the dynamics of cytoskeleton constituents (and hence, of cell shape and migration), homeostasis, and cell proliferation and differentiation. As an extracellular signal, at low, physiological concentrations, S100B protects neurons against apoptosis, stimulates neurite outgrowth and astrocyte proliferation, and negatively regulates astrocytic and microglial responses to neurotoxic agents, while at high doses S100B causes neuronal death and exhibits properties of a damage-associated molecular pattern protein. S100B also exerts effects outside the brain; as an intracellular regulator, S100B inhibits the postinfarction hypertrophic response in cardiomyocytes, while as an extracellular signal, (high) S100B causes cardiomyocyte death, activates endothelial cells, and stimulates vascular smooth muscle cell proliferation.
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Haryanto, Budi. "Indonesia: country report on children’s environmental health". Reviews on Environmental Health 35, n. 1 (26 marzo 2020): 41–48. http://dx.doi.org/10.1515/reveh-2019-0088.

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AbstractChildren’s bodies are in dynamic stages of development that make them more susceptible to harm from exposure to environmental agents. Children’s physical, physiological and behavioral traits can lead to increased exposure to toxic chemicals or pathogens. In addition, the social determinants of health interact with this exposure and create an increasing risk for further disparities among children. In Indonesia, the fourth most populated country in the world, children are under threat of exposure to contaminated water, air, food and soil, which can cause gastrointestinal and respiratory diseases, birth defects and neurodevelopmental disorders. A safe and balanced nutrition is still an unmet need for too many children. At the same time, the prevalence of obesity and the risk of later development of metabolic diseases, including diabetes and cardiovascular diseases, are increasing as a consequence of both unhealthy diets and inadequate physical activity. The risks of potential long-term toxicity, including carcinogenic, neurotoxic, immunotoxic, genotoxic, endocrine-disrupting and allergenic effects of many chemicals, are also close to their lives. This paper provides an overview of common disease risks in Indonesian children, including: acute hepatitis A, diarrheal diseases, dengue and malaria due to lack of water supply and sanitation, vectors, and parasites; asthma, bronchopneumonia, chronic obstructive pulmonary disease (COPD) and acute respiratory infections (ARIs) due to air pollution and climate change; some chronic diseases caused by toxic and hazardous waste; and direct or indirect consequences due to the occurrence of disasters and health emergencies.
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Nemecz, Dorota, Maciej Ostrowski, Marc Ravatin, Frederick Saul e Grazyna Faure. "Crystal Structure of Isoform CBd of the Basic Phospholipase A2 Subunit of Crotoxin: Description of the Structural Framework of CB for Interaction with Protein Targets". Molecules 25, n. 22 (13 novembre 2020): 5290. http://dx.doi.org/10.3390/molecules25225290.

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Crotoxin, from the venom of the South American rattlesnake Crotalus durissus terrificus, is a potent heterodimeric presynaptic β-neurotoxin that exists in individual snake venom as a mixture of isoforms of a basic phospholipase A2 (PLA2) subunit (CBa2, CBb, CBc, and CBd) and acidic subunit (CA1–4). Specific natural mutations in CB isoforms are implicated in functional differences between crotoxin isoforms. The three-dimensional structure of two individual CB isoforms (CBa2, CBc), and one isoform in a crotoxin (CA2CBb) complex, have been previously reported. This study concerns CBd, which by interaction with various protein targets exhibits many physiological or pharmacological functions. It binds with high affinity to presynaptic receptors showing neurotoxicity, but also interacts with human coagulation factor Xa (hFXa), exhibiting anticoagulant effect, and acts as a positive allosteric modulator and corrector of mutated chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR), implicated in cystic fibrosis. Thus, CBd represents a novel family of agents that have potential in identifying new drug leads related to anticoagulant and anti-cystic fibrosis function. We determined here the X-ray structure of CBd and compare it with the three other natural isoforms of CB. The structural role of specific amino acid variations between CB isoforms are analyzed and the structural framework of CB for interaction with protein targets is described.
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Husstedt, IW, D. Reichelt, U. Oelker-Grueneberg e S. Evers. "Neurotoxic effect of antiretroviral agents on CNS". Journal of the International AIDS Society 11, Suppl 1 (2008): P163. http://dx.doi.org/10.1186/1758-2652-11-s1-p163.

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Kurnik-Łucka, Magdalena, Gniewomir Latacz, Adrian Martyniak, Andrzej Bugajski, Katarzyna Kieć-Kononowicz e Krzysztof Gil. "Salsolinol—neurotoxic or Neuroprotective?" Neurotoxicity Research 37, n. 2 (15 novembre 2019): 286–97. http://dx.doi.org/10.1007/s12640-019-00118-7.

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AbstractSalsolinol (6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline), widely available in many edibles, is considered to alter the function of dopaminergic neurons in the central nervous system and thus, multiple hypotheses on its either physiological and/or pathophysiological role have emerged. The aim of our work was to revisit its potentially neurotoxic and/or neuroprotective role through a series of both in vitro and in vivo experiments. Salsolinol in the concentration range 10–250 μM did not show any significant release of lactate dehydrogenase from necrotic SH-SY5Y cells and was able in the concentration of 50 and 100 μM to rescue SH-SY5Y cells from death induced by H2O2. Its neuroprotective effect against neurotoxin 6-hydroxydopamine was also determined. Salsolinol was found to decrease significantly the reactive oxygen species level in SH-SY5Y cells treated by 500 μM H2O2 and the caspase activity induced by 300 μM of H2O2 or 100 μM of 6-hydroxydopamine. Serum levels of TNFα and CRP of salsolinol-treated rats were not significantly different from control animals. Both TNFα and CRP served as indirect markers of neurotoxicity and/or neuroprotection. Although the neurotoxic properties of salsolinol have numerously been emphasized, its neuroprotective properties should not be neglected and need greater consideration.
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Moro, Nicola, Lolita Dokshokova, Induja Perumal Vanaja, Valentina Prando, Sophie Julie A. Cnudde, Anna Di Bona, Riccardo Bariani et al. "Neurotoxic Effect of Doxorubicin Treatment on Cardiac Sympathetic Neurons". International Journal of Molecular Sciences 23, n. 19 (21 settembre 2022): 11098. http://dx.doi.org/10.3390/ijms231911098.

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Doxorubicin (DOXO) remains amongst the most commonly used anti-cancer agents for the treatment of solid tumors, lymphomas, and leukemias. However, its clinical use is hampered by cardiotoxicity, characterized by heart failure and arrhythmias, which may require chemotherapy interruption, with devastating consequences on patient survival and quality of life. Although the adverse cardiac effects of DOXO are consolidated, the underlying mechanisms are still incompletely understood. It was previously shown that DOXO leads to proteotoxic cardiomyocyte (CM) death and myocardial fibrosis, both mechanisms leading to mechanical and electrical dysfunction. While several works focused on CMs as the culprits of DOXO-induced arrhythmias and heart failure, recent studies suggest that DOXO may also affect cardiac sympathetic neurons (cSNs), which would thus represent additional cells targeted in DOXO-cardiotoxicity. Confocal immunofluorescence and morphometric analyses revealed alterations in SN innervation density and topology in hearts from DOXO-treated mice, which was consistent with the reduced cardiotropic effect of adrenergic neurons in vivo. Ex vivo analyses suggested that DOXO-induced denervation may be linked to reduced neurotrophic input, which we have shown to rely on nerve growth factor, released from innervated CMs. Notably, similar alterations were observed in explanted hearts from DOXO-treated patients. Our data demonstrate that chemotherapy cardiotoxicity includes alterations in cardiac innervation, unveiling a previously unrecognized effect of DOXO on cardiac autonomic regulation, which is involved in both cardiac physiology and pathology, including heart failure and arrhythmias.
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Shah, Arya, E. Matthew Hoffman, Michelle L. Mauermann, Charles L. Loprinzi, Anthony J. Windebank, Christopher J. Klein e Nathan P. Staff. "Incidence and disease burden of chemotherapy-induced peripheral neuropathy in a population-based cohort". Journal of Neurology, Neurosurgery & Psychiatry 89, n. 6 (8 febbraio 2018): 636–41. http://dx.doi.org/10.1136/jnnp-2017-317215.

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ObjectiveTo assess disease burden of chemotherapy-induced peripheral neuropathy (CIPN), which is a common dose-limiting side effect of neurotoxic chemotherapy. Late effects of CIPN may increase with improved cancer survival.MethodsOlmsted County, Minnesota residents receiving neurotoxic chemotherapy were identified and CIPN was ascertained via text searches of polyneuropathy symptoms in the medical record. Clinical records were queried to collect data on baseline characteristics, risk factors, signs and symptoms of CIPN, medications, impairments and International Classification of Diseases, Ninth Revision (ICD-9) diagnostic codes for all subjects.ResultsA total of 509 individuals with incident exposure to an inclusive list of neurotoxic chemotherapy agents between 2006 and 2008 were identified. 268 (52.7%) of these individuals were determined to have CIPN. The median time from incident exposure to first documented symptoms was 71 days. Patients with CIPN received a neuropathy ICD-9 diagnosis in only 37 instances (13.8%). Pain symptoms and use of pain medications were observed more often in patients with CIPN. Five-year survival was greater in those with CIPN (55.2%) versus those without (36.1%). Those with CIPN surviving greater than 5 years (n=145) continued to have substantial impairments and were more likely to be prescribed opioids than those without CIPN (OR 2.0, 1.06–3.69).ConclusionsResults from our population-based study are consistent with previous reports of high incidence of CIPN in the first 2 years following incident exposure to neurotoxic chemotherapeutic agents, and its association with significant pain symptomatology and accompanied long-term opioid use. Increased survival following exposure to neurotoxic chemotherapy and its long-term disease burden necessitates further study among survivors.
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Tesi sul tema "Neurotoxic agents Physiological effect"

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Samiayah, Ganesh Kumar School of Physiology &amp Pharmacology UNSW. "Pharmacokinetics, Cerebrovascular Permeability & Biotransformation of the Neurotoxic Plasticiser N-butylbenzenesulfonamide (NBBS)". Awarded by:University of New South Wales. School of Physiology & Pharmacology, 1997. http://handle.unsw.edu.au/1959.4/17597.

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The pharmacokinetics, oral bioavailability, cerebrovascular permeability and biotransformation of the neurotoxic plasticiser n-butylbenzenesulfonamide (NBBS) were studied in order that the human health risk due to environmental exposure to NBBS could be evaluated. The pharmacokinetics of NBBS was determined in Wistar rats, following intravenous administration of the isotopomer [13C6] NBBS (1 mg/kg in 0.9% saline). [13C6] NBBS is cleared from plasma at a rate of 5 ml/min by the liver. The plasticiser has a short distribution phase (t1/2 of 47 seconds) and a long terminal phase (t1/2 of 17 hours). Plasma [13C6] NBBS concentrations, 24 hours after administration, represented 0.04% of the administered dose. These data indicated rapid uptake into tissue, which was subsequently confirmed by monitoring tissue concentrations of [13C6] NBBS for upto 8 hours following administration. [13C6] NBBS was not accumulated by any of the tissues studied (brain, liver, kidney, muscle and adipose tissue). Oral bioavailability was determined by simultaneously administering native NBBS orally and [13C6] NBBS intravenously to Wistar rats. The plasticiser was found to be absorbed erratically and subject to first pass metabolism. Plasma concentrations of orally administered NBBS fluctuated over the duration of the experiment. Furthermore, limitations posed by the assay resulted in truncated oral curves. These factors precluded estimation of areas under the oral NBBS curves to infinity and partial area ratios were instead used to calculate absolute bioavailability (mean of 19%). Cerebrovascular permeability of NBBS was determined with [13C6] NBBS, in Sprague-Dawley rats, using the in-situ brain perfusion technique of Takasato et al. (1984). The uptake of [13C6] NBBS into brain was very rapid and flow limited. Assuming an average cerebral perfusion fluid flow rate of 0.11 ml/s/g, the calculated single pass extraction value for [13C6] NBBS is 99.9% with a Kin of 0.11 ml/s/g. This is in close agreement with experimental values for the 15 second saline perfusions (extraction = 98% - 125% and Kin = 0.108 - 0.137). Differences in regional brain distribution of the plasticiser were not found. In-vitro biotransformation studies revealed one phase I metabolite in incubates of NBBS containing human, rabbit and rat post-mitochondrial supernatant (S9 fraction). This metabolite is 2-hydroxy-n-butylbenzenesulfonamide (NBBS-OH hydroxylated in the Based on these data, environmental exposure to NBBS does not pose a significant human health risk.
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Fincher, Cynthia Ellen. "The Use of Single Photon Emission Computed Tomography to Indicate Neurotoxicity in Cases of Pesticide and Solvent Exposures". Thesis, University of North Texas, 1995. https://digital.library.unt.edu/ark:/67531/metadc277747/.

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This study examined the effect of neurotoxic chemical exposures on brain processes using Single Photon Emission Computed Tomography (SPECT). A control group carefully screened for good health and minimal chemical exposures was compared to two groups of patients diagnosed with health problems following exposure to pesticides or to organic solvents.
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Palvie, Stefanie Michelle. "An investigation into the neuroprotective effects of dehydroepiandrosterone". Thesis, Rhodes University, 2006. http://hdl.handle.net/10962/d1003260.

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Dehydroepiandrosterone, a C-19 steroid, is found endogenously with the highest circulating serum levels. It is converted to important steroids such as the sex hormones oestrogen and testosterone. DHEA has come under the spotlight as a purported “fountain of youth” due to its well-characterised age-related decline. The supplementation of DHEA in both the elderly and those with a pathophysiological deficiency has been shown to be of benefit, particularly with regard to wellbeing and depression. The role of DHEA in the periphery has not been elucidated beyond its role as a precursor hormone in sex steroid biosynthesis, though it has been established as a neuroactive neurosteroid, capable of exerting neuroprotective effects in the brain. Since the importance of free radicals in aging and neurodegeneration is well established, investigations were conducted on the ability of DHEA to inhibit free radical generation or scavenge existing free radicals. DHEA was able to significantly inhibit quinolinic acid-induced lipid peroxidation, a measure of membrane damage, over a range of concentrations, although the reduction did not appear to be dose-dependent. This was observed in both in vitro and in vivo studies. Thus, the ability of a compound to reduce the degree of lipid peroxidation may indicate its value as a neuroprotectant. However, DHEA did not significantly reduce cyanide induced generation of the superoxide free radical, suggesting that DHEA is not an effective free radical scavenger of the superoxide anion and that the reduction in lipid peroxidation does not occur through a scavenging mechanism. Apoptosis is a physiological process which is necessary for development and homeostasis. However, this form of programmed cell death can be initiated through various mechanisms and too much apoptotic cell death results in deleterious effects in the body. DHEA was shown not to induce apoptosis. Even the lowest concentration of DHEA investigated in this thesis shows a remarkable decrease in the degree of apoptosis caused by intrahippocampal chemical insult by the neurotoxin quinolinic acid. Cresyl violet was used to visualise tissue for histological examination which revealed that DHEA is able to preserve the normal healthy morphology of hippocampal cells which have been exposed to quinolinic acid. Cells maintained their integrity and showed little evidence of swelling associated with necrosis. Organ culture studies were performed by assessing the impact of DHEA on several pineal metabolites. The study revealed that DHEA exerted an effect on the metabolism of indoleamines in the pineal gland. Melatonin, the chief pineal hormone, did not appear to be affected while the concentrations of N-acetylserotonin, serotonin and methoxytryptamine showed significant alterations. Thus, the neuroprotective mechanism of DHEA does not appear to be mediated by an increase in the presence of melatonin. The biological importance of metal ions in neurodegeneration is also well established and thus the potential interaction between DHEA and metal ions was considered as a mechanism of action. Spectroscopic and electrochemical analyses were performed to determine whether DHEA is able to interact with metal ions as a ligand. These reveal that DHEA does not form a strong bond with the metals investigated, namely copper (II) and iron (III), but that a weak interaction is evident. These investigations were conducted in a rodent model, which has neither large amounts of endogenous DHEA, nor the enzymatic infrastructure present in humans. Thus, the theory that DHEA exerts its effects through downstream metabolic products is unlikely. However, these investigations reveal that there is merit in the statement that DHEA itself is a neuroprotective molecule, and confirm that the further investigation of DHEA is an advisable strategy in the war against neurodegeneration and aging.
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Shabani, Fariba. "Regulation of matrix metalloproteinases, their inhibitors and IL-8 in inflammatory rheumatic diseases : effects of cytokines and anti-rheumatic agents /". Title page and contents only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phs524.pdf.

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Davis, Christopher John. "Neuropharmacological investigations into the mechanisms of emesis caused by cytotoxic drugs and radiation". Thesis, University of Oxford, 1988. https://ora.ox.ac.uk/objects/uuid:b9afefde-a43e-415e-8754-ed2a8eaac620.

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Liu, Xiaoling. "Determination of whether the effects of statin drugs are mediated by phosphoinostide 3-kinase". Virtual Press, 2004. http://liblink.bsu.edu/uhtbin/catkey/1306853.

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Phosphoinositide 3-kinases (PI3Ks) are a family of proteins involved in many different aspects of cell signaling. To date, eight different human PI3K isoforms have been identified, and distinct roles are beginning to emerge for each family member. Statins, HMG co-A reductase inhibitors used clinically to lower LDL cholesterol levels, also act through the PI3K signaling pathway to regulate cholesterol independent of their lipid-lowering effects. In an effort to discover the role of pl 10f3 in mediating non-lipid lowering effects of pravastatin, a mutant of p110(3 was overexpressed in human coronary artery endothelial cells (HCAEC) to form a dominant negative model (p110(3 DN). Silence si-RNA as an alterative tool was also optimized to diminish p110(3 protein expression successfully. HepG2 3: RE was used to monitor statins function by assaying luciferase expression. Results from these studies will determine the contribution of p110f3 in mediating selective cellular responses to statin.
Department of Biology
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Oliva, Jean L. (Jean Louise). "The Teratogenic Effects of Nocodazole and Acrylamide in Mus Musculus". Thesis, University of North Texas, 1989. https://digital.library.unt.edu/ark:/67531/metadc500254/.

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In two separate experiments, weight adjusted doses of nocodazole and acrylamide were injected intraperitoneally at various time intervals into twelve week old female mice. Within the nocodazole experiment, the doses were injected at varying time intervals before and after mating. On day seventeen of gestation, the female mice were sacrificed and their uterine contents examined. Nocodazole induced a significant increase in reproductive pathology per total implants when administered one hour after mating to the (SECxC57BL)F, stock: 5.00% total deads, 70.23% moles, and 3.41% abnormal fetuses. Acrylamide treatment produced a significant reduction in live births when administered six hours after mating: 50.86% moles and 46.46% living fetuses per total implants.
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Wong, Suk-yu, e 黃淑如. "Study of anti-cancer and anti-viral activities of lanthanide and vanadium complexes". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B37674547.

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Yoshida, Makiko. "Plant sterols and glucomannan as hypocholesterolemic and hypoglycemic agents in subjects with and without type 2 diabetes". Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=80900.

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The objective of this research was to examine the effects of plant sterols and glucomannan on lipid profiles, plasma plant sterol levels and glycemic control in mildly hypercholesterolemic subjects. Thirteen type 2 diabetic and sixteen non-diabetic individuals participated in a randomized crossover trial consisting of 4 phases, of 21 days each. During the study period, subjects were supplemented with plant sterols and/or glucomannan. Overall reductions of total cholesterol and low-density lipoprotein (LDL) cholesterol concentrations were greater after consumption of plant sterols and glucomannan compared to plant sterol or glucomannan supplementation alone. Plasma lathosterol levels, indicators of cholesterol biosynthesis, were decreased after combination treatment. The results suggest that a combination of glucomannan and plant sterols substantially improve plasma lipids by reducing cholesterol absorption and synthesis simultaneously. Supplementation of plant sterols and glucomannan can thus be used as an effective treatment for management of circulating cholesterol levels and prevention of cardiovascular disease.
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Xu, Yang, e 徐阳. "Proteomic and biochemical characterization of the anti-cancer mechanism of tubeimoside-1 extracted from the Chinese herbalmedicine "Tu bei mu"". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44135968.

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Libri sul tema "Neurotoxic agents Physiological effect"

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United States. Congress. House. Committee on Science and Technology. Neurotoxins: At home and in the workplace : report. Washington: U.S. G.P.O., 1986.

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Oversight, United States Congress House Committee on Science and Technology Subcommittee on Investigations and. Neurotoxins at home and in the workplace: Hearings before the Subcommittee on Investigations and Oversight of the Committee on Science and Technology, House of Representatives, Ninety-ninth Congress, first session, October 8, 9, 1985. Washington: U.S. G.P.O., 1986.

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Nag, Devika. Biological neurotoxins in the environment. New Delhi: Dept. of Environment & Forests, Govt. of India., 1993.

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1943-, Ford M. G., Society of Chemical Industry (Great Britain). Pesticides Group., Society of Chemical Industry (Great Britain). Physiochemical and Biophysical Panel. e Neurotox '85 (1985 : University of Bath), a cura di. Neuropharmacology and pesticide action. Weinheim, Federal Republic of Germany: VCH, 1986.

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1952-, Eccles Christine U., e Annau Zoltan 1936-, a cura di. The Toxicity of methyl mercury. Baltimore: Johns Hopkins University Press, 1987.

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Y, Kao C., Levinson S. R e New York Academy of Sciences., a cura di. Tetrodotoxin, saxitoxin, and the molecular biology of the sodium channel. New York, N.Y: New York Academy of Sciences, 1986.

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G, Lunt George, e Society of Chemical Industry (Great Britain), a cura di. Neurotox '88: Molecular basis of drug & pesticide action : proceedings of Neurotox '88, molecular basis of drug & pesticide action, University of Nottingham, England, 10-15 April, 1988. Amsterdam: Excerpta Medica, 1988.

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Programme, United Nations Environment. Principles and methods for the assessment of neurotoxicity associated with exposure to chemicals. Geneva: World Health Organization ; Albany, NY : WHO Publications Center USA [distributor], 1986.

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1931-, Chambers P. L., Tuomisto Jouko e Chambers C. M, a cura di. Toxic interfaces of neurones, smoke, and genes: Proceedings of the European Society of Toxicology Meeting held in Kuopio, June 16-19, 1985. Berlin: Springer-Verlag, 1986.

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Grua, Bernadetta La, e Alessandro Molinelli. Statins: Pharmacology, clinical implications, and adverse effects. New York: Nova Biomedical/Nova Science Publishers, 2012.

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Capitoli di libri sul tema "Neurotoxic agents Physiological effect"

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Ohmoto, Yoshimasa, Seiji Takeda e Toyoaki Nishida. "Effect of Visual Feedback Caused by Changing Mental States of the Avatar Based on the Operator’s Mental States Using Physiological Indices". In Intelligent Virtual Agents, 315–24. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-67401-8_40.

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2

A. Badria, Farid. "Radiopharmaceuticals: On-Going Research for Better Diagnosis, Therapy, Environmental, and Pharmaceutical Applications". In Radiopharmaceuticals [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.99204.

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Abstract (sommario):
Radiopharmaceutical material is a pharmaceutical product or drug that may exert spontaneous degradation of unstable nuclei with nuclear particles or photons emission. Radiopharmaceuticals may be used in research, diagnosis, therapy, and environmental purposes. Moreover, radiopharmaceuticals act as radioactive tracers among patients via gamma-ray emissions. Therefore, the uses of radiopharmaceuticals as diagnostic agents may be given to patients to examine any biochemical, molecular biology, physiological, or anatomical abnormalities. Therapeutic radiopharmaceutical may be administered internally for therapeutic purposes via selective effect on certain abnormal cells or organs. The best known example for therapeutic radiopharmaceuticala is iodide131 for thyroid ablation in among patients with hyperthyroid. A third class of radiopharmaceutical is drug labeling which mainly used in research by using small amount of radioactive substances not for diagnostic purposes, but to investigate the metabolism, bio-distribution, pharmakodynamic, and pharmakokinetic of certain drugs in a nonradioactive form. This chapter focuses mainly on basic fundamentals of radiopharmaceutical chemistry, preparation, environmental, pharmaceutical, diagnostic, therapeutic, and research applications.
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Agrawal, Ranu. "Psyllium: A Source of Dietary Fiber". In Dietary Fibers. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.99372.

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Dietary fiber is commonly known as roughage. Fibers are mostly present in vegetables, whole grain, nuts, legumes, and fruits. This is an indigestible part of the food obtained by plants. It includes polysaccharides such as cellulose, hemicellulose, pectic substances, mucilages, gums and lignin as well. Dietary fiber has beneficial physiological effect on health, so it is included in daily diet to decrease occurrence of several diseases. In this sequence, this chapter describes about the dietary fiber, psyllium commonly known as Isabgol which is prepared from the seed of the Plantago ovata Forsk (Psyllium ispaghula). Psyllium is hydrophilic mucilloid, has the capacity to absorb water and increases in volume while absorbing water. Psyllium consists of mixed viscous polysaccharide in which about 35% soluble and 65% insoluble polysaccharides (cellulose, hemicellulose, and lignin) are present. This can be used as gelling, food thickener, emulsifying and stabilizing agents in some food products. Psyllium is a natural biopolymer which has high quantity of hemicelluloses consist of xylan backbone connected with arabinose, galacturonic acid and rhamnose units. Since last many years it is being used as therapeutic agent in several diseases like chronic constipation, inflammation of mucous membrane of GIT tract, duodenal ulcers, piles or diarrohoea etc. It may be source of renewable and biodegradable polymer.
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Saltzman, W. Mark. "Pharmacokinetics of Drug Distribution". In Drug Delivery. Oxford University Press, 2001. http://dx.doi.org/10.1093/oso/9780195085891.003.0012.

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Pharmacology, the study of agents and their actions, can be divided into two branches. Pharmacodynamics is concerned with the effects of a drug on the body and, therefore, encompasses dose–response relationships as well as the molecular mechanisms of drug activity. Pharmacokinetics, on the other hand, is concerned with the effect of the body on the drug. Drug metabolism, transport, absorption, and elimination are components of pharmacokinetic analysis. Physiology influences the distribution of drugs within the body; overall distribution depends on rates of drug uptake, rates of distribution between tissue compartments, and rates of drug elimination or biotransformation. Each of these phenomena potentially involves aspects of drug diffusion, permeation through membranes, and fluid movement that were introduced in the previous sections. The goal of pharmacokinetics is synthesis of these isolated basic mechanisms into a functional unit; this goal is most often achieved by development of a mathematical model that incorporates descriptions of the uptake, distribution, and elimination of a drug in humans or animals. This model can then be used to predict the outcome of different dosage regimens on the time course of drug concentrations in tissues. The development of a complete pharmacokinetic model for any given drug is a substantial undertaking, since the fate of any compound introduced into a whole organism is influenced by a variety of factors, and is usually complicated—in ways that are difficult to predict—by the presence of disease. In this section, pharamacokinetics will be introduced by first considering the simplest situation: an agent is introduced into a single body compartment from which it is also eliminated. While quite sophisticated compartmental models can be developed from this basic construct, it is frequently difficult to relate model parameters (such as the volume of specific compartments or the rate of transfer between compartments) to physiological or anatomical parameters. To avoid this difficulty, physiological pharmacokinetic models are frequently employed; in these models, the kinetics of drug uptake, distribution, and elimination from local tissue sites are predicted by constructing anatomically and biochemically accurate models of the tissue environment.
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Atti di convegni sul tema "Neurotoxic agents Physiological effect"

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Bortkiewicz, Alicja, Elżbieta Gadzicka, Marta Walczak, Marcin Kosobudzki, Zbigniew Jóźwiak, Piotr Viebig, Agata Szyjkowska, Teresa Makowiec-Dabrowska, Bronislaw Kapitaniak e Jadwiga Siedlecka. "Integrated System for Monitoring the Psychical and Physical Conditionsof Road Vehicle Drivers". In Applied Human Factors and Ergonomics Conference. AHFE International, 2020. http://dx.doi.org/10.54941/ahfe100392.

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From our previous research among bus drivers, in difficult, but not extreme situations, we observed an increase in blood pressure (up to 200mm Hg), cardiac arrhythmias, ischemia, etc. Such reactions may be dangerous to healthy people, but they are extremely risky for drivers with a history of cardiovascular or cerebrovascular incidents. Thus, certifying driving ability of such persons is a serious problem for the medical expert. In this case, tests in a driving simulator, where it is possible to arrange a variety of stressful situations and also to monitor the reaction of the cardiovascular system and brain electrical activity may be a great advantage. Therefore we developed a first-in-Poland integrated system for examination and training of road vehicle drivers, including model stand for simulating of driving vehicle under conditions of road traffic, and a set of methods of psychological and physiological tests to be applied for testing drivers. This simulator enables to assess physiological response to different traffic situations, to analyze the effects of work environment on psychical and physical abilities of drivers, to test the feasibility of the physiological methods for assessing the fatigue and drowsiness, to evaluate the effect of monotony and static loads on the development of driver's fatigue, to assess changes in psychomotor abilities of drivers resulting from exposure to harmful and noxious agents at workplace.
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Grassl, Erin D., Victor H. Barocas e John C. Bischof. "Effects of Freezing on the Mechanical Properties of Blood Vessels". In ASME 2004 International Mechanical Engineering Congress and Exposition. ASMEDC, 2004. http://dx.doi.org/10.1115/imece2004-60244.

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The mechanical properties of blood vessels are important to their ability to function properly. The effects of freezing/cooling on the mechanical properties are a concern for several reasons including preservation of vascular grafts, appropriate storage of samples prior to mechanical testing, and the effects and mechanisms of cryoplasty (cryotherapy for treatment of restenosis). Many have studied the effects of freezing vessels in the presence of cryoprotective agents (CPAs), and the results are mixed, depending on the type of artery and particular mechanical test. The few studies on freezing without CPAs have also given mixed results. To examine this issue further, we froze pig femoral arteries to −20 C in the absence of CPA, and then subjected them to uniaxial tensile testing. Our results suggest that freezing does have an effect on stress-strain properties, particularly in the low stress region corresponding to physiological conditions. The mechanisms of this change in mechanical properties may include the loss of smooth muscle viability, damage to extracellular matrix (ECM), or changes in alignment caused by ice crystal growth. Understanding these changes is important in understanding the mechanisms of cryoplasty, as well as choosing appropriate storage methods for tissues to be used in vascular grafts.
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BOUTHERIN-FALSON, O., e N. BLAES. "MODULATION of PROSTACYCLIN PRODUCTION BY HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS WITH ECGF/HEPARIN MEDIUM : ROLE OF CELLULAR DENSITY AT CONFLUENCE". In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643376.

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Prostacyclin (PGI2) is a major product of arachidonic acid metabolism in vascular endothelial cells. In addition to the role of exogenous agents, its production could be modulated by culture conditions : proliferative state, medium renewal, subcultivation... The use of endothelial cell growth factor (ECGF) associated with heparin has been shown to improve human endothelial cell proliferation. Here we report that human umbilical vein endothelial cells (HUVEC) grown in that medium produce less prostacyclin than without growth factor.HUVEC were cultured in RPMI-199 1:1 + 20% fetal calf serum, added or not with ECGF (Bovine hypothalamus extract BTI Cambridge, 24 ug/ml) and heparin (from porcine intestinal mucosa, Signa, 90 ug/ml). After 4 days in culture, medium was removed and replaced by Tyrode Hepes buffer and basal production was measured after 20 min. Cells were then submitted to 5 min thrombin to assess PGI2 production in stimulated conditions. PGI2 production was estimated by specific radioimmunoassay for 6 keto PGFjalpha. For each point, cell number in the culture was counted after Trypsin EDTA treatment. In the present study, cells grown in ECGF-heparin medium produce lower amount of PGI2, compared to heparin or control medium. This result was observed in both basal and stimulated conditions. For each medium (ECGF-heparin, heparin, control), correlations between PGI2 production per cell and log cell density were shown to be significantly negative.These observations suggest that ECGF effect on PGI2 production could be a consequence of its growth factor activity, notably by the fact that it leads to an endothelial monolayer made of more numerous cells. Since it is now suggested by a number of clinical observations that PGI2 is rather produced in pathological conditions, culture models showing a weak production of PGI2 appear in that connection doser to the physiological conditions.
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Rapporti di organizzazioni sul tema "Neurotoxic agents Physiological effect"

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Philosoph-Hadas, Sonia, Peter Kaufman, Shimon Meir e Abraham Halevy. Signal Transduction Pathway of Hormonal Action in Control and Regulation of the Gravitropic Response of Cut Flowering Stems during Storage and Transport. United States Department of Agriculture, ottobre 1999. http://dx.doi.org/10.32747/1999.7695838.bard.

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Original objectives: The basic goal of the present project was to increase our understanding of the cellular mechanisms operating during the gravitropic response of cut flowers, for solving their bending problem without affecting flower quality. Thus, several elements operating at the 3 levels o the gravity-induced signal transduction pathway, were proposed to be examined in snapdragon stems according to the following research goals: 1) Signaling: characterize the signal transduction pathway leading to the gravitropic response, regarding the involvement of [Ca2+]cyt as a mediator of IAA movement and sensitivity to auxin. 2) Transduction by plant hormones: a) Examine the involvement of auxin in the gravitropic response of flower stems with regard to: possible participation of auxin binding protein (ABP), auxin redistribution, auxin mechanism of action (activation of H+-ATPase) mediation by changes in [Ca2+]cyt and possible regulation of auxin-induced Ca2+ action b: calmodulin-activated or Ca2+-activated protein kinases (PK). b) Examine the involvement of ethylene in the gravitropic response of flower stems with regard to auxin-induced ethylene production and sensitivity of the tissue to ethylene. 3) Response: examine the effect of gravistimulation on invertase (associated with growth and elongation) activity and invertase gene expression. 4) Commercial practice: develop practical and simple treatments to prevent bending of cut flowers grown for export. Revisions: 1) Model systems: in addition to snapdragon (Antirrhinum majus L.), 3 other model shoe systems, consisting of oat (Avena sativa) pulvini, Ornithogalun 'Nova' cut flowers and Arabidopsis thaliana inflorescence, were targeted to confirm a more general mechanism for shoot gravitropism. 2 Research topics: the involvement of ABP, auxin action, PK and invertase in the gravitropic response of snapdragon stems could not be demonstrated. Alternatively, the involvement in the gravity signaling cascade of several other physiological mediators apart of [Ca2+]cyt such as: IP3, protein phosphorylation and actin cytoskeleton, was shown. Additional topics introduced: starch statolith reorientation, differential expression of early auxin responsive genes, and differential shoot growth. Background to the topic: The gravitropic bending response of flowering shoots occurring upon their horizontal placement during shipment exhibits a major horticultural problem. In spite of extensive studies in various aboveground organs, the gravitropic response was hardly investigated in flowering shoots. Being a complex multistep process that requires the participation of various cellular components acting in succession or in parallel, analysis of the negative gravitropic response of shoot includes investigation of signal transduction elements and various regulatory physiological mediators. Major achievements: 1) A correlative role for starch statoliths as gravireceptors in flowering shoot was initially established. 2) Differentially phosphorylated proteins and IP3 levels across the oat shoe pulvini, as well as a differential appearance of 2 early auxin-responsive genes in snapdragon stems were all detected within 5-30 minutes following gravistimulation. 3) Unlike in roots, involvement of actin cytoskeleton in early events of the gravitropic response of snapdragon shoots was established. 4) An asymmetric IAA distribution, followed by an asymmetric ethylene production across snapdragon stems was found following gravistimulation. 5) The gravity-induced differential growth in shoots of snapdragon was derived from initial shrinkage of the upper stem side and a subsequent elongation o the lower stem side. 6) Shoot bending could be successfully inhibited by Ca2+ antagonists (that serve as a basis for practical treatments), kinase and phosphatase inhibitors and actin-cytoskeleton modulators. All these agents did not affect vertical growth. The essential characterization of these key events and their sequence led us to the conclusion that blocking gravity perception may be the most powerful means to inhibit bending without hampering shoot and flower growth after harvest. Implications, scientific and agriculture: The innovative results of this project have provided some new insight in the basic understanding of gravitropism in flower stalks, that partially filled the gap in our knowledge, and established useful means for its control. Additionally, our analysis has advanced the understanding of important and fundamental physiological processes involved, thereby leading to new ideas for agriculture. Gravitropism has an important impact on agriculture, particularly for controlling the bending of various important agricultural products with economic value. So far, no safe control of the undesired bending problem of flower stalks has been established. Our results show for the first time that shoot bending of cut flowers can be inhibited without adverse effects by controlling the gravity perception step with Ca2+ antagonists and cytoskeleton modulators. Such a practical benefit resulting from this project is of great economic value for the floriculture industry.
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2

Droby, Samir, Joseph W. Eckert, Shulamit Manulis e Rajesh K. Mehra. Ecology, Population Dynamics and Genetic Diversity of Epiphytic Yeast Antagonists of Postharvest Diseases of Fruits. United States Department of Agriculture, ottobre 1994. http://dx.doi.org/10.32747/1994.7568777.bard.

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One of the emerging technologies is the use of microbial agents for the control of postharvest diseases of fruits and vegetables. A number of antagonistic microorganisms have been discovered which have the potential to effectively control postharvest diseases. Some of this technology has been patented and commercial products such as AspireTM (Ecogen Corporatin, Langhorne, PA, USA), Biosave 10TM and Biosave 11TM (Ecoscience Inc., Worchester, MA, USA) have been registered for commercial use. The principal investigator of this project was involved in developing the yeast-based biofungicide-AspireTM and testing its efficacy under commercial conditions. This research project was initiated to fill the gap between the knowledge available on development and commercial implementation of yeast biocontrol agents and basic understanding of various aspects related to introducing yeast antagonists to fruit surfaces, along with verification of population genetics. The main objectives of this study were: Study ecology, population dynamics and genetic diversity of the yeast antagonists Candida guilliermondii, C. oleophila, and Debaryomyces hansenii, and study the effect of preharvest application of the yeast antagonist C. oleophila naturally occurring epiphytic microbial population and on the development of postharvest diseases of citrus fruit during storage. Our findings, which were detailed in several publications, have shown that an epiphytic yeast population of grapefruit able to grow under high osmotic conditions and a wide range of temperatures was isolated and characterized for its biocontrol activity against green mold decay caused by Penicillium digitatum. Techniques based on random amplified polymorphic DNA (RAPD) and arbitrary primed polymerase chain reaction (ap-PCR), as well as homologies between sequences of the rDNA internal transcribed spacers (ITS) and 5.8S gene, were used to characterize the composition of the yeast population and to determine the genetic relationship among predominant yeast species. Epiphytic yeasts exhibiting the highest biocontrol activity against P. digitatum on grapefruit were identified as Candida guilliermondii, C. oleophila, C. sake, and Debaryomyces hansenii, while C. guilliermondii was the most predominant species. RAPD and ap-PCR analysis of the osmotolerant yeast population showed two different, major groups. The sequences of the ITS regions and the 5.8S gene of the yeast isolates, previously identified as belonging to different species, were found to be identical. Following the need to develop a genetically marked strain of the yeast C. oleophila, to be used in population dynamics studies, a transformation system for the yeast was developed. Histidine auxotrophy of C. oloephila produced using ethyl methanesulfonate were transformed with plasmids containing HIS3, HIS4 and HIS5 genes from Saccharomyces cerevisiae. In one mutant histidin auxotrophy was complemented by the HIS5 gene of S. cerevisiae is functionally homologous to the HIS5 gene in V. oleophila. Southern blot analysis showed that the plasmid containing the S. cerevisiae HIS5 gene was integrated at a different location every C. oleophila HIS+ transformant. There were no detectable physiological differences between C. oleophila strain I-182 and the transformants. The biological control ability of C. oleophila was not affected by the transformation. A genetically marked (with b-glucuronidase gene) transformant of C. oleophila colonized wounds on orange fruits and its population increased under field conditions. Effect of preharvest application of the yeast C. oleophila on population dynamics of epiphytic microbial population on wounded and unwounded grapefruit surface in the orchard and after harvest was also studied. In addition, the effect of preharvest application of the yeast C. oleophila on the development of postharvest decay was evaluated. Population studies conducted in the orchard showed that in control, non-treated fruit, colonization of wounded and unwounded grapefruit surface by naturally occurring filamentous fungi did not vary throughout the incubation period on the tree. On the other hand, colonization of intact and wounded fruit surface by naturally occurring yeasts was different. Yeasts colonized wounded surface rapidly and increased in numbers to about two orders of magnitude as compared to unwounded surface. On fruit treated with the yeast and kept on the tree, a different picture of fungal and yeast population had emerged. The detected fungal population on the yeast-treated intact surface was dramatically reduced and in treated wounds no fungi was detected. Yeast population on intact surface was relatively high immediately after the application of AspireTM and decreased to than 70% of that detected initially. In wounds, yeast population increased from 2.5 x 104 to about 4x106 after 72 hours of incubation at 20oC. Results of tests conducted to evaluate the effect of preharvest application of AspireTM on the development of postharvest decay indicated the validity of the approach.
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Altstein, Miriam, e Ronald J. Nachman. Rational Design of Insect Control Agent Prototypes Based on Pyrokinin/PBAN Neuropeptide Antagonists. United States Department of Agriculture, agosto 2013. http://dx.doi.org/10.32747/2013.7593398.bard.

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The general objective of this study was to develop rationally designed mimetic antagonists (and agonists) of the PK/PBAN Np class with enhanced bio-stability and bioavailability as prototypes for effective and environmentally friendly pest insect management agents. The PK/PBAN family is a multifunctional group of Nps that mediates key functions in insects (sex pheromone biosynthesis, cuticular melanization, myotropic activity, diapause and pupal development) and is, therefore, of high scientific and applied interest. The objectives of the current study were: (i) to identify an antagonist biophores (ii) to develop an arsenal of amphiphilic topically active PK/PBAN antagonists with an array of different time-release profiles based on the previously developed prototype analog; (iii) to develop rationally designed non-peptide SMLs based on the antagonist biophore determined in (i) and evaluate them in cloned receptor microplate binding assays and by pheromonotropic, melanotropic and pupariation in vivo assays. (iv) to clone PK/PBAN receptors (PK/PBAN-Rs) for further understanding of receptor-ligand interactions; (v) to develop microplate binding assays for screening the above SMLs. In the course of the granting period A series of amphiphilic PK/PBAN analogs based on a linear lead antagonist from the previous BARD grant was synthesized that incorporated a diverse array of hydrophobic groups (HR-Suc-A[dF]PRLa). Others were synthesized via the attachment of polyethylene glycol (PEG) polymers. A hydrophobic, biostablePK/PBAN/DH analog DH-2Abf-K prevented the onset of the protective state of diapause in H. zea pupae [EC50=7 pmol/larva] following injection into the preceding larval stage. It effectively induces the crop pest to commit a form of ‘ecological suicide’. Evaluation of a set of amphiphilic PK analogs with a diverse array of hydrophobic groups of the formula HR-Suc-FTPRLa led to the identification of analog T-63 (HR=Decyl) that increased the extent of diapause termination by a factor of 70% when applied topically to newly emerged pupae. Another biostablePK analog PK-Oic-1 featured anti-feedant and aphicidal properties that matched the potency of some commercial aphicides. Native PK showed no significant activity. The aphicidal effects were blocked by a new PEGylated PK antagonist analog PK-dF-PEG4, suggesting that the activity is mediated by a PK/PBAN receptor and therefore indicative of a novel and selective mode-of-action. Using a novel transPro mimetic motif (dihydroimidazole; ‘Jones’) developed in previous BARD-sponsored work, the first antagonist for the diapause hormone (DH), DH-Jo, was developed and shown to block over 50% of H. zea pupal diapause termination activity of native DH. This novel antagonist development strategy may be applicable to other invertebrate and vertebrate hormones that feature a transPro in the active core. The research identifies a critical component of the antagonist biophore for this PK/PBAN receptor subtype, i.e. a trans-oriented Pro. Additional work led to the molecular cloning and functional characterization of the DH receptor from H. zea, allowing for the discovery of three other DH antagonist analogs: Drosophila ETH, a β-AA analog, and a dF analog. The receptor experiments identified an agonist (DH-2Abf-dA) with a maximal response greater than native DH. ‘Deconvolution’ of a rationally-designed nonpeptide heterocyclic combinatorial library with a cyclic bis-guanidino (BG) scaffold led to discovery of several members that elicited activity in a pupariation acceleration assay, and one that also showed activity in an H. zea diapause termination assay, eliciting a maximal response of 90%. Molecular cloning and functional characterization of a CAP2b antidiuretic receptor from the kissing bug (R. prolixus) as well as the first CAP2b and PK receptors from a tick was also achieved. Notably, the PK/PBAN-like receptor from the cattle fever tick is unique among known PK/PBAN and CAP2b receptors in that it can interact with both ligand types, providing further evidence for an evolutionary relationship between these two NP families. In the course of the granting period we also managed to clone the PK/PBAN-R of H. peltigera, to express it and the S. littoralis-R Sf-9 cells and to evaluate their interaction with a variety of PK/PBAN ligands. In addition, three functional microplate assays in a HTS format have been developed: a cell-membrane competitive ligand binding assay; a Ca flux assay and a whole cell cAMP ELISA. The Ca flux assay has been used for receptor characterization due to its extremely high sensitivity. Computer homology studies were carried out to predict both receptor’s SAR and based on this analysis 8 mutants have been generated. The bioavailability of small linear antagonistic peptides has been evaluated and was found to be highly effective as sex pheromone biosynthesis inhibitors. The activity of 11 new amphiphilic analogs has also been evaluated. Unfortunately, due to a problem with the Heliothis moth colony we were unable to select those with pheromonotropic antagonistic activity and further check their bioavailability. Six peptides exhibited some melanotropic antagonistic activity but due to the low inhibitory effect the peptides were not further tested for bioavailability in S. littoralis larvae. Despite the fact that no new antagonistic peptides were discovered in the course of this granting period the results contribute to a better understanding of the interaction of the PK/PBAN family of Nps with their receptors, provided several HT assays for screening of libraries of various origin for presence of PK/PBAN-Ragonists and antagonists and provided important practical information for the further design of new, peptide-based insecticide prototypes aimed at the disruption of key neuroendocrine physiological functions in pest insects.
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