Lathyrism: A paralytic condition of the legs caused by ingestion of lathyrogens, especially BETA-AMINOPROPIONITRILE or beta-N-oxalyl amino-L-alanine, which are found in the seeds of plants of the genus LATHYRUS.Aminoacetonitrile: Cyanomethylamine.Sulfuric Acids: Inorganic and organic derivatives of sulfuric acid (H2SO4). The salts and esters of sulfuric acid are known as SULFATES and SULFURIC ACID ESTERS respectively.Sulfenic Acids: Oxy acids of sulfur with the general formula RSOH, where R is an alkyl or aryl group such as CH3. They are often encountered as esters and halides. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter.Water: A clear, odorless, tasteless liquid that is essential for most animal and plant life and is an excellent solvent for many substances. The chemical formula is hydrogen oxide (H2O). (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Barium Sulfate: A compound used as an x-ray contrast medium that occurs in nature as the mineral barite. It is also used in various manufacturing applications and mixed into heavy concrete to serve as a radiation shield.Anthelmintics: Agents destructive to parasitic worms. They are used therapeutically in the treatment of HELMINTHIASIS in man and animal.Mebendazole: A benzimidazole that acts by interfering with CARBOHYDRATE METABOLISM and inhibiting polymerization of MICROTUBULES.Albendazole: A benzimidazole broad-spectrum anthelmintic structurally related to MEBENDAZOLE that is effective against many diseases. (From Martindale, The Extra Pharmacopoeia, 30th ed, p38)Helminths: Commonly known as parasitic worms, this group includes the ACANTHOCEPHALA; NEMATODA; and PLATYHELMINTHS. Some authors consider certain species of LEECHES that can become temporarily parasitic as helminths.Encyclopedias as Topic: Works containing information articles on subjects in every field of knowledge, usually arranged in alphabetical order, or a similar work limited to a special field or subject. (From The ALA Glossary of Library and Information Science, 1983)Parasitic Diseases, Animal: Infections or infestations with parasitic organisms. The infestation may be experimental or veterinary.Helminthiasis: Infestation with parasitic worms of the helminth class.Spectrophotometry, Infrared: Spectrophotometry in the infrared region, usually for the purpose of chemical analysis through measurement of absorption spectra associated with rotational and vibrational energy levels of molecules. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Bromeliaceae: A plant family of the order Bromeliales, subclass Zingiberidae, class Liliopsida (monocotyledons).Quantum Theory: The theory that the radiation and absorption of energy take place in definite quantities called quanta (E) which vary in size and are defined by the equation E=hv in which h is Planck's constant and v is the frequency of the radiation.Spectroscopy, Fourier Transform Infrared: A spectroscopic technique in which a range of wavelengths is presented simultaneously with an interferometer and the spectrum is mathematically derived from the pattern thus obtained.Fast Foods: Prepared food that is ready to eat or partially prepared food that has a final preparation time of a few minutes or less.Models, Chemical: Theoretical representations that simulate the behavior or activity of chemical processes or phenomena; includes the use of mathematical equations, computers, and other electronic equipment.RestaurantsHaemonchus: A genus of parasitic nematode worms which infest the duodenum and stomach of domestic and wild herbivores, which ingest it with the grasses (POACEAE) they eat. Infestation of man is accidental.Haemonchiasis: Infection with nematodes of the genus HAEMONCHUS, characterized by digestive abnormalities and anemia similar to that from hookworm infestation.Strongylida: An order of nematodes of the subclass SECERNENTEA. Characteristics include an H-shaped excretory system with two subventral glands.Sheep Diseases: Diseases of domestic and mountain sheep of the genus Ovis.Antinematodal Agents: Substances used in the treatment or control of nematode infestations. They are used also in veterinary practice.Host-Parasite Interactions: The relationship between an invertebrate and another organism (the host), one of which lives at the expense of the other. Traditionally excluded from definition of parasites are pathogenic BACTERIA; FUNGI; VIRUSES; and PLANTS; though they may live parasitically.Receptors, Tachykinin: Cell surface proteins that bind TACHYKININS with high affinity and trigger intracellular changes influencing the behavior of cells. Three classes of tachykinin receptors have been characterized, the NK-1; NK-2; and NK-3; which prefer, respectively, SUBSTANCE P; NEUROKININ A; and NEUROKININ B.Tachykinins: A family of biologically active peptides sharing a common conserved C-terminal sequence, -Phe-X-Gly-Leu-Met-NH2, where X is either an aromatic or a branched aliphatic amino acid. Members of this family have been found in mammals, amphibians, and mollusks. Tachykinins have diverse pharmacological actions in the central nervous system and the cardiovascular, genitourinary, respiratory, and gastrointestinal systems, as well as in glandular tissues. This diversity of activity is due to the existence of three or more subtypes of tachykinin receptors.Neurokinin A: A mammalian neuropeptide of 10 amino acids that belongs to the tachykinin family. It is similar in structure and action to SUBSTANCE P and NEUROKININ B with the ability to excite neurons, dilate blood vessels, and contract smooth muscles, such as those in the BRONCHI.Receptors, Neurokinin-2: A class of cell surface receptors for tachykinins that prefers neurokinin A; (NKA, substance K, neurokinin alpha, neuromedin L), neuropeptide K; (NPK); or neuropeptide gamma over other tachykinins. Neurokinin-2 (NK-2) receptors have been cloned and are similar to other G-protein coupled receptors.Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of PAIN, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses.Receptors, Neurokinin-3: A class of cell surface receptors for tachykinins that prefers neurokinin B (neurokinin beta, neuromedin K) over other tachykinins. Neurokinin-3 (NK-3) receptors have been cloned and are members of the G-protein coupled receptor superfamily. They have been found in the central nervous system and in peripheral tissues.Neurokinin-1 Receptor Antagonists: Compounds that inhibit or block the activity of NEUROKININ-1 RECEPTORS.Plant Diseases: Diseases of plants.Arabidopsis: A plant genus of the family BRASSICACEAE that contains ARABIDOPSIS PROTEINS and MADS DOMAIN PROTEINS. The species A. thaliana is used for experiments in classical plant genetics as well as molecular genetic studies in plant physiology, biochemistry, and development.Soybeans: An annual legume. The SEEDS of this plant are edible and used to produce a variety of SOY FOODS.Cotyledon: A part of the embryo in a seed plant. The number of cotyledons is an important feature in classifying plants. In seeds without an endosperm, they store food which is used in germination. In some plants, they emerge above the soil surface and become the first photosynthetic leaves. (From Concise Dictionary of Biology, 1990)Salicylic Acid: A compound obtained from the bark of the white willow and wintergreen leaves. It has bacteriostatic, fungicidal, and keratolytic actions.Plant Leaves: Expanded structures, usually green, of vascular plants, characteristically consisting of a bladelike expansion attached to a stem, and functioning as the principal organ of photosynthesis and transpiration. (American Heritage Dictionary, 2d ed)Tobacco: A plant genus of the family SOLANACEAE. Members contain NICOTINE and other biologically active chemicals; its dried leaves are used for SMOKING.MercaptoethylaminesAminopropionitrile: Reagent used as an intermediate in the manufacture of beta-alanine and pantothenic acid.Patents as Topic: Exclusive legal rights or privileges applied to inventions, plants, etc.Wound Healing: Restoration of integrity to traumatized tissue.Cyanides: Inorganic salts of HYDROGEN CYANIDE containing the -CN radical. The concept also includes isocyanides. It is distinguished from NITRILES, which denotes organic compounds containing the -CN radical.Atrial Remodeling: Long-term changes in the electrophysiological parameters and/or anatomical structures of the HEART ATRIA that result from prolonged changes in atrial rate, often associated with ATRIAL FIBRILLATION or long periods of intense EXERCISE.Cicatrix: The fibrous tissue that replaces normal tissue during the process of WOUND HEALING.Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones.Bile: An emulsifying agent produced in the LIVER and secreted into the DUODENUM. Its composition includes BILE ACIDS AND SALTS; CHOLESTEROL; and ELECTROLYTES. It aids DIGESTION of fats in the duodenum.Tetrazoles2-Isopropylmalate Synthase: An enzyme that catalyzes the first step in the biosynthetic pathway to LEUCINE, forming isopropyl malate from acetyl-CoA and alpha-ketoisovaleric acid. This enzyme was formerly listed as EC Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated.Chenodeoxycholic Acid: A bile acid, usually conjugated with either glycine or taurine. It acts as a detergent to solubilize fats for intestinal absorption and is reabsorbed by the small intestine. It is used as cholagogue, a choleretic laxative, and to prevent or dissolve gallstones.

Synergistic induction of apoptosis in human leukemia cells (U937) exposed to bryostatin 1 and the proteasome inhibitor lactacystin involves dysregulation of the PKC/MAPK cascade. (1/44)

Cotreatment with a minimally toxic concentration of the protein kinase C (PKC) activator (and down-regulator) bryostatin 1 (BRY) induced a marked increase in mitochondrial dysfunction and apoptosis in U937 monocytic leukemia cells exposed to the proteasome inhibitor lactacystin (LC). This effect was blocked by cycloheximide, but not by alpha-amanitin or actinomycin D. Qualitatively similar interactions were observed with other PKC activators (eg, phorbol 12-myristate 13-acetate and mezerein), but not phospholipase C, which does not down-regulate the enzyme. These events were examined in relationship to functional alterations in stress (eg, SAPK, JNK) and survival (eg, MAPK, ERK) signaling pathways. The observations that LC/BRY treatment failed to trigger JNK activation and that cell death was unaffected by a dominant-interfering form of c-JUN (TAM67) or by pretreatment with either curcumin or the p38/RK inhibitor, SB203580, suggested that the SAPK pathway was not involved in potentiation of apoptosis. In marked contrast, perturbations in the PKC/Raf/MAPK pathway played an integral role in LC/BRY-mediated cell death based on evidence that pretreatment of cells with bisindolylmaleimide I, a selective PKC inhibitor, or geldanamycin, a benzoquinone ansamycin, which destabilizes and depletes Raf-1, markedly suppressed apoptosis. Furthermore, ERK phosphorylation was substantially prolonged in LC/BRY-treated cells compared to those exposed to BRY alone, and pretreatment with the highly specific MEK inhibitors, PD98059, U0126, and SL327, opposed ERK activation while protecting cells from LC/BRY-induced lethality. Together, these findings suggest a role for activation and/or dysregulation of the PKC/MAPK cascade in modulation of leukemic cell apoptosis following exposure to the proteasome inhibitor LC. (Blood. 2001;97:2105-2114)  (+info)

Alcohol-induced c-Fos expression in the Edinger-Westphal nucleus: pharmacological and signal transduction mechanisms. (2/44)

Mapping inducible transcription factors has shown that the Edinger-Westphal nucleus is preferentially sensitive to alcohol intoxication. Herein, we characterize the pharmacological and signal transduction mechanisms related to alcohol-induced c-Fos expression in Edinger-Westphal neurons. Using immunohistochemistry, we show that pretreatment with gamma-aminobutyric acid (GABA)-ergic antagonists (4 mg/kg bicuculline and 45 mg/kg pentylenetetrazole) attenuates induction of c-Fos expression by alcohol (2.4 g/kg, intraperitoneal). In addition, 10 mg/kg 2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl)4,5-dihydro-1H-imidazole (RX 821002), an alpha(2A/D)-adrenoceptor antagonist, and 20 mg/kg haloperidol, a dopamine antagonist, also block alcohol-induced c-Fos expression in Edinger-Westphal neurons. No effects were seen in alcohol-induced c-Fos after the pretreatment of 20 mg/kg propranolol (beta-adrenoceptor antagonist), 10 mg/kg 2-(2-(4-(2-methoxyphenyl)piperazin-1-yl) ethy)-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride (ARC 239) (alpha(2B/C)-adrenoceptor antagonist), or 30 mg/kg naltrexone (opioid antagonist). Although positive modulators for the GABA(A) receptor (20 mg/kg 3alpha-hydroxy-5alpha-pregnan-20-one and 10-30 mg/kg chlordiazepoxide) and opioid receptor (10 mg/kg morphine) produced significant elevations, agonists for alpha(2)-adrenoceptors (clonidine) and dopamine receptors (apomorphine) had no effect on Edinger-Westphal c-Fos expression. These findings suggest that alcohol-induced c-Fos expression in Edinger-Westphal results from direct interactions with GABA(A) receptors, which are modified by alpha(2A/D)-adrenoceptors and dopamine receptors. Also using immunohistochemistry to identify potential intracellular mechanisms associated with alcohol-induced c-Fos expression in Edinger-Westphal, we show time-dependent increases in serine 727 phospho-signal transducer and activator of transcription 3 (Stat3) but no changes in phospho-cAMP response element-binding protein and phospho-Elk1. Time-dependent increases in phospho-extracellular signal-regulated kinase (ERK) 1/2 were found to occur simultaneously with increases in serine 727 phospho-Stat3. Finally, blockade of ERK 1/2 phosphorylation with the mitogen-activated protein kinase (MEK) 1/2 inhibitor SL327 blocked alcohol-induced c-Fos expression, suggesting that alcohol induces c-Fos in Edinger-Westphal neurons through activation of the MEK1/2-ERK1/2-Stat3 pathway.  (+info)

Significant neuroprotection against ischemic brain injury by inhibition of the MEK1 protein kinase in mice: exploration of potential mechanism associated with apoptosis. (3/44)

MEK1/2 is a serine/threonine protein kinase that phosphorylates and activates extracellular signal-responsive kinase (ERK)1/2. In the present study we explored the role of MEK1/2 in ischemic brain injury using a selective MEK1/2 inhibitor, SL327, in mice. C57BL/6 mice were subjected to a 30-min occlusion of the middle cerebral artery (MCAO) followed by reperfusion. Western blot analysis demonstrated the immediate activation of MEK/ERK after reperfusion (within the first 10 min) in the ischemic brain; this activation was dose dependently blocked by SL327 (10-100 mg/kg, i.p.). A single dose of SL327 (100 mg/kg) administered 15 min before or 25 min after the onset of ischemia resulted in 63.6% (n = 18, p < 0.001) and 50.7% (n = 18, p < 0.01) reduction in infarct size, respectively, compared with vehicle-treated mice. Similarly, SL327 significantly reduced neurological deficits 1 to 3 days after reperfusion (n = 12, p < 0.01). The salutary effect of SL327-induced neuroprotection was independent of mitochondrial cytochrome c release or caspase-8-mediated apoptosis; however, SL327 markedly suppressed the levels of active caspase-3 and DNA fragmentation (as a measure of apoptosis) after ischemia/reperfusion. Our data suggest that the inhibition of MEK1/2 results in neuroprotection from reperfusion injury and that this protection may be associated with the reduction in apoptosis.  (+info)

A role for ERK MAP kinase in physiologic temporal integration in hippocampal area CA1. (4/44)

Recent studies demonstrate a requirement for the Extracellular signal Regulated Kinase (ERK) mitogen-activated protein kinase (MAPK) cascade in both the induction of long-lasting forms of hippocampal synaptic plasticity and in hippocampus-dependent associative and spatial learning. In the present studies, we investigated mechanisms by which ERK might contribute to synaptic plasticity at Schaffer collateral synapses in hippocampal slices. We found that long-term potentiation (LTP) induced with a pair of 100-Hz tetani does not require ERK activation in mice whereas it does in rats. However, in mice, inhibition of ERK activation blocked LTP induced by two LTP induction paradigms that mimicked the endogenous theta rhythm. In an additional series of studies, we found that mice specifically deficient in the ERK1 isoform of MAPK showed no impairments in tests of hippocampal physiology. To investigate ERK-dependent mechanisms operating during LTP-inducing stimulation paradigms, we monitored spike production in the cell body layer of the hippocampus during the period of theta-like LTP-inducing stimulation. Theta-burst stimulation (TBS) produced a significant amount of postsynaptic spiking, and the likelihood of spike production increased progressively over the course of the three trains of TBS independent of any apparent increase in Excitatory Post-Synaptic Potential (EPSP) magnitude. Inhibition of ERK activation dampened this TBS-associated increase in spiking. These data indicate that, for specific patterns of stimulation, ERK may function in the regulation of neuronal excitability in hippocampal area CA1. Overall, our data indicate that the progressive increase in spiking observed during TBS represents a form of physiologic temporal integration that is dependent on ERK MAPK activity.  (+info)

Preparation of (cyanomethylene)trimethylphosphorane as a new Mitsunobu-type reagent. (5/44)

(Cyanomethylene)trimethylphosphorane (CMMP) mediates Mitsunobu-type reactions, which are a versatile method for the alkylation of various nucleophiles (HA) with alcohols (ROH) to give RA. CMMP is quite effective for the reaction of carbon nucleophiles whose pK(a) value are higher than 13. CMMP, which is very sensitive to air and moisture, was synthesized in two steps starting from chloroacetonitrile.  (+info)

The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. (6/44)

The neurobiological underpinnings of mood modulation, molecular pathophysiology of manic-depressive illness, and therapeutic mechanism of mood stabilizers are largely unknown. The extracellular signal-regulated kinase (ERK) pathway is activated by neurotrophins and other neuroactive chemicals to produce their effects on neuronal differentiation, survival, regeneration, and structural and functional plasticity. We found that lithium and valproate, commonly used mood stabilizers for the treatment of manic-depressive illness, stimulated the ERK pathway in the rat hippocampus and frontal cortex. Both drugs increased the levels of activated phospho-ERK44/42, activated phospho-ribosomal protein S6 kinase-1 (RSK1) (a substrate of ERK), phospho-CREB (cAMP response element-binding protein) and phospho-B cell lymphoma protein-2 antagonist of cell death (substrates of RSK), and BDNF. Inhibiting the ERK pathway with the blood-brain barrier-penetrating mitogen-activated protein kinase (MAP kinase)/ERK kinase (MEK) kinase inhibitor SL327, but not with the nonblood-brain barrier-penetrating MEK inhibitor U0126, decreased immobility time and increased swimming time of rats in the forced-swim test. SL327, but not U0126, also increased locomotion time and distance traveled in a large open field. The behavioral changes in the open field were prevented with chronic lithium pretreatment. SL327-induced behavioral changes are qualitatively similar to the changes induced by amphetamine, a compound that induces relapse in remitted manic patients and mood elevation in normal subjects. These data suggest that the ERK pathway may mediate the antimanic effects of mood stabilizers.  (+info)

Sustained extracellular signal-regulated kinase 1/2 phosphorylation in neonate 6-hydroxydopamine-lesioned rats after repeated D1-dopamine receptor agonist administration: implications for NMDA receptor involvement. (7/44)

Extracellular signal-regulated kinase (ERK) 1/2, a well known regulator of gene expression, is likely to contribute to signaling events underlying enduring neural adaptations. Phosphorylated (phospho)-ERK was examined immunohistochemically after both single and repeated (i.e., sensitizing) doses of the partial D1-dopamine (DA) receptor agonist SKF-38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benazepine HCl) to adult rats lesioned as neonates (neonate lesioned) with 6-hydroxydopamine. Remarkably, prolonged phospho-ERK accumulated primarily in layers II-III of medial prefrontal cortex (MPC), where it declined gradually yet remained significantly elevated for at least 36 d after repeated doses of SKF-38393. Sustained (> or =7 d) phospho-ERK was observed for shorter periods in various other cortical regions but was not detectable in striatum or nucleus accumbens. At 36 d, an additional injection of SKF-38393 to sensitized rats restored phospho-ERK to maximal levels only in MPC when examined 7 d later. Phosphorylated cAMP response element-binding protein (CREB), examined 7 d after the sensitizing regimen, was observed exclusively in MPC, where it was abundant throughout all layers. Systemic injections of SL327 (alpha-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitri le), an inhibitor of the upstream ERK activator mitogen ERK kinase, attenuated both ERK and CREB phosphorylation in layers II-III of MPC. Pretreatment with the D1 antagonist SCH-23390 ((R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-OL maleate) inhibited the prolonged increase in MPC phospho-ERK, whereas the 5-HT2 receptor antagonist ketanserin (3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione tartrate) was ineffective. Competitive and noncompetitive NMDA receptor antagonists also blocked sustained ERK phosphorylation. Collectively, the present results demonstrate coupling of D1 and NMDA receptor function reflected in sustained activation of the ERK signaling pathway in MPC of SKF-38393-sensitized neonate-lesioned rats. Ultimately, long-lasting phosphorylation of ERK and CREB in MPC may play a pivotal role in any permanent adaptive change(s) in these animals.  (+info)

ERK kinase inhibition stabilizes the aryl hydrocarbon receptor: implications for transcriptional activation and protein degradation. (8/44)

The ultimate carcinogen and metabolite of benzo-[a]pyrene-7,8-dihydrodiol, benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide (+/-), stimulates apoptosis, and this process can be blocked by extracellular signal-regulated kinase (Erk) kinase inhibitors. However, we show here that Erk kinase inhibitors were unable to prevent B[a]P-7,8-dihydrodiol-induced apoptosis, leading us to speculate that Erk kinases are linked to regulation of the aryl hydrocarbon (Ah) receptor. Cotreatment of hepa1c1c7 cells with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and Erk kinase inhibitor PD98059, U0126, or SL327 led to enhanced nuclear accumulation of Ah receptor but with a reduced capacity to complement TCDD induction of Cyp1a1. This is explained in part by the ability of Erk kinase inhibitors to alter the steady-state levels of cellular Ah receptor, a result that leads to a dramatic induction in detectable receptor levels. These changes in cellular Ah receptor levels are associated with delayed degradation of the Ah receptor because TCDD-initiated degradation is reversed when cells are co-treated with TCDD and Erk kinase inhibitors. Erk kinase is linked to Ah receptor expression, as demonstrated by reductions in total Ah receptor levels after overexpression of constitutively active MEK1. In addition, Erk kinase activity modulates the transcriptional response because MEK1 overexpression enhances TCDD-initiated transactivation potential of the receptor. Thus, Erk kinase activity facilitates ligand-initiated transcriptional activation while targeting the Ah receptor for degradation. Immunoprecipitation experiments of the Ah receptor indicate that Erk kinase activity is associated with the receptor. It is interesting that the carboxyl region of the Ah receptor is associated with the transactivation region as well as the site for ubiquitination, indicating that Erk kinase-dependent phosphorylation targets the carboxyl region of the receptor.  (+info)

  • I guess we'll have to wait many years…" he told me, "A simple estimate we did in our publication on aminoacetonitrile (Belloche et al. (
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  • Organ specificity of the effects of D-penicillamine and of lathyrogen (aminoacetonitrile) on mechanical properties of connective and supporting tissue. (