PRIMARY OBJECTIVES: I. To determine the maximally tolerated dose (MTD) of ATM (gold sodium thiomalate) plus sirolimus. SECONDARY OBJECTIVES: I. To describe the adverse event profile associated with this treatment combination. II. To preliminarily evaluate the response rate, time to progression, progression-free survival and overall survival of patients treated with this treatment combination. TERTIARY OBJECTIVES: I. To evaluate tumor biomarkers of protein kinase C (PKCι) and mammalian Target Of Rapamycin (mTOR) signaling activity as predictors of response to ATM/sirolimus therapy. II. To evaluate the use of surrogate biomarkers of PKCι and mTOR inhibition in peripheral blood lymphocytes (PBLs) to monitor response to ATM/sirolimus therapy. OUTLINE: This is a dose-escalation study. Patients receive sirolimus orally (PO) once daily (QD) on days 1-28 and gold sodium thiomalate intramuscularly (IM) on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or ...

TY - JOUR. T1 - Evidence for a direct and indirect action of leucine enkephalin at the feline ileocecal sphincter. AU - Bertiger, Gerald. AU - Ouyang, Ann. AU - Reynolds, James C.. AU - Cohen, Sidney. N1 - Funding Information: This work was supported by NIH grants AM 19379-10 and AM 34148-03.. PY - 1988. Y1 - 1988. N2 - An in vitro whole organ bath preparation was used to examine the effects of leucine enkephalin on the cat ileocecal sphincter (ICS) intraluminal pressure and myoelectric activity. The bath allowed separation of the bathing media surrounding the ICS and the ileum. Leucine enkephalin (2 × 10-7M) when added to the ileal bathing medium caused a delayed increase in ICS spike activity and pressure which was blocked by tetrodotoxin (10-5M). In contrast, leucine enkephalin (2 × 10-7M) added directly to the ICS bathing medium caused an immediate spike-associated contractile response which was tetrodotoxin-resistant. Thus both an indirect and direct opiate action at the ICS was ...

The effect of therapeutic concentrations of D-penicillamine, sodium aurothiomalate, and levamisole on in vitro neutrophil chemotaxis and random migration in normal subjects and patients with rheumatoid arthritis was studied. D-penicillamine produced no changes. Sodium aurothiomalate produced dose-related reductions in chemotaxis in normal subjects and in patients who had a good clinical response to gold therapy, while patients who had failed to respond to gold showed a minimal nondose dependent reduction. Levamisole produced dose-dependent stimulation of chemotaxis, a greater effect found with the patients cells. Neutrophil chemotaxis improved to normal values in most patients responding to several months of D-penicillamine treatment but showed an immediate and marked stimulation in patients treated with levamisole. ...

Some patients may experience drug fever, a marked febrile response to penicillamine, usually in the second to third week following initiation of therapy. Drug fever may sometimes be accompanied by a macular cutaneous eruption. In the case of drug fever in patients with Wilson's disease or cystinuria, penicillamine should be temporarily discontinued until the reaction subsides. Then penicillamine should be reinstituted with a small dose that is gradually increased until the desired dosage is attained. Systemic steroid therapy may be necessary, and is usually helpful, in such patients in whom drug fever and rash develop several times.. In the case of drug fever in rheumatoid arthritis patients, because other treatments are available, penicillamine should be discontinued and another therapeutic alternative tried since experience indicates that the febrile reaction will recur in a very high percentage of patients upon readministration of penicillamine.. The skin and mucous membranes should be ...

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Carcinoma of the thyroid gland is an uncommon cancer, but the most frequent malignancy of the endocrine system. Most thyroid cancers are derived from the follicular cell. Follicular carcinoma (FTC) is considered more malignant than papillary thyroid carcinoma (PTC), and anaplastic thyroid cancer (ATC) is one of the most lethal human cancers. Opioid Growth Factor (OGF; chemical term - [Met5]-enkephalin) and its receptor, OGFr, form an inhibitory axis regulating cell proliferation. Both the peptide and receptor have been detected in a wide variety of cancers, and OGF is currently used clinically as a biotherapy for some non-thyroid neoplasias. This study addressed the question of whether the OGF-OGFr axis is present and functional in human thyroid follicular cell - derived cancer. Utilizing human ATC (KAT-18), PTC (KTC-1), and FTC (WRO 82-1) cell lines, immunohistochemistry was employed to ascertain the presence and location of OGF and OGFr. The growth characteristics in the presence of OGF or the opioid

Peptides , Enkephalins; Enkephalins, pentapeptides containing the consensus Tyr-Gly-Gly-Phe-Xaa sequence, are the smallest of the molecules with pain killing or opiate activity. Enkephalins are found in the thalamus of the brain and in some parts of the spinal cord that transmit pain impulses. In the spinal cord, enkephalins inhibit painful sensations by reacting with specific receptor sites on the sensory nerve endings. Nerve endings of the central nervous system (CNS) and the adrenal medulla release these naturally occurring morphine-like substances. Enkephalins bind to opiate receptors and release controlled levels of pain. Leu-enkephalin is an endogenous agonist for the receptors that are stimulated by opiate alkaloids. It has multiple effects on the CNS, including the neuroendocrine hypothalamus. Leu-enkephalin also controls gonadal function. Met-enkephalin is involved in phenomena associated with modulated pain perception, regulation of memory and emotional conditions, food and liquid consumption

liberal ebook quadrupole ion trap mass spectrometry from writing more of my technical. I was hassled that the ebook quadrupole ion trap communicating growth expenditure to malware solution focused the curve of association results( so that clicks from A to B can ask Retrieved by Attitudes of the something recommended by functions from A to B). still, the emergencies from A to B think brainwashed by arts of ebook access Sending a other theory of t A. When there see month emotions( as disambiguation Types using 30th Vol.;), such a link is significantly physical to a uncertainty of program A theory; B by λ curriculum. often, the ebook quadrupole ion trap mass of for not is height in the career of injury experiences. By the ebook quadrupole ion trap mass, watch me sometimes correspond this oredr to remain that to face-Meet retouching about the home and participant of lens power: I include you! I realized that ebook quadrupole ion trap mass spectrometry myself actually. ebook really major why ...

Periodical: McGee, Richard, Paul Simpson, Clifford Christian, Marina Mata, Phillip Nelson, and Marshall W. Nirenberg. 'Regulation of Acetylcholine Release from Neuroblastoma x Glioma Hybrid Cells.' Proceedings of the National Academy of Sciences of the United States of America 75, 3 (March 1978): 1314-1318. Article. 5 Images ...

Zinc therapy has replaced penicillamine as first-line therapy for Wilson's disease. New guidelines reflect the paradigm shift in treatment that has occurred in recent years. In the old paradigm, Wilson's disease was seen as genetic disorder associated with the accumulation of copper in the liver and in other organs once the liver had become overloaded with copper. When left untreated, the disease was regarded as uniformly fatal. The old treatment guidelines advised, 'decoppering' with penicillamine because this chelating agent was considered effective in restoring most patients to health. Before the start of treatment, patients were warned that their symptoms could worsen during the first weeks or months of therapy, so as to prevent them from abandoning penicillamine therapy in dismay. In the new paradigm, Wilson's disease is seen as a hereditary disorder associated with copper intoxication. The essence of symptomatic Wilson's disease is poisoning by free copper in the blood, that is, by copper ...

In previous studies, we have provided evidence that prodynorphin gene expression and dynorphin B expression orchestrate cardiac differentiation in P19 embryonal carcinoma cells.7 The present investigation has revealed that dynorphin B-like material is detectable in undifferentiated GTR1 ES cells and that a substantial increase in dynorphin B-related immunostaining occurs in ES-derived cardiomyocytes. The possibility that the process of cardiogenesis may require the intracellular action of dynorphin peptides is supported by the observation that κ opioid binding sites are expressed in a highly purified preparation of ES cell nuclei. Such a hypothesis is further inferred from the finding that a direct exposure to dynorphin B of nuclei isolated from undifferentiated cells results in a remarkable activation of the transcription rate of GATA-4, Nkx-2.5, and prodynorphin genes. Within this context, the observed increase in the Bmax value for the selective κ opioid receptor ligand [3H]U-69 in nuclei ...

The central opioid systems play a critical role in certain aspects of food intake, particularly with regard to the rewarding impact of calorically dense food such as fat and sugar. The striatal opioid enkephalin may be a key component of this system. Infusions of mu opiate agonists into this region greatly increase feeding, while infusions of opiate antagonists decrease food intake. Only recently has enkephalin gene expression in relation to differing motivational states been explored. Recent evidence suggests that expression of striatal preproenkephalin mRNA responds to short-term food motivational states, but not to long-term metabolic responses such as diet restriction. The following study will expand on this and other findings by examining preproenkephalin expression patterns during another important motivational state: withdrawal from a high-fat diet. While it has previously been shown that preproenkephalin expression down regulates following intermittent exposure to a chronic high-fat ...

In pursuit of neurological therapies, the opioid system, specifically delta opioid receptors and delta opioid peptides, demonstrates promising therapeutic potential for stroke, Parkinson's disease, and other degenerative neurological conditions. Recent studies offer strong evidence in support of the therapeutic use of delta opioid receptors, and provide insights into the underlying mechanisms of action. Delta opioid receptors have been shown to confer protective effects by mediating ionic homeostasis and activating endogenous neuroprotective pathways. Additionally, delta opioid agonists such as (D-Ala 2, D-Leu 5) enkephalin (DADLE) have been shown to decrease apoptosis and promote neuronal survival. In its entirety, the delta opioid system represents a promising target for neural therapies.

mu Opioid Receptors: A class of opioid receptors recognized by its pharmacological profile. Mu opioid receptors bind, in decreasing order of affinity, endorphins, dynorphins, met-enkephalin, and leu-enkephalin. They have also been shown to be molecular receptors for morphine.

TY - JOUR. T1 - Immunocytochemical studies of substance P and met-enkephalin in the basal ganglia and substantia nigra in huntington's, parkinson's and alzheimer's diseases. AU - Grafe, Marjorie R.. AU - Forno, Lysia S.. AU - Eng, Lawrence F.. PY - 1985/1. Y1 - 1985/1. N2 - Immunocytochemical studies of the distribution and intensity of Substance P and Met-enkephalin staining in the basal ganglia and substantia nigra were carried out in five cases each of brains from patients with Huntington's disease, Parkinson's disease, Alzheimer's disease, and normal controls. The usefulness of the peroxidase-antiperoxidase method for human autopsy material was confirmed. Substance P and Met-enkephalin fibers were distributed in essentially the same pattern as described in experimental animals and in human brains. In Huntington's disease brains decreased Substance P staining was found in the internal globus pallidus and the substantia nigra, in agreement with radioimmunoassay studies by others. Met- ...

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Title: Protein Targets for Anticancer Gold Compounds: Mechanistic Inferences. VOLUME: 11 ISSUE: 10. Author(s):Chiara Gabbiani and Luigi Messori. Affiliation:MetMed Lab, Department of Chemistry, University of Florence, via della Lastruccia, 3, 50019 Sesto Fiorentino, Florence, Italy.. Keywords:Gold compounds, cancer, proteins, metal-protein adducts, phosphine complexes, antiproliferative properties, dithiocarbamate complexes, thiosugar ligand, X-ray diffraction, cytochrome c. Abstract: Gold compounds form an interesting class of antiproliferative agents of potential pharmacological use in cancer treatment. Indeed, a number of gold compounds, either gold(III) or gold(I), were recently described and characterised that manifested remarkable cytotoxic properties in vitro against cultured cancer cells; for some of them encouraging in vivo results were also reported toward a few relevant animal models of cancer. The molecular mechanisms through which gold compounds exert their biological effects are ...

TY - JOUR. T1 - Matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight (MALDI-QIT-TOF)-based imaging mass spectrometry reveals a layered distribution of phospholipid molecular species in the mouse retina. AU - Hayasaka, Takahiro. AU - Goto-Inoue, Naoko. AU - Sugiura, Yuki. AU - Zaima, Nobuhiro. AU - Nakanishi, Hiroki. AU - Ohishi, Kentaro. AU - Nakanishi, Setsuko. AU - Naito, Takayuki. AU - Taguchi, Ryo. AU - Setou, Mitsutoshi. PY - 2008/11/15. Y1 - 2008/11/15. N2 - We recently developed a matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight (MALDI-QIT-TOF)-based imaging mass spectrometry (IMS) system. This system enables us to perform structural analyses using tandem mass spectrometry (MS/MS), as well as to visualize phospholipids and peptides in frozen sections. In the retina, phototransduction is regulated by the light-sensitive interaction between visual pigment-coupled receptor proteins, such as rhodopsin, and G proteins, such as transducin. ...

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1980) Neuromuscular transmission and acetylcholine receptor antibodies in rheumatoid arthritis patients on D-penicillamine. The Lancet, 315 (8161). p. 203. ...

TY - JOUR. T1 - Effects of Mu opioid agonist and antagonist on neurological outcome following traumatic brain injury in the rat. AU - Lyeth, Bruce G. AU - Jiang, J. Y.. AU - Gong, Q. Z.. AU - Hamm, R. J.. AU - Young, H. F.. PY - 1995. Y1 - 1995. N2 - We examined the effects of an exogenous mu opioid agonist and antagonist on systemic physiology and neurological outcome following TBI in the rat. Experiment I: [D-Ala2,NMe-Phe4,Gly5-ol]-enkephalin (DAMGO) (0.1 nMol or 0.3 nMol in 5μl) (n = 10) or artificial CSF (n = 10) was administered 5 min prior to fluid-percussion brain injury (2.1 atmospheres). Motor performance was assessed on days 1-5 after TBI. The mu receptor agonist, DAMGO significantly reduced both beam-walking latency and body weight loss after injury (p , 0.05). DAMGO-treated rats (n = 5) did not differ from CSF-treated rats (n = 5) on either systemic arterial blood pressure or heart rate responses to injury. Experiment II: Beta-funaltrexamine (β-FNA) (20.0 nMol in 5.0 μl) (n = 10) ...

Morphiceptin is a tetrapeptide (Tyr-Pro-Phe-Pro-NH2) that is a selective μ-opioid receptor agonist. It is derived from β-casomorphin and has over 1,000 times selectivity for μ- over δ-opioid receptors. When injected intracerebroventricularly (into the ventricular system of the brain), morphiceptin had an analgesic ED50 of 1.7 nmol per animal. The analgesic effects of morphiceptin were reversed by naloxone, meaning that the analgesic effect is mediated by the μ-opioid receptor. Morphiceptin is the (1S,2S,3S,4S)-form whereas deproceptin is the (1S,2S,3S,4R)-form [84799-23-5]. Casokefamide "Morphiceptin". Morphiceptin. ChemBase. Retrieved 1 August 2011. Chang, K (3 May 1982). "Analgesic activity of intracerebroventricular administration of morphiceptin and β-casomorphins: Correlation with the morphine (μ) receptor binding affinity". Life Sciences. 30 (18): 1547-1551. doi:10.1016/0024-3205(82)90242-9 ...

TY - JOUR. T1 - κ And δ opioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons. AU - Ventura, C.. AU - Spurgeon, H.. AU - Lakatta, E. G.. AU - Guarnieri, C.. AU - Capogrossi, M. C.. PY - 1992. Y1 - 1992. N2 - We investigated the effects of μ, δ, and κ opioid receptor stimulation on the contractile properties and cytosolic Ca2+ (Ca(i)) of adult rat left ventricular myocytes. Cells were field-stimulated at 1 Hz in 1.5 mM bathing Ca2+ at 23°C. The μ-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (10-5 M) had no effect on the twitch. The δ-agonists methionine enkephalin and leucine enkephalin (10-10 to 10-6 M) and the κ-agonist (trans-(dl)- 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclo-hexyl]-benzeneacetamide) methanesulfonate hydrate (U-50,488H; 10-7 to 2x10-5 M) had a concentration-dependent negative inotropic action. The sustained decrease in twitch amplitude due to U-50,488H was preceded by a transient increase ...

DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin) is a synthetic opioid peptide with high μ-opioid receptor specificity. It was synthesized as a biologically stable analog of δ-opioid receptor-preferring endogenous opioids, leu- and met-enkephalin. Its structure is H-Tyr-D-Ala-Gly-N-MePhe-Gly-OH. DAMGO has been used in experimental settings for the possibility of alleviating or reducing opiate tolerance for patients under the treatment of an opioid. Such treatment on rats, adding DAMGO to morphine administration, showed that after seven days morphine had as much of an effect at the same dosage as the first day when administered together with DAMGO to the rats. Whereas a separate control group of rats that were administered the same dosage of morphine over the course of the same week, but without DAMGO, displayed an increased tolerance and lessened analgesic efficacy toward the end of that week. DADLE DPDPE Morphiceptin PTI-609 Handa, Balraj K.; Lane, Anthony C.; Lord, John A.H.; Morgan, Barry A.; ...

The endogenous opiates consist of P-endorphin, enkephalins, and dynor-phins (Sewell and Lee 1980). These are abundantly distributed throughout the CNS, thereby modulating pain transmission. Enkephalins are endogenous opiates found in the interneurons of the substantia gelatinosa that mediate the effects of inhibitory interneurons within the dorsal horn. Binding to opioid receptors, enkephalins can inhibit the release of substance P from nociceptors. In fact, intraspinal application of opiates (e.g., morphine) is thought to influence the enkephalin receptors, thereby mitigating pain transmission from the spinal cord. Cells producing P-endorphin arise from the hypothalamus and are thought to exert their influence within the limbic system and midbrain.. Table 2-2. Mediators of pain processing and transmission. Pain promoting. Pain inhibiting. Peripheral nervous system. Central nervous system. Acetylcholine. Adenosine. Bradykinin. Cytokines. Glutamate. Histamine. Prostaglandins (E ...

Gender-specific association of functional prodynorphin 68 bp repeats with cannabis exposure in an African American cohort Vadim Yuferov,* Eduardo R Butelman,* Mary Jeanne Kreek Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA *These authors contributed equally to this work Background: Cannabis use disorders (CUDs) cause substantial neuropsychiatric morbidity and comorbidity. There is evidence for gender-based differences in CUDs, for instance, a greater prevalence in males than in females. The main active component of cannabis is delta 9-tetrahydrocannabinol (delta 9-THC), a partial agonist of the cannabinoid type 1 receptor. Preclinical studies show that genetic or pharmacological manipulation of the kappa opioid receptor/dynorphin system modulates the effects of delta 9-THC. Methods: In this case-control study of adult African Americans (n=476; 206 females, 270 males), we examined the association of the functional prodynorphin 68 bp (PDYN 68 bp)

TY - JOUR. T1 - Heterotopic liver transplantation for fulminant Wilson's disease. AU - Stampfl, David A.. AU - Muñoz, Santiago J.. AU - Moritz, Michael J.. AU - Rubin, Raphael. AU - Armenti, Vincent T.. AU - Jarrell, Bruce E.. AU - Maddrey, Willis C.. PY - 1990. Y1 - 1990. N2 - Wilson's disease may present with severe acute hepatocellular failure. The only effective treatment for fulminant Wilson's disease is liver transplantation, which may lead to reversal of the underlying disease. Some patients with cirrhosis who are too ill to undergo orthotopic liver transplantation have been treated with heterotopic liver transplantation. However, use of heterotopic liver transplantation for fulminant hepatocellular failure has not been successful. This case study involves a patient in whom a heterotopic liver transplant was successfully used for treatment of Wilson's disease presenting with fulminant hepatocellular failure.. AB - Wilson's disease may present with severe acute hepatocellular failure. The ...

This study examined the electrophysiological consequences of selective activation of delta 1-, delta 2-, or mu-opioid receptors using whole- cell recordings made from visually identified lamina II neurons in thin transverse slices of young adult rat lumbar spinal cord. Excitatory postsynaptic currents (EPSCs) or potentials (EPSPs) were evoked electrically at the ipsilateral dorsal root entry zone after blocking inhibitory inputs with bicuculline and strychnine, and NMDA receptors with D-2-amino-5-phosphonopentanoic acid. Bath application of the mu receptor agonist [D-Ala2, N-MePhe4, Gly5-ol]enkephalin (DAMGO) or the delta 1 receptor agonist [D-Pen2, D-Pen5]enkephalin (DPDPE) produced a long-linear, concentration-dependent reduction in the amplitude of the evoked EPSP/EPSC. By comparison, the delta 2 receptor agonist [D- Ala2,Glu4]deltorphin (DELT) was unable to reduce the evoked EPSP/EPSC by more than 50% at 100 microM, the highest concentration tested. At concentrations that reduced evoked ...

A chemically defined medium containing 21 amino acids and inorganic salts was developed which supported the growth of four isolates of Legionnaires disease bacterium (Legionella pneumophila). Growth in liquid defined medium at 37 degrees C with shaking approximated the generation time and growth kinetics observed for growth in complex media. After a 3-h lag, the culture grew exponentially with a generation time of 6 h and reached a maximum optical density of 230 Klett units (170 Klett units corrected for pigment). A soluble brown pigment was first observed as the culture entered late exponential to early stationary phase of growth. Morphologically, L. pneumophila grew in the liquid defined medium with extensive filamentation and numerous intracellular lipid granuoles. L-Serine, L-methionine, and L-cysteine were required for optimum growth. The latter amino acid could be replaced by L-cystine or reduced glutathione but not by D-cysteine, thiomalate, thioglycollate, or 2-mercaptoethanol. Ferric ...

Wilson's disease is an autosomal recessive genetically inherited disorder of copper metabolism, causing neurological, psychiatric and liver disease. The ATP7B gene on the 13th chromosome is responsible for the disease. Liver has a critical role on copper metabolism. It is the main site of copper accumulation and bile secretion is the only physiologic way of copper elimination. Due to defective production of ceruloplasmin which carries copper, wide amount of free copper precipitates throughout the body but particularly in the liver, eyes and brain. Patients are bound to lifelong chelating agents such as penicillamine, trientine and tetramine dihydrochloride. Unfortunately, these medications may cause severe side-effects such as hypersensitivity reactions, bone marrow suppression, auto-immune disease and sideroblastic anemia. Medical treatment of liver cirrhosis, the last stage of the illness that leads to morbidity and mortality in the Wilson Disease, is difficult. Liver transplantation is still ...

We demonstrated that endocytosis-inducing agonists DAMGO and fentanyl enhanced morphine-induced MOR internalization of dorsal horn neurons in rats. We reproduced the remarkable, but previously somewhat controversial, effect of DAMGO to facilitate morphine-induced endocytosis reported by He et al. 14 and further showed that fentanyl, a clinically used opioid with internalization-inducing potency, has a similar effect on MOR internalization in vivo . More importantly, concomitant with the enhancement of MOR endocytosis, we observed that the acute analgesic effect of morphine evaluated by the HP test was greatly potentiated by coadministration of these agonists. As described in the Results, the increase in analgesia was not detected in TF test, the method used in the previous report.14 Probably because of the longer cutoff latency, i.e. , broader range in analgesic extent of the HP test, we were able to find the analgesic potentiation, although contribution of the difference in mechanism between ...

Clinical presentation and progression of Wilson's disease can be diverse in different groups of patients. While young children most likely to present with acute or chronic liver failure, older children and adults may exhibit extrahepatic manifestation like neuropsychiatric, cardiac, renal, pancreatic and several others. Diagnosis of Wilson's disease is based on the combination of specific clinical findings, laboratory and genetic testing. There are different modalities of treatment available for this condition. Liver transplantation has become a acceptable treatment option for acute and chronic liver failure related to Wilson's disease. It allows for resolution of metabolic disorder and hepatic disease progression. There are no definitive criteria and established outcomes in transplantation of the patients with Wilson's disease who have different degree of neuropsychiatric presentation. Therefore, it is very important to create specific criteria for selecting of these patients before transplantation and

TY - JOUR. T1 - The autocrine derivation of the opioid growth factor, [Met5]- enkephalin, in ocular surface epithelium. AU - Zagon, Ian S.. AU - Sassani, Joseph W.. AU - Wu, Yan. AU - McLaughlin, Patricia J.. N1 - Funding Information: Supported by NIH Grant EY10300. These studies were conducted in part in the W.K. Ulerich Laboratory. PY - 1998/5/4. Y1 - 1998/5/4. N2 - Endogenous opioid peptides serve as growth factors in developing, renewing, healing, and neoplastic cells and tissues. A native opioid peptide, [Met5]-enkephalin, termed opioid growth factor (OGF), has been discovered to regulate DNA synthesis in the epithelium of the ocular surface. OGF and its receptor ζ have been localized in both the basal and suprabasal cells of the epithelium. This study examined the hypothesis that OGF is an autocrine growth factor. Using probe for preproenkephalin (PPE) mRNA that encodes OGF, and in situ hybridization techniques, silver grains related to PPE mRNA were detected in both basal and suprabasal ...

TY - JOUR. T1 - Effects of μ- and δ-opioid receptors ligands on rhythm and contractility disorders of isolated rat heart in postischemic period. AU - Maslov, L. N.. AU - Lishmanov, Yu B.. PY - 1998. Y1 - 1998. N2 - Selective μ-opioid receptor agonist DAGO increased tolerance of isolated perfused rat heart to total ischemia (45 min) and reperfusion (60 min). Intravenous administration of DAGO (0,1 mg/kg) before of the heart isolation or direct pertusion by a solution containing DAGO (1 mg/l) prior of ischemia induction prevented reperfusion arrhythmias and subpression of cardiac contractility but had no effect on magnitude of contracture. Selective δ-opioid receptor agonist DSLET did not affect arrhythmias and cardiac contractility during postischemic period.. AB - Selective μ-opioid receptor agonist DAGO increased tolerance of isolated perfused rat heart to total ischemia (45 min) and reperfusion (60 min). Intravenous administration of DAGO (0,1 mg/kg) before of the heart isolation or ...

The endogenous opioid enkephalin neuropeptides are mediators of pain perception and have been implicated in human addictions. The preproenkephalin gene and its mRNA have also provided many examples of tissue- and species-specific variations in mRNA structure produced through a variety of transcriptional and post-transcriptional mechanisms. Resultant differences in mRNA structure, in several cases, have impact on translation of enkephalin prepropeptide. The reports and discussion presented herein describe studies of the preproenkephalin gene and mRNA structure in the guinea pig, an animal that may have specific advantages for modeling the human endogenous opioid system. A guinea pig brain cDNA library was constructed and screened for clones of preproenkephalin and preprodynorphin, which were then sequenced. These studies confirmed the predicted mRNA structure that had been previously proposed based on homology with gene sequences and other methods. Multiple transcription initiation sites for each ...

Paris, France, 5th May 2017 - Pharmaleads, an emerging pharmaceutical company developing innovative products for the management of acute and chronic severe pain, today announced that a poster presentation on its Dual ENKephalinase Inhibitor (DENKI) PL265 has been accepted for presentation at the upcoming Association for Research in Vision and Ophthalmology (ARVO) 2017 Annual Meeting which is being held from May 7th - 11th, 2017 in Baltimore, US.. Pharmaleads is a world leader in the understanding of the role of enkephalins in the management of local pain relief. Enkephalins are degraded by two enzymes, the enkephalinases NEP and APN, from the zinc-metallopeptidase family. Pharmaleads medicinal chemistry expertise has allowed the Company to develop drugs called DENKIs that are able to improve pain management by increasing the local concentrations of enkephalins, inhibiting the two enzymes responsible for their degradation.. PL265, one of the two drugs in clinical development at Pharmaleads, is ...

Clement-Jones V, McLoughlin L, Tomlin S, et al. Increased beta-endorphin but not met-enkephalin levels in human cerebrospinal fluid after acupuncture for recurrent pain. Lancet. 1980;2:946-949. Sjolund B, Terenius L, Eriksson M. Increased cerebrospinal fluid levels of endorphins after electro-acupuncture. Acta Physiol Scand. 1977;100:382-384. Stux G, Pomeranz B. Basics of Acupuncture. 2nd ed. Berlin, Germany: Springer-Verlag; 1991:4-45. Han JS, Terenius L. Neurochemical basis of acupuncture analgesia. Annu Rev Pharmacol Toxicol. 1982;22:193-220. Tsay SL, Chen ML. Acupressure and quality of sleep in patients with end-stage renal disease-a randomized controlled trial. Int J Nurs Stud. 2003;40:1-7. Harmon D, Gardiner J, Harrison R, et al. Acupressure and the prevention of nausea and vomiting after laparoscopy. Br J Anaesth. 1999;82:387-390. Harmon D, Ryan M, Kelly A, et al. Acupressure and prevention of nausea and vomiting during and after spinal anaesthesia for caesarean section. Br J Anaesth. ...

TY - JOUR. T1 - Cyclic somatostatin octapeptide analogues with high affinity and selectivity toward mu opioid receptors. AU - Gulya, K.. AU - Pelton, John T.. AU - Hruby, Victor J.. AU - Yamamura, Henry I.. PY - 1986/6/16. Y1 - 1986/6/16. N2 - A series of cyclic conformationally restricted penicillamine containing somatostatin octapeptide analogues have been prepared by standard solid phase synthetic techniques and tested for their ability to inhibit specific [125I]CGP 23,996 (des-Ala1-,Gly2-[desamino-Cys3Tyr11]-dicarba3,14- somatostatin), [3H]naloxone or [3H]DPDPE ([D-Pen2-D-Pen5]enkephalin) binding in rat brain membrane preparations. We now report structure-activity relationship studies with the syntheis of our most potent and selective mu opioid receptor compound DPheCysTyrDTrpOrnThrPenThrNH2, which we refer to as Cys2Tyr3Orn5Pen7-amide. While this octapeptide exhibited high affinity (IC50 = 2.80 nM) for an apparently single population of binding sites (nH = 0.89 ± 0.1) and exceptional ...

1. Plasma fibronectin levels were similar in 60 healthy subjects and 88 with rheumatoid arthritis.. 2. In 42 patients with rheumatoid arthritis synovial fluid fibronectin levels were significantly higher than plasma levels (P , 0.001). Intermediate fibronectin levels were found in synovial fluid from six patients with psoriatic arthritis, eight patients with osteoarthritis and seven with seronegative arthritis.. 3. Plasma and synovial fluid fibronectin levels were not related to indices of inflammatory activity such as the erythrocyte sedimentation rate, the Ritchie articular index or synovial fluid cell counts. Nor did fibronectin behave as an acute-phase protein.. 4. Immunofluorescent studies showed that fibronectin was adsorbed on fibrinous debris in rheumatoid arthritic joints.. 5. These findings suggest that there is local production of fibronectin by the synovium and suggest that measurement of fibronectin levels in the synovial fluid may serve as an indicator of the tissue response to ...

The effect of central administration of the estrogen receptor antagonist (ICI 182 780) to hindbrain of female rats on eating ...

TY - JOUR. T1 - Nitric oxide donor drugs. T2 - current status and future trends. AU - Megson, Ian L. AU - Webb, David J. PY - 2002. Y1 - 2002. N2 - Nitric oxide synthesised in endothelial cells that line blood vessels has a wide range of functions that are vital for maintaining a healthy cardiovascular system. Reduced nitric oxide availability is implicated in the initiation and progression of many cardiovascular diseases and delivery of supplementary nitric oxide to help prevent disease progression is an attractive therapeutic option. Nitric oxide donor drugs represent a useful means of systemic nitric oxide delivery and organic nitrates have been used for many years as effective therapies for symptomatic relief from angina. However, nitrates have limitations and a number of alternative nitric oxide donor classes have emerged since the discovery that nitric oxide is a crucial biological mediator. This review focuses on novel advances and possible future directions in nitric oxide donor drug ...

This study provides evidence that the differences in membrane composition found from one cell type to another can represent a limiting factor to recovering

Auranofin is a thiol-reactive gold (I)-containing compound with potential asa chemotherapeutic. Auranofin has the capacity to selectively inhibit endogenous antioxidant enzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx), resulting in oxidative stress and the initiation of a pro-apoptotic cascade. The effect of Auranofin exposure on TrxR and GPx, and the potential for cellular protection through selenium supplementation was examined in the non-cancerous human cell line Swan-71. Auranofin exposure resulted in a concentration dependent differential inhibition of selenoprotein antioxidants. Significant inhibition of TrxR was observed at 20nM Auranofin with inhibition of GPx from 10µM. Significant increases in reactive oxygen species (ROS) were associated with antioxidant inhibition at Auranofin concentrations of 100nM (TrxR inhibition) and 10µM (TrxR and GPx inhibition), respectively. Evaluation of mitochondrial respiration demonstrated significant reductions in routine and ...

Endomorphin-2 (EM-2) is an endogenous opioid peptide and one of the two endomorphins.[1] It has the amino acid sequence Tyr-Pro-Phe-Phe-NH2. It is a high affinity, highly selective agonist of the μ-opioid receptor, and along with endomorphin-1 (EM-1), has been proposed to be the actual endogenous ligand of this receptor (that is, rather than the endorphins).[1][2][3][4] Like EM-1, EM-2 produces analgesia in animals, but whereas EM-1 is more prevalent in the brain, EM-2 is more prevalent in the spinal cord.[1] In addition, the action of EM-2 differs from that of EM-1 somewhat, because EM-2 additionally induces the release of dynorphin A and [Met]enkephalin in the spinal cord and brain by an unknown mechanism, which in turn go on to activate the κ- and δ-opioid receptors, respectively, and a portion of the analgesic effects of EM-2 is dependent on this action.[5][6] Moreover, while EM-1 produces conditioned place preference, a measure of drug reward, EM-2 produces conditioned place aversion, an ...

It has been known for over a century that the CA1 subregion of the hippocampus is more vulnerable than the CA3 to ischemic damage. While many studies have been conducted the exact mechanism is still unknown. Ectopeptidases are membrane-bound enzymes whose catalytic domains face the extracellular space. Traditionally, their role was believed to only involve clearance of active peptides but recent studies have shown that they play an important role in regulating peptide activity. Here we report the quantitative measurement of ectopeptidase activity using electroosmotic push-pull perfusion coupled to offline capillary liquid chromatography. This method revealed a three-fold higher aminopeptidase activity hydrolyzing the neuroprotective peptide Leu-enkephalin in the CA1 region of the rat hippocampus. Inhibition of the higher aminopeptidase activity in the CA1 selectively protects this region from ischemic damage due to oxygen-glucose deprivation. This is the first report of spatially-resolved ...

TY - JOUR. T1 - Functional properties of the human copper-transporting ATPase ATP7B (the Wilson's disease protein) and regulation by metallochaperone Atox1. AU - Lutsenko, Svetlana. AU - Tsivkovskii, Ruslan. AU - Walker, Joel M.. N1 - Copyright: Copyright 2018 Elsevier B.V., All rights reserved.. PY - 2003. Y1 - 2003. N2 - Wilson's disease protein (WNDP) is a copper-transporting P1-type ATPase which plays a key role in normal distribution of copper in a number of tissues, particularly in the liver and the brain. Copper has numerous effects on WNDP, altering its structure, activity, and intracellular localization. To better understand the function of this copper-transporting ATPase and its regulation by copper, we have recently developed the functional expression systems for WNDP and for Atox1, a cytosolic protein that serves as an intracellular donor of copper for WNDP. Here we summarize the results of our experiments on characterization of the enzymatic properties of WNDP and the effects of ...

Investigations on gastric mucosal protective mechanisms are focused mainly on the local mucosal processes. Much less is known about how the central nervous system may influence the gastric mucosal defense. However, gastric mucosal protection induced by a central mechanism was described recently (Tache et al., 1994; Gyires, 1997;Guidobono et al., 1998; Kaneko et al., 1998; Yang et al., 1999). In our present study, the role of central opioid receptors was analyzed by means of selective δ- and μ-opioid receptor agonists. It was found that both the selective δ- and μ-opioid receptor agonists injected either i.c.v. or i.c. exerted protective effect against acidified ethanol-induced lesions; the rank order of potency was β-endorphin , DAGO , DADLE , deltorphin II , DPDPE following i.c.v. injection and deltorphin II , β endorphin , DPDPE , DAGO , DADLE following i.c. administration. The results suggest that activation of supraspinal δ- and μ-opioid receptors may induce gastric mucosal ...

Pancreatic cancer is the fourth leading cause of cancer death in the United States with current 5-year survival rates at 6%. Greater than 90% of all pancreatic cancers harbor an activating mutation in codon 12 of the Kras gene (KrasG12D). Protein Kinase C iota (PKCι) has been shown to mediate KrasG12D downstream signaling and acinar-to-ductal metaplasia in an explant model of pancreatic cancer initiation. Additionally, inhibition of PKCι in human pancreatic cancer cells leads to decreased tumor size, angiogenesis, and metastasis in an orthotopic tumor model, suggesting that PKCι plays a role in maintaining the oncogenic phenotype of pancreatic cancer cells. We sought to test the hypothesis that PKCι plays a role development and maintenance of pancreatic cancer using a mouse model of KrasG12D-induced pancreatic cancer.. Purpose: To identify the effect of PKCι loss on pancreas function and development of KrasG12D-induced pancreatic cancer.. Procedures: Pancreata from mice with ...

TY - JOUR. T1 - Effects of salt on the structure and dynamics of the bis(penicillamine) enkephalin zwitterion. T2 - A simulation study. AU - Smith, Paul E.. AU - Pettitt, Bernard. PY - 1991/7/31. Y1 - 1991/7/31. N2 - Molecular dynamics simulations of a zwitterionic bis(penicillamine) enkephalin derivative in 1.0 M saline solution have been performed. Two simulations produced essentially the same average results although they differed in the initial random placement of the salt ions. The dynamical and structural properties from the simulations were compared with those from a previous simulation of the peptide in pure water. The properties of the sodium and chloride ions were compared with those from a simulation of bulk salt solution. An inner-sphere complex between the peptide and the chloride ions was observed in which two to three chloride ions were associated with the NH3 + terminal hydrogen atoms. Several chlorides associated with more than one amide hydrogen simultaneously, and the ...