Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current treatment protocol for postoperative pain is to infuse anesthetic solution around nerves or into the epidural space. This clinical practice is beset by the short duration of the anesthetic effect unless the infusion is continuous. Continuous infusion, however, requires hospitalization of the patients, thereby increasing medical costs. In addition, it also causes systemic accumulation of the drug. We reported herein a novel treatment for the postoperative pain by applying to the surgical site a biodegradable microsphere-gel system for prolonged and localized release of encapsulated anesthetic drugs. This lidocaine-containing biodegradable poly(D,L-lactic acid) (PLA) microsphere system, although being established previously by other investigators, was hindered by a burst release and a followed rapid release of the drug within several hours in vitro. In this article, we demonstrated that by a step-by-step modification of the formulation, prolonged release of lidocaine, up to several days in vitro, could be achieved. Differential scanning calorimetry revealed a lower glass transition temperature for these lidocaine-loaded microspheres comparing to that of lidocaine-free microspheres. This decreased Tg explained for the tendency of the lidocaine-loaded microspheres to physically fuse at higher temperatures. In vitro studies showed that microspheres, when loaded with 35% lidocaine, yielded a threefold increase in the degradation rate. The molecular weight of PLA of the drug-loaded microspheres was reduced by 50% within a period of 1 month. Based on the results (of prolonged lidocaine release and rapid PLA microsphere degradation), this lidocaine-loaded PLA microsphere system could offer a simple solution to the treatment of postoperative pain.
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PMID:Injectable microparticle-gel system for prolonged and localized lidocaine release. I. In vitro characterization. 1529 14

To identify the active components of honeybee venom in production of inflammation and pain-related behaviors, five major peptidergic subfractions were separated, purified and identified from the whole honeybee venom. Among them, four active peptidergic components were characterized as apamin, mast-cell degranulating peptide (MCDP), phospholipase A(2) (PLA(2))-related peptide and melittin, respectively. All five subfractions were effective in production of local inflammatory responses (paw edema) in rats although the efficacies were different. Among the five identified subfractions, only MCDP, PLA(2)-related peptide and melittin were able to produce ongoing pain-related behaviors shown as paw flinches, while only apamin and melittin were potent to produce both thermal and mechanical hypersensitivity. As shown in our previous report, melittin was the most potent polypeptide in production of local inflammation as well as ongoing pain and hypersensitivity. To further explore the peripheral mechanisms underlying melittin-induced nociception and hypersensitivity, a single dose of capsazepine, a blocker of thermal nociceptor transient receptor potential vanilloid receptor 1, was treated s.c. prior to or after melittin administration. The results showed that both pre- and post-treatment of capsazepine could significantly prevent and suppress the melittin-induced ongoing nociceptive responses and thermal hypersensitivity, but were without influencing mechanical hypersensitivity. The present results suggest that the naturally occurring peptidergic substances of the whole honeybee venom have various pharmacological potencies to produce local inflammation, nociception and pain hypersensitivity in mammals, and among the five identified reverse-phase high pressure liquid chromatography subfractions (four polypeptides), melittin, a polypeptide occupying over 50% of the whole honeybee venom, plays a central role in production of local inflammation, nociception and hyperalgesia or allodynia following the experimental honeybee's sting. Peripheral transient receptor potential vanilloid receptor 1 is likely to be involved in melittin-produced ongoing pain and heat hyperalgesia, but not mechanical hyperalgesia, in rats.
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PMID:Effects of bee venom peptidergic components on rat pain-related behaviors and inflammation. 1644 39

Glutamate is the main excitatory neurotransmitter in central nervous system (CNS) and NMDA receptors are one of the major classes of ionotropic glutamate receptors. NMDA receptors have been known to play critical roles in normal CNS activities, as well as in many pathological conditions, including both acute and chronic diseases. The discovery of glycine as a coagonist of NMDA receptors has led to intensive research of glycine/NMDA antagonists as potential CNS drugs. The robust efficacy of glycine/NMDA antagonists, such as ACEA-1021 (5), in animal model of brain ischemia, together with good safety profile in animal models and in clinical trials, suggested that this class of NMDA antagonists should have good chance of success in the clinic as neuroprotectants. The clinical trial of ACEA-1021 for stroke was discontinued, mainly due to low solubility and lack of metabolism of the drug that led to the observation of crystals in the urine of some of the patients. However, through SAR studies, compounds such as ACEA-1416 (10) have been identified with improved properties, such as higher in vivo potency and site for potential metabolism. Therefore these compounds should be able to overcome some of the liabilities of ACEA-1021 and potentially could be developed as neuroprotectants. Based on the preclinical and clinical studies of glycine/NMDA antagonists, as well as the clinical experiences with t-PA, initiation of treatment within a short time window after the onset of stroke could be critical for the success of these antagonists in clinical trials. This can be accomplished by implementing the procedure developed for t-PA clinical trials, with modification based on the safety profile of glycine/NMDA antagonists, for future clinical trial to administer the drug as soon as possible after stroke onset. In addition, glycine/NMDA antagonists also have other potential therapeutic applications, such as for the treatment of traumatic brain injury, pain, cocaine overdose and convulsions.
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PMID:Glycine/NMDA receptor antagonists as potential CNS therapeutic agents: ACEA-1021 and related compounds. 1671 7

The increasing use of mesh insertion for groin hernia repair is dashed by a worrying prevalence of chronic pain frequently related as a reaction to the biomaterial implantation. Thus, new biocompatible prosthesis, designed as a composite material associating polypropylene (PP) and long-term absorbable material, are now under development. In the present study, the typical commercially available Prolene mesh has been compared to two new meshes designed with 3-fold less PP, either alone (light PP) or associated with poly-L-lactic acid (PP-PLA) accounting for 90% of the mesh weight. These PP-mesh variants were implanted in an extraperitoneal position within the abdominal wall of 90 rats. Mesh adhesion and size were determined at autopsy 2, 4 and 8 weeks after implantation (10 animals per group) and morphometric parameters of the host tissues by light microscopy. Prolene and light PP-meshes presented intra-corporeal shrinkage and tissue adhesion, both more pronounced with light-PP, whilst PP-PLA meshes were not affected in spite of a strongest fibrosis. In contrast to Prolene and even more with light PP meshes, inflammation and cell-mediated immune responses were reduced without occurrence of angiogenesis or oedema. All these findings advocate together for a better tolerance of this new composite biomaterial, more likely due to a low macrophage response that appeared statistically correlated to the absence of mesh shrinkage and to a decreased adhesion to the tissue. On the basis of these experimental observations, it could be expected that the better tolerance of this composite biomaterial may avoid both long-term pain and recurrence when used as plug in groin hernia repair.
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PMID:In vivo evaluation of a new composite mesh (10% polypropylene/90% poly-L-lactic acid) for hernia repair. 1724

Dorsal root injury is known to induce alteration of the extracellular environment in the spinal cord and synaptic reorganization with degradation of injured primary afferent and sprouting of spared terminal. These changes affect behavioral sensitivity and sometimes lead to neuropathic pain. We have hypothesized that changes in extracellular proteolysis in the dorsal horn is involved in neuroplastic changes in the dorsal horn after nerve injury. Tissue type plasminogen activator (tPA) is a well-known extracellular serine protease and is involved in the modification of the extracellular matrix, which leads to neuroplastic changes such as long-term potentiation in the hippocampus. In the present study, we found a marked induction of tPA in activated astrocytes following L4/5 root injury and a resultant increase of proteolytic enzymatic activity in the dorsal horn. We also examined the involvement of tPA activity on mechanical hypersensitivity using a root ligation model which has been used for investigating radiculopathy pain behavior. Intrathecal and continuous administration of tPA inhibitor, tPA-STOP, suppressed root ligation-induced mechanical allodynia in a dose-dependent manner during an early stage of injury (0-4 days). In contrast, the delayed administration of tPA-STOP during the chronic stage of injury (10 days) did not affect pain behavior. These data suggest an important contribution of astrocytes in the dorsal horn to the pathophysiology of radiculopathy pain, and astrocyte-derived tPA and the proteolytic activity in the dorsal horn may be one of the essential factors involved in pain following root injury.
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PMID:Tissue type plasminogen activator induced in rat dorsal horn astrocytes contributes to mechanical hypersensitivity following dorsal root injury. 1729 72

A novel neurotoxic protein phospholipase A(2) (PLA(2)), molecular weight 13 881.83 Da, has been isolated from snake venom of Gloydius ussuriensis, named as Gln49-PLA(2), which shows weak lethal toxic, myotoxic and apparent anticoagulant activity, but lacks phospholipase activity. The Gln49-PLA(2) obviously induced an increase of the pain threshold in intoxicated 615 mice compared with the control group, suggesting it is a neurotoxin. Hot-plate tests also showed that its analgesic activity was dose-dependent, and naloxone antagonized the analgesic effect, implying the mechanism of action of Gln49-sPLA(2) is correlated with opioid receptors. Electrophysiology studies revealed decreases in the action potential and the nerve conduction velocity in isolated hoptoad (Bufo bufo gargarizans Cantor) sciatic nerve, indicating Gln49-PLA(2) most probably had effects on ion channels.
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PMID:Neurotoxic activity of Gln49 phospholipase A(2) from Gloydius ussuriensis snake venom. 1729 14

To achieve our aim of understanding the interactions between direct current and enzymes in solution, we exposed reconstituted Crotalus atrox venom to direct electric current by immersing two platinum thread electrodes connected to a voltage generator (between 0 and 8 V) into a reaction mixture for a few seconds. Then, we assayed the residual activity of phospholipases A(2) (PLA(2)),metalloproteinases, and phosphodiesterases, abundant in crotaline snake venoms and relevant in the pathophysiology of envenomation, characterized by hemorrhage, pain, and tissue damage. C. atrox venom phospholipase A(2) and metalloproteinases were consistently and irreversibly inactivated by direct current (between 0 and 0.7 mA) exposure. In contrast, C. atrox venom phosphodiesterases were not affected. Total protein content and temperature of the sample remained the same. Secretory pancreatic phospholipase A(2), homologue to snake venom phospholipases A(2), was also inactivated by direct current treatment. In order to understand the structural reasoning behind PLA(2) inactivation, circular dichroism measurements were conducted on homogeneous commercial pancreatic phospholipase A(2), and it was found that the enzyme undergoes structural alterations upon direct current exposure.
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PMID:Inactivation of phospholipase A2 and metalloproteinase from Crotalus atrox venom by direct current. 1736 44

Bee venom (BV) therapy (BVT), the therapeutic application of BV, has been used in traditional medicine to treat diseases, such as arthritis, rheumatism, pain, cancerous tumors, and skin diseases. BV contains a variety of peptides, including melittin, apamin, adolapin, the mast-cell-degranulating (MCD) peptide, enzymes (i.e., phospholipase [PL] A(2)), biologically active amines (i.e., histamine and epinephrine), and nonpeptide components which have a variety of pharmaceutical properties. BV has been reported to have anti-arthritis effects in several arthritis models. Melittin, a major peptide component of BV, has anti-inflammatory and anti-arthritis properties, and its inhibitory activity on nuclear factor kappaB (NF-kappaB) may be essential for the effects of BV. The anti-nociceptive effects of BV have also been demonstrated in thermal, visceral, and inflammatory pain models. Apcupoint stimulation (apipuncture) therapy into subcutaneous region may be important in the BV-induced anti-nociceptive effects. Multiple mechanisms, such as activation of the central and spinal opiod receptor, and alpha(2)-adrenergic activity, as well as activation of the descending serotonergic pathway have been suggested. The inhibition of c-Fos expression in the spinal cord by BV apipuncture in several nociceptive models is also reported to be a possible mechanism. BV also has anti-cancer activity. The cell cytotoxic effects through the activation of PLA(2) by melittin have been suggested to be the critical mechanism for the anti-cancer activity of BV. The conjugation of cell lytic peptide (melittin) with hormone receptors and gene therapy carrying melittin can be useful as a novel targeted therapy for some types of cancer, such as prostate and breast cancer.
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PMID:Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds. 1755 25

Scatophagus argus of the family Scatophagidae inflicts painful wounds in fishermen during handling. The clinical picture is characterized by excruciating and persistent local pain disproportionate to the size of injury, redness, swelling and a throbbing sensation that extends to the limbs, followed by dizziness. The biological properties of the S. argus venom were studied to assess its risk and lethal factors with regard to human welfare. In contrast to other fish venoms, S. argus showed relatively low LD50 (9.8 mg/kg via i.p.). Haemolytic activity in human erythrocytes was recorded. Platelet lysis expressed as LDH activity of lysed cells was dose dependent. S. argus venom failed to induce any clot in human plasma. No PLA(2) activity was found in S. argus venom. Mild proteolytic activity was observed. The injection of venom in mice produced lesions and nociception, which were not inhibited by antihistamine pheniramine maleate, suggesting that histamine was not involved in the inflammatory process. The increase in serum creatine kinase activity indicated myotoxicity. Cytotoxicity on HeLa cells was observed. The spectrum of activity in experimental animals of S. argus crude venom resembles those of other fish venoms previously studied and well correlated to the systemic manifestations that are described for S. argus envenomation.
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PMID:Biological and biochemical properties of Scatophagus argus venom. 1759 79

Pigmentation may result from melanocyte proliferation, melanogenesis, migration or increases in dendricity. Recently, it has been reported that secreted phospholipase A(2)(sPLA(2)) known as a component of bee venom (BV), stimulates melanocyte dendricity and pigmentation. BV has been used clinically to control rheumatoid arthritis and to ameliorate pain via its anti-inflammatory and antinociceptive properties. Moreover, after treatment with BV, pigmentation around the injection sites was occasionally observed and the pigmentation lasted a few months. However, no study has been done about the effect of BV on melanocytes. Thus, in the present study, we examined the effect of BV on the proliferation, melanogenesis, dendricity and migration in normal human melanocytes and its signal transduction. BV increased the number of melanocytes dose and time dependently through PKA, ERK, and PI3K/Akt activation. The level of cAMP was also increased by BV treatment. Moreover, BV induced melanogenesis through increased tyrosinase expression. Furthermore, BV induced melanocyte dendricity and migration through PLA(2) activation. Overall, in this study, we demonstrated that BV may have an effect on the melanocyte proliferation, melanogenesis, dendricity and migration through complex signaling pathways in vitro, responsible for the pigmentation. Thus, our study suggests a possibility that BV may be developed as a therapeutic drug for inducing repigmentation in vitiligo skin.
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PMID:Bee venom stimulates human melanocyte proliferation, melanogenesis, dendricity and migration. 1805 36


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