Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0599766 (functional recovery)
 13,441 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenine nucleotides speed structural and functional recovery when administered after experimental renal injury in the rat and stimulate proliferation of kidney epithelial cells. As cell migration is a component of renal regeneration after acute tubular necrosis, we have used an in vitro model of wound healing to study this process. High density, quiescent monkey kidney epithelial cultures were wounded by mechanically scraping away defined regions of the monolayer to simulate the effect of cell loss after tubular necrosis and the number of cells that migrated into the denuded area was counted. Migration was independent of cell proliferation. Provision of adenosine, adenine nucleotides, or cyclic AMP increased the number of migrating cells and accelerated repair of the wound. Other purine and pyrimidine nucleotides were not effective. Arginine-glycine-aspartic acid-serine peptide, which blocks the binding of extracellular fibronectin to its cell surface receptor, completely inhibited migration in the presence or absence of ADP. Very low concentrations of epidermal growth factor (K0.5 approximately 0.3 ng/ml) stimulated migration, whereas transforming growth factor-beta 2 was inhibitory (Ki approximately 0.2 ng/ml). Thus, adenosine and/or adenine nucleotides released from injured or dying renal cells, or administered exogenously, may stimulate surviving cells in the wounded nephron to migrate along the basement membrane, thereby rapidly restoring tubular structure and function.
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PMID:Adenine nucleotides stimulate migration in wounded cultures of kidney epithelial cells. 163 17

The phospholipid composition of normal peripheral nerve as a function of developmental age as well as that of Wallerian-degenerated nerve as a function of age at nerve transection and duration of Wallerian degeneration have been quantitated in rabbit sciatic nerve. During development, increases in the proportions of ethanolamine plasmalogen, sphingomyelin, and combined phosphatidyl serine plus phosphatidyl inositol and decreases in the proportions of phosphatidyl choline and phosphatidyl ethanolamine correlated well with the concurrent myelin accretion. During Wallerian degeneration, age-dependent changes in phospholipid composition were observed. The large and statistically significant increase in the proportion of phosphatidyl choline and decrease in the proportion of ethanolamine plasmalogen were manifest promptly in nerves transected at 2 weeks of age but in a delayed manner in nerves transected at 8, 12, and 20 weeks of age. The rate of loss of individual phospholipids was greater in nerves transected at younger ages. The findings from normal developing peripheral nerve may well serve as baseline data for subsequent studies of phospholipid composition in pathological peripheral nerve. The findings from Wallerian-degenerated peripheral nerve provide additional evidence for age-dependent chemical changes occurring in Wallerian-degenerated peripheral nerve that may be of significance in explaining the superior functional recovery from peripheral nerve injury observed in younger compared with older subjects.
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PMID:Peripheral nerve phospholipid composition: development in normal nerve and age-dependent changes in Wallerian degenerated nerve. 708 25

It is well known that activation of proteases in the lysosomes and cytosol is one of the mechanisms of ischemic injury. It might thus be beneficial to determine whether the addition of several clinically available protease inhibitors to a cardioplegic solution can improve its protective ability. Using an isolated working rat heart preparation, the effects of several protease inhibitors (serine protease inhibitors; nafamostat mesilate and gabexate mesilate, a thiol-protease inhibitor; NCO-700; and a urinary trypsin inhibitor, urinastatin) on the postischemic recovery of function and enzyme leakage were investigated in this study. These protease inhibitors were added to either the cardioplegic solution or reperfusion solution. The addition of each of the protease inhibitors, except urinastatin, to the cardioplegic solution improved the postischemic recovery of function and reduced enzyme leakage. The dose-response characteristics of these three protease inhibitors were bell shaped, and the optimal concentrations of nafamostat mesilate, gabexate mesilate, and NCO-700 were 5 microM, 100 microM, and 20 microM, respectively. In contrast to the results of the preischemic treatment study, the addition of any of the protease inhibitors to the perfusion medium during Langendorff reperfusion failed to improve the postischemic recovery of function and to reduce enzyme leakage. Surprisingly, the addition of NCO-700 to the reperfusion solution at a concentration of 5 microM or higher had rather harmful effects on both functional recovery and enzyme leakage. These findings suggest that serine and thiol proteases may play an important role in myocardial injury during ischemia, but not necessarily during reperfusion.
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PMID:Effects of protease inhibitors on postischemic recovery of the heart. 935 59

FK506 is a new FDA-approved immunosuppressant used for prevention of allograft rejection in, for example, liver and kidney transplantations. FK506 is inactive by itself and requires binding to an FK506 binding protein-12 (FKBP-12), or immunophilin, for activation. In this regard, FK506 is analogous to cyclosporin A, which must bind to its immunophilin (cyclophilin A) to display activity. This FK506-FKBP complex inhibits the activity of the serine/threonine protein phosphatase 2B (calcineurin), the basis for the immunosuppressant action of FK506. The discovery that immunophilins are also present in the nervous system introduces a new level of complexity in the regulation of neuronal function. Two important calcineurin targets in brain are the growth-associated protein GAP-43 and nitric oxide (NO) synthase (NOS). This review focuses on studies showing that systemic administration of FK506 dose-dependently speeds nerve regeneration and functional recovery in rats following a sciatic-nerve crush injury. The effect appears to result from an increased rate of axonal regeneration. The nerve regenerative property of this class of agents is separate from their immunosuppressant action because FK506-related compounds that bind to FKBP-12 but do not inhibit calcineurin are also able to increase nerve regeneration. Thus, FK506's ability to increase nerve regeneration arises via a calcineurin-independent mechanism (i.e., one not involving an increase in GAP-43 phosphorylation). Possible mechanisms of action are discussed in relation to known actions of FKBPs: the interaction of FKBP-12 with two Ca2+ release-channels (the ryanodine and inositol 1,4,5-triphosphate receptors) which is disrupted by FK506, thereby increasing Ca2+ flux; the type 1 receptor for the transforming growth factor-beta (TGF-beta 1), which stimulates nerve growth factor (NGF) synthesis by glial cells, and is a natural ligand for FKBP-12; and the immunophilin FKBP-52/FKBP-59, which has also been identified as a heat-shock protein (HSP-56) and is a component of the nontransformed glucocorticoid receptor. Taken together, studies of FK506 indicate broad functional roles for the immunophilins in the nervous system. Both calcineurin-dependent (e.g., neuroprotection via reduced NO formation) and calcineurin-independent mechanisms (i.e., nerve regeneration) need to be invoked to explain the many different neuronal effects of FK506. This suggests that multiple immunophilins mediate FK506's neuronal effects. Novel, nonimmunosuppressant ligands for FKBPs may represent important new drugs for the treatment of a variety of neurological disorders.
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PMID:FK506 and the role of immunophilins in nerve regeneration. 945 3

A rat four-vessel cerebral occlusion model was used to examine the effects of D-lactate and oxamate, a lactate dehydrogenase inhibitor, on cortical window superfusate levels of amino acids, glucose and L-lactate. Superfusate levels of aspartate, glutamate, taurine, GABA and phosphoethanolamine rose during ischemia and then declined during reperfusion. Glycine and alanine levels tended to increase during reperfusion, whereas glutamine levels were lower. Serine levels were not altered. Glucose levels declined rapidly during ischemia and recovered during reperfusion. Lactate levels were sustained during ischemia and increased during reperfusion. Unlike L-lactate, which attenuated ischemia/reperfusion (I/R) evoked amino acid release (J.W. Phillis, D. Song, L.L. Guyot, M.H. O'Regan, Lactate reduces amino acid release and fuels recovery of function in the ischemic brain, Neurosci. Lett. 272 (1999) 195-198), topical application of D-lactate (20 mM), which is not used as an energy substrate, enhanced the I/R release of aspartate, glutamate, GABA and taurine into cortical superfusates, and also elevated L-lactate levels above those in the controls. Glucose levels were not altered. Oxamate (20 mM) application elevated the pre-ischemia levels of alanine, glycine and GABA and those of GABA during ischemia. Levels of all amino acids, with the exception of phosphoethanolamine, were elevated during reperfusion. Oxamate, an inhibitor of lactate dehydrogenases 1 and 5, did not alter the pattern of efflux of glucose and L-lactate. In the presence of oxamate, L-lactate (20 mM) failed to inhibit amino acid release. The failure of D-lactate to attenuate amino acid release confirms the inability of this isomer to act as a metabolic substrate. The oxamate data indicate that inhibition of lactate dehydrogenase is detrimental to the viability of cortical cells during I/R, even though extracellular lactate levels are elevated. The pre-ischemia increases in alanine and glycine are suggestive of elevations in pyruvate as a result of the block of its conversion to lactate, with transamination reactions converting pyruvate to form these amino acids. In summary, the results further substantiate the concept of a role for L-lactate as a cerebral energy substrate.
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PMID:Further studies on the effects of topical lactate on amino acid efflux from the ischemic rat cortex. 1136 47

Rho kinases (ROCKs), the first Rho effectors to be described, are serine/threonine kinases that are important in fundamental processes of cell migration, cell proliferation and cell survival. Abnormal activation of the Rho/ROCK pathway has been observed in various disorders of the central nervous system. Injury to the adult vertebrate brain and spinal cord activates ROCKs, thereby inhibiting neurite growth and sprouting. Inhibition of ROCKs results in accelerated regeneration and enhanced functional recovery after spinal-cord injury in mammals, and inhibition of the Rho/ROCK pathway has also proved to be efficacious in animal models of stroke, inflammatory and demyelinating diseases, Alzheimer's disease and neuropathic pain. ROCK inhibitors therefore have potential for preventing neurodegeneration and stimulating neuroregeneration in various neurological disorders.
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PMID:Rho kinase, a promising drug target for neurological disorders. 1586 68

The mechanisms by which long-chain dietary polyunsaturated fatty acids (PUFAs) protect against cardiovascular disease are largely unknown. The present study determines the effects of eicosapentaenoic acid (EPA) and arachidonic acid (ARA) on the response of neonatal rat cardiomyocytes to simulated ischaemia (SI) and reperfusion (R). Myocytes isolated from 1-2 day old Wistar rat hearts were cultured with or without EPA or ARA and exposed to 1 h SI followed by 30 minutes reperfusion. Apoptosis was evaluated by caspase-3 activation, poly-(ADP-ribose) polymerase (PARP) cleavage and nuclear condensation. EPA (20microM) and ARA (20microM) significantly inhibited caspase-3 activation and PARP-cleavage and reduced the apoptotic index during reperfusion. Both fatty acids significantly increased ERK phosphorylation and decreased p38 phosphorylation during reperfusion. The mechanism of action of ARA on the MAPKs was further investigated with okadaic acid (to inhibit serine-threonine phosphatases) and orthovanadate (to inhibit tyrosine phosphatases). Vanadate, but not okadaic acid, significantly reduced ARA-induced inhibition of p38 phosphorylation, suggesting the involvement a tyrosine phosphatase during SI/R. Mitogen-activated protein kinase phosphatase-1 (MKP-1), a dual-specificity phosphatase, was targeted and a significant induction of MKP-1 by ARA and EPA was observed. It was demonstrated for the first time that EPA and ARA protect neonatal cardiac myocytes from ischaemia/reperfusion-induced apoptosis through activation of ERK as well as induction of a dual-specific phosphatase, causing dephosphorylation of the pro-apoptotic kinase, p38. The cardioprotective effects of EPA and ARA could also be demonstrated on the functional recovery of isolated perfused hearts subjected to global ischemia.
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PMID:Long-chain polyunsaturated fatty acids protect the heart against ischemia/reperfusion-induced injury via a MAPK dependent pathway. 1621 66

Microarray analyses indicate that ischemic and pharmacological preconditioning suppress overexpression of the non-long terminal repeat retrotransposon long interspersed nuclear element 1 (LINE-1, L1) after ischemia-reperfusion in the rat heart. We tested whether L1 overexpression is mechanistically involved in postischemic myocardial damage. Isolated, perfused rat hearts were treated with antisense or scrambled oligonucleotides (ODNs) against L1 for 60 min and exposed to 40 min of ischemia followed by 60 min of reperfusion. Functional recovery and infarct size were measured. Effective nuclear uptake was determined by FITC-labeled ODNs, and downregulation of L1 transcription was confirmed by RT-PCR. Immunoblot analysis was used to assess changes in expression levels of the L1-encoded proteins ORF1p and ORF2p. Immunohistochemistry was performed to localize ORF1/2 proteins in cardiac tissue. Effects of ODNs on prosurvival protein kinase B (Akt/PKB) expression and activity were also determined. Antisense ODNs against L1 prevented L1 burst after ischemia-reperfusion. Inhibition of L1 increased Akt/PKBbeta expression, enhanced phosphorylation of PKB at serine 473, and markedly improved postischemic functional recovery and decreased infarct size. Antisense ODN-mediated protection was abolished by LY-294002, confirming the involvement of the Akt/PKB survival pathway. ORF1p and ORF2p were found to be expressed in rat heart. ORF1p showed a predominantly nuclear localization in cardiomyocytes, whereas ORF2p was exclusively present in endothelial cells. ORF1p levels increased in response to ischemia, which was reversed by antisense ODN treatment. No significant changes in ORF2p were noted. Our results demonstrate that L1 suppression favorably affects postischemic outcome in the heart. Modifying transcriptional activity of L1 may represent a novel anti-ischemic therapeutic strategy.
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PMID:Inhibition of LINE-1 expression in the heart decreases ischemic damage by activation of Akt/PKB signaling. 1641 18

There are important differences between on-target military attacks against relatively well protected Armed Forces and nerve agent attacks initiated by terrorists against a civilian population. In contrast to military personnel, civilians are unlikely to be pre-treated with pyridostigmine and protected by personal protective equipment. Furthermore, the time after exposure when specific therapy can first be administered to civilians is likely to be delayed. Even conservative estimates suggest a delay between exposure and the first administration of atropine/oxime of at least 30 minutes. The organophosphorus nerve agents are related chemically to organophosphorus insecticides and have a similar mechanism of toxicity, but a much higher mammalian acute toxicity, particularly via the dermal route. Nerve agents phosphonylate a serine hydroxyl group in the active site of the enzyme, acetylcholinesterase (AChE), which results in accumulation of acetylcholine and, in turn, causes enhancement and prolongation of cholinergic effects and depolarisation blockade. The rate of spontaneous reactivation of AChE is variable, which partly accounts for differences in acute toxicity between the nerve agents. With soman in particular, an additional reaction occurs known as 'aging'. This consists of monodealkylation of the dialkylphosphonyl enzyme, which is then resistant to spontaneous hydrolysis and reactivation by oximes. Monodealkylation occurs to some extent with all dialkylphosphonylated AChE complexes; however, in general, is only of clinical importance in relation to the treatment of soman poisoning, where it is a very serious problem. With soman, aging occurs so fast that no clinically relevant spontaneous reactivation of AChE occurs before aging has taken place. Hence, recovery of function depends on resynthesis of AChE. As a result, it is important that an oxime is administered as soon after soman exposure as possible so that some reactivation of AChE occurs before all the enzyme becomes aged. Even though aging occurs more slowly and reactivation occurs relatively rapidly in the case of nerve agents other than soman, early oxime administration is still clinically important in patients poisoned with these agents. Experimental studies on the treatment of nerve agent poisoning have to be interpreted with caution. Some studies have used prophylactic protocols, whereas the drugs concerned (atropine, oxime, diazepam) would only be given to a civilian population after exposure. The experimental use of pyridostigmine before nerve agent exposure, although rational, is not of relevance in the civilian context. With the possible exception of the treatment of cyclosarin (GF) and soman poisoning, when HI-6 might be preferred, a review of available experimental evidence suggests that there are no clinically important differences between pralidoxime, obidoxime and HI-6 in the treatment of nerve agent poisoning, if studies employing pre-treatment with pyridostigmine are excluded.
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PMID:The role of oximes in the treatment of nerve agent poisoning in civilian casualties. 1728

Exogenous insulin therapy improves endothelial function in insulin resistant patients, indirectly indicating that nitric oxide synthase activity and NO production may be impaired. Insulin stimulates production of NO by activating a signaling pathway including insulin receptor substrate-1, phosphatidylinositol-3-kinase and protein kinase B (PKB/Akt). Angiotensin II type I (AT1) receptor-evoked oxidative stress is implicated in the inactivation of NO, impairing endothelium-dependent vasodilatation. Blocking the actions of Angiotensin II with an AT1 receptor antagonist (Losartan), has beneficial effects in patients with insulin resistance or type 2 diabetes mellitus. This study investigated whether elevated Angiotensin II influences myocardial insulin resistance, insulin signaling and NO production in a rat model of diet-induced obesity (DIO) by antagonizing the actions of the AT1 receptor with Losartan. Isolated, perfused hearts, Western blotting and flow-cytometric methods were utilized to determine myocardial function, expression and phosphorylation of key proteins and NO production, respectively. Results showed that hearts from DIO rats are insulin resistant (higher serine phosphorylation of IRS-1, lower insulin-stimulated phosphorylation of PKB/Akt and eNOS, lower NO production) and had poorer functional recovery and larger infarct development after ischaemia/reperfusion. Losartan improved the impaired functional recovery, and NO production and enhanced eNOS expression and phosphorylation and reduced infarct size in hearts from the DIO animals. Data obtained from Losartan treatment also revealed that Angiotensin II signaling modulates myocardial PKB/Akt expression. We conclude that Angiotensin II signaling exacerbates inhibition of NO production in insulin resistance and that this can be improved by AT1 antagonism.
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PMID:ANG II type I receptor antagonism improved nitric oxide production and enhanced eNOS and PKB/Akt expression in hearts from a rat model of insulin resistance. 2115 3


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