Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In adult patients with ESRD, calcific uremic arteriolopathy (CUA) is an uncommon but life-threatening complication. No effective therapy exists, although anecdotal case reports highlight the use of sodium thiosulfate (STS), a calcium-chelating agent with antioxidant properties. CUA is rare in children, and STS use has not been reported. The objective of this study was to determine the influence of STS treatment on three patients with CUA in a pediatric chronic dialysis unit. The patients were between 12 and 21 yr of age; two were male; and primary diagnoses were obstructive uropathy, renal dysplasia, and calcineurin nephrotoxicity. Time from ESRD to CUA diagnosis was 1, 9, and 20 yr. Diagnosis was made by tissue biopsy and three-phase bone scan. Pain was the presenting symptom. Initial treatment included discontinuation of calcitriol and use of non-calcium-based phosphate binders and low-calcium dialysate concentration. STS dosage was 25 g/1.73 m(2) per dose intravenously after each hemodialysis session. For optimization of removal of calcium deposits, patient three received a combination of STS and continuous venovenous hemofiltration for the first 10 d. All patients demonstrated rapid pain relief. Within weeks, skin induration and joint mobility of the extremities improved. Radiographic evidence of reduction in the calcium deposits occurred within 3 mo of initiation of STS. The only complication was prolonged QT interval in one patient as a result of hypocalcemia, who was resolved by use of a higher dialysate calcium concentration. STS seems well tolerated in children and young adults with CUA and has mild adverse effects. For determination of its efficacy, optimum dosage, duration of therapy, and dialysis modality, controlled trials are needed.
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PMID:Sodium thiosulfate treatment for calcific uremic arteriolopathy in children and young adults. 1769 42

Agonist-induced desensitization of the transient receptor potential vanilloid receptor-1 (TRPV1) is one of the key strategies that offer a way to alleviate neuropathic and inflammatory pain. This process is initiated by TRPV1 receptor activation and the subsequent entry of extracellular Ca(2+) through the channel into sensory neurones. One of the prominent mechanisms responsible for TRPV1 desensitization is dephosphorylation of the TRPV1 protein by the Ca(2+)/calmodulin-dependent enzyme, phosphatase 2B (calcineurin). Of several consensus phosphorylation sites identified so far, the most notable are two sites for Ca(2+)/calmodulin dependent kinase II (CaMKII) at which the dynamic equilibrium between the phosphorylated and dephosphorylated states presumably regulates agonist binding. We examined the mechanisms of acute Ca(2+)-dependent desensitization using whole-cell patch-clamp techniques in human embryonic kidney (HEK) 293T cells expressing the wild type or CaMKII phosphorylation site mutants of rat TRPV1. The nonphosphorylatable mutant S502A/T704I was capsaicin-insensitive but the S502A/T704A construct was fully functional, indicating a requirement for a specific residue at position 704. A point mutation at the nearby conserved residue R701 strongly affected the heat, capsaicin and pH-evoked currents. As this residue constitutes a stringent CaMKII consensus site but is also predicted to be involved in the interaction with membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)), these data suggest that in addition to dephosphorylation, or as its consequence, a short C-terminal juxtamembrane segment adjacent to the transient receptor potential box composed of R701 and T704 might be involved in the decelerated gating kinetics of the desensitized TRPV1 channel.
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PMID:Functional changes in the vanilloid receptor subtype 1 channel during and after acute desensitization. 1786 38

Upregulation of CCR2 chemokine receptor expression by dorsal root ganglion (DRG) neurons is an important process in the development and maintenance of neuropathic pain. CCR2 is not expressed by DRG neurons under normal conditions but is upregulated in several animal models of neuropathic pain where its signaling is excitatory. However, the molecular mechanisms underlying neuronal upregulation of CCR2 have not been investigated. We examined the promoter region of the CCR2 gene and found that a binding site for the nuclear factor of activated T-cells (NFAT) was conserved among species. The NFAT element was functional since the CCR2 promoter was activated by a constitutively active form of calcineurin A, whereas a point mutation in the NFAT binding site abrogated it. Activation of the NFAT pathway in the DRG neuronal cell line F11 increased CCR2 promoter activity and induced CCR2 transcription. Moreover, depolarization of cultured DRG neurons induced de novo synthesis of CCR2 mRNA, which was blocked by the calcineurin inhibitors cyclosporin A and FK506. These data indicate that CCR2 is a target of the NFAT pathway and suggest that tonic excitation of DRG neurons in association with chronic pain may lead to neuronal CCR2 upregulation via activation of the NFAT pathway.
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PMID:Activation of the nuclear factor of activated T-cells (NFAT) mediates upregulation of CCR2 chemokine receptors in dorsal root ganglion (DRG) neurons: a possible mechanism for activity-dependent transcription in DRG neurons in association with neuropathic pain. 1794 92

The reflex sympathetic dystrophy syndrome (RSDS) in organ transplant recipients has only previously been reported in patients treated with calcineurin inhibitors. We retrospectively analyzed 393 renal transplant patients treated with sirolimus, 9 of whom developed RSDS. All the patients reported varying degrees of pain in the legs, affecting the knees, ankles, and/or feet, plus cutaneous erythema. The onset of pain ranged from 1-6 months after transplantation. At the time of diagnosis of RSDS, the mean serum creatinine was 1.4 mg/dL (range 1.0-1.7) and bone scintigraphy with 99mTc pyrophosphate showed increased uptake in all cases. The symptoms remitted 3-10 months after treatment (mean, 4 months) with calcitriol, with or without nifedipine or calcitonin, and in one case with suppression of sirolimus. We conclude that sirolimus therapy may induce RSDS in renal transplant recipients.
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PMID:Sympathetic dystrophy associated with sirolimus therapy. 1821 35

Calcineurin-inhibitor-induced pain syndrome (CIPS), a rare complication seen in patients with organ transplants, is associated with the use of calcineurin inhibitors (CIs) such as cyclosporine (CSP) and tacrolimus (FK). Patients with this syndrome usually present with severe leg pain. This case report demonstrates the successful pain control of this pain syndrome in a 42-year-old female patient who had been given CIs (FK and CSP) as an immunosuppressive agent after a bone marrow transplant. Twenty-one days after the transplantation, she complained of severe pain in her bilateral lower extremities; this lasted several weeks, and was resistant to ordinary analgesics such as intramuscular pentazocine, intravenous morphine, and even oral nifedipine, which is generally accepted as an effective analgesic agent for the pain in this syndrome. Due to the presence of allodynia, our patient's pain had neuropathic pain-like characteristics, unlike the pain in previously reported patients with other organ transplants. Her pain was successfully relieved by the administration of oral amytriptyline, clonazepam, oxycodone, and intravenous lidocaine, all of which ordinarily have an analgesic effect on neuropathic pain. CIPS in patients with hematopoietic stem cell transplants treated with FK may have a mechanism by which neuropathic pain may develop that is different from that in patients with other organ transplants.
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PMID:Calcineurin-inhibitor-induced pain syndrome after bone marrow transplantation. 1830 17

1. The kidneys are the key organs to maintain the balance of the different electrolytes in the body and the acid-base balance. Progressive loss of kidney function results in a number of adaptive and compensatory renal and extrarenal changes that allow homeostasis to be maintained with glomerular filtration rates in the range of 10-25 ml/min. With glomerular filtration rates below 10 ml/min, there are almost always abnormalites in the body's internal environment with clinical repercussions. 2. Water Balance Disorders: In advanced chronic kidney disease (CKD), the range of urine osmolality progressively approaches plasma osmolality and becomes isostenuric. This manifests clinically as symptoms of nocturia and polyuria, especially in tubulointerstitial kidney diseases. Water overload will result in hyponatremia and a decrease in water intake will lead to hypernatremia. Routine analyses of serum Na levels should be performed in all patients with advanced CKD (Strength of Recommendation C). Except in edematous states, a daily fluid intake of 1.5-2 liters should be recommended (Strength of Recommendation C). Hyponatremia does not usually occur with glomerular filtration rates above 10 ml/min (Strength of Recommendation B). If it occurs, an excessive intake of free water should be considered or nonosmotic release of vasopressin by stimuli such as pain, anesthetics, hypoxemia or hypovolemia, or the use of diuretics. Hypernatremia is less frequent than hyponatremia in CKD. It can occur because of the provision of hypertonic parenteral solutions, or more frequently as a consequence of osmotic diuresis due to inadequate water intake during intercurrent disease, or in some circumstance that limits access to water (obtundation, immobility). 3. Sodium Balance Disorders: In CKD, fractional excretion of sodium increases so that absolute sodium excretion is not modified until glomerular filtration rates below 15 ml/min (Strength of Recommendation B). Total body content of sodium is the main determinant of extracellular volume and therefore disturbances in sodium balance will lead to clinical situations of volume depletion or overload: Volume depletion due to renal sodium loss occurs in abrupt restrictions of salt intake in advanced CKD. It occurs more frequently in certain tubulointerstitial kidney diseases (salt losing nephropathies). Volume overload due to sodium retention can occur with glomerular filtration rates below 25 ml/min and leads to edema, arterial hypertension and heart failure. The use of diuretics in volume overload in CKD is useful to force natriuresis (Strength of Recommendation B). Thiazides have little effect in advanced CKD. Loop diuretics are effective and should be used in higher than normal doses (Strength of Recommendation B). The combination of thiazides and loop diuretics can be useful in refractory cases (Strength of Recommendation B). Weight and volume should be monitored regularly in the hospitalized patient with CKD (Strength of Recommendation C). 4. Potassium Balance Disorders: In CKD, the ability of the kidneys to excrete potassium decreases proportionally to the loss of glomerular filtration. Stimulation of aldosterone and the increase in intestinal excretion of potassium are the main adaptive mechanisms to maintain potassium homeostasis until glomerular filtration rates of 10 ml/min. The main causes of hyperkalemia in CKD are the following: Use of drugs that alter the ability of the kidneys to excrete potassium: ACEIs, ARBs, NSAIDs, aldosterone antagonists, nonselective beta-blockers, heparin, trimetoprim, calcineurin inhibitors. Determination of serum potassium two weeks after the initiation of treatment with ACEIs/ARBs is recommended (Strength of Recommendation C). Routine use of aldosterone antagonists in advanced CKD is not recommended (Strength of Recommendation C). Abrupt reduction in glomerular filtration rate: Constipation. Prolonged fasting. Metabolic acidosis. A low-potassium diet is recommended with GFR less than 20 ml/min, or GFR less than 50 ml/min if drugs that raise serum potassium are taken (Strength of Recommendation C). In the absence of symptoms or electrocardiographic abnormalities, review of medications, restriction of dietary potassium and use of oral ion exchange resins are usually sufficient therapeutic measures (Strength of Recommendation C). If symptoms and/or electrocardiographic abnormalities are present, the usual parenteral pharmacological measures should be used (10% calcium gluconate, insulin and glucose, salbutamol, resins, diuretics) (Strength of Recommendation A). Parenteral bicarbonate and ion exchange resins in enemas are not recommended as first-line treatment (Strength of Recommendation C). Hemodialysis should be considered in patients with glomerular filtration rates below 10 ml/min (Strength of Recommendation C). 5. Acid-Base Disorders in CKD: Moderate metabolic acidosis (Bic 16-20) mEq/L is common with glomerular filtration rates below 20 ml/min, and favors bone demineralization due to the release of calcium and phosphate from the bone, chronic hyperventilation, and muscular weakness and atrophy. Its treatment consists of administration of sodium bicarbonate, usually orally (0.5-1 mEq/kg/day), with the goal of achieving a serum bicarbonate level of 22-24 mmol/L (Strength of Recommendation C). Limitation of daily protein intake to less than 1 g/kg/day is also useful (Strength of Recommendation C). Use of sevelamer as a phosphate binder aggravates metabolic acidosis since it favors endogenous acid production and therefore acidosis should be monitored and corrected if it occurs (Strength of Recommendation C). Hypocalcemia should always be corrected before metabolic acidosis in CKD (Strength of Recommendation B). Metabolic acidosis is an infrequent disorder and requires exogenous alkali administration (bicarbonate, phosphate binders) or vomiting.
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PMID:[Electrolyte and acid-base balance disorders in advanced chronic kidney disease]. 1901 44

Neurologic complications are common after solid organ transplantation and are associated with significant morbidity. Approximately one-third of transplant recipients experiences neurologic alterations with incidence ranging from 10% to 59%. The complications can be divided into such of those common to all types of transplant and others of those specific to transplanted organ. The most common complication seen with all types of transplanted organ is neurotoxicity attributable to immunosuppressive drugs, followed by seizures, opportunistic central nervous system (CNS) infections, cardiovascular events, encephalopathy and de novo CNS neoplasms. Amongst immunosuppressants, calcineurin inhibitors are the main drugs involved in neurotoxicity, leading to complications which ranges from mild symptoms, such as tremors and paresthesia to severe symptoms, such as disabling pain syndrome and leukoencephalopathy. Neurologic complications of liver transplantation are more common than that of other solid organ transplants (13-47%); encephalopathy is the most common CNS complication, followed by seizures; however, central pontine myelinolysis can appear in 1-8% of the patients leading to permanent disabilities or death. In kidney transplanted patients, stroke is the most common neurologic complication, whereas cerebral infarction and bleeding are more typical after heart transplantation. Metabolic, electrolyte and infectious anomalies represent common risk factors; however, identification of specific causes and early diagnosis are still difficult, because of patient's poor clinical status and concomitant systemic and metabolic disorders, which may obscure symptoms.
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PMID:Neurologic complications after solid organ transplantation. 1907 32

Activation of primary afferent nociceptors produces acute, short-lived pain, and tissue or nerve injury induces long-term enhancement of nociceptive processing, manifested as hypersensitivity to thermal and mechanical stimulation. Here we used a chemical-genetic and pharmacological approach to study the contribution of the receptor tyrosine kinase, type 2 (TrkB) to the generation and maintenance of injury-induced persistent pain. We performed the studies in wild-type mice and transgenic (TrkB(F616A)) mice that express mutant but fully functional TrkB receptors. By injecting a small molecule derivative of the protein kinase inhibitor protein phosphatase 1 (1NM-PP1), it is possible to produce highly selective inhibition of TrkB autophosphorylation in adult mice, without interfering with the activity of other protein kinases. We report that oral administration of 1NM-PP1, at doses that blocked phosphorylation of TrkB in the spinal cord, had no effect in behavioral tests of acute heat, mechanical, or chemical pain sensitivity. However, the same pretreatment with 1NM-PP1 prevented the development of tissue- or nerve injury-induced heat and mechanical hypersensitivity. Established hypersensitivity was transiently reversed by intraperitoneal injection of 1NM-PP1. Although interfering with TrkB signaling altered neither acute capsaicin nor formalin-induced pain behavior, the prolonged mechanical hypersensitivity produced by these chemical injuries was prevented by 1NM-PP1 inhibition of TrkB signaling. We conclude that TrkB signaling is not only an important contributor to the induction of heat and mechanical hypersensitivity produced by tissue or nerve injury but also to the persistence of the pain.
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PMID:TrkB signaling is required for both the induction and maintenance of tissue and nerve injury-induced persistent pain. 1940 18

Calcineurin may be involved in affecting nociceptive processes in multiple circumstances. It is conceivable that interfering with calcineurin's normal role in contributing to glial resting membrane potential, via its effects on the ion channel (TRESK) [tandem-pore-domain weakly inward rectifying potassium channels (TWIK)-related spinal cord potassium channels] may facilitate nociception. Another aspect of calcineurin function may be its role in the pronociceptive signaling of nuclear factor of activated T-cells (NFAT). NFAT activation via mediators (e.g. Substance P, brain-derived neurotrophic factor, nerve growth factor, bradykinin) appears to be dependent on calcineurin function. This calcineurin-regulated NFAT signaling may subsequently lead to transcription of pronociceptive genes as well as upregulation of pronociceptive chemokine receptors in the dorsal root ganglion. In fact, multiple articles have described the clinical use of calcineurin-inhibitors leading to pain, a phenomenon referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Thus, it appears that calcineurin functions may encompass actions which promote or dampen nociceptive processes. A greater understanding of the physiology of calcineurin, especially as it relates to modulating nociception may lead to the development of novel analgesic targets in attempts to optimally alleviate patient discomfort.
Pain Physician
PMID:Calcineurin as a nociceptor modulator. 1966 90

The ACTN3 gene encodes for the alpha-actinin-3 protein, which has an important structural function in the Z line of the sarcomere in fast muscle fibers. A premature stop codon (R577X) polymorphism in the ACTN3 gene causes a complete loss of the protein in XX homozygotes. This study investigates a possible role for the alpha-actinin-3 protein in protecting the fast fiber from eccentric damage and studies repair mechanisms after a single eccentric exercise bout. Nineteen healthy young men (10 XX, 9 RR) performed 4 series of 20 maximal eccentric knee extensions with both legs. Blood (creatine kinase; CK) and muscle biopsy samples were taken to study differential expression of several anabolic (MyoD1, myogenin, MRF4, Myf5, IGF-1), catabolic (myostatin, MAFbx, and MURF-1), and contraction-induced muscle damage marker genes [cysteine- and glycine-rich protein 3 (CSRP3), CARP, HSP70, and IL-6] as well as a calcineurin signaling pathway marker (RCAN1). Baseline mRNA content of CSRP3 and MyoD1 was 49 + or - 12 and 67 + or - 25% higher in the XX compared with the RR group (P = 0.01-0.045). However, satellite cell number was not different between XX and RR individuals. After eccentric exercise, XX individuals tended to have higher serum CK activity (P = 0.10) and had higher pain scores than RR individuals. However, CSRP3 (P = 0.058) and MyoD1 (P = 0.08) mRNA expression tended to be higher after training in RR individuals compared with XX alpha-actinin-3-deficient subjects. This study suggests a protective role of alpha-actinin-3 protein in muscle damage after eccentric training and an improved stress-sensor signaling, although effects are small.
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PMID:Protective role of alpha-actinin-3 in the response to an acute eccentric exercise bout. 2050 67


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