Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parathyroid hormone-like peptide (PLP) is elaborated from certain tumors and is thought to play a role in the etiology of humoral hypercalcemia of malignancy. The amino-terminal portion of this peptide has a sequence homology with parathyroid hormone PTH. We have compared the agonist potency of the synthetic human amino-terminal 1-34 peptide [human (h)PLP-(1-34)] with that of intact PTH and its amino terminal fragment [hPTH-(1-34)] in the renal and metatarsal cytochemical bioassays (CBA). Furthermore, the antagonist activity of the truncated amino terminal molecule [hPLP-(3-34)] has been compared to that of [Norleu8.18,Tyr34]bovine PTH-(3-34)NH2, and we have also tested their ability to stimulate enzyme activities thought to be associated with bone formation and resorption. In the renal CBA, both PLP-(1-34) and hPTH-(1-34) were equipotent with intact hPTH. In the metatarsal CBA, although the two amino-terminal peptides were equipotent, they elicited an earlier response than the intact PTH molecule. In both assay systems the truncated PLP analog [hPLP-(3-34)] was a more potent antagonist of both PTH and PLP activity than was [Norleu8.18,Tyr34]bovine PTH-(1-34)NH2. In acute studies, hPLP-(1-34) and hPTH-(1-34) stimulated alkaline phosphatase and glucose 6-phosphate dehydrogenase activity in osteoblasts to a similar extent, and both peptides stimulated tartrate-resistant acid phosphatase and succinate dehydrogenase activity in osteoclasts. Longer exposure to the peptides resulted in stimulation of enzyme activity in osteoclasts but not osteoblasts, although there was no difference in potency between the two molecules.
 ...
PMID:Bioactivity of parathyroid hormone and parathyroid hormone-like peptide: agonist and antagonist activities of amino-terminal fragments as assessed by the cytochemical bioassay and in situ biochemistry. 200 12

Epithelial cells isolated from rat intestine were analyzed for their responsiveness in vitro to parathyroid hormone (PTH) and to 1,25-dihydroxycholecalciferol [1,25-(OH)2D3]. Criteria included determination of whether the agonists promoted extracellular liberation of lysosomal enzyme activities above control values during incubation in Ringer's solution at 22 C. PTH-augmented release of the representative hydrolase activities, cathepsin B and acid phosphatase, to the particle-free supernatant fraction of the medium was evident within 5 min of hormone treatment and was sustained in statistically significant degree for at least 30 min to greater than 20% above control levels. Basal release rarely exceeded 15% of the total cellular content of these enzymic activities. Lactate and succinate dehydrogenase activities were undetectable in the particle-free supernatant fraction under conditions of maximal hormone effect, indicating integrity of the cells and selectivity of the organellar response. Treatment of corresponding cells with 1,25-(OH)2D3 resulted in similar time of onset, magnitude, and duration of response. The most sensitive indicator of limited lysosomal labilization by either hormone was beta-N-acetyl-D-glucosaminidase activity, which underwent accentuated extracellular liberation in the presence of as little as 10(-16) M PTH or 10(-11) M 1,25-(OH)2D3, the latter eliciting a response of greater than 40% above control levels. Parathyroidectomy diminished basal release of the hydrolase activities and sensitized the intestinal cells to the action of PTH vs. preparations from intact or sham-operated animals, as judged by excess liberation of the glycosidase. Nontarget lung cells failed to respond to supramaximal levels of either hormone by the criterion of reduced latency of lysosomal hydrolases. In additional acute experiments with intestinal cells, both PTH and 1,25-(OH)2D3 promoted enhanced 45Ca2+ accumulation above control values. Collectively, these data indicate that PTH is capable of provoking direct effects on intestinal cells, similar in onset and extent to those elicited by 1,25-(OH)2D3.
 ...
PMID:Early actions of parathyroid hormone and 1,25-dihydroxycholecalciferol on isolated epithelial cells from rat intestine: I. Limited lysosomal enzyme release and calcium uptake. 689 18

In vivo, bicarbonate can affect proximal tubule intermediary metabolism, including gluconeogenesis, ammoniagenesis and maintenance of the mitochondrial substrate supply. In vitro, rabbit proximal tubule cells (RPTC) in primary culture revert from gluconeogenesis to glycolysis and their mitochondrial metabolism remains lower than in vivo. To determine whether the bicarbonate buffer system could have an effect on these deregulations, RPTC in primary culture grown in the absence of insulin and glucose in the culture medium were developed either with the standard sodium bicarbonate buffer with 5% CO2 or with a Hepes hydrogen ion buffer in the presence of 0.5% CO2. Duration of the bicarbonate-free cultures was increased until at least day 17 after seeding, compared with day 11 in bicarbonate-buffered cultures. As could be expected, succinate dehydrogenase activity remained stable as a function of time in bicarbonate-free cultures while an early marked decrease of this activity occurred from seeding in cultures developed in the presence of bicarbonate buffer. Compared to bicarbonate-buffered cells, higher phosphoenolpyruvate carboxykinase activity concomitant with lower intracellular lactate dehydrogenase activity was observed in cultures developed in the absence of bicarbonate, which is indicative of closer carbohydrate metabolism orientation to the in vivo situation for RPTC. Immunofluorescence staining of RPTC with monoclonal antibodies directed to neutral endopeptidase (NEP), and dipeptidyl-peptidase IV (DPP II) showed similar extensive labelling with DPP and NEP in both culture conditions. Confocal microscopy analysis of NEP subcellular distribution, showed exclusive targetting of NEP to the apical plasma membranes. In both models, cAMP production was stimulated by parathyroid hormone and unaffected by arginine vasopressin. In conclusion, bicarbonate withdrawal from the culture medium (without changing the pH of the medium) allows a marked improvement of mitochondrial capacity and carbohydrate metabolism pattern without any loss of differentiated properties.
 ...
PMID:Effects of the medium HCO3-/CO2 buffer system on differentiation and intermediary metabolism properties of rabbit proximal tubule cells in primary culture. 897 88

The aim of the present study was to analyze the functional importance for the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTHR1) gene P2 promoter activity of the putative proximal Myc-associated zinc finger protein (MAZ) site localized at position bp -45 to -39 bp, taking advantage of a G/A mutation identified at position -40 in the human sequence. Wild-type 'full-length' (1285P2) and truncated (760P2) promoter sequences were inserted upstream to the luciferase basic (pLucB) and enhancer (pLucE) reporter gene expression vectors. Transient transfections in osteoblast-like SaOS-2 cells and renal cells (RC.SV3A2) showed that the -40 G/A mutation significantly impaired transcriptional activity of wild-type 1285P2-pLucB and 760P2-pLucE promoter constructs. Further truncation of the P2 sequence demonstrated that the sequence -109/-37 bp was essential for promoter activity. Co-transfection with a MAZ expression vector did not modify the wild-type 1285P2-pLucB construct reporter activity but significantly increased 2-fold the mutated construction activity (P<0.05). Electrophoretic mobility shift assays using SaOS-2 nuclear extracts and a double-stranded DNA fragment encompassing the -45 to -39 putative MAZ site (ds-MAZ-oligo) disclosed two specific DNA-protein complexes. Complex II (fast moving) had a lower affinity for the mutated MAZ motif than for the wild-type MAZ motif while complex I (slow moving) had the same affinity for both wild-type or mutated MAZ sequences. Competition studies with Sp1 consensus oligonucleotide (ds-Sp1-oligo) markedly reduced complex I intensity, with a concomitant increase in that of complex II. Finally, ribonuclease protection assays showed that P2-specific PTHR1 mRNA transcript expression was significantly decreased in SaOS-2 cells transfected with ds-MAZ-oligo as compared with that for control (P<0.001) and ds-Sp1-oligo (P<0.05). Taken together, our studies suggest that the putative -45 to -39 MAZ-binding site regulates the constitutive activity of human PTHR1 P2 promoter.
 ...
PMID:Functional importance of Myc-associated zinc finger protein for the human parathyroid hormone (PTH)/PTH-related peptide receptor-1 P2 promoter constitutive activity. 1476 95

Endocrine surgeons should maintain a high index of suspicion when patients are diagnosed with clinical signs or symptoms of parathyroid carcinoma. Although rare, the best chance for cure of these patients is at the time of the initial operation. Surgical resection of recurrent disease can provide effective palliation and can sometimes be assisted using gamma-probe directed dissection of sestamibi-labeled tumor tissue. Treatment of hyperparathyroidism in the setting of multiple endocrine neoplasia type 1 (MEN-1), particularly in the reoperative setting, can be aided by using the rapid intraoperative parathyroid hormone assay to judge the adequacy of parathyroid debulking. In addition, in selected cases, the gamma probe can assist in identifying the location of ectopic or autografted sestamibi-labeled parathyroid tissue. Patients with incidental adrenal masses rarely require fine needle aspiration to exclude metastatic cancer. Fine needle aspiration, if performed, should never precede hormone evaluation to exclude pheochromocytoma. Patients who are diagnosed with incidental adrenal masses in the setting of a prior or concurrent cancer diagnosis are equally likely to have a primary adrenal mass as they would be to have metastatic cancer in the adrenal gland. Pheochromocytomas occasionally develop in patients with MEN-1. In suspicious cases, molecular identification of an MEN-1 mutation can be used to confirm the diagnosis. Preoperative hormone evaluation of a patient with an adrenal incidentaloma should include evaluation for subclinical Cushing's syndrome through an overnight 1-mg dexamethasone suppression test. Identification of this condition allows for safe peri- and postoperative steroid hormone replacement, with very slow withdrawal of exogenous steroids to allow the opposite adrenal gland to recover and avoid postoperative Addisonian crisis. Paragangliomas are more commonly multifocal and malignant compared to pheochromocytomas. Evaluation of patients with paragangliomas should include radiographic staging for multifocality and metastatic disease, and postoperative hormone and radiographic follow-up evaluation should be performed. Consideration should be given to genetic testing for von Hippel-Lindau and succinate dehydrogenase mutations. Surgical treatment of rare functioning pancreatic and duodenal endocrine tumors, such as metastatic sporadic insulinoma and MEN-1-associated gastrinoma, can provide effective palliation. Surgical treatment should be integrated into a comprehensive treatment scheme that recognizes the natural history of the disease and incorporates appropriate adjunctive therapies and follow-up strategies.
 ...
PMID:Unusual functioning endocrine tumors. 1523 9

Thyroid paragangliomas are rare tumors that arise from the inferior laryngeal paraganglia. Most patients are female and present with an asymptomatic thyroid nodule. Histologically, the tumor is composed of cells arranged in a well-defined nest (zellballen) pattern surrounded by a thin fibrovascular stroma. It is a diagnostic pitfall and is occasionally misdiagnosed as follicular neoplasm, medullary thyroid carcinoma, intrathyroid parathyroid proliferation, and especially secondary neuroendocrine tumors. Immunohistochemical stains (cytokeratin, parathyroid hormone, thyroid transcription factor 1, tyrosine hydroxylase, chromogranin A, synaptophysin, S100, calcitonin, carcinoembryonic antigen) are essential in establishing the diagnosis. Loss of succinate dehydrogenase complex, subunit B (SDHB), immunoexpression can be used to triage genetic testing because some mutations are associated with a higher risk for developing metastasis. Total thyroidectomy or lobectomy for solitary lesion is the preferred treatment. Elective lymph node dissection is usually not indicated. Postoperatively, patients should receive hormonal evaluation for functional disease and imaging for evaluation of multifocal or metastatic disease.
...
PMID:Thyroid Paraganglioma. 2623 Jun 1