Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effective therapy (Rx) in primary hypertension (PH) for 50 years, has featured sympathetic nervous system (SNS) mechanisms. Ganglionic blockers and reserpine were pre-eminent in the 1940s (mydriasis, ileus, impotence, peptic ulcer). Guanethidine, and in the 1960s clonidine and methyldopa, were step II agents to thiazide Rx in the 1950s. Reserpine depletes brain (depression) and peripheral (PPH) noradrenaline (NA) storage sites, guanethidine depleted NA storage via blockade of reuptake. Venomotor sympathoplegia resulted in postural hypertension. An analogue, metaiodobenzyguandine is used in diagnosis and Rx of pheochromocytoma. Clonidine lowers both central and PPH neuronal NA release via both stimulation of alpha agonist adrenoreceptors (sedation) and specific imadazoline binding sites (IBS). Methyldopa lowers pressure via PPH induced NA release (retrograde ejaculation) and via alphamethyl NA on central alpha-2 receptors (depression). The alpha-2 and alpha-2 receptor antagonists (alphaRA) cause reflex tachycardia and first-dose hypotension. Recently a two-fold incidence of congestive heart failure after alphaRA in treated primary hypertensives question their role in PH. The beta RA, with or absent alphaRA, remain premier since the 1970s due to mortality benefit in systolic dysfunction and post myocardial infarction, certifying the role of the SNS in the pathogenesis and sequelae and Rx of PH. The future includes beta RA, specific IBS agents, angiotensin (AII) RA with avid presynaptic AII affinity and vasopeptidase inhibitiors that raise peptides and suppress SNS.
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PMID:Sympatholytic therapy in primary hypertension: a user friendly role for the future. 1198 8

Sodium azide is a white crystalline solid used in the manufacture of the explosive lead azide. It is the principal chemical used to generate nitrogen gas in automobile safety airbags and airplane escape chutes and is a broad-spectrum biocide used in both research and agriculture. Toxicology and carcinogenicity studies were conducted by administering sodium azide (greater than 99% pure) in distilled water by gavage to groups of male and female F344/N rats once daily, 5 days per week for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-Day Studies: Rats received 0, 5, 10, 20, 40, or 80 mg/kg sodium azide. All male and female rats receiving 40 or 80 mg/kg and two of five female rats receiving 20 mg/kg died during the first week of the studies. Clinical findings of toxicity included lethargy and inactivity. No grossly observable lesions were present in any of the dose groups. 13-Week Studies: Rats received 0, 1.25, 2.5, 5, 10, or 20 mg/kg sodium azide. Seven of 9 males and all 10 females receiving 20 mg/kg died before the end of the studies. Final mean body weights of treated rats were within 10% of those of the controls. Compound-related clinical findings of toxicity in the 20 mg/kg dose groups included lethargy and labored breathing. Histopathologic lesions induced by sodium azide were limited to the brain (necrosis of the cerebrum and thalamus) and lung (congestion, hemorrhage, and edema), and were observed in rats receiving 20 mg/kg that died during the studies. Body Weights, Feed Consumption, and Survival in the 2-Year Studies: Because compound-related deaths were observed in the groups receiving 20 mg/kg in the 13-week studies, lower dose levels were used in the 2-year studies. Two-year studies were conducted by administering 0, 5, or 10 mg/kg sodium azide to groups of 60 male and 60 female rats. Dose-related depression in mean body weight was observed throughout the study period. Mean feed consumption values in low- and high-dose groups were lower than control values. Survival of high-dose rats of each sex was significantly (P<0.05) lower than controls (males-control, 24/60; low-dose, 27/60; high-dose, 9/60; females-37/60; 43/60; 21/59). The reduced survival was attributed to brain necrosis and cardiovascular collapse induced by sodium azide. Neoplastic and Nonneoplastic Effects in the 2-Year Studies: There were no compound-related increases in incidences of neoplasms in rats. Significantly decreased incidences were observed for certain neoplasms, including mononuclear cell leukemia in male rats (control, 33/60; low-dose, 28/60; high-dose, 14/60), adrenal gland pheochromocytoma in male rats (26/55; 16/56; 6/54), mammary gland fibroadenoma in female rats (20/60; 11/60; 8/59), and pituitary gland neoplasms in female rats (37/60; 28/60; 17/59). These decreases reflected to some extent, but could not be attributed solely to, the reduced survival of the high-dose groups. Compound-related nonneoplastic brain lesions (necrosis of the cerebrum and thalamus) were observed at significantly (P<0.001) increased incidences in high-dose male and female rats. The increased incidence of lung congestion observed in this dose group was considered due to cardiovascular collapse secondary to brain necrosis. Genetic Toxicology: Sodium azide was mutagenic in Salmonella typhimurium strains TA100 and TA1535, with or without exogenous metabolic activation (S9); it was not mutagenic in strain TA1537 or TA98. In cytogenetic tests with Chinese hamster ovary cells, sodium azide induced sister chromatid exchanges, but not chromosomal aberrations, in the presence and the absence of S9. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of sodium azide in male or female F344/N rats administered 5 or 10 mg/kg. Sodium azide induced necrosis in the cerebrum and the thalamus of the brain in both male and female rats. Synonyms: Azide, Azium, Smite
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PMID:NTP Toxicology and Carcinogeneis Studies of Sodium Azide (CAS: 26628-22-8) in F344 Rats (Gavage Studies). 1263 70

Tris(2-ethylhexyl)phosphate is one of a family of triakyl phosphates that have been widely used as fire retardants and plasticizers. Another triakyl phosphate, tris(2,3-dibromopropyl)phosphate (Tris-BP), once used as a flame retardant in children's sleepwear, has been shown to be carcinogenic, but tris(2-ethylhexyl)phosphate has not been previously studied. Tris(2-ethylhexyl)phosphate, a clear, viscous liquid, is used as a component of vinyl stabilizers, grease additives, and flame-proofing compositions; however, it is used primarily as a plasticizer for vinyl plastic and synthetic rubber compounds. In 1974, approximately 3 million pounds of tris(2-ethylhexyl)phosphate was produced in the United States; imports during that year were negligible. Substantial human exposure probably occurs during production of tris(2-ethylhexyl)phosphate and during the manufacture and use of products containing it, but data on the magnitude of exposure are not available. Two-year toxicology and carcinogenesis studies of tris(2-ethylhexyl)phosphate were conducted by administering the test chemical in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 male and 50 female F344/N rats and B6C3F1 mice. Male rats received doses of 2,000 or 4,000 mg/kg body weight, female rats received 1,000 or 2,000 mg/kg, and male and female mice received 500 or 1,000 mg/kg. Fifty vehicle control animals of each sex and species received 10 ml/kg body weight (rats) or 3.3 ml/kg (mice) corn oil by gavage on the same schedule. Inflammation of the gastric mucosa in mice and mild weight depression in rats and mice were the only dose-related effects observed in the preliminary studies. In the 2-year studies, survival rates and mean body weight gains of dosed female rats and dosed mice were comparable to those of their perspective controls. Survival rates of dosed male rats were comparable to that of the vehicle controls, but body weight gains were depressed. One nonneoplastic lesion, follicular cell hyperplasia of the thyroid, was observed at increased incidences in dosed male and female mice. Two compound-related increased incidences of neoplasms could not be discounted. In male rats, the incidence of pheochromocytoma of adrenal glands increased with dose (2/50, 4%; 9/50, 18%; 12/50, 24%). There were also two additional malignant pheochromocytomas in the high dose group. However, the incidence of adrenal pheochromocytoma in vehicle controls of this study (2/50, 4%) was low compared with the 25% incidence observed in two previous studies in this laboratory or the overall historical incidence of 18% observed throughout the Program, and thus the evidence of carcinogenicity was considered to be equivocal. In female mice, the incidence of hepatocellular carcinoma (0/48; 4/50; 7/50) in high dose animals (1,000 mg/kg) was significantly increased relative to that of the vehicle controls. Decreased incidences were observed for acinar cell adenomas of the pancreas in dosed male rats (14/50, 28%; 5/48, 10%; 2/49, 4%) and for fibroadenomas of the mammary glands in low dose female rats (11/50, 22%; 2/50, 4%; 7/50, 14%). Hemangiosarcomas of the circulatory system in male mice (7/50, 14%; 0/50; 1/49, 2%) and lymphomas of the hematopoietic system in female mice (14/49, 29%; 10/50, 20%; 6/50, 12%) were decreased compared with vehicle controls. A decrease in the incidence of lymphomas and an increased incidence of carcinomas of the liver in female mice (both seen in this study) were observed in studies of di(2-ethylhexyl)adipate. Increased incidences of liver carcinomas and decreased incidences of mammary fibroadenomas were observed also in female rats in the di(2-ethylhexyl)phthalate studies. A possible link among these three chemicals may be metabolic conversion to 2-ethylhexanol. Tris(2-ethylhexyl)phosphate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of 9000 x g (S9) fractions from Aroclor 1254-induced Sprague-Dawley rat or Syrian hamster liver. An audit of the experimental data from these carcinogeneoclor 1254-induced Sprague-Dawley rat or Syrian hamster liver. An audit of the experimental data from these carcinogenesis studies was conducted by the National Toxicology Program. No data discrepancies were found that significantly influenced the final interpretations of these experiments. Under the conditions of these studies, a comparison of concurrent and historical controls indicated that there was equivocal evidence of carcinogenicity in male F344/N rats receiving 2,000 and 4,000 mg/kg tris(2-ethylhexyl)phosphate, as evidenced by increased incidences of pheochromocytomas of the adrenal glands. There was no evidence of carcinogenicity in female F344/N rats or in male B6C3F1 mice receiving tris(2-ethylhexyl)phosphate. There was some evidence of carcinogenicity in female B6C3F1 mice that received 1,000 mg/kg tris(2-ethylhexyl)phosphate, as shown by an increased incidence of hepatocellular carcinoma. Tris(2-ethylhexyl)phosphate was associated with increased incidences of follicular cell hyperplasia of the thyroid gland in male and female B6C3F1 mice. Synonyms and Trade Names: TOF; trioctyl phosphate; phosphoric acid tri(2-ethylhexyl) ester; Flexolreg. TOF; Kronitexreg.
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PMID:NTP Toxicology and Carcinogenesis Studies of Tris(2-ethylhexyl)phosphate (CAS No. 78-42-2) In F344/N Rats and B6C3F1 Mice (Gavage Studies). 1274 80

A 59-year-old male was admitted to the emergency department because of sustained chest oppression. Electrocardiography revealed J type ST depression and peaked T wave in leads II, III, aVF, and V4-V6. No stenosis was found in the coronary arteries by urgent coronary angiography. Left ventricular abnormal wall movement with akinesis in the base and hyperkinesis in the apical area was observed and improved on the 12th day. Myocardial scintigraphy with iodine-123-metaiodobenzylguanidine showed completely defective images and decreased accumulation in the base with combined thallium-201 and iodine-123-beta-methyl-p-iodophenyl-pentadecanoic acid. Myocardial biopsy on the 12th day disclosed contraction band necrosis. The diagnosis was catecholamine-induced cardiomyopathy caused by pheochromocytoma.
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PMID:[Pheochromocytoma with reversal of tako-tsubo-like transient left ventricular dysfunction: a case report]. 1524 78

Allelic variants in the promoter region of the serotonin transporter (5-HTT) gene have been implicated in several psychiatric disorders and personality traits. In particular, two common alleles in a variable repeat sequence of the promoter region (SLC6A4) have been differentially associated with a display of abnormal levels of anxiety and affective illness in individuals carrying the "s" allele. The aim of this study was to compare the basal cerebral metabolic activity of non-psychiatric subjects in fronto-limbic structures to determine whether differences exist in basal metabolic activity within this functional polymorphism. PET scans with fluorine-18 fluorodeoxyglucose as radiotracer were performed in 71 non-psychiatric subjects previously screened for psychopathology and subsequently genotyped for SLC6A4; PET images were compared with SPM2 according to s/s (n = 27), s/l (n = 25), and l/l (n = 19) groups considering a significance threshold in a priori selected areas of P < 0.001 and an extent threshold > or =5 voxels. The analysis showed an effect of interest among the three genotype groups in right anterior cingulate gyrus (ACC), left middle frontal gyrus, and left posterior cingulate gyrus (PCC). Comparison between l/l vs. s/s showed increased metabolism for l/l in left middle frontal gyrus and an increase for s/s in right ACC and left PCC. Comparison between s/s vs. s/l showed an increase for s/s in left PCC and right ACC. Increased basal metabolism in fronto-limbic structures for the s/s group may be conceived as an "overactive metabolic state" of these structures, possibly related to an increased susceptibility for developing an anxiety-depression spectrum disorder.
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PMID:Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism. 1585 Jul 37

The occurrence of a photorespiratory 2-phosphoglycolate metabolism in cyanobacteria is not clear. In the genome of the cyanobacterium Synechocystis sp. strain PCC 6803, we have identified open reading frames encoding enzymes homologous to those forming the plant-like C2 cycle and the bacterial-type glycerate pathway. To study the route and importance of 2-phosphoglycolate metabolism, the identified genes were systematically inactivated by mutagenesis. With a few exceptions, most of these genes could be inactivated without leading to a high-CO(2)-requiring phenotype. Biochemical characterization of recombinant proteins verified that Synechocystis harbors an active serine hydroxymethyltransferase, and, contrary to higher plants, expresses a glycolate dehydrogenase instead of an oxidase to convert glycolate to glyoxylate. The mutation of this enzymatic step, located prior to the branching of phosphoglycolate metabolism into the plant-like C2 cycle and the bacterial-like glycerate pathway, resulted in glycolate accumulation and a growth depression already at high CO(2). Similar growth inhibitions were found for a single mutant in the plant-type C2 cycle and more pronounced for a double mutant affected in both the C2 cycle and the glycerate pathway after cultivation at low CO(2). These results suggested that cyanobacteria metabolize phosphoglycolate by the cooperative action of the C2 cycle and the glycerate pathway. When exposed to low CO(2), glycine decarboxylase knockout mutants accumulated far more glycine and lysine than wild-type cells or mutants with inactivated glycerate pathway. This finding and the growth data imply a dominant, although not exclusive, role of the C2 route in cyanobacterial phosphoglycolate metabolism.
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PMID:The plant-like C2 glycolate cycle and the bacterial-like glycerate pathway cooperate in phosphoglycolate metabolism in cyanobacteria. 1687

We describe a 36-year-old woman with inverted Takotsubo cardiomyopathy caused by pheochromocytoma crisis. In the acute phase, her electrocardiogram showed ST segment depression in lead II, III, aVF and V2 through V5. On day 14, tall upright T-waves were observed in leads V2 through V5 despite heart failure and basal to midventricular ballooning improved on day 4, and all electrocardiographic abnormalities finally normalized after surgical removal of the pheochromocytomas. This is the first report of electrocardiographic course of inverted Takotsubo cardiomyopathy, and these findings seem as if the inverted electrocardiographic findings are contrary to those of apical ballooning.
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PMID:Inverted Takotsubo contractile pattern caused by pheochromocytoma with tall upright T-waves, but not typical deep T-wave inversion. 1872 26

Preclinical and clinical investigations have shown the involvement of dysregulation of hypothalamic-pituitary-adrenal (HPA) axis in the pathogenesis of depression. Hypercortisolemia and the associated hippocampal atrophy were observed in patients with depression, which could be ameliorated by the treatment with antidepressants. Therefore, neuroprotection has been proposed to be one of the acting mechanisms of antidepressant. Previous studies in our laboratory have demonstrated the antidepressant-like activity of total glycosides of peony (TGP) in mice. This study aimed to examine the effect of TGP treatment on corticosterone-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. Treating the cells with corticosterone at 200 muM for 48 h caused apoptotic cell death. The cytotoxicity was associated with the activation of caspase-3 activity and the decrease in the mRNA ratio of bcl-2 to bax. TPG treatment at increasing doses (1-10 mg/l) protected against the corticosterone-induced toxicity in PC12 cells in a dose-dependent manner. The cytoprotection afforded by TGP treatment was associated with the inhibition of caspase-3 activity and the up-regulation of bcl-2/bax mRNA ratio. The anti-apoptotic effect of TGP is therefore likely mediated by the suppression of the mitochondrial pathway leading to apoptosis.
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PMID:Peony glycosides protect against corticosterone-induced neurotoxicity in PC12 cells. 1921 37

Hypericum perforatum L. has been used traditionally as an antidepressant for the treatment of mild to moderate depression. In a previous study, a flavonoid-rich extract of Hypericum perforatum L. (FEHP) was prepared and its antioxidant activity was determined by a series of models in vitro. In the present study, the protective effects of FEHP against hydrogen peroxide-induced apoptosis in rat pheochromocytoma line PC12 cells were investigated by MTT assay, lactate dehydrogenase (LDH) release assay, flow cytometry analysis and DNA fragmentation assay. Following a 4 h exposure of PC12 cells to H2O2, a significant decrease in the cell viability and increased levels of LDH release were observed. However, pretreatment of PC12 cells with FEHP prior to H2O2 exposure elevated the cell viability, decreased the levels of LDH release and decreased the occurrence of apoptotic cells. Also, the intensity of H2O2-induced DNA laddering was inhibited in a dose-dependent fashion by a DNA fragmentation assay. These results suggested that FEHP possessed protective effects against H2O2-induced apoptosis in PC12 cells and FEHP might be useful in the treatment of oxidative stress-related neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease.
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PMID:Protective effects of a flavonoid-rich extract of Hypericum perforatum L. against hydrogen peroxide-induced apoptosis in PC12 cells. 1954 87

Preclinical and clinical investigations have shown hippocampal neuronal atrophy and destruction were observed in patients with depression, which could be ameliorated by the treatment with antidepressants. Therefore, neuroprotection has been proposed to be one of the acting mechanisms of antidepressant. Paeoniflorin, a monoterpene glycoside, has been reported to display antidepressant-like effects in animal models of behavioral despair. The present study aimed to examine the protective effect of paeoniflorin on glutamate-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. The results showed that pretreatment with paeoniflorin elevated cell viability, inhibited apoptosis, decreased levels of intracellular reactive oxygen species and malondialdehyde, and enhanced activity of superoxide dismutase in glutamate-treated PC12 cells. Pretreatment with paeoniflorin also reversed the increased intracellular Ca(2+) concentration and the reduced Calbindin-D28K mRNA level caused by glutamate in PC12 cells. The results suggest that paeoniflorin exerts a neuroprotective effect on glutamate-induced neurotoxicity in PC12 cells, at least in part, via inhibiting oxidative stress and Ca(2+) overload. This neuroprotective effect may be one of the action pathways accounting for the in vivo antidepressant activity of paeoniflorin.
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PMID:Protective effects of paeoniflorin against glutamate-induced neurotoxicity in PC12 cells via antioxidant mechanisms and Ca(2+) antagonism. 2057 99


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