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Query: UNIPROT:P06889 (Mol)
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The overall goal of this study was to determine if activation of the nitric oxide synthetic pathway suppressed basal ventricular performance and the responsiveness to beta-adrenergic stimulation characteristic of cardiac function in the 8-week streptozotocin (60 mg/kg, i.v.) diabetic (STZ-Db) rat. Left ventricular performance was measured in isolated working hearts, before and at the peak response to 0.8 microM dobutamine, in the absence or presence of NG-nitro-L-arginine methyl ester (L-NAME, 1 mM), a non-selective inhibitor of nitric oxide synthase (NOS). Ventricular performance was suppressed in the STZ-Db heart under basal (decreased heart rate, cardiac output, aortic flow -dP/dt) and dobutamine-stimulated (diminished rise in +dP/dt and maximum systolic pressure) conditions. L-NAME had minimal effects on basal or dobutamine-stimulated ventricular performance in control hearts. In contrast, L-NAME infusion in hearts from STZ-Db returned the depressed heart rate to control values, which was correlated with an increase in aortic flow. In addition, the dobutamine-stimulated rise in maximum systolic pressure and +dP/dt were similar in the control and STZ-Db rats in the presence of l-NAME. Western blot analysis detected the presence of inducible nitric oxide synthase (NOS) and a significant (P<0.001) increase in the constitutive NOS in ventricular myocytes from STZ-Db rats. These data suggest that an increased production of nitric oxide by NOS in ventricular myocytes from STZ-Db animals suppressed basal ventricular performance and the responsiveness to beta-adrenergic stimulation in diabetic hearts.
J Mol Cell Cardiol 1997 Sep
PMID:Inhibition of nitric oxide synthase by L-NAME improves ventricular performance in streptozotocin-diabetic rats. 929 63

Properties of the myocardial PM-FABP were studied in normal and STZ-diabetic rats. The fluorescent fatty acids trans-parinaric and cis-parinaric acids were used as analogs of straight-chain (saturated) and kinked-chain (unsaturated) fatty acids respectively. Parinaric acid binding was sensitive to trypsin. Trans-parinaric acid binding was more sensitive to this protease than the binding of cis-parinaric acid. Based on the difference in sensitivity of parinaric acid binding we believe that there are two separate binding sites associated with myocardial PM-FABP; one for unsaturated fats and the other for saturated fats. Diabetes enhanced both cis- and trans-parinaric acid binding capacity in cardiomyocytes; cis-parinaric acid by 2 fold and trans-parinaric acid by 2.6 fold. In addition, there was a concomitant accumulation of free fatty acids and triglycerides in the hearts of the diabetic animals. There was a 2.2 fold increase for fatty acids and a 1.6 fold increase for trigylcerides. This association between myocardial fatty acid build-up and enhanced myocardial PM-FABP during diabetes suggest that this carrier protein might have contributed to lipid accumulation in the hearts of the diabetic rats.
Mol Cell Biochem 1997 Nov
PMID:Characteristics of the myocardial PM-FABP: effect of diabetes mellitus. 940 73

Effect of the antidiabetic agent pioglitazone on the insulin-mediated activation of protein phosphatase-1 was examined in diabetic hepatocytes. Streptozotocin-induced diabetes in Sprague Dawley rats caused a significant decrease in the activation of glycogen synthase in hepatocytes isolated from these animals. There was an inverse correlation between the in vivo hyperglycemic condition and the in vitro activation of glycogen synthase in liver cells (r = 0.93, p < 0.001). Long term incubation of diabetic hepatocytes with insulin and dexamethasone caused significant (p < 0.001) improvement in the activation of glycogen synthase activation. When incubated along with hormones, pioglitazone enhanced their action (p < 0.05-0.01). Diabetic hepatocytes were also characterized by 50% decrease in the activity of protein phosphatase-1, the enzyme which dephosphorylates and activates glycogen synthase. Pioglitazone potentiated the acute stimulatory effect of insulin on protein phosphatase-1 in normal hepatocytes but not in diabetic hepatocytes. Long term incubation of diabetic hepatocytes with insulin ameliorated the decrease in the protein phosphatase-1 activity in these cells. This stimulatory long-term effect of insulin was significantly (p < 0.05) enhanced by the antidiabetic agent pioglitazone.
Mol Cell Biochem 1998 May
PMID:Insulin action on protein phosphatase-1 activation is enhanced by the antidiabetic agent pioglitazone in cultured diabetic hepatocytes. 960 28

Streptozotocin (STZ) is believed to induce pancreatic beta cell death in mice by depleting the cell of NAD+NADH. The drug is known to cause a greater depletion of beta cell NAD+NADH in C57bl/6J mice than in Balb/c mice. To investigate the basis for this strain difference, we compared the effects of streptozotocin on poly(ADP-ribose)polymerase (PARP) activation - the major site of NAD consumption, and on mitochondrial activity - the major site of NAD production.%A significant strain difference was demonstrated in STZ-induced PARP activation (fmol NAD incorporated/min/microgram DNA+/-s.e.m.: Balb/c control 2.28+/-0.14, Balb STZ 3.11+/-0.25; C57bl/6J control 2.57+/-0.29, C57bl/6J STZ 4.17+/-0.24). In comparison, no strain difference could be demonstrated in hydrogen-peroxide-induced PARP activation. No strain differences could be detected in the activity of STZ-treated islet mitochondria as measured by determining ATP production (pmol/microgram protein/h+/-s. e.m.: Balb/c control 0.20+/-0.02, Balb/c STZ 0.15+/-0.02; C57bl/6J control 0.23+/- 0.03, C57bl/6J STZ 0.15+/-0.02) or by 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) dye reduction (change in optical density/mg protein+/-s.e.m.: Balb/c control 10.19+/-0.62, Balb/c STZ 6.01+/-1.17; C57bl/6J control 6. 15+/-0.98, C57bl/6J STZ 5.81+/-0.96).% The strain difference in STZ-induced NAD depletion appears to be due to a difference in NAD consumption and not a difference in a mitochondrial process involved in replacing decreasing NAD concentrations. It is unlikely that a strain difference in the enzymic activity of PARP is responsible for strain differences in the effects of STZ, as no strain differences in hydrogen-peroxide-induced PARP activation could be detected. Thus the greater PARP activation, NAD depletion and beta cell death observed in C57bl/6J islets may be due to greater levels of DNA damage or differences in the DNA excision repair processes.
J Mol Endocrinol 1999 Feb
PMID:Poly(ADP-ribose)polymerase activation determines strain sensitivity to streptozotocin-induced beta cell death in inbred mice. 992 81

Studies involving the transplantation of human islets in Type I diabetics have been of significant value both in documenting the potential importance of islet transplantation as a therapeutic modality, and in defining some of the problems which must be overcome before this approach can be used in large numbers of patients. The currently limited supply of adult human pancreatic glands, and the fact that chronic immunosuppression is required to successfully transplant islets into patients, indicate that techniques must be further developed and refined for allo- and xenografting of isolated islets from human and animal sources to diabetic patients. An increasing body of evidence using microencapsulation techniques strongly suggests that this will be achieved during the next few years. Data from our laboratory in rodents and dogs indicate that these systems can function for extended periods of time. In one study, insulin independence was achieved in spontaneously diabetic dogs by islet microencapsulation inside uncoated alginate gel spheres (Mr exclusion >600 kD). No synthetic materials or membrane coatings were employed in this study. Spheres containing canine islets were implanted into the peritoneum of 4 diabetic dogs. The animals received low-dose CsA (levels below readable limits by HPLC at 3 weeks). Implantation of these spheres completely supplanted exogenous insulin therapy in the dogs for 60 to >175 days. Blood glucose concentration averaged 122+/-4 mg/dl for these animals during the first 2 months. The glycosylated hemoglobin (HbAIC) levels during this period dropped from 6.7+/-0.5% to 4.2+/-0.2% (P<0.001). IVGTT K-values at 1 and 2 months postimplantation were 1.6+/-0.1 (P<0.002) and 1.9+/-0.1 (P<0.001), respectively compared with 0.71+/-0.3 before implantation. In a second group of studies, bovine islets were immobilized inside a new type of selectively permeable "microreactor" (Mr exclusion <150 kD) and implanted into the peritoneum of 33 STZ-induced diabetic rats without any immunosuppression. Diabetes was promptly reversed, and normoglycemia maintained for periods of several weeks to months. Immunohistochemical staining of microreactors recovered from these animals revealed well-granulated beta-cells consistent with functionally active insulin synthesis and secretion. To test further the secretory function of the islets, some of the explanted microreactors were incubated in media containing either basal or stimulatory concentrations of glucose. The islets responded with an approximately 3- to 5-fold average increase above basal insulin secretion. These results are encouraging, and may have important implications in assessing the potential role of these microencapsulation systems as therapy for human insulin-dependent diabetes.
J Mol Med (Berl) 1999 Jan
PMID:Transplantation of islets using microencapsulation: studies in diabetic rodents and dogs. 993 Sep 64

The effect of increasing extracellular calcium concentration on spontaneous transmitter release was studied at both soleus (slow) and fast extensor digitorum longus (EDL) nerve terminals of control and streptozotocin-induced diabetic (STZ-D) young C57 BL mice (7 months old) depolarized by high (20 mM) extracellular potassium [K]o. Diabetes was induced by i.p. injection with a single dose of streptozotocin (200 mg/kg) at the age 5 months and the electrophysiological studies were carried out after 8 more weeks. By using intracellular recording, miniature endplate potentials (MEPPs) were first recorded in a normal [K]o Krebs solution. Subsequently, MEPPs were recorded in high [K]o Krebs solution with 4 different Ca concentrations: Ca-free/ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetra acetic acid (EGTA), 0.5, 1.5 and 2 mM Ca. MEPP frequency was lower at STZ-D than control nerve terminals in EDL but not soleus. However, MEPP frequency was progressively higher at both EDL and soleus of STZ-D than control with increasing Ca concentration in Krebs that contained 20 mM [K]o. In STZ-D slow soleus muscle, depolarization produced 0.7, 4.3, 41.6 and 62.7 vs 1.4, 2.8, 20.7 and 31.6 Hz for control in the 4 different Ca concentrations. In STZ-D fast EDL muscle, depolarization produced 0.5, 4.9, 48.2 and 66.8 vs 1.2, 2.5, 27 and 35.4 Hz for control in the 4 different Ca concentrations. Bimodal and unimodal MEPP amplitude were present at both slow and fast nerve terminals. However, depolarization increased the percentage of bimodal MEPP amplitude in STZ-D compared to control (p<0.01) mice in EDL but not soleus. The results revealed that these changes in muscle firing pattern may provide a protective effect against diabetes-induced neuropathy at the neuromuscular junction.
Cell Mol Biol (Noisy-le-grand) 1999 Mar
PMID:Depolarization affects neuromuscular junction of streptozotocin-diabetic mice. 1023 Jul 36

TFIIIA-type zinc fingers have been found in a number of eucaryotic transcription factors as DNA-binding motifs. In plants, as many as 30 proteins have been reported that have either one, two, three or four zinc fingers. Plant zinc-finger proteins are characterized by long spacers of diverse lengths between adjacent fingers and a highly conserved sequence, QALGGH, located within a putative DNA-contacting surface of each finger. In vitro DNA-binding experiments with two-fingered proteins of petunia have revealed that these proteins bind to target DNA sequences in a manner that is distinctive from that of their animal counterparts: (1) they specifically recognize the spacing between two core sites in target DNA, (2) they have a unique base-determinant position. Regulatory functions have been assigned to some of the TFIIIA-type zinc finger proteins in Arabidopsis, petunia and chinese cabbage. SUPERMAN, AtZFP1, PetSPL3 and BcZFP1 have been implicated in the developmental regulation of various floral and vegetative organs, presumably through the control of cell division and/or expansion in particular cell types. Several anther-specific zinc-finger proteins in petunia are presumed to be involved in the regulation of gametogenesis in both reproductive and non-reproductive tissues of anther. STZ and ZPT2-2 are implicated in the response of plants to or tolerance for various stresses.
Plant Mol Biol 1999 Apr
PMID:Zinc-finger proteins: the classical zinc finger emerges in contemporary plant science. 1038 Jul 95

The metabolic and secretory responses to D-glucose and/or D-fructose were measured in pancreatic islets prepared from either control rats or animals that had been injected with streptozotocin during the neonatal period (STZ rats). The STZ rats displayed higher plasma D-glucose concentrations, but lower plasma insulin concentrations, islet insulin content, as well as basal and nutrient-stimulated insulin release. This coincided with lower rates of D-[U-(14)C]hexose oxidation and D-[5-(3)H]hexose utilization. In both control and STZ rats, D-fructose failed to affect significantly the metabolism of d-glucose, while the aldohexose increased the ratio between D-[U-(14)C]fructose oxidation and D-[5-(3)H]fructose conversion to (3)HOH. Such a ratio was higher than that found with radioactive D-glucose in islets exposed to both hexoses, whether in control or STZ rats, indicating a far-from-negligible contribution of fructokinase to the phosphorylation of D-fructose. Despite these analogies between both the respective fate of D-glucose and D-fructose and the reciprocal metabolic effects of the two hexoses in islets from control and STZ rats, the secretory response to the ketohexose in islets from STZ rats was preferentially suppressed, relative to that evoked by the aldohexose. This gives support to the idea that the insulinotropic action of D-fructose may not be entirely accounted for by its nutritional value in islet cells.
Mol Genet Metab 1999 Sep
PMID:Metabolic and secretory response to D-fructose in pancreatic islets from adult rats injected with streptozotocin during the neonatal period. 1047 86

The in vivo effects of bis(maltolato)oxovanadium (IV) (BMOV) on the activity of protein serine kinases in skeletal muscle of STZ-diabetic Wistar rats were studied. BMOV was administered to STZ-diabetic rats at a concentration of 0.75 mg/ml for 8 weeks. Chronic BMOV treatment completely normalized plasma glucose levels in the diabetic animals after 8 weeks of treatment. Insulin-stimulated ERK-1 and ERK-2 activity was markedly increased in STZ-diabetic rats. Chronic BMOV treatment normalized the activity of ERK-2 in the diabetic treated animals, whereas the activity of ERK-1 was unaffected. In contrast to ERK-1 and ERK-2, the activity of the ribosomal S6 kinase p90rsk was decreased in STZ-diabetic rats. BMOV treatment restored the activity to normal levels. Basal p70 S6K activity was increased about 2.5-fold in the untreated diabetic group and no further increase in activity was observed after insulin stimulation. BMOV treatment did not correct the changes in p70 S6K activity in either the basal or insulin-stimulated states. In conclusion (i) the activity of ERK-1, ERK-2 and p90rsk were altered in skeletal muscle of STZ-diabetic rats; (ii) the glucoregulatory effects of BMOV were accompanied by concurrent improvement in the activities of ERK-2 and p90rsk; and (iii) there appears to be a dissociation between the activation of ERK-2 and p90rsk, suggesting that the regulation of p90rsk may be much more complex in vivo.
Mol Cell Biochem 1999 Dec
PMID:Effects of bis(maltolato) oxovanadium (IV) on protein serine kinases in skeletal muscle of streptozotocin-diabetic rats. 1070 3

Streptozotocin (STZ)-induced diabetes causes an upregulation in the expression of endothelin (ET) receptors in the rat prostate (Eur J Pharmacol 310:197, 1996). We examined the effects of insulin treatment, started 8 weeks after the induction of diabetes, on the expression and distribution of ET receptors and their respective mRNAs in the rat prostate. The densities, pharmacological properties and distribution of ET receptors in the rat prostate were examined using radioligand receptor binding and autoradiographic studies, and gene expression of ET receptors was evaluated utilizing the reverse transcription-polymerase chain reaction (RT-PCR). STZ-injected rats had smaller prostates and reduced serum testosterone levels than control and insulin treated diabetic animals. ET receptor density was shown to be significantly higher in the prostate from diabetic rats than those from either control or insulin treated diabetic animals. The pharmacological profile of prostatic ET receptors was similar in all groups (approximately 80% ET(A); 20% ET(B) subtype). ET receptors were predominantly localized to the prostatic stroma. Induction of diabetes increased the expression of mRNA levels of ET(A) and ET receptors, and insulin treatment reversed this upregulation to control levels. These results indicate that (1) ET receptor subtypes are expressed in the rat prostate as transcription and translation products; (2) insulin can normalize the diabetes-induced upregulation in the expression of ET receptors and their respective mRNAs; and (3) diabetes-induced regression of the prostate may involve an alteration in ET receptors.
Mol Cell Biochem 2000 Jul
PMID:Expression of endothelin receptor subtypes and their messenger RNAs in diabetic rat prostate: effect of insulin treatment. 1097 52


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