Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The extranuclear endogenous mono-ADP-ribosylation of proteins was monitored in cellular preparations of retina, superior cervical ganglion, dorsal root ganglia and peripheral nerve. At least 6 protein fractions are ADP-ribosylated in the crude extract fraction from retina control preparations, while in diabetic rats the number of retina labeled proteins and the extent of labeling are highly reduced. In the superior cervical ganglion labeling was present in 10 proteins, in diabetics it was greatly decreased. Treatment of diabetic rats with silybin, a flavonoid mono-ADP-ribosyltransferase inhibitor, did not affect hyperglycemia, but prevented the alteration of extent of protein ADP-ribosylation. These data suggest that proteins of retina and peripheral ganglia are excessively ADP-ribosylated in vivo. The effects of silybin treatment on excessive mono-ADP-ribosylation of proteins was associated with the prevention of reduction of substance P-like immunoreactivity levels, that is typical of diabetic neuropathy. In the membrane fraction of sciatic nerve Schwann cells, at least 9 proteins were ADP-ribosylated, diabetes caused a marked increase of labeling. A comparable increase involving the same proteins is triggered by chronic nerve injury and by corticosteroid treatment. Silybin treatment of diabetic rats prevented such an increase. We propose that the inhibition of excessive protein mono-ADP-ribosylation by silybin prevented the onset of diabetic neuropathy. While the effects on Schwann cells is likely indirect and secondary to the improvement of diabetic axonopathy.
 ...
PMID:Endogenous mono-ADP-ribosylation in retina and peripheral nervous system. Effects of diabetes. 919 68

We have recently demonstrated that prosaposin is a neurotrophic and myelinotrophic factor with the active trophic sequence located at the N-terminal region of the saposin C domain. There are also reports that prosaposin mRNA is increased distal to a physical nerve injury and that exogenous prosaposin treatment induces subsequent neuronal sprouting, suggesting involvement in repair processes. In the present study, we show that prosaposin mRNA is significantly (p < 0.05) elevated in the peripheral nerve of streptozotocin-diabetic rats, a model of insulin-deficient diabetes in which nerve injury arises from the metabolic trauma of hyperglycemia and its consequences. A 14 amino acid peptide derived from the neurotrophic region of prosaposin prevented the development of deficits in both large and small fiber function caused by diabetes in rats. The dose-dependent prevention of nerve conduction slowing by TX 14(A) was accompanied by preservation of axonal caliber and sodium-potassium ATPase activity, while prevention of thermal hypoalgesia was associated with attenuation of the decline in nerve substance P levels. It is concluded that nerve subject to the metabolic injury of uncontrolled diabetes responds by increasing prosaposin gene expression, and that prosaposin-derived neurotrophic peptides may provide a novel therapeutic approach to treatment of diabetic and other peripheral neuropathies.
 ...
PMID:Prosaposin gene expression and the efficacy of a prosaposin-derived peptide in preventing structural and functional disorders of peripheral nerve in diabetic rats. 1037 53

Diabetes-induced embryo malformations and growth retardation are correlated with a variety of biochemical changes including oxidative stress. In this study, we show that the morphological alterations are correlated with progressive and selective changes of mRNA expression in specific neurotrophic factors. At embryological stage E-17, diabetes affected both embryo growth and NGF mRNA expression, which was reduced by as much as 90 and 56% in target tissues of sensory system such as tongue and intestine, respectively. The reduction in retina and heart was around 50%. Conversely, the mRNA expression of low-affinity neurotrophin receptor p75 was increased. At birth, BDNF mRNA expression was affected with a significant generalized reduction,while in vibrissae we observed a reduction of BDNF and p75 mRNAs and an increase of NGF. At postnatal day 14, pups from diabetic mothers showed reduced muscle levels of IGF-I, while we observed a partial impairment of substance P axonal transport at postnatal day 28. Treatment of diabetic mothers with silybin, a flavonoid with antioxidant properties, prevented most of the changes in neurotrophic factor expression and substance P axonal transport with no effects on hyperglycemia and embryo growth retardation. These results indicate that oxidative stress may influence neurotrophic factor synthesis in target territories during development. In addition, these data suggest that nervous system abnormalities observed in diabetic embryopathy may also derive by insufficient neurotrophic factor biosynthesis involving sequentially NGF in the embryo and BDNF and IGF-I in the early postnatal days. Insulin treatment of diabetic mothers normalized hyperglycemia and body growth, with consequent regular embryonic and postnatal development.
 ...
PMID:Progressive and selective changes in neurotrophic factor expression and substance p axonal transport induced by perinatal diabetes: protective action of antioxidant treatment. 1044 Sep 1

Gastric emptying was measured in non-obese diabetic (NOD) and in obese diabetic mice. The feces were collected and the water content was determined. The neuroendocrine peptides known to regulate gastrointestinal motility, namely secretin, gastric inhibitory peptide (GIP), motilin, somatostatin, peptide YY (PYY), substance P, vasoactive intestinal polypeptide (VIP) and galanin, were measured in tissue extracts of different segments of the gut by radioimmunoassay. Whereas the gastric emptying of NOD mice was significantly slower than that of controls, that of the obese diabetic mice was unaltered. The gastric emptying of NOD mice, but not that of obese diabetic mice, correlated with the blood glucose level. The feces weight and water content in NOD mice was significantly higher than controls. The feces water content in obese diabetic mice was significantly lower than that of controls. The concentrations of antral somatostatin, VIP and galanin, and duodenal secretin as well as jejunal motilin in NOD mice were higher than those of controls. Duodenal GIP and colonic PYY concentration in NOD mice was lower than controls. Duodenal GIP and VIP, and colonic somatostatin and VIP levels were lower in obese diabetic mice than controls. Secretin and motilin levels correlated with gastric emptying in NOD mice. The high duodenal concentration of secretin might reflect high synthesis and release of this hormone, and may therefore be among the factors that caused slow gastric emptying in the NOD mice. The increase in concentration of motilin observed in NOD mice may be caused by impaired release of this hormone as a result of hyperglycemia. Whereas the high concentrations of antral VIP and galanin and the low level of colonic PYY in diabetic NOD mice may contribute to the development of diarrhea in NOD mice, the decreased levels of duodenal and colonic VIP and colonic somatostatin in obese diabetic mice may account for the constipation encountered in these animals.
 ...
PMID:Gastric emptying in animal models of human diabetes: correlation to blood glucose level and gut neuroendocrine peptide content. 1260 81

We examined the effects of C-peptide replacement on unmyelinated fiber function in the hind paw, sural nerve C-fiber morphometry, sciatic nerve neurotrophins, and the expression of neurotrophic receptors and content of neuropeptides in dorsal root ganglia in type 1 diabetic BB/Wor-rats. C-peptide replacement from onset of diabetes had no effect on hyperglycemia, but it significantly prevented progressive thermal hyperalgesia and prevented C-fiber atrophy, degeneration, and loss. These findings were associated with preventive effects on impaired availability of nerve growth factor and neurotrophin 3 in the sciatic nerve and significant prevention of perturbed expression of insulin, insulin growth factor-1, nerve growth factor, and neurotrophin 3 receptors in dorsal root ganglion cells. These beneficial effects translated into prevention of the decreased content of dorsal root ganglia nociceptive peptides such as substance P and calcitonin gene-related peptide. From these findings we conclude that replacement of insulinomimetic C-peptide prevents abnormalities of neurotrophins, their receptors, and nociceptive neuropeptides in type 1 BB/Wor-rats, resulting in the prevention of C-fiber pathology and nociceptive sensory nerve dysfunction. The data indicate that perturbed insulin/C-peptide action plays an important pathogenetic role in nociceptive sensory neuropathy and that C-peptide replacement may be of benefit in treating painful diabetic neuropathy in insulin-deficient diabetic conditions.
 ...
PMID:C-peptide prevents nociceptive sensory neuropathy in type 1 diabetes. 1549 55

Substance P (SP) is involved in the pathophysiology of several psychiatric disorders and is considered a central stress neurotransmitter. Endogenous SP does not inhibit the initial extent of the HPA axis response to restraint stress, but reduces the duration of the stress suggesting that SP plays an important role in the transition between acute and chronic stress. Stress hormones can alter metabolic functions in white adipose tissue and liver. The HPA axis is the endocrine pathway that promotes lipolysis elevating free fatty acid levels (FFA) in blood, besides indirectly causing hyperglycemia. In the present study, changes in the blood levels of stress markers in the anxiogenic-like effects of SP, as evaluated on the elevated plus-maze (EPM), were studied in adult male rats. Serum corticosterone was used as the traditional stress marker, while the plasma FFA and glucose were used as alternative anxiety/stress markers. Our findings show: (a) elevated corticosterone levels, confirming the aversive situation induced by SP (behaviorally assessed in the EPM) and indicating SP as a "chemical" stressor; (b) elevated levels of FFA and glucose, indicators of stress-induced mobilization of energy substrates, confirming the stressor effect of SP; (c) FFA levels can be used as an accurate, sensitive and reliable index of acute stress situations, including in the anxiogenic-like effect of SP, with the FFA response being as good as corticosterone as a stress marker in this case; (d) NK1 receptors involvement in the underlying mechanisms of the behavioral and metabolic effects of SP. Finally, our study indicates that some of these physiological variables are positively related to the stressor intensity.
 ...
PMID:Involvement of NK1 receptors in metabolic stress markers after the central administration of substance P. 1754 Apr 63

Substance P (SP), a sensory nerve derived neuropeptide, has been implicated in wound repair. Our hypothesis was that oxidative effects of elevated glucose and fatty acid levels as seen with diabetes mellitus inhibit SP-mediated endothelial cell directional migration and proliferation. Using a 2% agarose gel, immortalized human microvascular endothelial cells (HMEC-1) were plated into a 1.5-mm well, and agonist (SP; 10(-4) mol/L) was loaded into a 3-mm well; controls included NaCl, albumin (bovine serum albumin), and vascular endothelial cell growth factor. The SP receptor antagonist spantide 1 was used to confirm SP specificity. Elevated glucose (40 mmol/L) and fatty acids (40 micromol/L) were added to the medium with and without vitamin E and vitamin C treatment to determine whether endothelial cell responses to SP were altered by metabolic perturbations and whether they could be recovered with antioxidant treatment. Using computer-assisted image analysis, migration distance was measured. Cells were counted using a hemocytometer. Human microvascular endothelial cell 1 migration toward the SP exceeded NaCl or bovine serum albumin; vascular endothelial cell growth factor had similar effects. The SP receptor antagonist, spantide, inhibited SP-induced HMEC-1 migration. Substance P treatment was associated with increased cell number. Ki-67 staining was increased in SP-treated cells compared with controls. Elevated glucose and fatty acid levels diminished cell migration toward SP. The antioxidants vitamins C and E significantly improved proliferation but only marginally improved migration. Our data suggest that glucose and fatty acids perturb SP-induced HMEC-1 migration and proliferation in an agarose gel migration model.
 ...
PMID:Elevated glucose and fatty acid levels impair substance P-induced dermal microvascular endothelial cell migration and proliferation in an agarose gel model system. 1929 89

We identified ventrolateral medullary nuclei in which thyrotropin-releasing hormone (TRH) regulates glucose metabolism by modulating autonomic activity. Immunolabeling revealed dense prepro-TRH-containing fibers innervating the rostroventrolateral medulla (RVLM) and nucleus ambiguus (Amb), which contain, respectively, pre-sympathetic motor neurons and vagal motor neurons. In anesthetized Wistar rats, microinjection of the stable TRH analog RX77368 (38-150 pmol) into the RVLM dose-dependently and site-specifically induced hyperglycemia and hyperinsulinemia. At 150 pmol, blood glucose reached a peak of 180+/-18 mg% and insulin increased 4-fold. The strongest hyperglycemic effect was induced when RX77368 was microinjected into C1 area containing adrenalin cells. Spinal cord transection at cervical-7 abolished the hyperglycemia induced by RVLM RX77368, but not the hyperinsulinemic effect. Bilateral vagotomy prevented the rise in insulin, resulting in a prolonged hyperglycemic response. The hyperglycemic and hyperinsulinemic effects of the TRH analog in the RVLM was peptide specific, since angiotensin II or a substance P analog at the same dose had weak or no effects. Microinjection of RX77368 into the Amb stimulated insulin secretion without influencing glucose levels. In conscious type 2 diabetic Goto-Kakizaki (GK) rats, intracisternal injection of RX77368 induced a remarkably amplified hyperglycemic effect with suppressed insulin response compared to Wistar rats. RX77368 microinjected into the RVLM of anesthetized GK rats induced a significantly potentiated hyperglycemic response and an impaired insulin response, compared to Wistar rats. These results indicate that the RVLM is a site at which TRH induces sympathetically-mediated hyperglycemia and vagally-mediated hyperinsulinemia, whereas the Amb is mainly a vagal activating site for TRH. Hyperinsulinemia induced by TRH in the RVLM is not secondary to the hyperglycemic response. The potentiated hyperglycemic and suppressed hyperinsulinemic responses in diabetic GK rats indicate that an unbalanced "sympathetic-over-vagal" activation by TRH in brainstem RVLM contributes to the pathophysiology of impaired glucose homeostasis in type 2 diabetes.
 ...
PMID:Potent hyperglycemic and hyperinsulinemic effects of thyrotropin-releasing hormone microinjected into the rostroventrolateral medulla and abnormal responses in type 2 diabetic rats. 2045 19

We investigated whether progressive sensory neuropathy was accompanied by changes in whole-body insulin sensitivity (WBIS) in rats made diabetic by streptozotocin (STZ). The effects of early and late insulin supplementation were also studied. The STZ-treated rats failed to gain weight and exhibited stable hyperglycemia and low plasma insulin levels with a decrease in nerve conduction velocity (NCV) measured in A and C fibers of the saphenous nerve. A decreased sensory neuropeptide (SNP) release such as that of substance P, somatostatin, and calcitonin gene-related peptide determined from organ fluid of tracheal preparations subjected to electrical field stimulation also occurred in diabetic animals. These features were accompanied by a decrease in WBIS measured by hyperinsulinemic-euglycemic glucose clamping and a decrease in insulin-stimulated glucose uptake in cardiac and gastrocnemius muscle. When insulin supplementation with slow-release implants (2 IU/d) was started 4 weeks after STZ injection, blood glucose level normalized. Both insulin sensitivity and sensory nerve function reflected in either NCV or SNP release completely recovered by the 12th post-STZ week. When the insulin implants were applied from the eighth post-STZ week, both WBIS and glucose uptake remained significantly decreased, with a seriously impaired NCV and SNP release with strong hyperglycemia. Late insulin supplementation, however, even by using double implantation from the 10th post-STZ week, was unable to restore blood glucose, WBIS, NCV, and SNP release by the 12th week. Insulin resistance occurs in parallel with sensory neuropathy in STZ-diabetic rats. Both can be improved by early but not late insulin supplementation.
 ...
PMID:Insulin resistance occurs in parallel with sensory neuropathy in streptozotocin-induced diabetes in rats: differential response to early vs late insulin supplementation. 2215 24

Substance P (SP) is a neuropeptide, predominantly released from sensory nerve fibers, with a potentially protective role in diabetic corneal epithelial wound healing. However, the molecular mechanism remains unclear. We investigated the protective mechanism of SP against hyperglycemia-induced corneal epithelial wound healing defects, using type 1 diabetic mice and high glucose-treated corneal epithelial cells. Hyperglycemia induced delayed corneal epithelial wound healing, accompanied by attenuated corneal sensation, mitochondrial dysfunction, and impairments of Akt, epidermal growth factor receptor (EGFR), and Sirt1 activation, as well as decreased reactive oxygen species (ROS) scavenging capacity. However, SP application promoted epithelial wound healing, recovery of corneal sensation, improvement of mitochondrial function, and reactivation of Akt, EGFR, and Sirt1, as well as increased ROS scavenging capacity, in both diabetic mouse corneal epithelium and high glucose-treated corneal epithelial cells. The promotion of SP on diabetic corneal epithelial healing was completely abolished by a neurokinin-1 (NK-1) receptor antagonist. Moreover, the subconjunctival injection of NK-1 receptor antagonist also caused diabetic corneal pathological changes in normal mice. In conclusion, the results suggest that SP-NK-1 receptor signaling plays a critical role in the maintenance of corneal epithelium homeostasis, and that SP signaling through the NK-1 receptor contributes to the promotion of diabetic corneal epithelial wound healing by rescued activation of Akt, EGFR, and Sirt1, improvement of mitochondrial function, and increased ROS scavenging capacity.
 ...
PMID:Substance P promotes diabetic corneal epithelial wound healing through molecular mechanisms mediated via the neurokinin-1 receptor. 2500 76


<< Previous 1 2 3 Next >>