[Diabetic neuropathy].
Explore the source record for details and available documents.
Aldehyde Reductase↗
Biomedical subjects
Soroku Yagihashi
Publications and source records attributed to Soroku Yagihashi.
A case of pancreatoblastoma prenatally diagnosed as intraperitoneal cyst.
Pancreatoblastoma in childhood is a very rare malignant tumor, but is considered to have a relatively good prognosis because of its low metastatic potential. We report 1-day-old female infant who was recently found to have an intraabdominal cyst on prenatal ultrasound examination. The tumor was a unilocular, cystic mass without invasion or metastasis to other organs, allowing total resection. It was diagnosed postnatally with pancreatoblastoma.
Cysts↗
Novel mechanism of chronic exposure of oleic acid-induced insulin release impairment in rat pancreatic beta-cells.
A sustained, high circulating level of free fatty acids (FFAs) is an important risk factor for the development of insulin resistance, islet beta-cell dysfunction, and pathogenesis of type 2 diabetes. Here, we report a novel mechanism of chronic exposure of oleic acid (OA)-induced rat insulin release impairment. Following a 4-day exposure to 0.1 mM OA, there was no significant difference in basal insulin release when comparing OA-treated and untreated islets in the presence of 2.8 mM glucose, whereas 16.7 mM glucose-stimulated insulin release increased 2-fold in control, but not in OA-treated, islets. Perforated patch-clamp recordings showed that untreated beta-cells exhibited a resting potential of -62.1 +/- 0.9 mV and were electrically silent, whereas OA-treated beta-cells showed more positive resting potentials and spontaneous action potential firing. Cell-attached single-channel recordings revealed spontaneous opening of ATP-sensitive potassium (K(ATP)) channels in control, but not in OA-treated, beta-cells. Inside-out excised patch recordings showed similar activity in both OA-treated and untreated beta-cells in the absence of ATP on the inside of the cellular membrane, whereas in the presence of ATP, K(ATP) channel activity was significantly reduced in OA-treated beta-cells. Electron microscopy demonstrated that chronic exposure to OA resulted in the accumulation of triglycerides in beta-cell cytoplasm and reduced both the number of insulin-containing granules and insulin content. Collectively, chronic exposure to OA closed K(ATP) channels by increasing the sensitivity of K(ATP) channels to ATP, which in turn led to the continuous excitation of beta-cells, depletion of insulin storage, and impairment of glucose-stimulated insulin release.
Adenosine Triphosphate↗
Pancreatic malignant fibrous histiocytoma, inflammatory myofibroblastic tumor, and inflammatory pseudotumor related to autoimmune pancreatitis: characterization and differential diagnosis.
Malignant fibrous histiocytoma (MFH) and inflammatory myofibroblastic tumor (IMT) are uncommon primary non-epithelial cell tumors of the pancreas. In addition, there are inflammatory pseudotumors (IPT) that may arise in the course of autoimmune pancreatitis (AIP). In the English language literature, only 24 cases of IMT and nine cases of MFH in the pancreas have been reported to date. We investigated three individual spindle cell tumors of the pancreas that were identified as MFH, IMT, and IPT, respectively, using immunohistochemical and molecular analysis. Both the MFH and the IMT, but not the IPT, showed nuclear p53 expression and mutations of the p53 gene. The MFH and the IMT also had higher mitotic and Ki-67 (MIB-1) indexes than the IPT. The IPT was found to be a tumor-like case of AIP. Many IgG4-positive plasma cells, which are considered to be a feature of AIP, were found in all three tumors. It is concluded that in this series of spindle cell tumors of the pancreas, apart from immunohistochemical features, the demonstration of p53 mutations may be helpful in distinguishing true neoplastic tumors from pseudotumors such as IPTs arising in the context of AIP.
Adult↗
Prolonged ischemic conduction failure after reperfusion in diabetic nerve.
Diabetic nerve exhibits morphological vulnerability to ischemia and reperfusion, in contrast to its physiological resistance to ischemic conduction failure (RICF). To examine the sequence of ischemic conduction failure after reperfusion in diabetic nerve, we measured sciatic-tibial nerve conduction before and during 30-180 min of ischemia and after reperfusion for up to 1 week in streptozocin (STZ)-induced diabetic rats. RICF in diabetic rats was confirmed during ischemia. After reperfusion, control nerves showed an immediate recovery in amplitude of compound muscle action potential (CMAP) following ischemia for 120 min or less, and delayed recovery after 150 min of ischemia. In contrast, recovery in diabetic nerves was delayed even after 1 h of ischemia. Ischemia for 75 min in diabetic nerve resulted in either delayed or no recovery of the CMAP upon reperfusion. Following ischemia for 90 or 120 min, axonal degeneration was observed in diabetic nerve. Thus, severe ischemia for 60 or 75 min causes prolonged ischemic conduction failure in diabetic nerve, compared with 150 min in control nerve. In conclusion, diabetic nerve shows delayed recovery of ischemic conduction failure after brief ischemia, compared to controls, suggesting that patients with diabetic neuropathy have a worse prognosis when faced with nerve ischemia.
Animals↗
Three-year inhibition of aldose reductase on development of symptomatic neuropathy in diabetic patients.
Explore the source record for details and available documents.
Action Potentials↗
Aldose reductase-deficient mice are protected from delayed motor nerve conduction velocity, increased c-Jun NH2-terminal kinase activation, depletion of reduced glutathione, increased superoxide accumulation, and DNA damage.
The exaggerated flux through polyol pathway during diabetes is thought to be a major cause of lesions in the peripheral nerves. Here, we used aldose reductase (AR)-deficient (AR(-/-)) and AR inhibitor (ARI)-treated mice to further understand the in vivo role of polyol pathway in the pathogenesis of diabetic neuropathy. Under normal conditions, there were no obvious differences in the innervation patterns between wild-type AR (AR(+/+)) and AR(-/-) mice. Under short-term diabetic conditions, AR(-/-) mice were protected from the reduction of motor and sensory nerve conduction velocities observed in diabetic AR(+/+) mice. Sorbitol levels in the sciatic nerves of diabetic AR(+/+) mice were increased significantly, whereas sorbitol levels in the diabetic AR(-/-) mice were significantly lower than those in diabetic AR(+/+) mice. In addition, signs of oxidative stress, such as increased activation of c-Jun NH(2)-terminal kinase (JNK), depletion of reduced glutathione, increase of superoxide formation, and DNA damage, observed in the sciatic nerves of diabetic AR(+/+) mice were not observed in the diabetic AR(-/-) mice, indicating that the diabetic AR(-/-) mice were protected from oxidative stress in the sciatic nerve. The diabetic AR(-/-) mice also excreted less 8-hydroxy-2'-deoxyguanosine in urine than diabetic AR(+/+) mice. The structural abnormalities observed in the sural nerve of diabetic AR(+/+) mice were less severe in the diabetic AR(-/-) mice, although it was only mildly protected by AR deficiency under short-term diabetic conditions. Signs of oxidative stress and functional and structural abnormalities were also inhibited by the ARI fidarestat in diabetic AR(+/+) nerves, similar to those in diabetic AR(-/-) mice. Taken together, increased polyol pathway flux through AR is a major contributing factor in the early signs of diabetic neuropathy, possibly through depletion of glutathione, increased superoxide accumulation, increased JNK activation, and DNA damage.
Aldehyde Reductase↗
Immunohistochemical expressions of cytokeratins, mucin core proteins, p53, and neuroendocrine cell markers in epithelial neoplasm of appendix.
Epithelial neoplasms of appendix are infrequent, and their pathological features are not fully characterized. We collected 33 cases of appendiceal tumors and examined immunohistochemically the expression of cytokeratins (CK, CK7, and CK20), mucin core protein (MUC1, MUC2, MUC5AC, and MUC6), E-cadherin, chromogranin A, and p53 protein. Gene analysis of TP53 was also conducted on exons 5 to 8. Clinically, mucinous tumors were predominant in females. Immunohistochemically, all the tumors expressed CK20, whereas CK7 was positive in one third of the cases. Similarly, MUC2 was expressed in all the tumors, whereas MUC1 and MUC5AC were detected in about a half of the cases. Although chromogranin A-positive cells are generally sparse in normal appendix, they were more common in mucinous tumors than in nonmucinous tumors. Contrary to the previous data reported (Mod Pathol 2002;15:599-605), mucinous carcinoma exhibited a higher frequency of p53-positive cells (mean 29%) compared with mucinous adenoma (2.8%) (P < .001), whereas nonmucinous tumors showed high levels of p53-positive cells to similar extent (51%-67%) in both adenoma and carcinoma. The high expression of p53 protein coincided with the presence of mutations in multiple sites of TP53 gene in mucinous tumors. This is the first report that characterized the immunophenotypic profile of appendiceal epithelial neoplasms with an emphasis of a higher frequency of p53 positivity in mucinous carcinoma cases compared with mucinous adenoma in the appendix.
Aged↗
Inflammatory pseudotumour (plasma cell granuloma) arising in the maxillary sinus.
CONCLUSIONS: Inflammatory pseudotumours in the maxillary sinus may present as malignant tumours and manifest locally aggressive features characteristic of such tumours. Despite their locally destructive features, they pursue a benign course after local excision. OBJECTIVE: Inflammatory pseudotumour (plasma cell granuloma) is an uncommon non-neoplastic lesion comprising a proliferation of spindle myofibroblasts and chronic inflammatory cells. Despite its benign histopathological nature, it may exhibit aggressive behaviour that is yet to be characterized in the head and neck area. MATERIAL AND METHODS: We present the cases of two adult patients with inflammatory pseudotumour arising from the maxillary sinus. Immunohistochemistry and polymerase chain reaction for immunoglobulin from tissue sections were performed to confirm the polyclonality of the infiltrating plasma cells. RESULTS: CT and MRI disclosed expansive soft masses eroding surrounding soft and bony tissues. Histopathologically, the lesions were unencapsulated and composed of numerous plasma cells, histiocytes and spindle cells with minimal nuclear pleomorphism.
Adult↗
Role of advanced glycation end products and their receptors in development of diabetic neuropathy.
Diabetic neuropathy is a life-threatening complication involving both peripheral and autonomic nerves. The hyperglycemia-induced polyol pathway as well as enhanced oxidative stress are among the factors implicated in the pathogenesis of diabetic neuropathy. Their effects are possibly exerted by direct nerve tissue damage or mediated by endothelial injury or vascular dysfunction. Formation of advanced glycation end product (AGE) is another important candidate for the cause of peripheral neuropathy. Indeed, the levels of AGEs were increased in the serum and also in the peripheral nerves obtained from diabetic patients. Structural and functional proteins of those nerves are also glycated, resulting in impaired nerve function and characteristic pathologic alterations. In addition, interaction between AGEs and their receptors induce biological effects on the target tissues for diabetic complications. In the peripheral nerve, the receptor for AGE (RAGE) is expressed in endothelial and Schwann cells. It is thus anticipated that interactions between AGEs and RAGE facilitate endoneural vascular dysfunction, leading to microangiopathy in the peripheral nerve. The roles of these mechanisms, in particular on the molecular mechanisms of AGE-RAGE interactions in the development of diabetic neuropathy are largely still speculative and yet to be explored.
Animals↗
[Role of cytokine in diabetic neuropathy].
Explore the source record for details and available documents.
Animals↗
[Early diagnosis of peripheral neuropathy in patients with impaired glucose tolerance (IGT)].
Explore the source record for details and available documents.
Diabetic Neuropathies↗
[Perspective for the treatment of diabetic neuropathy: translation from molecular studies to bedside].
Drastic increase in a population of diabetic patients urges to establish effective treatment or management of peripheral neuropathy, the most common complication of diabetes. Recent studies emphasize the occurrence of peripheral neuropathy in patients with impaired glucose tolerance, which condition is now shown to augment polyol pathway as well as non-enzymatic protein glycation in the peripheral nerve, exerted by postprandial hyperglycemia. Such metabolic cascades in turn result in tissue-specific alterations of cellular signaling, represented by decreased protein kinase C (PKC) activity and Na, K-ATPase activity in the peripheral nerve and contrariwise increased PKC activity in microvessels. The decrease in nerve PKC activity was demonstrated to associate with reduced membrane alpha-isoform expression and the increase in vessel PKC activity was due to membrane beta-isoform expression, respectively. Dual mechanisms of nerve and vascular alterations in addition to multiple metabolic factors may operate in the development of diabetic neuropathy in a complicated manner. Consequently, inhibition of hyperglycemia as well as specific intervention of single molecules related to altered cellular signaling is the essential approach for the primary prevention of diabetic neuropathy.
Aldehyde Reductase↗
Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment.
Both nuclear factor erythroid 2 45 kDa subunit (p45) and BTB and CNC homolog 1 (Bach) transcription factors can form dimers with one of the small Maf proteins, and these heterodimers bind to the musculoaponeurotic fibrosarcoma oncogene (Maf) recognition element (MARE). MARE is known to act as a critical cis-regulatory element of erythroid and megakaryocytic genes. Although detailed analyses of p45-null mutant mice and small maf compound mutant mice revealed that these factors are both critical for platelet production, the functional contributions of Bach1 and the relationship or redundancy between Bach1 and p45 in megakaryocytes remain to be clarified. To address these issues, we generated transgenic lines of mice bearing human BACH1 cDNA under the control of the GATA-1 locus hematopoietic regulatory domain. The transgenic mouse lines showed significant thrombocytopenia associated with impaired maturation of the megakaryocytes, and they developed myelofibrosis. The megakaryocytes in the transgenic mice exhibited reduced proplatelet formation, and the modal ploidy class of megakaryocytes was 2N, indicating the impairment of endomitosis. Transcription of the p45 target genes was down-regulated and we indeed found that BACH1 binds to the thromboxane synthase gene, one of the target genes for p45 in megakaryocytes. These findings thus provide evidence that BACH1 acts as a transcriptional repressor in the regulation of MARE-dependent genes in megakaryocytes.
Animals↗
Peripheral nerve endoneurial microangiopathy and necrosis in rats with insulinoma.
Peripheral nerve pathology related to chronic hyperinsulinemia and hypoglycemia has yet to be fully explored. Here we conducted a systematic quantitative analysis of morphological alterations in peripheral sensory and motor nerve fibers and endoneurial microvasculature in longstanding insulinoma-carrying rats (I-rats; n=12). Age-matched normal rats (n=6) served as controls. Over the 15-month observation period, two of I-rats developed paresis of the hind limbs when their blood glucose level fell below 1.7 mmol/l. These animals showed a massive myelinated fiber loss associated with active degeneration of residual myelinated fibers and multiple endoneurial microvascular occlusions at the sciatic nerve level. The rest of the non-paretic I-rats showed a decreased density of large myelinated fibers with axonal degeneration in the peroneal nerve and an increased density of small myelinated fibers with preserved morphology in the sural nerve. This was associated with endoneurial microangiopathic changes indicative of endoneurial ischemia/hypoxia in the sciatic and peroneal nerves, and an increase in endoneurial microvascular density in the sciatic and sural nerves. In conjunction with previous data, these findings suggest that the observed increase in endoneurial microvascular density may be a compensatory response to endoneurial ischemia/hypoxia induced by chronic hyperinsulinemia in I-rats without paresis. In conclusion, the present study showed characteristic morphological alterations in peripheral sensory and motor nerve fibers associated with microangiopathy indicative of endoneurial ischemia/hypoxia in the sciatic and peroneal nerves, and provides the first evidence for the occurrence of endoneurial necrosis in the sciatic nerve, to which the hind limb paresis can be ascribed in I-rats.
Animals↗
Expression of retinoic acid-inducible gene-I in vascular smooth muscle cells stimulated with interferon-gamma.
Vascular smooth muscle cells (SMC) play an important role in atherogenesis and vasospasm. Interferon-gamma (IFN-gamma) is a potent cytokine that regulates immune and inflammatory responses by inducing multiple genes in many types of cells including SMC. Retinoic acid-inducible gene-I (RIG-I) is a putative RNA helicase, but its physiological function is not known. RIG-I is induced in leukemic cells by retinoic acid or in endothelial cells by lipopolysaccharide. We have studied the expression of RIG-I in cultured SMC from human umbilical artery. IFN-gamma stimulated SMC to express RIG-I mRNA and protein in concentration- and time-dependent manners. Immunohistochemical analysis revealed the expression of RIG-I in SMC in vivo. We conclude that RIG-I may play some pathophysiological role in immune and inflammatory reactions in SMC.
Adolescent↗
Reduced cell replication and induction of apoptosis by advanced glycation end products in rat Schwann cells.
We investigated the effects of advanced glycation end products (AGEs) derived from glucose, glyceraldehyde, and glycolaldehyde (designated as AGE-1, -2, and -3, respectively) on the viability, replication rate, and cytokine production of cultured Schwann cells. AGE-2 and -3, but not AGE-1, induced apoptosis, and significantly decreased the viability measured by MTT assay. The decrease was prevented completely by antioxidant alpha-lipoic acid and was prevented partially by p38 mitogen-activated protein kinase inhibitor SB202190. The decrease in mitochondrial membrane potential by AGE-2 and -3 was also observed. In addition, AGE-2 and -3 significantly suppressed the replication rate as shown by reduced bromodeoxyuridine uptake, whereas they enhanced the release of TNF-alpha and IL-1beta into the medium and activated nuclear factor-kappaB. The effects of AGE-1 on these measures were equivocal. The series of events elicited by AGE-2 and -3 may be responsible for some of the aspects of pathogenetic mechanisms in patients with diabetic neuropathy.
Animals↗
Nitric oxide generation and poly(ADP ribose) polymerase activation precede beta-cell death in rats with a single high-dose injection of streptozotocin.
Streptozotocin (STZ) is widely used for the induction of diabetes in animals by causing destruction of pancreatic beta cells. This experiment was designed to elucidate the sequential process of beta-cell destruction in rats with a single high-dose injection of STZ. At 0, 2, 5, 8 and 24 h after injection, rats were perfused with Krebs-Ringer buffer with dichlorofluorescein diacetate (DCF-DA), a marker for free radicals, and the pancreata were pathologically analyzed. Injection of STZ rapidly elicited an increase in fluorescence of DCF-DA in beta cells at 2 h after the injection. The fluorescence was diminished by carboxy-PTIO, a specific scavenger of nitric oxide (NO), but not by L-NAME, an inhibitor of NO synthase. During this process, an inducible form of NO synthase was not detected. Thereafter, upregulated expression of poly(ADP ribose) polymerase (PARP) and massive beta-cell death were detected at 5-8 h after injection. Migration of macrophages into the islet was conspicuous at 24 h, clearing up the debris of destroyed beta cells. Nicotinamide, a PARP inhibitor, significantly inhibited beta-cell death without apparent suppression of NO generation at 2 h. The current study documented serial processes of STZ-induced beta-cell death, starting with NO generation and PARP activation followed by a clearance with macrophages, where the activation of PARP plays a central role in beta-cell death.
Animals↗