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Biomedical subjects

T Miyata

Publications and source records attributed to T Miyata.

At least 325 records · Page 18Linked to original sources
PubMed1996

Monocyte/macrophage response to beta 2-microglobulin modified with advanced glycation end products.

We recently found that acidic beta 2-microglobulin (beta 2m), a major isoform of beta 2m in amyloid fibrils of patients with dialysis-related amyloidosis (DRA), contained early Amadori products and advanced glycation end products (AGEs) formed nonenzymatically between sugar and protein. Further analysis revealed that acidic beta 2m induces monocyte chemotaxis and macrophage secretion of bone-resorbing cytokines, suggesting the involvement of acidic beta 2m in the pathogenesis of DRA. Acidic beta 2m, however, is a mixture of heterogeneous molecular adducts due to various types of modification. In the present study, we investigated the modification responsible for the biological activity of acidic beta 2m toward monocytes/macrophages. The presence of a fair amount of beta 2m species with deamidation was detected in acidic beta 2m isolated from urine of non-diabetic long-term hemodialysis patients, but deamidated beta 2m had no biological activity. In contrast, normal beta 2m acquired the activity upon incubation with glucose in vitro. Among the glycated beta 2m, the pigmented and fluorescent beta 2m that formed after a long incubation period, that is, AGE-modified beta 2m, exhibited biological activity, whereas beta 2m modified with Amadori products, major Maillard products in acidic beta 2m, had no such activity. These findings suggest that AGEs, although only a minor constituent of acidic beta 2m, are responsible for monocyte chemotaxis and macrophage secretion of cytokines, implicating the contribution of AGEs to bone and joint destruction in DRA.

Adult↗
PubMed1996

Pathophysiology of advanced glycation end-products in renal failure.

beta 2-Microglobulin is a major constituent of amyloid fibrils in dialysis-related amyloidosis, a serious complication leading to bone and joint destruction in long-term haemodialysis patients. However, the molecular pathogenesis of this complication remains unknown. Intact beta 2-microglobulin per se seems an unlikely contributor to the pathogenesis, because no difference in the plasma levels of intact beta 2-microglobulin has yet been found between haemodialysis patients with and without this complication. Some investigators have therefore focused on the modification of this molecule. Recent studies have revealed a new modification of beta 2-microglobulin in amyloid fibrils-the advanced glycation end-products (AGEs) formed by a non-enzymatic reaction between sugar aldose and protein. Further studies have suggested that the interaction of AGE-modified beta 2-microglobulin with monocyte/macrophage and osteoclast/osteoblast gives a plausible albeit partial explanation for the mechanism of bone and joint destruction in dialysis-related amyloidosis. This article discusses the pathophysiology of AGEs in renal failure and the modification of beta 2-microglobulin with AGEs, especially focusing on their structure and pathological role in dialysis-related amyloidosis.

Amyloid↗
PubMed1996

Possible involvement of advanced glycation end-products in bone resorption.

Advanced glycation end-products (AGEs) are formed in long-lived matrix proteins by a non-enzymatic reaction with sugar. We recently demonstrated the presence of AGEs in amyloid fibrils of dialysis-related amyloidosis, one of the characteristic features of which is an accelerated bone resorption around amyloid deposits. This suggested a potential link of AGEs in bone resorption and led us to investigate whether AGEs enhance bone resorption. An immunohistochemical study using anti-AGE antibody revealed positive immunostaining for AGEs in bone tissues from elderly subjects. AGE-modified proteins were shown to stimulate monocyte/macrophage to secrete bone-resorbing cytokines such as interleukin-1 beta, interleukin-6 and tumour necrosis factor- alpha. AGE-modified proteins enhanced net calcium efflux in cultured neonatal mouse calvariae to a much greater extent than unmodified proteins. Furthermore, when mouse unfractionated bone cells containing osteoclasts were cultured on dentin slices, AGE-modified proteins increased the number of resorption pits formed by osteoclasts, whereas their normal counterparts or those modified with the early glycation products did not. These findings suggest that AGEs enhance bone resorption by osteoclasts. The modification of bone matrices with AGEs might, therefore, play a pathophysiological role not only in the remodelling of senescent bone matrix tissues, but also in dialysis-related amyloidosis or osteoporosis associated with diabetes and ageing.

Aged↗
PubMed1996

Advanced glycation end-products in diabetic nephropathy.

Advanced glycation end-products (AGEs) are the pigmented and fluorescent adduct formed by a non-enzymatic reaction between sugar and protein. Since AGEs are generated in high glucose milieu, then induce the structural and functional alteration of matnx proteins, and have biological effects on various kinds of cells including mesangial cells, AGEs have been implicated in tissue damage of diabetic nephropathy. To elucidate the factor(s) that determine the AGEs level in diabetic nephropathy, we quantitated the plasma pentosidine level of different status of diabetic nephropathy by HPLC assay. The plasma pentosidine level in diabetic nephropathy was found to be determined by factors such as renal function control of glucose and the patient's age; of these, renal function was the most critical factor. For a better understanding of the pathological role of AGEs in diabetic nephropathy, we then examined renal tissues of diabetic nephropathy immunohistochemically using antibodies specific for AGE proteins. Immunohistochemistry revealed the positive immunostaining for AGEs in the expanded mesangial area of diffuse diabetic glomerulosclerosis. The degree of staining was stronger than that in patients of IgA nephropathy with a similar degree of mesangial expansion. The nodular lesions, characteristic of diabetic nephropathy, were also stained positive for AGEs. These findings suggests a potential link of AGEs accumulation, which may be determined by renal function, control of glucose and age, to renal tissue damage in diabetic nephropathy.

Animals↗
PubMed1996

Evolution of gene families and relationship with organismal evolution: rapid divergence of tissue-specific genes in the early evolution of chordates.

To determine a possible relationship between organismal and molecular evolution, the divergence patterns of gene families were examined by taking special notice of functional difference, tissue distribution, and intracellular localization of the members. A phylogenetic analysis of 25 different gene families revealed interesting patterns of divergence of these families: Most gene duplications giving rise to different functions antedate the vertebrates-arthropods separation. On the other hand, in a group of members carrying virtually identical function to one another but differing in tissue distribution (tissue-specific isoform), most gene duplications have occurred independently in each of vertebrates and arthropods after the separation of the two animal groups. In family members encoding molecules localizing in cell compartments (compartmentalized isoforms), the gene duplications antedate the animals-fungi separation. In the cases of the Ca2+ pump and rab subfamilies, the compartmentalized isoforms were shown to have diverged during the early evolution of eukaryotes. A phylogenetic analysis of the tissue-specific isoforms from 26 different subfamilies revealed extensive gene duplications and rapid rates of amino acid substitutions in the early evolution of chordates before the separation of fishes and tetrapods. On the contrary, the genetic variations are relatively low in the later period. This pattern of evolution observed at the molecular level is correlated well with that of tissue evolution based on fossil evidence and morphological data, and thus evolution at the two levels may be related.

Animals↗
PubMed1996

Pyridine derivatives stimulate phosphatidylcholine secretion in primary cultures of rat type II pneumocytes.

We have examined the effects of pyridine derivatives on phosphatidylcholine secretion in primary cultures of rat type II pneumocytes. Of 12 pyridine derivatives, 4-aminopyridine, 4-dimethylaminopyridine and 4-pyrolidinopyridine had a stimulatory effect on phosphatidylcholine secretion, whereas other derivatives had little effect. The stimulatory effect of 4-aminopyridine was concentration- and time-dependent, and was inhibited by the acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (3 microM), an intracellular Ca2+ chelator. In addition, the stimulatory effect of 4-aminopyridine was suppressed by W-7(N-(6-aminohexyl)-5-chloro-1-napthalene-sulphonamide)(10 microM), a calmodulin inhibitor, and sphingosine (10 microM) and staurosporine (0-1 microM), protein kinase C inhibitors. These results indicate that several pyridine derivatives stimulate phosphatidylcholine secretion in type II pneumocytes.

4-Aminopyridine↗
PubMed1996

Studies on the magnitude and the mechanism of cough potentiation by angiotensin-converting enzyme inhibitors in guinea-pigs: involvement of bradykinin in the potentiation.

One adverse effect of the angiotensin-converting enzyme (ACE) inhibitors used for treatment of hypertension and congestive heart failure is the production of dry coughs. Imidapril is a new type of ACE inhibitor with a very low incidence of coughs. The magnitude and the mechanism of cough potentiation of imidapril and other ACE inhibitors has been studied in guinea-pigs. In normal guinea-pigs single and repeated dosing of imidapril at 0.1 to 100 mg kg-1 had no effect on capasaicin- or citric acid-induced coughs. Single and repeated dosing of enalapril and captopril at 10 to 30 mg kg-1, respectively, significantly increased the number of capsaicin-induced coughs. Repeated dosing of 1 mg kg-1 enalapril also significantly augmented the capsaicin cough. In bronchitic guinea-pigs imidapril also had no effect on the coughs induced by the two stimulants. Enalapril and captopril significantly increased the number of coughs induced not only by capsaicin but also by citric acid. Lower doses of enalapril were enough to augment the capsaicin-induced coughs, whereas medium to large doses failed to augment the cough irrespective of the protocol of administration. Bradykinin-induced discharges of the vegal afferents from the lower airway were significantly increased by enalaprilat but not by imidaprilat. Capsaicin-induced discharges of the afferents were, on the other hand, significantly depressed by enalaprilat, but not by imidaprilat. Interestingly, enalaprilat depression of the discharges was significantly reversed by Hoe-140, a bradykinin B2 receptor blocker. In guinea-pigs pretreated with a low dose of enalapril, arterial infusion of bradykinin significantly potentiated the coughs induced by capsaicin. The results indicated that imidapril was less potent than enalapril and captopril in potentiating cough responses induced by capsaicin and citric acid in guinea-pigs, and further suggest that bradykinin might be a key substance in the mechanism of the potentiation of coughs associated with ACE inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Dexamethasone suppresses mucus production and MUC-2 and MUC-5AC gene expression by NCI-H292 cells.

Excessive production of airway mucus is a characteristic feature of many chronic inflammatory lung diseases. Although current pharmacological approaches to excessive mucus production are limited, glucocorticoids appear to be the most effective among a few useful drugs. The exact evidence for the effectiveness of glucocorticoids on mucus production has not been fully elucidated to date. The purpose of this study is to clarify the effect of dexamethasone on mucus production and mucin gene expression in a human pulmonary mucoepidermoid carcinoma cell line (NCI-H292). NCI-H292 cells produced hyaluronidase-resistant high-molecular-weight glycoconjugates (HMWG), which elute in the void volume on Sepharose CL-4B column chromatography. Dexamethasone significantly suppressed the basal production of [3H]glucosamine-or [3H]serine-labeled HMWG in NCI-H292 cells. In Northern blot analysis, dexamethasone attenuated steady-state mRNA levels of MUC-2 and MUC-5AC mucin genes. These data indicate that dexamethasone suppresses the basal production of HMWG and decreases steady-state mRNA levels of mucin genes in airway mucus-producing cancer cells.

Carcinoma↗
PubMed1996

Therapy-related chronic myelomonocytic leukaemia with bone marrow eosinophilia associated with der(11)t(1;11)(q21;q14).

A 19-year-old male with chronic myelomonocytic leukaemia (CMML) with bone marrow eosinophilia terminating in myeloblastic transformation is described. Before the appearance of CMML, he received a total dose of 2,894 mg of nimustine for the treatment of a pontine glioma over 12 years. Peripheral blood count showed leucocytosis with mature neutrophils and monocytes. Bone marrow smears showed myeloid hyperplasia with increased blasts and abnormal eosinophils and dysplastic features in the myeloid and megakaryocytic cells. A karyotype analysis of the bone marrow cells indicated 46, XY, der(11)t(1;11)(q21;q14). No bcr/abl rearrangement was observed in the cells. He was treated with hydroxyurea to control the leucocyte count, but myeloblastic transformation developed.

Antineoplastic Agents↗
PubMed1996

Factor VII hyperactivity and endothelial cell damage are found in elderly hypertensives only when concomitant with microalbuminuria.

We studied the relationship among albuminuria, factor VII (FVII) hyperactivity, and endothelial cell damage in 6 elderly hypertensive subjects. The plasma levels of activated FVII (FVIIa), FVII coagulant activity, FVII antigen (FVIIag), von Willebrand factor (vWF), and thrombomodulin were measured to assess FVII hyperactivity and endothelial cell damage, and urinary albumin excretion rate (UAE) was calculated using 12-hour nighttime (7 pm to 7 am) urine collection (mean for 2 consecutive nights). We performed 24-hour ambulatory blood pressure monitoring in all 61 hypertensive patients and classified them into a white-coat hypertension group (n=12) and a sustained hypertension group (n=49). For the levels of FVII, vWF, and thrombomodulin, there were no differences between the white-coat hypertension group and normotensive control subjects (n=25). In the sustained hypertensive group, only the microalbuminuric subgroup (UAE, 15 to 300 microgram/min: n=30) showed significant elevation compared with the normotensive group for the level of FVIIa (mean [95% confidence interval]: 4.0 [3.6 to 4.4] versus 3.0 [2.6 to 3.3] ng/mL, P<.001), the FVIIa/FVIIag ratio (an indicator of activation of FVII zymogen to FVIIa) (1.33 [1.19 to 1.50] versus 1.04 [0.92 to 1.19], P<.01), the level of vWF (188 [165 to 214] % versus 144 [129 to 160] %, P<.01), and thrombomodulin (11.7 [10.3 to 13.3] versus 9.3 [8.5 to 10.3] ng/mL, P<.01). In contrast, none of these levels in the normoalbuminuric hypertensive group (UAE <15 microgram/min, n=19) differed from that in the normotensive control group. These results suggest that among elderly hypertensives, only those with microalbuminuria show enhancement of FVII activation and endothelial cell damage, while patients with white-coat hypertension and normoalbuminuric hypertensives do not show these accompanying abnormalities. Thus, increased levels of FVII activity and markers of endothelial cell damage might account for the higher risk of cardiovascular events in essential hypertension with microalbuminuria.

Aged↗
PubMed1996

Takayasu arteritis: clinical characteristics and the role of genetic factors in its pathogenesis.

Takayasu arteritis is a chronic vasculitis, the aetiology of which is still unknown. Several characteristic clinical manifestations have led scientists to consider the possibility of the genetic factors in the aetiology, conjecture which is supported by HLA analysis. Recent attention has focused on the different clinical manifestations among Asian and South American countries and further progress is likely to stem from international network studies.

Adult↗
PubMed1996

Surgical treatment of abdominal aortic aneurysms in octogenarians.

Due to the increase in life span and the decrease in mortality associated with aortic surgery, many geriatric patients now undergo surgery for abdominal aortic aneurysms (AAAs). Therefore, we studied our surgical results for AAAs in an elderly population to assess the value of such operations. Twenty-six patients aged 80 years or older underwent surgery during an 11-year period from 1984 to 1994 at our institutions, and their outcomes were compared with those of 212 younger patients. The ratio of ruptured to non-ruptured AAAs was significantly higher in the older patients (aged 80 years or older) than in the younger patients (aged 79 years or younger), and aneurysm size in cases of non-rupture was greater in older patients than in younger patients. For octogenarians with non-ruptured AAAs, the survival rate was 85.7% at 5 years, compared with 43.6% at 3 years for those with ruptured AAAs, and these figures were not significantly different from those in younger patients. The present findings support the value of our active surgical approach for octogenarians with AAAs. We believe that an aggressive approach for octogenarians will decrease the incidence of ruptured AAAs and contribute to better patient survival.

Adult↗
PubMed1996

Effect of leukotriene D4 on tracheal mucociliary transport velocity in quails.

We investigated the effect of leukotriene D4 (LTD4) on tracheal mucociliary transport in quails. Topical application of LTD4 (0.2-2 ng) to tracheal mucosa dose-dependently increased mucociliary transport velocity (MCTV) in 5 or 10 min after application. Forty minutes after application of 2 ng of LTD4, MCTV was decreased to about 84% of that in the control group. Both the transient increase and the subsequent decrease induced by 2 ng of LTD4 were blocked by ONO-1078 (Pranlukast: 4-oxo-8-[4-(4-phenylbutoxy)-benzoylamino]-2-(tetrazol-5-yl)- 4H- 1-benzopyran) (0.03-3 mg/kg, i.m.), a specific leukotriene antagonist. These results suggest that LTD4 possesses a biphasic effect on tracheal mucociliary transport through leukotriene receptors.

Animals↗
PubMed1996

Accumulation of albumin-linked and free-form pentosidine in the circulation of uremic patients with end-stage renal failure: renal implications in the pathophysiology of pentosidine.

Pentosidine is an advanced glycation end product and its formation is shown to be closely related to oxidative processes. Recent studies have shown that pentosidine levels are increased not only in plasma and matrix proteins from diabetic patients, but also markedly in nondiabetic hemodialysis patients. Currently, the mechanism of accumulation and kinetics of pentosidine formation in hemodialysis patients remain unknown. Gel filtration of uremic plasma revealed that plasma pentosidine exists in the albumin fraction (approximately 90%) and, interestingly, in free form (approximately 5%) as well. Plasma free pentosidine was undetectable in subjects with normal renal function. There was a significant correlation between the plasma levels of albumin-linked and free pentosidine in hemodialysis patients. Kinetic studies indicated that dietary pentosidine was absorbed into the circulation and that, after either oral or intravenous administration of pentosidine to intact or nephrectomized rats, the plasma free pentosidine level was closely linked to the level of renal function. These findings demonstrate that: (1) Pentosidine accumulates as albumin-linked and in free form in the circulation of uremic patients; (2) dietary pentosidine can be absorbed into the circulation, thus being one possible origin of circulating free pentosidine; (3) free pentosidine may accumulate as a result of decreased glomerular filtration; and (4) the mechanism of accumulation of albumin-linked pentosidine is not related to high glucose levels. It suggests the simultaneous accumulation, during renal failure, of either unknown pentosidine precursor(s) or catalyst(s) of glycoxidation, independent of glucose.

Animals↗