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Biomedical subjects

M Ise

Publications and source records attributed to M Ise.

At least 19 recordsLinked to original sources
PubMed2000

An oral sorbent reduces overload of indoxyl sulphate and gene expression of TGF-beta1 in uraemic rat kidneys.

BACKGROUND: An oral adsorbent (AST-120) delays the progression of chronic renal failure (CRF). The aims of the present study are to determine the effects of AST-120 on the localization of indoxyl sulphate in uraemic rat kidneys, and to examine whether AST-120 reduces the renal cortical gene expression of transforming growth factor (TGF)-beta1, tissue inhibitor of metalloproteinase (TIMP)-1 and pro-alpha1(I)collagen, and ameliorates glomerular and tubulointerstitial injuries in uraemic rats. METHODS: Two weeks after 5/6-nephrectomy, 10 rats were divided into pairs such that both rats in each pair exhibited almost the same levels of serum creatinine, blood urea nitrogen and creatinine clearance. One rat from each pair was assigned to a control uraemic group, the other to a uraemic group which received AST-120 everyday for 11 weeks. The localization of indoxyl sulphate was studied by immunohistochemistry using a monoclonal anti-indoxyl sulphate antibody we had developed. The renal cortical gene expression was studied by using northern blotting. RESULTS: Rats treated with AST-120 showed decreased levels of serum creatinine, blood urea nitrogen and urinary protein as well as increased levels of creatinine clearance as compared with control uraemic rats. AST-120 markedly decreased indoxyl sulphate levels in both serum and urine. Immunohistochemistry demonstrated that indoxyl sulphate was localized in the renal proximal tubular epithelial cells, especially of dilated tubules, and that AST-120 markedly reduced the tubular staining of indoxyl sulphate. AST-120 attenuated interstitial fibrosis, tubular injury as well as glomerular sclerosis, and reduced the renal gene expression of TGF-beta1, TIMP-1 and pro-alpha1(I)collagen. CONCLUSIONS: AST-120 reduces the gene expression of TGF-beta1, TIMP-1 and pro-alpha1(I)collagen in the kidneys, and delays the progression of CRF, at least in part, by alleviating the overload of indoxyl sulphate on remnant proximal tubular epithelial cells.

Adsorption↗
PubMed1999

Mechanism of oral absorbent AST-120 in lipid abnormalities in experimental uremic rats.

BACKGROUND: We have reported that oral sorbent AST-120 (AST) is effective in delaying the induction of dialysis in patients with chronic renal failure (CRF) because of its effect on lipid metabolism. To clarify the precise mechanism of AST in lipid abnormalities in CRF, we examined the effect of AST on plasma lipid profile, total bile acids (TBA), and lipoprotein lipase (LPL) activity in experimental uremic rats. METHODS: Uremic rats were prepared using male Wistar rats by ligating 5/6 of the renal artery. Uremic rats were randomly divided into two groups as follows: a control group in which rats were maintained on the standard diet and an AST group in which rats were maintained on a diet containing 5 g of AST per 100 g of standard diet for 10 weeks. Plasma LPL activity was measured as free fatty acid (FFA) generation after intravenous administration of heparin. RESULTS: Plasma creatinine at 1.5 +/- 0.1 mg/dl was lower in the AST group than the 1.9 +/- 0.5 mg/ml level in the control group. AST significantly decreased plasma total cholesterol from 192 +/- 29 to 142 +/- 25 mg/dl, triglycerides from 198 +/- 71 to 99 +/- 38 mg/dl, and TBA from 19.6 +/- 2.6 mumol/liter to 8.8 +/- 3.5 mumol/ml. Plasma LPL activity at 0.22 +/- 0.01 mumol FFA/min/hr was significantly higher in the AST group than 0.15 +/- 0.03 mumol FFA/min/hr in the control group. CONCLUSIONS: These results suggest that AST may improve plasma lipid abnormalities by binding to bile acids in the intestinal lumen and preventing their reabsorption and inhibiting the reduction of LPL activity in experimental uremic rats.

Administration, Oral↗
PubMed1999

[Refractory multiple myeloma preceded by extramedullary plasmacytoma of lymph node--a case report and review of the literature].

It has been reported that extramedullary plasmacytoma (EMP) tends to be characterized by an indolent clinical course and lower incidence of progression to multiple myeloma. Primary plasmacytoma of lymph nodes is extremely rare and details of its clinical picture remain unclarified. We recently encountered an unusual case of EMP of lymph nodes that progressed to refractory multiple myeloma only 18 months later. A 74-year-old woman was admitted to our hospital because of a painless swelling in the right inguinal region. A tumor was removed surgically, and a histological diagnosis of EMP of the lymph nodes was made. Bence Jones protein (BJP) was detected in the urine, but there was no other evidence of systemic myelomatosis. The patient received local irradiation, which resulted in the elimination of BJP. Eighteen months later, however, a tumor developed in her right stemo-clavicular joint. A bone survey revealed multiple osteolytic lesions, and many atypical plasma cells were observed in the bone marrow, indicating multiple myeloma. The patient deteriorated despite several regimens of combination chemotherapy, and died four and a half years after the initial diagnosis of EMP.

Aged↗
PubMed1998

[Successful treatment with CPT-11 and adriamycin for hemophagocytic syndrome associated with intravascular lymphomatosis].

A 75-year-old man was admitted because of non-Hodgkin's lymphoma (histology undetermined) of the rib. A complete remission was achieved after CHOP therapy and irradiation. One year later, high fever, thrombocytopenia and liver dysfunction developed. Bone marrow aspirate revealed a hypoplastic marrow with hemophagocytic histiocytes, and a diagnosis of hemophagocytic syndrome (HPS) was made. Although no lymphomatous lesions were detected, HPS due to relapsed lymphoma was strongly suspected. The patient received MEVP therapy including etoposide and prednisolone, but without any improvement. Soon after the initiation of CPT-11 and adriamycin (ADM) therapy, all symptoms of HPS disappeared. This combination chemotherapy was repeated over a three-week span, and the patient remained in partial remission for the next 10 months. In November 1997, a tumor developed in the paranasal sinus, and the patient died three months later. The autopsy disclosed many B lymphoma cells filling the small vessels of almost all organs, and a final diagnosis of intravascular lymphomatosis (IVL) was made. These findings indicate that combination CPT-11 and ADM therapy is effective for cases of IVL accompanied by HPS that are refractory to conventional chemotherapies.

Aged↗
PubMed1997

Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys.

We recently reported that the serum levels of indoxyl sulfate, a dietary protein metabolite, are increased in both uremic rats and patients, and that the administration of indoxyl sulfate to uremic rats accelerates the progression of glomerular sclerosis. Thus, we hypothesize that the overload of protein metabolites such as indoxyl sulfate on nephrons promotes the progression of chronic renal failure (CRF). Recent studies revealed that tubulointerstitial injury is of equal or greater importance than glomerular sclerosis in determining whether progressive renal dysfunction will ensue in various renal diseases. In the present study, to clarify the role of indoxyl sulfate in the progression of CRF, the expressions of genes related to tubulointerstitial fibrosis such as transforming growth factor (TGF)-beta 1, tissue inhibitor of metalloproteinases (TIMP-1) and pro-alpha 1(I) collagen were examined in the renal cortex of 5/6-nephrectomized uremic rats given indoxyl sulfate. In the first experiment, the administration of indoxyl sulfate for five weeks significantly increased the mRNA levels of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in the uremic rats given indoxyl sulfate compared with the control uremic rats, accompanied by a significant decline in renal function and worsening of glomerular sclerosis. In the second experiment, the administration of indoxyl sulfate for 2.5 weeks also increased the expression of the mRNA levels with no significant decline in the renal function. In conclusion, these findings indicate that the overload of the protein metabolite indoxyl sulfate on remnant nephrons is involved in the increased bioactivity of TGF-beta 1 in uremic kidneys, which enhances the renal expression of TIMP-1 and type 1 collagen, leading to the progression of CRF.

Administration, Oral↗
PubMed1997

Indoxyl sulfate and progression of renal failure: effects of a low-protein diet and oral sorbent on indoxyl sulfate production in uremic rats and undialyzed uremic patients.

We have previously demonstrated that indoxyl sulfate is a stimulating factor for the progression of glomerular sclerosis in uremic rats. In this study we determined if a low-protein diet or oral sorbent (AST-120) could reduce the serum and urine levels of indoxyl sulfate in 5/6-nephrectomized uremic rats and undialyzed uremic patients. The uremic rats were treated by fasting or AST-120 for 2 days. The serum and urine levels of indoxyl sulfate dramatically decreased 1-2 days after fasting or AST-120 treatment. We then measured the serum and urine levels of indoxyl sulfate and calculated protein intake from urinary amounts of urea nitrogen using Maroni's equation in 80 undialyzed uremic patients with creatinine clearance less than 30 ml/min. The serum and urine levels of indoxyl sulfate were significantly lower in the patients on a low-protein diet than in those in the normal-protein diet group. Administration of AST-120 significantly decreased serum and urine levels of indoxyl sulfate in 22 undialyzed uremic patients. In conclusion, a low-protein diet or AST-120 reduced the serum and urine levels of indoxyl sulfate, a stimulating factor for glomerular sclerosis, in both uremic rats and undialyzed uremic patients.

Administration, Oral↗
PubMed1997

Indoxyl sulfate stimulates renal synthesis of transforming growth factor-beta 1 and progression of renal failure.

We recently demonstrated that the administration of indoxyl sulfate (dietary protein metabolite) to 5/6-nephrectomized rats accelerated the progression of chronic renal failure by increasing the transforming growth factor (TGF)-beta 1 synthesis in the kidneys, which enhanced the renal expressions of tissue inhibitor of metalloproteinase (TIMP)-1 and type 1 collagen, leading to renal fibrosis. The aim of the present study was to clarify the mechanism by which the administration of indoxyl sulfate increases TGF-beta 1 in the kidneys of uremic rats. Since infiltrative monocytes are suggested to be an important source of TGF-beta 1 in tubulointerstitial fibrosis, we examined the effect of indoxyl sulfate administration to uremic rats on the renal gene expression of intercellular adhesion molecule (ICAM)-1, which is involved in the infiltration of monocytes to kidneys. Indoxyl sulfate administration was observed to enhance the mRNA levels of ICAM-1 as well as those of TGF-beta 1, TIMP-1 and pro alpha 1 (I) collagen in the renal cortex of 5/6-nephrectomized uremic rats. In addition, we demonstrated in vitro that the addition of indoxyl sulfate significantly increased the synthesis of TGF-beta 1 in cultured proximal tubular cells. Thus, the overload of indoxyl sulfate in uremic kidneys increased the infiltration of monocytes and directly increased the synthesis of TGF-beta 1 in proximal tubular cells.

Animals↗
PubMed1996

Modulation of rhythmical slow activity, long-term potentiation and memory by muscarinic receptor agonists.

We investigated the cholinergic modulation of hippocampal rhythmical slow activity (or theta activity), long-term potentiation and a behavioral memory task. The intravenous administration of the muscarinic receptor agonists, AF102B ((+/-)-cis-2-methyl-spiro(1,3-oxathiolane-5,3') quinuclidine hydrochloride hemihidrate) and oxotremorine, induced rhythmical slow activity at doses of 1.0 mg/kg and 0.01 mg/kg, respectively. Long-term potentiation of population spike amplitude in the hippocampal CA1, which was induced by tetanic stimulation to the Schaffer collateral/commissural fiber, was increased by AF102B (1.0 mg/kg i.v.) and oxotremorine (0.01 mg/kg i.v.). Oral administration of AF102B and oxotremorine improved scopolamine-induced memory deficits in a passive avoidance task in mice at doses of 1.0 mg/kg and 0.2 mg/kg, respectively. The correspondence of the effective doses of muscarinic receptor agonists in these three experiments suggested the cholinergic correlation of rhythmical slow activity, long-term potentiation and memory.

Administration, Oral↗
PubMed1994

Progression of glomerular sclerosis in experimental uremic rats by administration of indole, a precursor of indoxyl sulfate.

In uremia there is a marked elevation of serum levels of indoxyl sulfate due to its decreased renal clearance. Indoxyl sulfate is synthesized in the liver from indole which is produced by bacteria in the intestines. To determine the role of indoxyl sulfate in the progression of chronic renal failure, we administered indole, the precursor of indoxyl sulfate, to subtotally nephrectomized uremic rats. The oral administration of indole increased the serum levels of creatinine and blood urea nitrogen and decreased creatinine, inulin, and p-aminohippuric acid clearances. The glomerular sclerosis index in the indole-treated rats was higher than in the control uremic rats. After oral administration, indole could not be detected in the urine, but large amounts of its metabolite, indoxyl sulfate. Thus, indole administration stimulated glomerular sclerosis in a uremic model through the production of indoxyl sulfate.

Animals↗
PubMed1994

Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis.

To determine the role of indoxyl sulfate in the progression of glomerular sclerosis, the serum level of indoxyl sulfate was measured in patients with uremia, and the effect of oral administration of indoxyl sulfate on renal function and renal histology was studied in subtotally nephrectomized uremic rats. Further, the effects of a low-protein diet and oral sorbent (AST-120) administration on the serum and urine levels of indoxyl sulfate were studied in different groups of subtotally nephrectomized uremic rats. We noted a marked elevation of serum level of indoxyl sulfate in the patients with uremia. The oral administration of indoxyl sulfate to the uremic rats increased the serum creatinine and blood urea nitrogen levels and decreased creatinine clearance, inulin clearance, and p-aminohippuric acid clearance. The glomerular sclerosis index in the indoxyl sulfate-administered uremic rats was higher than in the control uremic rats. A low-protein diet and AST-120 administration decreased the serum and urine levels of indoxyl sulfate, the blood urea nitrogen level, the urinary protein level, and the glomerular sclerosis index in the uremic rats as compared with those on a high-protein diet. Thus, indoxyl sulfate, a circulating uremic toxin, stimulated the progression of glomerular sclerosis in the uremic model. A low-protein diet and AST-120 reduced the serum and urine levels of indoxyl sulfate and suppressed the progression of glomerular sclerosis.

Aged↗
PubMed1993

Suppressive effect of an oral sorbent on the accumulation of p-cresol in the serum of experimental uremic rats.

Serum p-cresol and phenol are markedly accumulated in uremic patients. To determine if an oral sorbent (AST-120) can decrease their serum concentrations in the uremic state, an oral sorbent was administered to experimental nephrectomized uremic rats. In uremic rats fed with oral sorbent, the serum concentration and the urinary excretion of p-cresol were markedly and significantly lower than those in control uremic rats, while those of phenol tended to be low in the uremic rats with oral sorbent as compared with control uremic rats. The concentrations of serum creatinine and blood urea nitrogen were significantly decreased in the uremic rats with oral sorbent. These findings demonstrate that oral sorbent adsorbs especially p-cresol in the intestine and prevents the accumulation of p-cresol in the serum of uremic rats.

Administration, Oral↗
PubMed1992

Suppressed serum and urine levels of indoxyl sulfate by oral sorbent in experimental uremic rats.

In uremic patients, the serum concentration of indoxyl sulfate is markedly increased. To determine if oral sorbent (AST-120) suppresses the endogenous synthesis of indoxyl sulfate, it was administered to experimental uremic rats, and the serum concentration and urinary excretion of indoxyl sulfate were quantified by high-performance liquid chromatography. Oral sorbent decreased both the serum concentration and urinary excretion of indoxyl sulfate, suggesting that there was suppression of the endogenous synthesis of indoxyl sulfate by the oral sorbent. Oral sorbent did not decrease the serum concentration and urinary excretion of hippuric acid, but it did alleviate the deterioration of renal function in the experimental uremic rats.

Adsorption↗
PubMed1992

Effects of oral adsorbent in the rat model of chronic renal failure.

The effects of oral adsorbent, AST-120 (Kureha Chemical Ind. Co., Tokyo), were studied in the rat model of subtotal nephrectomy. In 34 female Sprague-Dawley rats, three quarters of the renal mass were removed from the left kidney by ligation of 3 branches of the left renal artery. One week later, the right kidney was removed. Two days after right nephrectomy, control rats were fed standard rat chow ad libitum, while AST-120-treated rats were fed standard rat chow containing AST-120 ad libitum. The animals were observed for 9 weeks. Of the control rats, some became severely ill and appeared to be almost dying before 9 weeks, while paired AST-120-treated rats appeared well. Body weight was maintained better in AST-120-treated rats than in control rats. At completion of the study, levels of BUN and serum creatinine were lower and glomerular filtration rate and renal plasma flow rate were higher in AST-120-treated than in control rats (p < 0.05), although there was no statistically significant difference in proteinuria. Serum uremic peak 2a measured by high-performance liquid chromatography, which is considered to correspond to uremic toxins, was statistically lower in AST-120-treated rats (p < 0.05). Finally, a marked reduction in the degree of glomerular sclerosis was noted in AST-120-treated versus control rats (p < 0.05). The results indicate that AST-120 is effective in the treatment of chronic renal failure in terms of reducing uremic symptoms as well as preserving renal function and glomerular architecture. The data also indicate that a reduction in uremic toxins could delay the progressive damage of renal function and glomerular architecture in chronic renal failure.

Adsorption↗
PubMed1992

[Effect of oral adsorbent (AST-120) in the rat model of chronic renal failure induced by adriamycin].

The effect of AST-120 was examined in the rat model of CRF induced by adriamycin (ADM), which is known to induce focal glomerular sclerosis (GS). ADM (2mg/kg) was injected intravenously twice at a 3-wk interval. After 14 wks, rats were paired with control (C) and AST-120 (A) groups according to levels of BUN and proteinuria. Then, the rats were fed regular rat chow with (A, n = 10) or without (C, n = 10) AST-120. After 28 wks, there were more GS in C. Averaged sclerosis index (SI, 0-4 scale) in C was 1.97 (0.94-3.22), while 1.61 (0.60-2.97) in A. When GS was advanced in C (SI > 2.0), largely ameliorated SI was noted in A (2.61 vs. 1.97, C vs. A, p < 0.05 by paired W-test, n = 5 each). Also, in these rats, BUN, serum creatinine and Ht were all improved in A (p < 0.05). Thus, AST-120 was effective in CRF rats induced by ADM when uremia was advanced. The data also indicates that a reduction of uremic toxins could improve glomerular histology and renal function in CRF.

Animals↗
PubMed1992

Dietary protein loading and the oral adsorbent AST-120 in the progression of chronic renal failure in the rat.

Excess protein intake enhances the progression of renal failure. The oral carbonaceous adsorbent, AST-120, was found experimentally and clinically to retard the progression of renal failure. This study was designed to determine whether deterioration of renal function by dietary protein loading can be prevented or mitigated by this oral adsorbent. Rats with uremia induced by partial renal infarction were fed a normal or high-protein diet for 70 days with or without AST-120, in which the inorganic phosphate content was adjusted to the same level. The survival rate deteriorated with the high dietary protein, but was improved from 30% to 100% with AST-120. Dietary protein loading reduced renal function, based on creatinine clearance. AST-120 improved renal function and renal histopathology not only in the normal diet group but in the high-protein group as well. The progression of renal failure induced by protein loading is thus shown to be prevented by oral AST-120. The mechanism for its action remains to be clarified.

Administration, Oral↗
PubMed1992

[Effect of oral adsorbent AST-120 in rats with chronic renal failure--mechanism of progression of renal failure by dietary protein].

Progression of renal insufficiency was evaluated in partially nephrectomized Sprague-Dawley rats at the age of 10 weeks, fed on the low (6%), usual (20%), and high (36%) protein diet (group 6C, 20C, and 36C). Effects of oral adsorbent AST-120 on these experimental uremic models were also examined (group 6A, 20A, 36A). All the rats underwent paired feeding, and survived during the experimental period of 3 weeks. GFR (inulin clearance) and RPF (para-amino hippurate clearance), as well as Ccr was measured before the sacrifice. Initial serum creatinine and Ccr were 1.7 mg/dl and 0.27 ml/min. The rats of group 36C showed progressive elevation of serum creatinine level and decrease in Ccr. At the end of the study, GFR was significantly lower in group 36C than in group 6C and 20C (0.19, 0.68, 0.87 ml/min respectively). Significant elevation of filtration fraction in group 36C suggested that the decrease in GFR mainly resulted from low RPF. Even in group 36C, no glomerular sclerosis was histologically demonstrated in the remnant kidney, and the mean planar area of the remnant glomeruli was significantly small, which might reflect low RPF. Tubulo-interstitial changes like dilatation of the urinary space and tubular epithelial flattening were prominent in group 36C. Beneficial effect of AST-120 was obvious in high protein diet groups. GFR and RPF were rather well preserved in group 36A (0.36 and 0.78 ml/min) with normal filtration fraction. Tubulo-interstitial damage was evidently mild in group 36A. These data suggested the presence of some humoral factors, which can be adsorbed by AST-120 in gastrointestinal tract, and responsible for the deterioration of renal function and tubulo-interstitial damage induced by high protein diet in the uremic condition. Besides hyperfiltration and glomerular hypertrophy, such humoral factors as suggested in this study may contribute to the progression of chronic renal failure to some extent.

Adsorption↗
PubMed1991

Inhibitory effect of oral sorbent on accumulation of albumin-bound indoxyl sulfate in serum of experimental uremic rats.

Serum indoxyl sulfate, which is markedly accumulated in uremic patients, cannot be removed efficiently by hemodialysis due to its albumin binding. To determine if oral adsorbent (AST-120) can decrease its serum concentration in uremic state, oral adsorbent was administered to experimental nephrectomized uremic rats. Uremic rats fed with oral adsorbent showed a significantly lower serum concentration of indoxyl sulfate compared to control uremic rats, even when serum concentrations of urea nitrogen and creatinine were not significantly decreased in the uremic rats fed with oral adsorbent. Indoxyl sulfate was detected only at a lower concentration in bile as compared with the serum of uremic rats. These results suggest that oral adsorbent adsorbs indole, a precursor of indoxyl sulfate, in the intestine and prevents the accumulation of indoxyl sulfate in uremic rats.

Administration, Oral↗