Insulin-induced GLUT4 recycling in rat adipose cells by a pathway insensitive to brefeldin A.
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3-O-Methylglucose↗
Biomedical subjects
H Sekihara
Publications and source records attributed to H Sekihara.
Genetic control of in vivo tumor necrosis factor production in mice.
We report on the genetic effect on in vivo production of tumor necrosis factor (TNF)-alpha induced by lipopolysaccharides (LPS) using various congenic mouse strains. B10.A, Bl0.A(3R), B10.AQR, B10.A(5R), and B10.S(7R) produced significantly high TNF-alpha compared with B10.BR, B10.S, C57BL/10, B10.A(2R), B10.A(4R), B10.G, B10.DA(80NS), and B10.RIII(71NS). This suggests that LPS-induced TNF-alpha production is genetically controlled by H-2. Mice with the same alleles on K, A, E, or S loci produced various (high or low) levels of TNF-alpha, thus indicating that regulatory genes are located outside these loci. All strains with H-2Dd produced significantly high levels of TNF-alpha, but strains with other alleles in the H-2D locus produced low levels. Thus, TNF-alpha production appears to be genetically linked to H-2D itself or H-2D linked genes and the allele d is linked to a high responder gene. This was the case with the A background. C3H/HeN (H-2k), however, showed a high TNF-alpha production, suggesting the presence of another controlling gene outside H-2. In addition, high TNF-alpha productivity was transmitted into F1 mice (B10.A X B10.BR) in a dominant fashion. Both LPS-stimulated and unstimulated TNF-alpha mRNA expression in splenic macrophages were enhanced in high responder strains. Thus, we conclude that TNF-alpha production is closely related to genes within or linked to the H-2D locus as well as others outside H-2.
Animals↗
Interleukin-6 (IL-6) in patients with Behçet's disease.
We have examined the levels of interleukin-6 (IL-6) in plasma and supernatants of peripheral blood mononuclear cells (PBMC) from patients with Behçet's disease and healthy controls using a sensitive enzyme-linked immunosorbent assay (ELISA). Plasma IL-6 level was not detected in any subjects. The IL-6 concentrations in culture supernatants of patients with active Behçet's disease were significantly high compared with patients with inactive disease and healthy controls. Moreover, we investigated IL-6 gene expression in cultured PBMC from patients with Behçet's disease. IL-6 gene expression was enhanced in active patients compared with inactive patients. These results show that IL-6 may play a role in the pathogenesis of Behçet's disease.
Adult↗
Hepatic HCV-RNA as a predictor of outcome after interferon therapy in patients with chronic hepatitis C.
Measurement of serum HCV-RNA is a useful index for evaluating the antiviral effect of interferon therapy in chronic hepatitis C. In the present study, we investigated whether the detection of hepatic HCV-RNA after interferon treatment, using a polymerase chain reaction assay, predicted long-term response to therapy in patients with chronic hepatitis C. Thirty-three patients underwent liver biopsies before and after interferon therapy. Histology and clinical courses were compared after treatment. Before therapy, serum and hepatic HCV-RNA was detected in specimens from 32 (97%) and 33 (100%) patients, respectively. Serum HCV-RNA became undetectable in samples from 22 (67%) patients; however, in 10 of these patients (45%), serum HCV-RNA levels relapsed after therapy. Hepatic HCV-RNA became undetectable in 14 patients after therapy and the serum aminotransferase concentration remained within normal limits during and following (24-92 weeks) therapy in 12 of these patients (86%). All 11 patients with detectable hepatic HCV-RNA also had serum HCV-RNA and elevated aminotransferase concentrations refractory to therapy. The absence of hepatic HCV-RNA at the end of interferon treatment thus predicted a long-term complete response to therapy with a sensitivity of 100%, a specificity of 90% and an accuracy of 94%. We conclude that hepatic rather than serum HCV-RNA is a more useful index for the prediction of the long-term efficacy of interferon therapy.
Adult↗
Efficacy of ursodeoxycholic acid in combination with interferon-alpha in treating chronic hepatitis C: results of a long-term follow-up trial.
Ursodeoxycholic acid (UDCA) has recently been combined with interferon (IFN) in the treatment of individuals with chronic hepatitis C. However, whether its addition results in a long-term favourable response to IFN remains unclear. A prospective randomized trial of IFN alone versus IFN plus UDCA was therefore undertaken in 52 patients with chronic hepatitis C. All patients received a 24 week course of IFN-alpha (6 x 10(6) U/day for 2 weeks and then three times a week for 22 weeks) and half also received UDCA (600 mg/day) with IFN and then alone for 48 additional weeks. Normalization of serum alanine transaminase (ALT) concentrations at 0, 24 and 48 weeks after cessation of IFN therapy was apparent in 77, 42 and 42% of patients in the IFN-alone group and in 77, 54 and 42% of patients in the IFN plus UDCA group, respectively. There was no significant difference between the two groups with regard to response rate to IFN and the addition of UDCA to IFN treatment had no significant effect on hepatitis C virus (HCV) viraemia. During the follow-up period, 10 of 20 patients with normal serum ALT at the end of IFN treatment relapsed in the IFN-alone group compared with 11 of 20 patients in the IFN plus UDCA group. Among these relapsed patients, serum ALT concentration was significantly lower in the IFN plus UDCA group than in the IFN-alone group during the follow-up period. Twenty-four weeks after cessation of IFN therapy, the percentage of patients with HCV-RNA in their serum who showed a normalization of serum ALT concentrations was significantly higher in the IFN plus UDCA group than in the IFN-alone group (44 vs 6%). Thus, although the addition of UDCA was not associated with a favourable long-term response to HCV viraemia, it did reduce the risk and the severity of relapse following the cessation of IFN therapy.
Alanine Transaminase↗
Tissue-specific regulation of angiotensinogen gene expression in spontaneously hypertensive rats.
Angiotensinogen is expressed in many tissues besides the liver. Recent studies have suggested that abnormalities in the regulation of angiotensinogen gene expression may be involved in the development of hypertension. However, little information is available concerning the functional significance of tissue angiotensinogen. In this study, we measured plasma angiotensinogen concentration by radioimmunoassay and examined the expression of tissue angiotensinogen by Northern blot analysis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Although plasma angiotensinogen concentration in SHR was comparable to that in WKY at 6 weeks of age, it was increased significantly at 14 weeks of age in SHR and became higher than that in WKY. The levels of hepatic angiotensinogen mRNA were similar in SHR and WKY, and the levels of aortic, adrenal, and renal angiotensinogen mRNAs were lower in SHR than in WKY at both 6 and 14 weeks of age. Brain angiotensinogen expression in SHR was higher than in WKY at 6 weeks of age and was comparable to that in WKY at 14 weeks of age. On the other hand, cardiac and fat angiotensinogen mRNA levels were significantly increased at 14 weeks of age in SHR. These results demonstrate that the expression of tissue angiotensinogen is regulated differently in SHR and WKY and indicate that the development of hypertension is accompanied at least temporally with increases in plasma angiotensinogen concentration as well as cardiac and adipogenic angiotensinogen mRNA in SHR.
Angiotensinogen↗
Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1 and identification of insulin receptor substrate-2.
To clarify the physiological roles of insulin receptor substrate-1 (IRS-1) in vivo, we made mice with a targeted disruption of the IRS-1 gene locus. Mice homozygous for targeted disruption of the IRS-1 gene were born alive but were retarded in embryonal and postnatal growth. They also had resistance to the glucose-lowering effects of insulin, insulin-like growth factor-1 (IGF-1) and factor-2 (IGF-2). These data suggest the existence of both IRS-1-dependent and IRS-1-independent pathways for signal transduction of insulin and IGFs. Moreover, we identified tyrosine phosphorylation of a 190-kDa protein (pp 190) as a novel substrate (IRS-2) for insulin receptor kinase in livers of IRS-1 deficient mice which can bind both P13-kinase and Ash/Grb2.
Animals↗
Augmented production of tumor necrosis factor-alpha in obese mice.
Non-insulin-dependent diabetes mellitus develops in obesity. The insulin resistance of this disease may be mediated by tumor necrosis factor-alpha (TNF-alpha). In particular, the TNF-alpha derived from adipose tissues might be involved in the induction of peripheral insulin resistance in rodent models of obesity. In general, monocytes/macrophages have been considered as the major source of TNF-alpha. This study was designed to examine the potential production of TNF-alpha from monocyte/macrophages in obese mice. In obese (ob/ob) and obese diabetic (db/db) mice, both of which are known to have severe insulin resistance, unstimulated serum bioactivity of TNF-alpha was significantly higher than that in lean control mice. Spontaneous TNF-alpha mRNA expression in splenic macrophages was also enhanced in obese mice, but not in monosodium-L-glutamate (MST)-induced obese mice which have no insulin resistance. In addition, both ob/ob and db/db mice produce more TNF-alpha than lean mice upon in vivo lipopolysaccharide (LPS) stimulation. The LPS-induced increase in serum TNF-alpha activity was not observed in MSG-induced obese mice. Taken together, it is postulated that TNF-alpha produced by monocytes/macrophages may also play an important role in the genesis of insulin resistance in obesity. Further study is needed to reveal the mechanism of enhanced TNF-alpha production in obese states and its possible etiologic relevance to obesity.
Animals↗
[Pharmacological action of 9alpha-fluorohydrocortisone as a mineralocorticoid].
The action of 9 alpha-fluorohydrocortisone (fludrocortisone) as a potent mineralocorticoid was reviewed. Fludrocortisone shows mineralocorticoid activity as potent as aldosterone and causes sodium-retention and kaliuresis when injected intravenously in man. The duration of the action of fludrocortisone in longer than that of aldosterone. Therefore, fludrocortisone is more pertinent to clinical use than aldosterone. Fludrocortisone is administered as a mineralocorticoid in case of Addison's disease and postoperative Cushing syndrome. It is also used to relieve hyperkalemia or to ameliorate hyponatremia.
Addison Disease↗
Twelve-year follow-up of patient with adrenal androgen-producing tumour.
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Adenoma↗
Ouabain causes kaliuresis and works synergistically with aldosterone in vivo.
The effect of ouabain on urinary Na and K excretion was compared with that of aldosterone by injecting 0.1 or 0.5 mg ouabain or 0.25 micrograms aldosterone. The administration of 0.25 micrograms aldosterone caused sodium-retention without kaliuresis, whereas the administration of 0.5 mg ouabain caused kaliuresis without sodium-retention. These results indicate that ouabain is a kaliuretic agent. The effect of a combination of aldosterone and ouabain was evaluated by injecting 0.25 micrograms aldosterone simultaneously with 0.1 or 0.5 mg ouabain. The combination of aldosterone and ouabain caused both sodium-retention and kaliuresis. These results indicate that ouabain works synergistically with aldosterone to increase mineralocorticoid action by inducing K depletion from the cells in various tissues.
Aldosterone↗
19-Oxoandrost-4-ene-3,17-dione amplifies the action of aldosterone.
The amplification of the action of aldosterone by 19-oxoandrost-4-ene-3,17-dione (19-oxo-A-dione) was evaluated by mineralocorticoid bioassays using adrenalectomized rats. Pretreatment of rats with 19-oxo-A-dione did not cause any significant change in urinary Na/K ratio. However, aldosterone caused a significantly lower urinary Na/K ratio and Na excretion in rats pretreated with 19-oxo-A-dione than in rats without pretreatment. These results indicate that the sodium-retaining action of aldosterone is amplified by pretreatment with 19-oxo-A-dione.
Adrenalectomy↗
5 alpha-Dihydro-11-deoxycorticosterone as a mineralocorticoid agonist and antagonist: evidence for a weak mineralocorticoid as an antagonist of potent mineralocorticoids.
To evaluate the possibility that 5 alpha-dihydro-11-deoxycorticosterone (5 alpha-DH-DOC), a weak mineralocorticoid, is an antagonist of a more potent mineralocorticoid, aldosterone, 0.25 microgram aldosterone was injected into adrenalectomized rats simultaneously with 200-800 micrograms 5 alpha-DH-DOC and urinary Na/K ratio and Na and K excretion were evaluated. Urinary Na/K ratio and Na excretion were significantly lower than those of control rats regardless of whether rats were treated with 0.25 microgram aldosterone alone or 400-800 micrograms 5 alpha-DH-DOC alone. Urinary Na/K ratio and Na excretion of rats given a combination of 0.25 microgram aldosterone plus 400-800 micrograms 5 alpha-DH-DOC were significantly higher than those of rats given 0.25 microgram aldosterone alone. None of the treatment caused significant changes in urinary K excretion. The results demonstrate that 5 alpha-DH-DOC, a weak mineralocorticoid, is an antagonist of the sodium-retaining action of a more potent mineralocorticoid, aldosterone. Progesterone which has weak mineralocorticoid activity is also known as an antagonist of more potent mineralocorticoids. The results of the present study demonstrate further evidence that weak mineralocorticoids may work as antagonists of more potent mineralocorticoids.
Aldosterone↗
Plasma 19-hydroxyandrostenedione is elevated in patients with high renin essential hypertension.
OBJECTIVES: We have reported that 19-hydroxyandrostenedione (19-OH-A-dione) functions as an amplifier of the sodium-retaining and hypertensive action of aldosterone. We therefore measured 19-hydroxyandrostenedione in hypertensive patients. PATIENTS AND MEASUREMENTS: We studied 53 normal male control subjects and 63 male patients with essential hypertension (48 patients with normal renin essential hypertension and 15 patients with high renin essential hypertension). Plasma 19-OH-A-dione levels were measured by RIA. RESULTS: Plasma 19-OH-A-dione concentrations in control subjects and patients with normal and high renin essential hypertension were 115 +/- 46 (mean +/- SD), 112 +/- 49 and 201 +/- 79 pmol/l, respectively. Patients with high renin essential hypertension showed significantly higher 19-OH-A-dione concentrations than did control subjects. The evaluation of the correlation between plasma 19-OH-A-dione concentrations and plasma renin activity revealed that plasma 19-OH-A-dione concentrations in hypertensive subjects rose gradually with an increase in plasma renin activity. Therefore, a significant correlation was found between plasma renin activity and plasma 19-OH-A-dione (r = 0.586, P < 0.001). In contrast, in control subjects, no significant correlation was found between plasma renin activity and plasma 19-OH-A-dione (r = 0.059, P > 0.05). CONCLUSIONS: The secretion of 19-OH-A-dione from the adrenal cortex is under the control of the renin-angiotensin system in hypertensives but not in normotensives.
Adult↗
19-Hydroxyandrostenedione amplifies the hypertensive action of mineralocorticoids in rats.
We have reported that 19-hydroxyandrostenedione (19-OH-A-dione) amplifies the sodium-retaining action of aldosterone. To evaluate whether it also amplifies the hypertensive action of small doses of aldosterone, mononephrectomized rats were given 0.5 mg aldosterone, 10 mg 19-OH-A-dione or a combination of both once a week for 19 weeks, and changes in blood pressure were evaluated. Rats were given 154 mmol NaCl/l to drink. The blood pressure of controls, rats given aldosterone alone, 19-OH-A-dione alone or a combination of both in week 19 were 137 +/- 4 (S.E.M.), 146 +/- 7, 147 +/- 4 and 191 +/- 8 mmHg respectively. The blood pressure of rats given the combination was significantly higher than any of the other three groups. These results indicate that 19-OH-A-dione amplifies the hypertensive action of aldosterone and may be considered a potent hypertensive agent in the presence of aldosterone. To evaluate whether 19-OH-A-dione amplifies the hypertensive action of small doses of deoxycorticosterone acetate (DOCA), another experiment was carried out in which similar rats were given 5 mg DOCA or a combination of 5 mg DOCA and 10 mg 19-OH-A-dione once a week for 8 weeks. The blood pressure of controls, rats given DOCA alone and a combination of DOCA and 19-OH-A-dione in week 8 were 139 +/- 5, 166 +/- 7 and 208 +/- 12 mmHg respectively. The blood pressure of rats given a combination of DOCA and 19-OH-A-dione was significantly higher than that of control rats or the rats given DOCA alone. These results indicate that 19-OH-A-dione can also amplify the hypertensive action of DOCA. It is concluded that 19-OH-A-dione amplifies the hypertensive action of mineralocorticoids as well as the sodium-retaining action of aldosterone.
Aldosterone↗
[Drug enhancement of cortisol and glucocorticoid metabolism].
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Adrenal Insufficiency↗
Ouabain as an amplifier of mineralocorticoid-induced hypertension.
Ouabain has recently been reported to be an endogenous Na, K-ATPase inhibitor. To evaluate whether it exerts hypertensive action itself or amplifies the hypertensive action of small doses of mineralocorticoids, 5 mg deoxycorticosterone acetate (DOCA), 1 mg ouabain, or a combination of both were injected into mononephrectomized rats weekly for 6 weeks, and changes in blood pressure were evaluated. The blood pressures of control, DOCA-treated, ouabain-treated, and the combination treatment group at the sixth week were 138 +/- 3 (SE), 160 +/- 6, 144 +/- 6, and 201 +/- 14 mmHg, respectively. The blood pressure of rats given DOCA or ouabain alone was not significantly different from that of controls. In contrast, the blood pressure of rats given the combination of DOCA and ouabain was significantly higher than that of control rats and those given DOCA or ouabain separately. Cardionephromegaly and histopathological changes found in rats given the combination of DOCA and ouabain were consistent with the effects of an elevation of blood pressure. Further evaluation revealed that the amplification effect of ouabain on the hypertensive action of DOCA was dose dependent, with the minimum dose that caused the amplification effect being 0.25 mg/week. These results indicate that ouabain, although devoid of hypertensive action itself, amplifies the hypertensive action of small doses of DOCA and can cause a hypertensive state similar to that induced by larger doses of DOCA. It is inferred that the amplification effect of ouabain on mineralocorticoids is important in the genesis of hypertension.
Animals↗
Synthesis of 3 beta,16 beta,19-trihydroxyandrost-5-en-17-one and 16 beta,19-dihydroxyandrost-4-ene-3,17-dione and their 19-oxo derivatives.
3 beta,16 beta,19-Trihydroxyandrost-5-en-17-one (12) was synthesized from 5 alpha-bromo-3 beta-acetoxy-6 beta,19-epoxyandrostan-17-one (2) through acetoxylation at C-16 beta of the enol acetate 4 with lead tetraacetate and reductive cleavage of the epoxide ring with zinc dust yielding the 3 beta,16 beta-diacetoxy-19-hydroxy steroid 11, followed by hydrolysis of the acetoxy groups with sulfuric acid. Jones oxidation of compound 11 followed by the acid hydrolysis gave the 19-oxo steroid 15. 5 alpha-Bromo-3 beta-hydroxy-16 beta-acetoxy-6 beta,19-epoxyandrostan-17-one (8), obtained by selective hydrolysis of the 3-formate 5 with ammonium hydroxide, was oxidized with Jones reagent to afford the 3-oxo steroid 16, which was converted into the 19-hydroxy derivative 17 by treatment with zinc dust. 16 beta,19-Dihydroxyandrost-4-ene-3,17-dione (18) and its 19-oxo derivative 21 were obtained from compound 17 through a similar reaction sequence.
Androstenedione↗