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Biomedical subjects

M Hosoi

Publications and source records attributed to M Hosoi.

At least 19 recordsLinked to original sources
PubMed1998

Pain modulatory actions of cytokines and prostaglandin E2 in the brain.

Proinflammatory cytokines such as IL-1, IL-6, and TNF alpha are known to enhance nociception at peripheral inflammatory tissues. These cytokines are also produced in the brain. We found that an intracerebroventricular injection of IL-1 beta only at nonpyrogenic doses in rats reduced the paw-withdrawal latency on a hot plate and enhanced the responses of the wide dynamic range neurons in the trigeminal nucleus caudalis to noxious stimuli. This hyperalgesia, as assessed by behavioral and neuronal responses, was blocked by pretreatment with IL-1 receptor antagonist (IL-1Ra), Na salicylate, or alpha melanocyte-stimulating hormone, indicating the involvement of IL-1 receptors and the synthesis of prostanoids. IL-6 and TNF alpha at nonpyrogenic doses also induced hyperalgesia in a prostanoid-dependent way. Furthermore, the preoptic area (POA) was most sensitive to IL-1 beta (5-50 pg/kg) in the induction of behavioral hyperalgesia. The maximal response was obtained 30 min after injection of IL-1 beta at 20 pg/kg. On the other hand, an injection of IL-1 beta (20-50 pg/kg) into the ventromedial hypothalamus (VMH) prolonged the paw-withdrawal latency maximally 10 min after injection. This analgesia, as well as the intraPOA IL-1 beta-induced hyperalgesia, was completely blocked by IL-1Ra or Na salicylate. Our previous study has revealed that i.c.v. injection of PGE2 induces hyperalgesia through EP3 receptors and analgesia through EP1 receptors by its central action. The results, taken together, suggest (1) that IL-1 beta at lower doses in the brain induces hyperalgesia through EP3 receptors in the POA and (2) that the higher doses of brain IL-1 beta produces analgesia through EP1 receptors, probably, in the VMH.

Animals↗
PubMed1998

Treating nonulcer dyspepsia considering both functional disorders of the digestive system and psychiatric conditions.

Nonulcer dyspepsia (NUD) is a common syndrome, but the optimal treatments have yet to be established. This study was performed to determine the most effective treatment for NUD. Subjects were recruited through the Department of General Internal Medicine at the Kyushu University Hospital because of their somatic symptoms. When no organic lesions were found, the patients were directed to consult our department (Psychosomatic Medicine); 194 consecutive NUD patients were studied. All subjects were assessed psychiatrically with the Structured Clinical Interview for DSM-III-R(SCID). Patients with serious NUD were hospitalized, and randomly divided into control (N = 42) and experimental groups (N = 86). The controls were treated with physical treatment alone. The experimental group received psychiatric treatment in addition, based on the results of SCID. The experimental group showed a significant improvement compared with the controls (P < 0.0001). The treatment for NUD taking into consideration both the physical and psychiatric conditions is highly effective.

Adult↗
PubMed1997

Biphasic modulation in the trigeminal nociceptive neuronal responses by the intracerebroventricular prostaglandin E2 may be mediated through different EP receptors subtypes in rats.

To determine which prostaglandin E2 (PGE2) receptor subtypes are involved in the brain-derived PGE2-induced changes in nociception, we injected synthetic EP1, EP2 and EP3 receptor agonists (0.01 fmol to 10 nmol) into the lateral cerebroventricle (LCV) of urethane-anesthetized rats and observed the changes in the responses of the wide dynamic range (WDR) neurons in the trigeminal nucleus caudalis to noxious pinching of facial skin. The enhancement and suppression of the nociceptive responses of the WDR neurons were observed after the LCV injection of MB28767 (an EP3 receptor agonist) at a low dose range (1-100 fmol) and 17-phenyl-omega-trinor PGE2 (an EP1 receptor agonist) at high doses (1-10 nmol), respectively. Furthermore, the suppression of nociceptive neuronal responses after the LCV injection of PGE2 (1 nmol) was completely blocked by SC19220 (an EP1 receptor antagonist, 300 nmol). On the other hand, butaprost (an EP2 receptor agonist) at any doses tested (0.1 fmol to 1 nmol) had no effect on the nociceptive responses. The LCV injection of MB28767 (10 fmol) and 17-phenyl-omega-trinor PGE2 (1 nmol), which respectively enhanced and suppressed the nociceptive neuronal responses, did not affect the responses of the low threshold mechanoreceptive neurons to innocuous tactile stimuli. These results provide electrophysiological evidence that brain-derived PGE2 induces mechanical hyperalgesia and hypoalgesia through EP3 and EP1 receptors, respectively, in the rat.

Analgesics↗
PubMed1997

Protein kinase C delta inhibits the proliferation of vascular smooth muscle cells by suppressing G1 cyclin expression.

To elucidate the physiological role of protein kinase C (PKC) delta, a ubiquitously expressed isoform in vascular smooth muscle cells (VSMC), PKC delta was stably overexpressed in A7r5 cells, rat clonal VSMC. The [3H]thymidine incorporation in A7r5 overexpressed with PKC delta (DVs) was suppressed to 37.1 +/- 16.3% (mean +/- S.D.) of the level in control or A7r5 transfected with vector alone (EVs). The reduction of [3H]thymidine incorporation was strongly correlated with overexpressed PKC levels. Moreover, transient transfection of a dominant negative mutant of PKC delta restored the reduced proliferation in DVs. Flow cytometry analysis demonstrated that DVs were arrested in the G0/G1 phase of the cell cycle. Expression of cyclins D1 and E and retinoblastoma protein phosphorylation were reduced, while the protein levels of p27 were elevated in DVs as compared with EVs. There were no significant differences in the expression of c-fos, c-jun, c-myc, cyclin D2, D3, cyclin-dependent kinase 2, cyclin-dependent kinase 4, and p21 among the clones. We conclude that PKC delta inhibits the proliferation of VSMC by arresting cells in G1 via mainly inhibiting the expression of cyclin D1 and cyclin E.

Animals↗
PubMed1997

Biphasic alteration in the trigeminal nociceptive neuronal responses after intracerebroventricular injection of prostaglandin E2 in rats.

To investigate the role of prostaglandin E2 (PGE2) in the brain in nociception electrophysiologically, we injected PGE2 (0.1 fmol(-1) nmol) into the lateral cerebroventricle (LCV) of anesthetized rats and observed the changes of the responses of the wide dynamic range (WDR) neurons in the trigeminal nucleus caudalis to noxious pinching of facial skin. The LCV injection of PGE2 at 1 fmol and 10 fmol enhanced the responses of the majority of WDR neurons to noxious stimuli, whereas that of PGE2 at 100 pmol and 1 nmol suppressed them. The enhancement and suppression of the nociceptive responses of WDR neurons were observed 15-25 min and 5-15 min after injection of PGE2 at 10 fmol (3.53 pg) and 1 nmol (353 ng), respectively. On the other hand, the LCV injection of PGE2 at both 10 fmol and 1 nmol had no effect on the responses of the low threshold mechanoreceptive neurons to skin brushing. These results provide electrophysiological evidence that brain-derived PGE2 has biphasic effects on nociception, i.e., it induces mechanical hyperalgesia at lower doses and hypoalgesia at higher doses in rats.

Activity Cycles↗
PubMed1997

Prostaglandin E receptor EP3 subtype is involved in thermal hyperalgesia through its actions in the preoptic hypothalamus and the diagonal band of Broca in rats.

The effects of microinjection of prostaglandin E2 (PGE2) (0.5 fg-500 pg/0.2 microl) into the medial part of the preoptic area (MPO) on nociception were studied using a hot-plate test in rats. The intraMPO microinjection of PGE2 only at non-pyrogenic doses (5-50 fg) reduced the paw-withdrawal latency, suggesting hyperalgesia. Maximal reduction was obtained 15 min after the injection of PGE2 at 50 fg. Subsequently, to determine which types of prostanoid receptors are involved in the hyperalgesic effect of PGE2 in the MPO, we administered PGE2 receptor agonists, i.e., 17-phenyl-omega-trinor PGE2 (an EP1 receptor agonist), butaprost (an EP2 receptor agonist) and M&B28767 (an EP3 receptor agonist) into the MPO and observed the nociceptive behavior. The intraMPO injection of M&B28767 (0.005 fg-50 pg), like that of PGE2, exhibited a U-shaped dose response characteristic, i.e., a significant decrease of the paw-withdrawal latency only at 0.05-5 fg with the maximal response at 0.5 fg. However, neither the administration of EP1 (0.5 fg-50 ng) nor EP2 (0.5 fg-500 pg) agonists had any effect on nociception. The microinjection of M&B28767 at 0.5 fg into the other parts of preoptic hypothalamus (the lateral part of the preoptic area and the median preoptic nucleus) and the diagonal band of Broca (DBB) produced hyperalgesia similar to the intraMPO-induced hyperalgesia in terms of magnitude and time course. Microinjection of M&B28767 (0.5 fg) into either the paraventricular nucleus, the ventromedial hypothalamus, the lateral hypothalamic area or the septal nucleus had no effect on nociception. These findings suggest that PGE2 at non-pyrogenic doses in the brain induces hyperalgesia, at least in part, through its actions on EP3 receptors in the preoptic hypothalamus and the DBB in rats.

Alprostadil↗
PubMed1997

Intrarenal hemodynamic abnormalities in diabetic nephropathy measured by duplex Doppler sonography.

Intrarenal hemodynamics were studied by duplex Doppler sonography in 112 inpatients with type II diabetes mellitus (DM; 65 males, 47 females, 58 +/- 13 years old). The resistive index (RI) and pulsatility index (PI) of the interlobar arteries were calculated. The patients were divided into four groups: group I consisted of patients with urinary albumin excretion (UAE) < 20 micrograms/min (N = 42), group II with 20 < or = UAE < 200 (N = 28), group III with UAE > or = 200 (N = 25), and group IV with serum creatinine > or = 1.5 mg/dl (N = 17). Both RI and PI values in groups II, III, and IV were significantly higher than those in the controls (age- and sex-matched healthy persons, N = 37; P < 0.001), and those in group IV were significantly higher than those in groups I, II, and III (P < 0.0001). Multiple regression analysis revealed that RI values in DM patients were significantly affected by creatinine clearance, age, and duration of diabetes (R2 = 0.554, P < 0.0001). When intima-medial thickness (IMT) of the femoral and carotid arteries were measured by B-mode ultrasonography, RI values were significantly correlated with both the femoral and carotid arterial IMT. These results demonstrate that intrarenal hemodynamic abnormalities are present in type II DM patients with nephropathy, and that intrarenal hemodynamics are affected by decreased glomerular function and also probably by advanced arteriosclerosis.

Aged↗
PubMed1997

Effect of polymorphism of apolipoprotein E and angiotensin-converting enzyme genes on arterial wall thickness.

We examined the association between the polymorphism of the apolipoprotein E (apoE) and the ACE genes and the intima-media thickness (IMT) of the carotid and femoral arteries measured using ultrasonography. The values of IMT of each artery were significantly higher in NIDDM patients (n = 356) than in control subjects (n = 235). The E4 allele or the D allele did not affect clinical characteristics, including age, fasting plasma glucose, total cholesterol, HDL cholesterol, LDL cholesterol, or blood pressure, in NIDDM or control subjects. No difference in the carotid IMT value was noted among the apoE genotypes in control or diabetic subjects. The carotid IMT was significantly higher in diabetic patients with the DD genotype (1.200 +/- 0.586 mm) than in those with the II genotypes (0.990 +/- 0.364 mm). Neither the E4 allele nor the D allele affected the femoral IMT in control or diabetic subjects. Multiple regression analysis demonstrated that the carotid IMT of NIDDM patients was associated with age, the D allele, and LDL cholesterol but not with the E4 allele, whereas that of control subjects was associated with age, sex, systolic blood pressure, LDL cholesterol, and HDL cholesterol, inversely. These results suggested that the E4 allele was not associated with the carotid or femoral IMTs, but that the D allele was statistically associated with carotid IMT in NIDDM patients but not control subjects. However, since the association was weak (2.3% explanatory power), its biological significance remains to be determined.

Adolescent↗
PubMed1997

[PTH, PTHrP, and CGRP in hypertension research].

Parathyroid hormone (PTH), a key hormone regulating plasma Ca level, is elevated in some essential hypertension, and conversly, hyperparathyroidism is associated with elevated blood pressure. However, such an effect would be paradoxical because PTH is a potent vasodilator. Parathyroid hormone-related peptide (PTHrP), which could act in a autocrine and paracrine manner in vascular smooth muscle cells and endothelial cells, would be a more potent vasodilator and could be produced in hypertensive vascular tissue. Calcitonin gene related peptide (CGRP), 37-amino acid neuropeptide results from alternative processing from calcitonin gene, is vasodilating peptide, and is localized in the central and peripheral nervous system involved in cardiovascular regulation. In some essential hypertensive patients, CGRP is reported to be at a low level.

Animals↗
PubMed1996

Inhibition of peripheral interleukin-1 beta-induced hyperalgesia by the intracerebroventricular administration of diclofenac and alpha-melanocyte-stimulating hormone.

The present study was undertaken to investigate whether or not the endogeneous mechanisms in the brain can modulate the changes in nociception produced by peripherally-administered interleukin-1 beta (IL-1 beta) in rats. We administered diclofenac and alpha-melanocyte-stimulating hormone (alpha-MSH) into the lateral cerebroventricle (LCV) 10 min before the intraperitoneal (i.p.) injection of recombinant human IL-1 beta (rhIL-1 beta, 1 ng/kg-100 ng/kg) and then observed the changes in nociception using a hot-plate test. The i.p. injection of rhIL-1 beta (10 ng/kg and 100 ng/kg) reduced the paw-withdrawal latency without affecting the colonic temperature. The maximal reduction in the paw-withdrawal latency was observed 30 min after the i.p. injection of rhIL-1 beta at 100 ng/kg. The rhIL-1 beta (100 ng/kg)-induced hyperalgesia was inhibited by the LCV injection of both diclofenac (1 ng) and alpha-MSH (100 ng). The LCV injection of either diclofenac (1 ng) or alpha-MSH (100 ng) was found to have no effect on nociception by itself. These findings therefore suggest that the hyperalgesia induced by peripheral IL-1 beta can be modulated by a cyclooxygenase pathway of the arachidonate and alpha-MSH in the brain.

Animals↗
PubMed1996

Angiotensin-converting enzyme gene polymorphism is associated with carotid arterial wall thickness in non-insulin-dependent diabetic patients.

BACKGROUND: The insertion/deletion (I/D) polymorphism of the ACE gene has been shown to be associated with cardiovascular disease in healthy subjects as well as in patients with non-insulin-dependent diabetes mellitus (NIDDM). We investigated the relationship between the ACE gene polymorphism and the wall thickness of both carotid and femoral arteries in NIDDM patients. METHODS AND RESULTS: We measured the intimal plus medial thickness (IMT) of both carotid and femoral arteries using high-resolution B-mode ultrasonography in 288 Japanese NIDDM patients (160 men, 128 women). No significant differences among the three genotypes were found with respect to age, sex, duration of diabetes, body mass index, blood pressure, plasma glucose, hemoglobin AIC, total cholesterol, triglycerides, HDL cholesterol, or cigarette-years. Plasma ACE levels were strongly associated with I/D polymorphism, with an additive effect of the D alleles. The carotid IMT of the patients carrying the D allele (DD+ID genotype) was significantly higher than that of the patients not carrying the D allele (II genotype) (P = .037), whereas the femoral IMT was not affected by the I/D polymorphism. Multiple regression analysis demonstrated that the risk factors for carotid IMT of patients with NIDDM were age, non-HDL cholesterol, and D allele of the ACE gene (R2 = .155, P < .0001). CONCLUSIONS: The D allele of the ACE gene may be a risk factor for the development of wall thickening of the carotid but not the femoral artery in NIDDM patients.

Adolescent↗
PubMed1996

Angiotensin converting enzyme gene polymorphism and renal artery resistance in patients with insulin dependent diabetes mellitus.

The present study was carried out to elucidate whether renal hemodynamic changes are associated with angiotensin converting enzyme (ACE) gene polymorphism in patients with insulin dependent diabetes mellitus (IDDM). We studied 32 Japanese patients with IDDM (aged 15 +/- 3 years in mean +/- SD) without renal failure or retinopathy. Renal hemodynamics were examined by duplex Doppler sonography and arterial resistance index was calculated. ACE genotypes were determined by polymerase chain reaction amplification. Resistance index (RI) of arcuate arteries in IDDM patients with DD genotype was significantly elevated, being 0.64 +/- 0.04, 0.66 +/- 0.05, and 0.71 +/- 0.05 for II, ID and DD genotype groups, respectively (II vs. DD, p < 0.02). In patients with DD genotype with normoalbuminuria (n = 27), it was also significantly elevated in DD genotype patients (II vs. DD, p < 0.02). In addition, multiple regression analysis with a forward elimination procedure showed that only the ACE genotype was associated with RI of arcuate arteries (R2 = 0.24, p < 0.01) among the parameters of sex, age, IDDM duration, body mass index, HbA1c, plasma glucose levels, serum levels of total cholesterol and creatinine, urinary albumin excretion index, mean blood pressure and ACE genotype. The present study demonstrated that renal arterial resistance is elevated in IDDM patients with DD genotype. ACE gene polymorphism which could be linked to intrarenal circulatory disturbance may be associated with the initiation and progression of diabetic nephropathy.

Adolescent↗
PubMed1996

The fumagillin analogue TNP-470 inhibits DNA synthesis of vascular smooth muscle cells stimulated by platelet-derived growth factor and insulin-like growth factor-I. Possible involvement of cyclin-dependent kinase 2.

The effect of an angiogenesis inhibitor, TNP-470, on DNA synthesis and its underlying signaling cascades stimulated by platelet-derived growth factor (PDGF)-BB and insulin-like growth factor (IGF)-I were examined in bovine vascular smooth muscle cells (SMCs). PDGF-BB (10 ng/mL)- and IGF-I (100 ng/mL)-stimulated increase in DNA synthesis was completely abolished by simultaneous treatment with TNP-470 (1.0 ng/mL). TNP-470 had no effects on PDGF receptor autophosphorylation or early signal transduction, such as activation of mitogen-activated protein kinase and immediate early gene expression. PDGF-BB induced an increase in mRNA levels of cyclin D1, cyclin-dependent kinase (cdk) 4, and cdk2, as well as the activity of cdk2, which preceded the G1/S boundary, as estimated by the kinetics of DNA synthesis. The PDGF-BB-induced activation of cdk2 was inhibited by TNP-470, which was correlated with decreased cdk2 mRNA levels. In contrast, TNP-470 had no or less marked effect on cyclin D1 and cdk4 mRNA levels induced by PDGF-BB. TNP-470 also inhibited a much smaller increase in cdk2 mRNA levels and activation stimulated by IGF-I. In conclusion, TNP-470 potently inhibits DNA synthesis of SMCs, and this inhibition is associated with decreased levels of cdk2 mRNA and activity.

Animals↗
PubMed1995

The opposing effects of interleukin -1 beta microinjected into the preoptic hypothalamus and the ventromedial hypothalamus on nociceptive behavior in rats.

The effects of microinjections of recombinant human interleukin-1 beta (rhIL-1 beta) into the hypothalamus and neighboring basal forebrain on nociceptive behavior were studied using a hot-plate test in rats. The microinjection of rhIL-1 beta at doses between 5 pg/kg and 50 pg/kg into the medial part of the preoptic area (MPO) reduced the paw-withdrawal latency. The maximal reduction was obtained 30 min after the injection of rhIL-1 beta at 20 pg/kg. RhIL-1 beta (20 pg/kg)-induced hyperalgesia was completely blocked by the simultaneous injection of IL-1 receptor antagonist (IL-1ra, 20 ng/kg), Na salicylate (200 ng/kg) or alpha-melanocyte-stimulating hormone alpha-MSH, 20 ng/kg). The intra-MPO injection of rhIL-1 beta at doses of less than 5 pg/kg or more than 50 pg/kg (up to 2 ng/kg) into the paraventricular nucleus, the lateral hypothalamic area and the septal nucleus had no effect on nociception. The microinjection rhIL-1 beta (20 pg/kg-50 pg/kg) into the ventromedial hypothalamus produced a prolongation of the paw-withdrawal latency. A maximal prolongation was obtained 10 min after the injection of rhIL-1 beta at 50 pg/kg. This reaction was also blocked by the simultaneous injection of IL-1ra (50 ng/kg) and Na salicylate (500 ng/kg). These findings indicate that IL-1 beta in the MPO and the VMH produces hyperalgesia and analgesia, respectively, while, in addition, both effects are mediated by IL-1 receptors and the synthesis of prostaglandins.

Animals↗
PubMed1995

Intracerebroventricular injection of interleukin-6 induces thermal hyperalgesia in rats.

We assessed the effect of interleukin-6 (IL-6) in the brain on nociception by using the hot-plate test in rats. Recombinant human IL-6 (rhIL-6, 30 pg-300 ng) was microinjected into the lateral cerebroventricle (LCV) and the paw-withdrawal latency was then measured for 60 min after injection. RhIL-6 at 300 pg reduced the paw-withdrawal latency at 15 min after injection. Further increase of rhIL-6 doses to 3, 30 and 300 ng resulted in the decreased paw-withdrawal latency at 15 and 30 min. Although the peak responses observed at 3-300 ng did not differ significantly, the time taken for recovery tended to be longer with increasing doses. The rhIL-6 (30 ng)-induced reduction of the paw-withdrawal latency was completely blocked by the co-injection of either Na salicylate (30 ng, LCV) or alpha-melanocyte stimulating hormone (30 ng, LCV), an anti-cytokine substance. However, it was not affected by the co-injection of IL-1 receptor antagonist (30 ng, LCV) which had been previously shown to be able to block IL-1 beta-induced hyperalgesia. These findings indicate that IL-6 in the brain induces hyperalgesia by its prostanoids-dependent action in rats. The hyperalgesic action of central IL-6 thus does not appear to depend on the action of IL-1.

Animals↗
PubMed1995

Effects of 17 beta-oestradiol and 5 alpha-dihydrotestosterone on the expression of the muscle and heart types of lactate dehydrogenase isozymes in the masseter muscle of developing mice.

17 beta-oestradiol (E2) and/or 5 alpha-dihydrotestosterone (5 alpha-DHT) had no effect on the expression of isozymes of lactate dehydrogenase (LDH) in the masseter muscle of intact male mice. However, treatment with E2 restored the level of the muscle (M) type of LDH isozyme, which had been reduced by testectomy, to that found in intact male mice treated with vehicle only. Moreover, 5 alpha-DHT alone was more effective than E2 in increasing the relative level of this isozyme in testectomized mice. 5 alpha-DHT had a more significant effect on the increase in the relative level of the M-type LDH isozyme when combined with E2. These results suggest that androgens promote, in the presence of oestrogens, the postnatal changes in the characteristics of the masseter muscle of developing male animals.

Animals↗
PubMed1995

Beta-glycerophosphate accelerates calcification in cultured bovine vascular smooth muscle cells.

Calcification is a common feature of advanced atherosclerotic lesions and is being reemphasized as a clinically significant element of vascular disease. However, the scarcity of in vitro models of vascular calcification preclude studying its molecular and cellular mechanism. In the present study, we describe an in vitro calcification in which diffuse calcification can be induced by culturing bovine vascular smooth muscle cells (BVSMC) in the presence of beta-glycerophosphate, ascorbic acid, and insulin in a manner analogous to in vitro mineralization by osteoblasts. Calcification was confirmed by von Kossa staining and 45Ca accumulation. Factor analysis revealed that beta-glycerophosphate is the most important factor for this calcification process, suggesting that alkaline phosphatase (ALP) may be involved. As predicted, high levels of ALP expression were detected by ALP assay and Northern blot analysis. Functional significance of ALP was confirmed by demonstrating that levamisole, a specific inhibitor of ALP, inhibited BVSMC calcification in a dose-dependent manner. Bisphosphonates such as etidronate and pamidronate potently inhibited BVSMC calcification, suggesting that hydroxyapatite formation may be involved. Importantly, expression of osteopontin mRNA was dramatically increased in calcified BVSMC compared with uncalcified control cells. These data suggest that beta-glycerophosphate can induce diffuse calcification by an ALP-dependent mechanism and that this in vitro calcification system is useful for analyzing the molecular and cellular mechanisms of vascular calcification.

Alkaline Phosphatase↗