Biomedical subjects

Junichi Tanaka

Publications and source records attributed to Junichi Tanaka.

At least 37 records · Page 2Linked to original sources

PubMed2003

Trisoxazole macrolide toxins mimic the binding of actin-capping proteins to actin.

Marine macrolide toxins of trisoxazole family target actin with high affinity and specificity and have promising pharmacological properties. We present X-ray structures of actin in complex with two members of this family, kabiramide C and jaspisamide A, at a resolution of 1.45 and 1.6 A, respectively. The structures reveal the absolute stereochemistry of these toxins and demonstrate that their trisoxazole ring interacts with actin subdomain 1 while the aliphatic side chain is inserted into the hydrophobic cavity between actin subdomains 1 and 3. The binding site is essentially the same as the one occupied by the actin-capping domain of the gelsolin superfamily of proteins. The structural evidence suggests that actin filament severing and capping by these toxins is also analogous to that of gelsolin. Consequently, these macrolides may be viewed as small molecule biomimetics of an entire class of actin-binding proteins.

Actins↗

PubMed2003

Drinking decreases the noradrenaline release in the median preoptic area caused by hypovolemia in the rat.

Previous observations have suggested that the noradrenergic system in the median preoptic nucleus (MnPO) is implicated in the regulation of body fluid balance and cardiovascular function. The present study was carried out to investigate whether water intake alters the release of noradrenaline (NA) in the MnPO area caused by hypovolemia in freely moving rats. Nonhypotensive hypovolemia was induced by subcutaneous polyethylene glycol (PEG), and extracellular levels of NA were measured using intracerebral microdialysis techniques. Subcutaneous injections of PEG (30%, 5 ml) significantly enhanced the NA release in the MnPO area. Water ingestion significantly attenuated the elevation in the NA release in the MnPO area induced by the PEG treatment. These results show the involvement of the noradrenergic system in the MnPO in the maintenance of body fluid volume, and suggest that the system may play an important role in the elicitation of hypovolemia-induced dipsogenic response.

Animals↗

PubMed2003

Activation of cholinergic pathways from the septum to the subfornical organ area under hypovolemic condition in rats.

In urethane-anesthetized rats, extracellular concentrations of acetylcholine (ACh) in the region of the subfornical organ (SFO) in response to electrical stimulation of the septum and hypovolemia were monitored with in vivo microdialysis methods. Repetitive electrical stimulation (500 microA, 5-20 Hz) of the medial septum significantly increased dialysate ACh concentrations in the region of the SFO. Non-hypotensive hypovolemia caused by subcutaneous administration of polyethylene glycol (PEG, 30%, 5 ml) elicited significantly increased ACh levels in the region of the SFO. The hypovolemia-induced ACh release was attenuated by microinjection of the local anesthetic lidocaine (2%, 0.2 microl) into the medial septum. These results suggest that septal cholinergic pathways to the SFO area may be activated under the hypovolemic condition.

Acetylcholine↗

PubMed2003

GABAergic modulation of noradrenaline release in the median preoptic nucleus area in the rat.

Microdialysis was employed to investigate whether gamma-aminobutyric acid (GABA) receptor mechanisms are involved in the regulation of noradrenaline (NA) release in the median preoptic nucleus (MnPO) in awake, freely moving rats. Perfusion with the GABA receptor antagonists as well as agonists was performed in the region of the MnPO through a microdialysis probe and dialysate levels of NA were measured. Perfusion with either bicuculline (10 and 50 microM), a GABA(A) receptor antagonist, or phaclofen (10 and 50 microM), a GABA(B) receptor antagonist, enhanced the release of NA in the MnPO area. Higher-dose perfusion with the GABA(A) agonist muscimol (50 microM) or the GABA(B) agonist baclofen (250 microM) decreased dialysate NA in the MnPO area. An iso-osmotic reduction of fluid volume following subcutaneous treatment with polyethylene glycol (PEG, 30%, 5 ml) significantly increased the NA level in the MnPO area. The increased levels of NA caused by the PEG treatment were attenuated by perfusion with muscimol (10 microM), but not by baclofen (50 microM). These results show the participation of both GABA(A) and GABA(B) receptors in the modulation of the release of NA in the MnPO area, and imply that the GABA(A) receptor mechanism may play an important role in the noradrenergic regulatory system of body fluid balance.

Animals↗

PubMed2003

Noradrenaline release in the median preoptic nucleus area caused by hemorrhage in the rat.

The present study was designed to examine whether noradrenergic projections from the A1 cell group in the ventrolateral medulla to the median preoptic nucleus (MnPO) transmit information from the peripheral baroreceptors. In urethane-anesthetized male rats, extracellular concentrations of noradrenaline (NA) in the region of the MnPO in response to hemorrhage (5 or 10 ml/kg) were monitored with in vivo microdialysis methods. Hemorrhage significantly increased the NA release in the MnPO area. The enhancement of NA release in the MnPO area caused by hemorrhage was significantly attenuated by previous injections of the local anesthetic lidocaine (2 %, 0.2 microl), but not by saline (0.2 microl), into the A1 region. These results suggest that the noradrenergic projections from the A1 region are important for carrying the peripheral baroreceptor information to the MnPO.

Anesthetics, Local↗

PubMed2003

Drinking attenuates the noradrenaline release in the lateral hypothalamic area induced by angiotensin II activation of the subfornical organ in rats.

Experiments were conducted to investigate the role of noradrenergic systems in the lateral hypothalamus area (LHA) in the water intake caused by injection of angiotensin II (ANG II) into the subfornical organ (SFO) in rats. Intracerebral microdialysis techniques were utilized to quantify the extracellular content of noradrenaline (NA) in the LHA. Microinjection of ANG II into the SFO significantly increased NA release in the LHA when water was not available for drinking. The increase in the release of NA in the LHA was significantly attenuated by water intake. In urethane-anesthetized rats, injections of ANG II into the SFO significantly enhanced the release of NA in the LHA that accompanied an elevation in mean arterial pressure (MAP). Intravenous administration of the alpha-agonist metaraminol, on the other hand, significantly decreased the NA release in the LHA that accompanied an increase in MAP, suggesting that the enhanced NA release in the LHA caused by ANG II into the SFO may be not mediated by increasing in arterial pressure. These results show the involvement of the noradrenergic systems in the LHA in the dipsogenic response induced by angiotensinergic activation of the SFO.

Adrenergic alpha-Agonists↗

PubMed2003

Reduced dipsogenic response induced by angiotensin II activation of subfornical organ projections to the median preoptic nucleus in estrogen-treated rats.

The present study was carried out to investigate whether estrogen modulates the drinking response induced by activation of angiotensinergic neural pathways from the subfornical organ (SFO) to the median preoptic nucleus (MnPO). Microinjection of angiotensin II (ANG II, 10(-10) M, 0.2 microl) into the SFO elicited drinking in ovariectomized (OVX) female rats that were treated with either propylene glycol (PG) vehicle or estrogen benzoate (EB). The amount of water intake induced by the ANG II injection was significantly greater in the PG-treated than in the EB-treated animals. In both groups of female rats, previous injections of saralasin (Sar, 10(-10) M, 0.2 microl), a specific ANG II antagonist, into the MnPO resulted in the significant attenuation of the drinking response to ANG II, showing that the ANG II-induced drinking response may be mediated in part by the angiotensinergic SFO projections to the MnPO. Injections of ANG II (10(-10) M, 0.2 microl) into the MnPO caused drinking in both groups, while no significant difference was found between the groups in the amount of water intake. These results suggest that increases in the circulating level of estrogen may attenuate the drinking response induced by ANG II activation of the SFO projections to the MnPO.

Angiotensin II↗

PubMed2003

GABAergic modulation of the ANG II-induced drinking response in the rat medial preoptic nucleus.

The present study was designed to examine the participation of gamma-aminobutyric acid (GABA) receptor mechanisms in the medial preoptic nucleus (MPO) in the drinking response caused by angiotensin II (ANG II) activation of the subfornical organ (SFO) in the awake rat. Local administration of ANG II (5 pmol, 50 nl) into the SFO elicited drinking. The water intake induced was significantly attenuated by previous injections (50 nl) into the MPO of the GABA(A) agonist muscimol (0.5, 5 and 50 pmol), but not by the GABA(B) agonist baclofen (0.5, 5 and 50 pmol) or vehicle, into the MPO. On the other hand, the ANG II-induced water intake was significantly enhanced by previous injections (50 nl) into the MPO of the GABA(A) antagonist bicuculline (0.5 and 5 pmol), but not the GABA(B) antagonist phaclofen (0.05, 0.5 and 5 pmol). Muscimol (50 nmol) injected into the MPO significantly reduced the water intake elicited by intracellular fluid depletion (i.e., hypertonic saline: 2 M, 2 ml/kg bw ip), whereas bicuculline (5 pmol) was without effect. These results show the involvement of the GABAergic system within the MPO in the dipsogenic responses induced by ANG II acting at the SFO and intracellular fluid depletion, and suggest that the system may serve to attenuate the ANG II-induced dipsogenic response through GABA(A) receptors.

Angiotensin II↗

PubMed2003

Angiotensin II reduces serotonin release in the rat subfornical organ area.

In the present study we used intracerebral microdialysis techniques to examine whether angiotensin II (ANG II) modulates the release of serotonin (5-hydroxytryptamine, 5-HT) in the subfornical organ (SFO) in freely moving rats. Extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the region of the SFO were significantly decreased by microinjection of ANG II (10 pmol, 50 nl), but not by vehicle, into the dialysis site. No significant changes in the 5-HT and 5-HIAA levels caused by ANG II were observed in the sites away from the SFO. Water ingestion significantly enhanced the amount of the decrease in the 5-HT and 5-HIAA concentrations in the SFO area elicited by the ANG II injection. These results show that ANG II may reduce the release of 5-HT in the SFO area, and imply that the 5-HT receptor mechanism in the SFO area may participate in the elicitation of the drinking behavior to ANG II.

Angiotensin II↗

PubMed2003

PML nuclear bodies and neuronal intranuclear inclusion in polyglutamine diseases.

In polyglutamine diseases, accumulation in the nucleus of mutant proteins induces the formation of neuronal intranuclear inclusions (NIIs). The nucleus is compartmentalized into structural and functional domains, which are involved in NII formation. Promyelocytic leukemia protein (PML), a major component of nuclear bodies, and mSin3A, a component of the transcription co-repressor complex, were used to investigate how the intranuclear domains/sites relate to NII formation in SCA2, SCA3, SCA7, SCA17 and DRPLA brains. We demonstrate that the size of PML-positive intranuclear structures was larger in pathological brains than in control ones and that these structures contained mutant proteins. PML colocalized only with small NIIs, which maintained the ring-like structure of normal nuclear bodies. Enlarged ring-like PML-positive structures, devoid of mutant proteins, were also found and might represent structures where mutant polyglutamine proteins have been successfully processed. These data suggest that NIIs originate from nuclear bodies, where mutant proteins accumulate for degradation.

Adolescent↗

PubMed2003

New cytotoxic furanosesterterpenes from an Okinawan marine sponge, Ircinia sp.

Five new sesterterpenes have been isolated from a lipophilic extract of a sponge, Ircinia sp., and their structures elucidated by spectroscopic and chemical methods. The absolute configurations of two metabolites (1, 3) were established by chemical degradation. These compounds showed moderate cytotoxicity against KB cells.

Animals↗

PubMed2003

Outcomes of hip fracture surgery in patients aged > or = 90 years.

The outcomes of 60 patients aged > or = 90 years with hip fractures who underwent surgery between 1995 and 1998 were reviewed. Average follow-up was 21 months (range: 4-47 months). All patients experienced pain relief within 2 months postoperatively. Thirty-four of 60 patients failed to attain their preinjury ambulatory status. The ability to walk 2 months postoperatively was observed more frequently in patients without severe dementia. Patients who were unable to walk postoperatively had a greater chance of dying than those who regained the ability to walk. No surgery related deaths occurred. Six months postoperatively, 2 (3%) patients had died; 1 year postoperatively, 9 (15%) had died. Therefore, patients aged > or = 90 years benefit from surgical treatment of hip fractures.

Aged↗

PubMed2003

[A case of multiple superficial esophageal cancers with liver cirrhosis successfully treated by radiotherapy].

We report a case of multiple superficial esophageal cancers with liver cirrhosis successfully treated by radiotherapy. The patient was a 55-year-old man with liver cirrhosis who was under the treatment of internists at our hospital. Upper digestive tract endoscopic examination revealed multiple superficial esophageal cancers. We performed radiotherapy because pancytopenia was found in his peripheral blood data. The treatment was started on a outpatient basis, but the patient was hospitalized after sixteen treatments were finished because of hematemesis. Total irradiation was 66 Gy, and complete reduction was obtained. Eight months after the treatment, the patient shows no signs of recurrence. These results suggest that radiotherapy is an effective treatment for multiple superficial esophageal cancer.

Carcinoma, Squamous Cell↗

PubMed2002

The action of the A1 noradrenergic region on the activity of subfornical organ neurons in the rat.

Electrical stimulation of the A1 noradrenergic region of the ventrolateral medulla produced synatic excitation (n = 19, 9%), inhibition (n = 5, 2%) or no effect (n = 184, 89%) in the activity of a total of 208 neurons in the subfornical organ (SFO) in male rats under urethane anesthesia. Almost all (n = 18) of the excitatory responses (n = 19) were blocked by microiontophoretically-applied phentolamine, an alpha-adrenergic antagonist, but not by timolol, a beta-adrenergic antagonist. The inhibitory response of all the neurons (n = 5) tested was prevented by iontophoretically applied timolol, but not by phentolamine. Approximately a half (n = 9) of SFO neurons that demonstrated the excitatory response to A1 region stimulation exhibited an increase in neuronal activity in response to hemorrhage (10 ml/kg b.w.t.), while remaining neurons (n = 10) were unresponsive. Hemorrhage did not cause any change in the activity of all the neurons (n = 5) that demonstrated the inhibitory response to A1 region stimulation. These results suggest that the medullary inputs to approximately 10% of SFO neurons tested are mediated by alpha-adrenergic excitatory and beta-adrenergic inhibitory pathways, and imply that a part of the excitatory pathways may transmit the peripheral baroreceptor information.

Animals↗

PubMed2002

GABAergic systems in the nucleus tractus solitarius regulate noradrenaline release in the subfornical organ area in the rat.

Previous studies have shown that catecholaminergic neurons in the nucleus tractus solitarius (NTS) with ascending projections to the subfornical organ (SFO) are highly sensitive to gamma-aminobutyric acid (GABA). To clarify the role of the GABAergic system in the NTS in the regulation of the activity of noradrenergic NTS projections to the SFO, the present study was carried out to investigate the effects of local administration (50 nl) of GABA, the GABA(A) agonist muscimol, the GABA(B) agonist baclofen, the GABA(A) antagonist bicuculline or the GABA(B) antagonist phaclofen into the NTS on the release of noradrenaline (NA) in the region of the SFO using microdialysis techniques in rats under urethane anesthesia. Microinjections of GABA (10(-4) - 10(-2) M) into the region of the NTS significantly decreased the NA release in the SFO area. Injections of either muscimol (10(-4) - 10(-2) M) or baclofen (10(-5) - 10(-3) M) into the NTS region significantly attenuated the NA release in the SFO area. Injections of bicuculline (10(-5) and 10(-4) M), but not phaclophen (10(-6) - 10(-4) M), into the NTS region significantly enhanced the NA release in the SFO area, suggesting that the GABAergic system in the NTS may tonically inhibit the NA release in the SFO area through a GABA(A) receptor mechanism. Neither injection of these drugs in any of the doses used in this study into the NTS region caused any significant changes in the NA release in the sites away from the SFO. Injections of vehicle (50 nl) into the NTS region had no significant effect on the NA release in either the SFO area or the sites away from the SFO. These results suggest that the GABAergic system in the NTS may serve to decrease the release of NA in the SFO area and the two types of GABA receptors are involved in the modulation of the NA release.

Analysis of Variance↗

PubMed2002

Influences of intranuclear inclusion on nuclear size - morphometric study on pontine neurons of neuronal intranuclear inclusion disease cases.

In looking for a possible influence of nuclear inclusions (NIs) on neurodegeneration in human brains, we quantified morphological features of pontine neurons of three unrelated cases of neuronal intranuclear inclusion disease (NIID) and five control cases. Cross-sectional area of each neuronal nucleus and the indices for its deformity (long axis/short axis and circularity index defined as deviation from the perfect circle) were measured on pontine sections and their relation to NIs was statistically analyzed. Cross-sectional area of neuronal nuclei harboring ubiquitin-immunopositive NIs was significantly larger (110.6+/-1.6 micro m(2), mean +/- SE), while that of nuclei not harboring NIs was smaller (77.8+/-1.5 micro m(2)) than that in controls (90.5+/-0.7 micro m(2)). This difference remained significant even when the cross-sectional area occupied by NIs was subtracted from that of the nucleus harboring the NI (97.4+/-1.5 micro m(2)). This could hardly be explained if nuclear shrinkage is accelerated in the presence of NI. On the contrary, NI formation in pontine neurons of NIID might be linked, either directly or indirectly, to a mechanism, which counteracts rather than accelerates nuclear shrinkage. Because nuclear deformity was apparent even in neurons with NIs, whose nuclei were significantly larger than controls, the nuclear deformity is not secondary to its shrinkage and represents another aspect of neurodegeneration independent of nuclear shrinkage. Association of NIs to neurons of larger nuclear size in NIID brain indicates that NIs are not necessarily toxic to neurons.

Adult↗

PubMed2002

Decreased monoamine release in the median preoptic area following ventricular treatment with the angiotensin II antagonist saralasin in normotensive and spontaneously hypertensive rats.

Previous findings have shown that some of the neurons in the median preoptic nucleus (MnPO) receive both catecholaminergic inputs from the brainstem and angiotensinergic inputs from the subfornical organ (SFO), and that alterations in the function of the brain renin-ANG system are implicated in hypertension, especially in spontaneous hypertensive rats (SHR). In an attempt to clarify the action of these inputs on MnPO neurons and to find the difference in the action between normotensive Wistar-Kyoto (WKY) rats and SHR, we used microdialysis to investigate the effects of injections of saralasin (Sar), an angiotensin II (ANG II) antagonist, into the third ventricle (3V) on monoamine release in the MnPO area of awake WKY and SHR. The content of noradrenaline (NA) in the MnPO area was significantly higher in SHR. No significant differences were observed between WKY and SHR in the concentrations of dopamine (DA) and of its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). In both WKY and SHR, Sar (Sar, 5 microg in 1 microl, three injections at 2-h intervals) injected into the 3V significantly decreased the extracellular concentrations of NA, DOPAC and HVA in the MnPO area. The decreases were much greater in SHR than in WKY rats. Similar injections of saline vehicle had no significant effect on the extracellular levels of NA, DA and the metabolites. These results suggest that central angiotensinergic circuits may serve to increase NA and DA release in the MnPO area, and support that a disorder in the ANG system may contribute, in part, to the elevated blood pressure of SHR.

Angiotensin II↗

PubMed2002

Attenuated drinking response induced by angiotensinergic activation of subfornical organ projections to the paraventricular nucleus in estrogen-treated rats.

The present study was carried out to examine whether estrogen modulates the drinking response caused by activation of neural pathways from the subfornical organ (SFO) to the hypothalamic paraventricular nucleus (PVN) in the female rat. Microinjection of angiotensin II (ANG II) into the SFO elicited drinking in ovariectomized female rats that were treated with either propylene glycol (PG) vehicle or estradiol benzoate (EB). The amount of water intake induced by the ANG II injection was significantly greater in the PG-treated than in the EB-treated animals. In both groups, previous injections of either saralasin, an ANG II antagonist, or phentolamine, an alpha-adrenoceptor antagonist, bilaterally into the PVN resulted in the significant attenuation of the drinking response to ANG II, whereas similar injections of saline vehicle into the PVN were without effect. These results suggest that the circulating estrogen may act to reduce the drinking response that is mediated through angiotensinergic and alpha-adrenergic mechanisms in the PVN in response to angiotensinergic activation of SFO efferent projections.

Angiotensins↗