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Biomedical subjects

S Sakurada

Publications and source records attributed to S Sakurada.

At least 55 records · Page 3Linked to original sources
PubMed1999

Inhibition of IL-6 and IL-8 induction from cultured rheumatoid synovial fibroblasts by treatment with aurothioglucose.

Gold compounds have long been used in the treatment of rheumatoid arthritis (RA). However, their actions in RA have not been clarified. In this study, we examined the effect of one of the monovalent gold compounds, aurothioglucose (AuTG), on the IL-1-induced production of IL-6, IL-8 and granulocyte macrophage colony stimulating factor (GM-CSF) from rheumatoid synovial fibroblasts (RSF) isolated from three RA patients. IL-6 and IL-8 induction but not GM-CSF induction was inhibited in most of the RSF after pretreatment with AuTG. Since gene expression of these cytokines is known to be under the control of a common transcription factor, NF-kappaB, the effect of AuTG on the cellular localization of NF-kappaB (p65 subunit) and on NF-kappaB-DNA binding was examined. Although AuTG treatment did not prevent NF-kappaB nuclear translocation, AuTG blocked the DNA-binding activity of NF-kappaB when examined in vitro. Morphologically, both metal-specific cell staining using p-dimethylaminobenzylidene rhodamine and transmission electron microscopic examinations demonstrated the accumulation of metal gold in the cytoplama and some organella (mitochondria and lysosomes) of the AuTG-treated RSF. These results indicate that one of the anti-rheumatic actions of AuTG might be through its inhibitory action on NF-kappaB.

Antirheumatic Agents↗
PubMed1999

Core temperature and sweating onset in humans acclimated to heat given at a fixed daily time.

The thermoregulatory functions of rats acclimated to heat given daily at a fixed time are altered, especially during the period in which they were previously exposed to heat. In this study, we investigated the existence of similar phenomena in humans. Volunteers were exposed to an ambient temperature (Ta) of 46 degrees C and a relative humidity of 20% for 4 h (1400-1800) for 9-10 consecutive days. In the first experiment, the rectal temperatures (Tre) of six subjects were measured over 24 h at a Ta of 27 degrees C with and without heat acclimation. Heat acclimation significantly lowered Tre only between 1400 and 1800. In the second experiment, six subjects rested in a chair at a Ta of 28 degrees C and a relative humidity of 40% with both legs immersed in warm water (42 degrees C) for 30 min. The Tre and sweating rates at the forearm and chest were measured. Measurements were made in the morning (0900-1100) and afternoon (1500-1700) on the same day before and after heat acclimation. Heat acclimation shortened the sweating latency and decreased the threshold Tre for sweating. However, these changes were significant only in the afternoon. The results suggest that repeated heat exposure in humans, limited to a fixed time daily, alters the core temperature level and thermoregulatory function, especially during the period in which the subjects had previously been exposed to heat.

Acclimatization↗
PubMed1999

Thermoregulatory responses to acute heat loads in rats following spontaneous running.

Earlier studies showed that spontaneous exercise training in rodents shifted their core temperature and thermoeffector thresholds to high levels. The present study investigated heat loss and heat production responses to acute heat loads of exercise-trained rats. The exercise-trained rats were allowed to run in a running wheel freely for 6 months, while the sedentary controls were denied access to the wheel during the same period. Then, they were loosely restrained and put in a direct calorimeter. After thermal equilibrium had been attained, they were warmed for 30 min with an intraperitoneal electric heater (internal heating). At least 2 h later, the rats were externally warmed for 90 min by raising the ambient temperature from 24 to 38C (external warming). Hypothalamic temperature (Thy), evaporative and nonevaporative heat loss (R+C+K) and heat production were measured. Internal and external heating significantly increased Thy. During internal heating, the magnitude of the increase in Thy was significantly smaller and the amount of increase in (R+C+K) was significantly greater in the exercise-trained rats than in the controls. The slope showing the relationship between Thy and (R+C+K) in the trained rats was significantly steeper than that in the controls. During external warming, the magnitude of increase in Thy of the exercise-trained rats was significantly greater than that of the controls. The slope showing the relationship between Thy and (R+C+K) in the trained rats was not different from that in the controls. Changes in evaporative heat loss and heat production during the two types of heat load did not differ between the two groups. The results suggest that, in rats, exercise training with voluntary running improves heat tolerance through enhancing nonevaporative heat loss response. However, this may be the case only when the rats are subjected to a direct internal heat load.

Animals↗
PubMed1999

Effects of forced walking stress on formalin-induced paw licking in mice.

This study examined the effects of exposing mice to forced walking stress on formalin-induced paw licking. At each observation period (0.5-6 h) after exposure to forced walking stress, a significant antinociceptive effect (stress-induced analgesia, SIA) was observed only in the second phase (from 10 to 30 min), but not in the first phase (from 0 to 10 min) of formalin-induced paw licking in mice. The present data showed that SIA induced by exposure to forced walking stress was dependent on duration of the stress (0.5-4 h). SIA was dose-dependently antagonized by the NMDA receptor antagonist dizocilipine (0.01-0.04 mg/kg) but not by naloxone (10 mg/kg). Thus, the present results suggest that exposure to forced walking stress could cause SIA which may be involved in the nonopioid system via NMDA receptors.

Analgesia↗
PubMed1999

Changes in beta-endorphin and stress-induced analgesia in mice after exposure to forced walking stress.

In this study, we attempted to clarify the correlation between changes in the level of beta-endorphin (beta-EP) in the mouse brain and the stress-induced analgesia (SIA) after exposing animals to forced walking stress. The immunohistochemical distribution of beta-EP after stress was first analyzed quantitatively in mice and then more specifically using a microphotometry system with results showing that the fluorescence intensity of beta-EP in the peri-aqueductal gray matter (PAG) and arcuate nucleus of the medial basal hypothalamus (ARC) was increased 6 h after exposure to forced walking stress. Further, SIA was examined after exposing animals to the forced walking stress and the formalin test. At 6 h after forced walking stress, significant SIA was observed in the second phase (from 10 to 30 min after formalin injection) of the formalin-induced paw licking behavior, but not in the first phase (from 0 to 10 min after formalin injection). This SIA was antagonized by beta-EP-(1-27), an opioid epsilon receptor antagonist. In nonstressed mice, the injection of beta-EP produced a reduction in formalin-induced paw-licking in the second phase. A significant antinociceptive effect by beta-EP was well antagonized by beta-EP-(1-27). Thus, the present results suggest that the increase in beta-EP levels in PAG and/or ARC may be involved in SIA after exposure of mice to the forced walking stress.

Analgesia↗
PubMed1998

Molecular analysis of constitutive IL-1alpha gene expression in human melanoma cells: autocrine stimulation through NF-kappaB activation by endogenous IL-1alpha.

Constitutive production of/and acquired resistance to anti-proliferative cytokines are implicated in pathogenesis and progression of human melanoma cells. Human melanoma cells A375-C6 are sensitive to interleukin 1 (IL-1) anti-proliferative effect and do not produce IL-1. After long period of culture we have obtained cells which acquired resistance to IL-1. The resistant cells exhibited constitutive production of IL-1α. To analyse the mechanisms that lead to the expression of IL-1α in the cells, we transfected of the resistant clone A375-R8 with CAT (chloramphenicol acetyltransferase) expression plasmids linked to a 5'-flanking deletion mutants of the human IL-1α gene. Two nucleotide regions (--103 to --70 bp) and (--70 to --47 bp) from the start of the first exon appeared to contain a positive regulatory element(s) while the one --421 to --103 bp contained a negative regulatory element(s).The --103 to --70 bp region contained the consensus NF(-k)B (nuclear factor-kB) binding motif.(Immunofluorescence analysis revealed that NF-kB is activated in A375-R8 cells. IL-1 receptor antagonist (IL-1Ra) decreased the level of IL-1α mRNA and production of IL-1α. IL-1Ra also inhibited the localization of p65 in the nuclei and CAT activity in transfectants with the plasmids containing NF-kB binding motif. These results indicate that endogenous IL-1α stimulates the gene expression and production of IL-1α in an autocrine manner through activation of NF-kB.

Autocrine Communication↗
PubMed1998

Parallel stimulations of in vitro and in situ [35S]GTPgammaS binding by endomorphin 1 and DAMGO in mouse brains.

Metabotropic activities of endomorphin 1, a candidate for endogenous mu-opioid receptor ligands, were examined in comparison with the actions of [D-Ala2, N-Me-Phe4, Gly5ol]-enkephalin/DAMGO, a well-known synthetic mu-opioid agonist. Endomorphin 1 stimulated [35S]GTPgammaS binding to synaptic membranes from the mouse amygdala in a naloxone-reversible manner. DAMGO had the same effect in such preparations. In in situ [35S]GTP-gammaS binding experiments using brain sections, both endomorphin 1 and DAMGO similarly stimulated this binding in specific cellular locations throughout the brain regions. These findings strongly support the view that endomorphin 1 selectively acts on a mu-opioid receptor.

Amygdala↗
PubMed1998

Fluorescent microspheres are superior to radioactive microspheres in chronic blood flow measurements.

The accuracy of the fluorescent (FM) and radioactive microsphere (RM) techniques is similar in acute experiments but has not been established in chronic experiments. In the present study various combinations (at least pairs) of FM and/or RM labels were injected simultaneously between 2 mo and 5 min before each animal was killed. Blood flow was determined in many organs. Intramethod mean difference and variation did not change over time for FM but increased significantly for RM (from 1.8 +/- 1.4 to 25.6 +/- 21.8% and from 4.4 +/- 3.2 to 32.4 +/- 23.0% at 5 min and 2 mo, respectively). Also the FM-RM intermethod mean difference and variation increased (from -0.5 +/- 8.5 to 40.8 +/- 23.8% and from 23. 6 +/- 4.6 to 71.8 +/- 34.3%, respectively). After 2 mo, blood flow estimations were 20-50% lower with the various RM, whereas brain and liver blood flow values varied even more between isotopes. Underestimation started within 1 day for 51Cr and within 2 wk for 141Ce, 95Nb, and 85Sr. We conclude that FM are superior to RM for blood flow determination in experiments lasting longer than 1 day, presumably because of leaching of isotopes from RM.

Animals↗
PubMed1998

Thermoeffector thresholds and preferred ambient temperatures of the FOK rat.

The FOK is an inbred rat strain with a genotypic adaptation to hot environments. The present study compared the thermoeffector thresholds and preferred ambient temperatures (Tpref) of the FOK rat with those of other rat strains. Male FOK, WKAH, and Donryu rats were used. First, they were loosely restrained and placed individually in a metabolic chamber with an ambient temperature of 26.0 degrees C. Their hypothalamic temperature (T(hy)), tail skin temperature (Tsk), and heat production (M) were measured. After thermal equilibrium had been attained, the rats were gradually warmed and then cooled using an intravenous thermode. The threshold T(hy) values for tail skin vasodilation and cold-induced thermogenesis were defined as the points at which sharp increases in Tsk and M occurred, respectively. The two thresholds of the FOK rat were lower than those of the WKAH and Donryu rats. In a second set of experiments, the FOK and WKAH rats were placed individually in a thermocline. Their intra-abdominal temperatures (T(ab)) were measured by a biotelemetry system, and the rats' Tpref values were estimated with the thermal gradient. Mean T(ab) and Tpref over a 24-h period for the FOK rat were significantly lower than those of the WKAH rat. The results suggest that in the FOK rat the control ranges of autonomic and behavioral thermoregulation are lower than those of the other rat strains examined. This contributes to the maintenance of core temperature at low levels.

Animals↗
PubMed1998

A role for gastrointestinal endotoxins in enhancement of heat tolerance by physical fitness.

To further elucidate mechanisms underlying the higher heat tolerance of physically fit compared with sedentary people, we have investigated the possibility that endotoxins (of gastrointestinal origin) act, as in the normal development of fever, to raise body temperature and therefore reduce heat tolerance. In an initial series of experiments, five physically fit and four sedentary sheep were exposed twice at rest to an environment of 42/35 degrees C (dry/wet bulb temperature). When animals were given normal saline i.v., rectal temperature (Tre) rose at a significantly higher rate in sedentary than in fit animals; this confirms that heat tolerance is improved by physical fitness. Treatment with i.v. indomethacin did not affect the rate of rise of Tre in fit animals. In sedentary animals, however, Tre was lowered to approximate that of fit animals. Because indomethacin blocks prostaglandin pathways involved in endotoxin-induced fever, the indomethacin-induced improvement of heat tolerance of sedentary but not fit animals supports the contention that endotoxins play a role in determining that difference in heat tolerance. In a second series of experiments, quantitative cardiovascular measurements were made by using radioactive microspheres. Under normothermic conditions, blood flows in the brain, ileum, and diaphragm were higher in fit than in sedentary animals. During hyperthermia up to Tre of 42 degrees C (in a 42/39 degrees C environment), fit compared with sedentary animals exhibited 1) a greater increase in cardiac output, 2) an increase in blood flow through arteriovenous anastomoses to higher and better maintained levels, 3) less reduction in blood flow to the ileum, and 4) greater increase in blood flows to the myocardium, turbinates, nasal mucosa, and respiratory muscles. Endotoxins are likely to come from the gut lumen, because reduction of gut blood flow forms part of the normal response to heat stress. We suggest that improvement of heat tolerance by physical fitness is caused by a greater cardiovascular capacity that permits not only greater perfusion of heat-loss tissues but the maintenance of a better gastrointestinal tract blood supply, thereby better maintaining the normal barrier to movement of endotoxins from gut lumen to plasma. Sedentary people, with their lower cardiovascular capacity, redistribute more blood flow away from the gut during environmentally induced hyperthermia, thus allowing endotoxin-induced fever to aggravate hyperthermia.

Animals↗
PubMed1998

Comparison of opioid activity between a N-terminal tetrapeptide analogue of dermorphin, H-Tyr-D-Arg-Phe-beta-Ala-OH and morphine.

The antinociceptive properties of dermorphin tetrapeptide analog, H-Tyr-D-Arg-Phe-beta-Ala-OH (TDAPA) were compared with morphine in mice. In the tail-pressure test, subcutaneously (s.c.) injected TDAPA and morphine produced significant antinociceptive activity. Pretreatment with naloxonazine (35 mg/kg, s.c., 24 h before testing) significantly antagonized the activity induced by TDAPA, but not morphine. The ED50 values of TDAPA changed from 0.39 mg/kg to 1.7 mg/kg by naloxonazine pretreatment In the formalin test, both TDAPA and morphine exhibited dose-related antinociceptive activity with ED50 values of 0.49 mg/kg and 2.5 mg/kg, respectively. Both drug activities were significantly antagonized by naloxonazine. These results indicate different mechanisms of action for TDAPA and morphine, suggesting TDAPA is highly selective for the mu 1-opioid receptor and may be clinically useful.

Analgesics, Opioid↗
PubMed1998

Changes in core temperature and thermoeffector thresholds in exercise-trained rats.

Spontaneous running in a running wheel has emerged as an alternative method of exercise in small animals. The present study investigated how exercise training with a running wheel affects core temperature level and thermoeffector thresholds in rats. Female rats were allowed to run freely in the wheel for 6 months. Sedentary controls did not exercise during the same period. After the exercise training period, they were loosely restrained and their threshold core temperatures for tail skin vasodilation and cold-induced thermogenesis were determined by warming or cooling the animals by use of a chronically implanted intravenous thermode. Resting and threshold core temperatures of the exercise-trained rats were higher than those of the sedentary controls. The results suggest that in rat, exercise training with a running wheel shifts threshold temperatures for heat loss and heat production to high levels, which may result in a rise in core temperature level.

Animals↗
PubMed1998

Comparison of effect of [D-Arg2,Sar4]-dermorphin (1-4) and morphine on mouse small intestinal transit and electrically evoked contraction of guinea pig ileum.

[D-Arg2,Sar4]-dermorphin (1-4) [DAS-DER (1-4)] was compared with morphine for the capacity to affect mouse gastrointestinal transit and electrically evoked contractions of the guinea pig ileum (GPI). A single subcutaneous injection with DAS-DER (1-4) and morphine dose-dependently inhibited gastrointestinal transit of charcoal in mice. DAS-DER (1-4) with ID50 of 0.053 mg/kg was 26 times more potent than morphine with ID50 of 1.38 mg/kg. The inhibitory effects of DAS-DER (1-4) and morphine were completely inhibited by pretreatment with 1 mg/kg naloxone, an opioid receptor antagonist. The GPI contraction was inhibited by DAS-DER (1-4) with an IC50 of 6.9 +/- 0.7 nM and morphine with an IC50 of 295.0 +/- 11.8 nM, respectively. These effects were also inhibited by preincubation with naloxone. Repeated subcutaneous injections of DAS-DER (1-4) and morphine to guinea pigs produced tolerance to the inhibitory effect on electrically evoked contractions of GPI. Moreover, a marked cross tolerance was seen in guinea pigs made tolerant to DAS-DER (1-4) or morphine. The present study indicates that pharmacological profiles of DAS-DER (1-4) as assayed by the gastrointestinal transit and stimulated contractions of the GPI were almost similar to that of morphine.

Analgesics, Opioid↗
PubMed1997

Endotoxin shock-associated hypothermia. How and why does it occur?

In sum, our results indicate that LPS shock-associated hypothermia involves the following major mechanisms: 1) a decrease in the threshold Tb for activation of cold thermogenesis; 2) the resultant widening of the interthreshold zone; and 3) cold-seeking behavior. We speculate that, in severe systemic inflammation, this hypothermia constitutes an adaptive response.

Animals↗
PubMed1997

Body core temperature of rats subjected to daily exercise limited to a fixed time.

Several timed daily environmental cues alter the pattern of nycthemeral variations in body core temperature in rodents. The present study investigated the effect of timed exercise on variations of daily body core temperature. Male rats were housed in cages with a running wheel at an ambient temperature of 24 degrees C with a 12:12 h light/dark cycle. Timed daily exercise rats (TEX) were allowed access to the wheel for 6 h in the last half of the dark phase, freely exercising rats (FEX) could run at any time, and sedentary rats (NEX) were not allowed to run. After a 3-week exercise period, all animals were denied access to the wheel. The intraabdominal temperatures (Tab) and spontaneous activities of rats were measured for 6 days after the exercise period. The Tab values of the TEX rats were significantly higher than those of the other two groups only in the last half of the dark phase, while Tab in the FEX and NEX rats showed no significant difference. The specific Tab changes in the TEX rats lasted for 2 days after the exercise period. Spontaneous activity levels were higher in the TEX rats than the FEX and NEX rats in the last half of the dark phase for 1 day after the exercise period. The results suggest that daily exercised limited to a fixed time per day modifies nycthemeral variations of body core temperature in rats so that the temperature increases during the period when the animals had previously exercised. Such a rise in body core temperature is partly attributed to an increase in the spontaneous activity level.

Animals↗