INCS suppresses H1R gene expression

The purpose of this study is to examine the effect of intranasal corticosteroid (INCS) administration on histamine H1 receptor (H1R) gene expression in the nasal mucosa of healthy participants and the effects of dexamethasone on basal and histamine-induced H1R mRNA expression, and histamine-induced phosphorylation of extracellular signal-regulated kinase (ERK) in HeLa cells. Sixteen healthy participants were given INCS once daily for a week. After pretreatment of dexamethasone, HeLa cells were treated with histamine. Levels of H1R mRNA and phosphorylation of ERK were measured using real time PCR and immunoblot analysis, respectively. Levels of H1R mRNA in the nasal mucosa of healthy participants receiving INCS was significantly decreased. Dexamethasone suppressed basal levels of H1R mRNA, and histamine-induced up-regulation of H1R mRNA and ERK phosphorylation in HeLa cells. These data suggested that corticosteroid inhibited both basal transcription and histamine-induced transcriptional activation of H1R through its suppression of ERK phosphorylation in the signaling pathway involved in H1R gene transcription. It is further suggested that pre-seasonal prophylactic administration of INCS suppresses both basal and pollen-induced upregulation of H1R gene expression in the nasal mucosa of patients with pollinosis, leading to prevention of the exacerbation of nasal symptoms during peak pollen season

Super-responder to pirfenidone therapy in IPF

Background : Pirfenidone (PFD), an anti-fibrosis drug for idiopathic pulmonary fibrosis (IPF), suppresses disease progression and delays decline of forced vital capacity. However, this drug rarely makes marked improvement of pulmonary function, chest high-resolution computed tomography (HRCT) findings and hypoxia. Case presentation : A 59 year-old-man, who was a former smoker and had a history of alcoholic liver cirrhosis, developed exertional dyspnea and was referred to our hospital. HRCT showed honeycomb changes with surrounding ground-glass opacity (GGO) in a predominantly basal and subpleural distribution. He was diagnosed with IPF and the treatment with PFD was started. At 16 months after the start of treatment, the predicted forced vital capacity value markedly improved from 82.9% to 98.6%. His resting-state partial pressure of arterial oxygen while breathing room air increased from a minimum of 54.7 mmHg (at 2 months treatment) to 72.5 mmHg. The GGO observed at diagnosis disappeared in HRCT. But after 32 months of treatment, his general condition got worse gradually, and he died from chronic progression of IPF after 48 months of treatment. Conclusion : Our case suggests that a complication of chronic liver disease and the existence of GGO may be characteristics of super-responder to PFD treatment for IPF patients

Cytotoxic actions of 2,2-dibromo-3-nitrilopropionamide, a biocide in hydraulic fracturing fluids, on rat thymocytes

2,2-Dibromo-3-nitrilopropionamide (DBNPA) is a major biocide in hydraulic fracturing fluids. Most biocides in fracturing fluids are considered to have low acute toxicity to mammals, but little information is available in the literature regarding the toxic actions of DBNPA on mammalian cells. This information is important to suggest the DBNPA toxicity on wild mammals. In this study, the effects of DBNPA on rat thymocytes were studied using flow cytometric techniques in order to further characterize the cytotoxicity of DBNPA for its safe use. DBNPA at 3-7.5 μM produced a steep concentration-dependent increase in cell lethality. At 5 μM, DBNPA significantly depolarized membranes with disturbance of asymmetrical distribution of membrane phospholipids. The lethal effect of DBNPA was completely abolished under cold conditions, and was augmented in the presence of ethanol. It is suggested that the lethal action of DBNPA is linked to changes in membrane fluidity. Because the concentration-dependent change of DBNPA-induced lethal action was very steep under in vitro conditions, the adverse actions of DBNPA on wild mammals are concerning, even though such reports have not yet surfaced

Effects of Oral Glucosamine Hydrochloride Administration on Plasma Free Amino Acid Concentrations in Dogs

We examined the effects of oral glucosamine hydrochloride (GlcN), N-acetyl-d-glucosamine (GlcNAc) and d-glucose (Glc) administration on plasma total free amino acid (PFAA) concentrations in dogs. The PFAA concentrations increased in the control group and the GlcNAc group at one hour after feeding, and each amino acid concentration increased. On the other hand, in the GlcN group and the Glc group PFAA concentrations decreased at one hour after feeding. A significant decrease in amino acid concentration was observed for glutamate, glycine and alanine. Our results suggest the existence of differences in PFAA dynamics after oral administration of GlcN and GlcNAc in dogs

Efficacy of a Novel Narrow Knife with Water Jet Function for Colorectal Endoscopic Submucosal Dissection

Backgrounds. With respect to the knife’s design in colorectal endoscopic submucosal dissection (ESD), diameter, water jet function, and electric power are important because these relate to efficient dissection. In this study, we analyzed a novel, narrow ball tip-typed ESD knife with water jet function (Flush knife BT-S, diameter: 2.2 mm, length: 2000 mm, Fujifilm Co., Tokyo, Japan) compared to a regular diameter knife (Flush knife BT, diameter: 2.6 mm, length: 1800 mm). Methods. In laboratory and clinical research, electric power, knife insertion time, vacuum/suction amount with knife in the endoscopic channel, and water jet function were analyzed. We used a knife 2.0 mm long for BT-S and BT knives. Results. The BT-S showed faster mean knife insertion time (sec) and better vacuum amount (ml/min) compared to the BT (insertion time: 16.7 versus 21.6, p<0.001, vacuum amount: 38.0 versus 14.0, p<0.01). Additionally, the water jet function of the BT-S was not inferior. In 39 colorectal ESD cases in two institutions, there were mean 4.7 times (range: 1–28) of knife insertion. Suction under knife happened 59% (23/39) and suction of fluid could be done in 100%. Conclusions. Our study showed that the narrow knife allows significantly faster knife insertion, better vacuum function, and effective clinical results

High-intensity interval training using electrical stimulation ameliorates muscle fatigue in chronic kidney disease-related cachexia by restoring mitochondrial respiratory dysfunction

BackgroundExercise, especially high-intensity interval training (HIIT), can increase mitochondrial respiratory capacity and enhance muscular endurance, but its systemic burden makes it difficult to safely and continuously prescribe for patients with chronic kidney disease (CKD)-related cachexia who are in poor general condition. In this study, we examined whether HIIT using electrical stimulation (ES), which does not require whole-body exercise, improves muscle endurance in the skeletal muscle of 5/6 nephrectomized rats, a widely used animal model for CKD-related cachexia.MethodsMale Wistar rats (10 weeks old) were randomly assigned to a group of sham-operated (Sham) rats and a group of 5/6 nephrectomy (Nx) rats. HIIT was performed on plantar flexor muscles in vivo with supramaximal ES every other day for 4 weeks to assess muscle endurance, myosin heavy-chain isoforms, and mitochondrial respiratory function in Nx rats. A single session was also performed to identify upstream signaling pathways altered by HIIT using ES.ResultsIn the non-trained plantar flexor muscles from Nx rats, the muscle endurance was significantly lower than that in plantar flexor muscles from Sham rats. The proportion of myosin heavy chain IIa/x, mitochondrial content, mitochondrial respiratory capacity, and formation of mitochondrial respiratory supercomplexes in the plantaris muscle were also significantly decreased in the non-trained plantar flexor muscles from Nx rats than compared to those in plantar flexor muscles from Sham rats. Treatment with HIIT using ES for Nx rats significantly improved these molecular and functional changes to the same degrees as those in Sham rats. Furthermore, a single session of HIIT with ES significantly increased the phosphorylation levels of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK), pathways that are essential for mitochondrial activation signaling by exercise, in the plantar muscles of both Nx and Sham rats.ConclusionThe findings suggest that HIIT using ES ameliorates muscle fatigue in Nx rats via restoration of mitochondrial respiratory dysfunction with activation of AMPK and p38 MAPK signaling. Our ES-based HIIT protocol can be performed without placing a burden on the whole body and be a promising intervention that is implemented even in conditions of reduced general performance status such as CKD-related cachexia

Kihi-to, a herbal traditional medicine, improves Abeta(25–35)-induced memory impairment and losses of neurites and synapses

<p>Abstract</p> <p>Background</p> <p>We previously hypothesized that achievement of recovery of brain function after the injury requires the reconstruction of neuronal networks, including neurite regeneration and synapse reformation. Kihi-to is composed of twelve crude drugs, some of which have already been shown to possess neurite extension properties in our previous studies. The effect of Kihi-to on memory deficit has not been examined. Thus, the goal of the present study is to determine the <it>in vivo </it>and <it>in vitro </it>effects of Kihi-to on memory, neurite growth and synapse reconstruction.</p> <p>Methods</p> <p>Effects of Kihi-to, a traditional Japanese-Chinese traditional medicine, on memory deficits and losses of neurites and synapses were examined using Alzheimer's disease model mice. Improvements of Aβ(25–35)-induced neuritic atrophy by Kihi-to and the mechanism were investigated in cultured cortical neurons.</p> <p>Results</p> <p>Administration of Kihi-to for consecutive 3 days resulted in marked improvements of Aβ(25–35)-induced impairments in memory acquisition, memory retention, and object recognition memory in mice. Immunohistochemical comparisons suggested that Kihi-to attenuated neuritic, synaptic and myelin losses in the cerebral cortex, hippocampus and striatum. Kihi-to also attenuated the calpain increase in the cerebral cortex and hippocampus. When Kihi-to was added to cells 4 days after Aβ(25–35) treatment, axonal and dendritic outgrowths in cultured cortical neurons were restored as demonstrated by extended lengths of phosphorylated neurofilament-H (P-NF-H) and microtubule-associated protein (MAP)2-positive neurites. Aβ(25–35)-induced cell death in cortical culture was also markedly inhibited by Kihi-to. Since NF-H, MAP2 and myelin basic protein (MBP) are substrates of calpain, and calpain is known to be involved in Aβ-induced axonal atrophy, expression levels of calpain and calpastatin were measured. Treatment with Kihi-to inhibited the Aβ(25–35)-evoked increase in the calpain level and decrease in the calpastatin level. In addition, Kihi-to inhibited Aβ(25–35)-induced calcium entry.</p> <p>Conclusion</p> <p>In conclusion Kihi-to clearly improved the memory impairment and losses of neurites and synapses.</p

Effect of combined treatment with alendronate and calcitriol on femoral neck strength in osteopenic rats

<p>Abstract</p> <p>Background</p> <p>Hip fracture is associated with pronounced morbidity and excess mortality in elderly women with postmenopausal osteoporosis. Many drugs have been developed to treat osteoporosis and to reduce the risk of osteoporotic fractures. We investigated the effects of combined alendronate and vitamin D₃treatment on bone mass and fracture load at the femoral neck in ovariectomized (OVX) rats, and evaluated the relationship between bone mass parameters and femoral neck strength.</p> <p>Methods</p> <p>Thirty 12-week-old female rats underwent either a sham-operation (n = 6) or OVX (n = 24). Twenty weeks later, OVX rats were further divided into four groups and received daily doses of either saline alone, 0.1 mg/kg alendronate, 0.1 μg/kg calcitriol, or a combination of both two drugs by continuous infusion via Alzet mini-osmotic pumps. The sham-control group received saline alone. After 12 weeks of treatment, femoral necks were examined using peripheral quantitative computed tomography (pQCT) densitometry and mechanical testing.</p> <p>Results</p> <p>Saline-treated OVX rats showed significant decreases in total bone mineral content (BMC) (by 28.1%), total bone mineral density (BMD) (by 9.5%), cortical BMC (by 26.3%), cancellous BMC (by 66.3%), cancellous BMD (by 29.0%) and total cross-sectional bone area (by 30.4%) compared with the sham-control group. The combined alendronate and calcitriol treatments improved bone loss owing to estrogen deficiency. On mechanical testing, although OVX significantly reduced bone strength of the femoral neck (by 29.3%) compared with the sham-control group, only the combined treatment significantly improved the fracture load at the femoral neck in OVX rats to the level of the sham-controls. The correlation of total BMC to fracture load was significant, but that of total BMD was not.</p> <p>Conclusion</p> <p>Our results showed that the combined treatment with alendronate and calcitriol significantly improved bone fragility of the femoral neck in OVX osteopenic rats.</p

Associations of a PTPN11 G/A polymorphism at intron 3 with Helicobactor pylori seropositivity, gastric atrophy and gastric cancer in Japanese

<p>Abstract</p> <p>Background</p> <p>Previous studies have revealed the significance of <it>Helicobacter pylori </it>(<it>H. pylori</it>) infection as a risk factor of gastric cancer. Cytotoxin-associated gene A (<it>cagA</it>) positivity has been demonstrated to determine the clinical outcome of <it>H. pylori </it>infection in the presence of SHP-2 (src homology 2 domain-containing protein tyrosine phosphatase-2). This study aimed to examine the formerly reported association of G/A <it>PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) </it>polymorphism (rs2301756) with gastric atrophy, as well as the association with gastric cancer in a Japanese population using a large sample size.</p> <p>Methods</p> <p>Study subjects were 583 histologically diagnosed patients with gastric cancer (429 males and 154 females) and age- and sex-frequency-matched 1,636 non-cancer outpatients (1,203 males and 433 females), who visited Aichi Cancer Center Hospital between 2001–2005. Serum anti-<it>H. pylori </it>IgG antibody and pepsinogens were measured to evaluate <it>H. pylori </it>infection and gastric atrophy, respectively. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by a logistic model.</p> <p>Results</p> <p>Among <it>H. pylori </it>seropositive non-cancer outpatients, the age- and sex-adjusted OR of gastric atrophy was 0.82 (95% CI 0.62–1.10, <it>P </it>= 0.194) for <it>G/A</it>, 0.84 (95% CI 0.39–1.81, <it>P </it>= 0.650) for <it>A/A</it>, and 0.83 (95% CI 0.62–1.09, <it>P </it>= 0.182) for <it>G/A</it>+<it>A/A</it>, relative to <it>G/G </it>genotype, and that of severe gastric atrophy was 0.70 (95% CI 0.47–1.04, <it>P </it>= 0.079), 0.56 (95% CI 0.17–1.91, <it>P </it>= 0.356), and 0.68 (95% CI 0.46–1.01, <it>P </it>= 0.057), respectively. Among <it>H. pylori </it>infected subjects (<it>H. pylori </it>seropositive subjects and seronegative subjects with gastric atrophy), the adjusted OR of severe gastric atrophy was further reduced; 0.62 (95% CI 0.42–0.90, <it>P </it>= 0.012) for <it>G/A</it>+<it>A/A</it>. The distribution of the genotype in patients with gastric cancer was not significantly different from that for <it>H. pylori </it>infected subjects without gastric atrophy.</p> <p>Conclusion</p> <p>Our study results revealed that those with the <it>A/A </it>genotype of <it>PTPN11 </it>rs2301756 polymorphism are at lower risk of severe gastric atrophy, but are not associated with a decreased risk of gastric cancer, which partially supported our previous finding that the polymorphism in the <it>PTPN11 </it>gene encoding SHP-2 was associated with the gastric atrophy risk in <it>H. pylori </it>infected Japanese. The biological roles of this <it>PTPN11 </it>polymorphism require further investigation.</p