The effect of erythromycin on the inflammation caused by exposure to cigarette smoke was investigated in this study. Mice were exposed either to cigarette smoke or to environmental air (control), and ...some mice exposed to cigarette smoke were treated with oral erythromycin (100 mg/kg/day for 8 days). Pulmonary inflammation was assessed by determining the cellular content of bronchoalveolar lavage (BAL) fluid. The messenger RNA (mRNA) levels of various mediators, including keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, surfactant protein (SP)-D, granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, interleukin (IL)-6 in lung tissue were determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. The exposure to cigarette smoke increased significantly the numbers of neutrophils ( P = 0.029), macrophages ( P = 0.029), and lymphocytes ( P = 0.029) recovered in BAL fluid. Moreover, mRNA levels of KC ( P = 0.029), MIP-2 ( P = 0.029), SP-D ( P = 0.029), and GM-CSF ( P = 0.057) in the lung tissue were higher in mice exposed to cigarette smoke than in mice exposed to environmental air. In the erythromycin-treated mice that were exposed also to cigarette smoke, both neutrophil and lymphocyte counts were significantly lower in the BAL fluid than those in the vehicle-treated mice ( P = 0.029). Erythromycin-treated mice exposed to cigarette smoke showed a trend of lower mRNA levels of KC and TNF-α in the lung tissue than those in the vehicle-treated mice, although the statistical significance was not achieved ( P = 0.057). Our data demonstrated that erythromycin prevented lung inflammation induced by cigarette smoke, in parallel to the reduced mRNA levels of KC and TNF-α.
The low molecular weight organic compound bromovalerylurea (BU) has long been used as a hypnotic/sedative. In the present study, we found that BU suppressed mRNA expression of proinflammatory factors ...and nitric oxide release in lipopolysaccharide (LPS)-treated rat primary microglial cell cultures. BU prevented neuronal degeneration in LPS-treated neuron-microglia cocultures. The anti-inflammatory effects of BU were as strong as those of a synthetic glucocorticoid, dexamethasone. A rat hemi-Parkinsonian model was prepared by injecting 6-hydroxydopamine into the right striatum. BU was orally administered to these rats for 7 days, which ameliorated the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and alleviated motor deficits. BU suppressed the expression of mRNAs for interferon regulatory factors (IRFs) 1, 7 and 8 in the right (lesioned) ventral midbrain as well as those for proinflammatory mediators. BU increased mRNA expression of various neuroprotective factors, including platelet-derived growth factor and hepatocyte growth factor, but it did not increase expression of alternative activation (M2) markers. In microglial culture, BU suppressed the LPS-induced increase in expression of IRFs 1 and 8, and it reduced LPS-induced phosphorylation of JAK1 and STATs 1 and 3. Knockdown of IRFs 1 and 8 suppressed LPS-induced NO release by microglial cells. These results suggest that suppression of microglial IRF expression by BU prevents neuronal cell death in the injured brain region, where microglial activation occurs. Because many Parkinsonian patients suffer from sleep disorders, BU administration before sleep may effectively ameliorate neurological symptoms and alleviate sleep dysfunction.
•The hypnotic bromovalerylurea (BU) suppressed LPS-induced microglial activation.•Oral BU prevented neurodegeneration in the rat model of 6-OHDA-induced Parkinsonism.•BU suppressed proinflammatory factor expression in the Parkinsonian rat brain.•BU suppressed interferon regulatory factors 1 and 8 expression by microglia.
In order to develop a novel oral formulation that can safely improve the intestinal absorption of poorly absorbable drugs, polyamines such as spermine (SPM) and spermidine (SPD) was examined as an ...absorption enhancing adjuvant in rats. The absorption of rebamipide, classified into BCS Class IV, from colon was significantly improved by SPM or SPD, and the enhancing ability of SPM was larger than that of SPD. As a possible mixing and/or interaction of polyamines with bile acids were expected, the combinatorial use of sodium taurocholate (STC) with polyamines was also examined. The absorption of rebamipide was drastically improved by the combinatorial use of SPM or SPD with STC. As STC itself did not enhance the absorption of rebamipide so much, it was considered that polyamines and STC had a synergistic enhancing effect. In-vivo oral absorption study was also performed to investigate the effectiveness and safety of polyamines and their combinatorial use with STC in rats. Although the enhancing effect slightly attenuated comparing with the in-situ loop study, the absorption of rebamipide was significantly improved and the combinatorial use of 10 mM SPM with 25 mM STC showed the largest enhancing effect. Histopathological studies clearly showed that any significant change in stomach and duodenum was not caused by SPM (10 mM), SPD (10 mM) or their combinatorial use with STC (25 mM) at 1.5 or 8.0 h after oral administration. Taken all together, polyamines, especially SPM, and its combinatorial use with STC could improve the absorption of poorly absorbable drugs without any significant changes in gastrointestinal tract after oral administration in rats.
Large and powerful Typhoon No. 19 (Typhoon Hagibis) made landfall on the Izu Peninsula on 12 th October 2019, and it brought widespread and record-breaking torrential rain across Japan, especially in ...Eastern Japan. Emergency warning was issued in Tokyo and 12 prefectures, and many slope failures and debris flows were caused. It marked the largest number of sediment disaster occurrences by a typhoon since 1982 that the statistics have been started to be recorded. 952 sediment disasters were caused by the typhoon (as of 24 th December 2019), and 16 people were killed and one person is missing. In Tohoku region, most disasters happened in Iwate, Miyagi, and Fukushima prefectures. From 1 : 00 am, 12 th October to 12 : 00 am, 13 th October (two days) total precipitation (observed by AMeDAS of Japan Meteorological Agency) was 594 mm in Hippo, Marumori-machi, Miyagi prefecture, and 466.5 mm in Fudai, Iwate prefecture. From the above, Japan Society of Erosion Control Engineering organized “Emergency investigation team for the sediment disasters in Tohoku region caused by Typhoon No. 192019” and performed the investigation for three times. The survey results have been published with the title “Sediment disasters caused by Typhoon Hagibis on October, 2019 in Tohoku region” to the Journal of Japan Society of Erosion Control Engineering, volume 72, No. 6, in 2020 (in Japanese, with English Abstract). This paper provides, as part of a brief summary of these findings.
Purpose
We evaluated the effects of an alpha-glucosidase inhibitor, voglibose, on cardiovascular events in patients with a previous myocardial infarction (MI) and impaired glucose tolerance (IGT).
...Methods
This prospective, randomized, open, blinded-endpoint study was conducted in 112 hospitals and clinics in Japan in 3000 subjects with both previous MI and IGT receiving voglibose (0.6 mg/day,
n
= 424) or no drugs (
n
= 435) for 2 years. The Data and Safety Monitoring Board (DSMB) recommended discontinuation of the study in June 2012 after an interim analysis when the outcomes of 859 subjects were obtained. The primary endpoint was cardiovascular events including cardiovascular death, nonfatal MI, nonfatal unstable angina, nonfatal stroke, and percutaneous coronary intervention/coronary artery bypass graft. Secondary endpoints included individual components of the primary endpoint in addition to all-cause mortality and hospitalization due to heart failure.
Results
The age, ratio of males, and HbA
1
C were 65 vs. 65 years, 86 vs. 87%, and 5.6 vs. 5.5% in the groups with and without voglibose, respectively. Voglibose improved IGT; however, Kaplan–Meier analysis showed no significant between-group difference with respect to cardiovascular events 12.5% with voglibose vs. 10.1% without voglibose for the primary endpoint (95% confidence interval, 0.82–1.86); there were no significant differences in secondary endpoints.
Conclusion
Although voglibose effectively treated IGT, no additional benefits for cardiovascular events in patients with previous MI and IGT were observed. Voglibose may not be a contributing therapy to the secondary prevention in patients with MI and IGT.
Trial Registration
Clinicaltrials.gov
number: NCT00212017
Abstract only
142
Background: Prognosis of HER2-positive metastatic breast cancer (MBC) has been dramatically improved by trastuzumab (Tmab). More recently, newer anti-HER2 agents such as lapatinib, ...pertuzumab and T-DM1 have prolonged survival. Despite the efficacy of these drugs, most patients develop progressive disease during or after treatment, and alternative anti-HER2 agents plus chemotherapies are required in subsequent lines of treatment. However, there are few evidence on efficacy of Tmab-containing regimens after disease progression. Gemcitabine (GEM) is non-cross resistant to anthracycline and taxane. Preclinical studies have shown that the combination of Tmab and GEM has synergistic effect against HER2-positive breast cancer cell lines. SBP-01 study assessed the efficacy and safety of the combination of Tamb and GEM in patients with HER2-positive MBC previously treated with anti-HER2 therapy. Methods: SBP-01 study included patients treated with one or more anti-HER2 directed regimens for MBC. Patients were administered with GEM 1250 mg/m
2
on days 1 and 8 of each 21-day cycle and Tmab 4mg/kg loading dose and then 2mg/kg weekly. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival, and safety. Results: Between June 2011 and June 2014, 35 patients were enrolled. Patients had ER positive tumor (37.1%), a median of 2 metastatic organ sites, visceral metastasis (80.0%), prior (neo) adjuvant Tmab (22.9%) and a median of 2 prior chemotherapy regimens for MBC. Previous HER2-directed drugs included Tmab (94.3%), lapatinib (37.1%), T-DM1 (8.6%) and pertuzumab (2.9%). ORR was 22.9% (95% CI, 8.6%-36.8%). Median PFS was 146 days. Patients with stable disease response received a median of 7 cycles (6-28 cycles) of treatment. Grade3/4 leukopenia (20.0%) and neutropenia (48.6%) were observed. All non-hematological toxicities were less than grade3. Conclusions: The Combination Tmab and GEM is effective and well-tolerated regimen for patients previously treated with HER2-directed therapy, and appears to make disease stable for long time period. Clinical trial information: UMIN000005881.
Objective and design: The histone acetylation processes, which are believed to play a critical role in the regulation of many inflammatory genes, are reversible and regulated by histone ...acetyltransferases (HATs), which promote acetylation, and histone deacetylases (HDACs), which promote deacetylation. We studied the effects of lipopolysaccharide (LPS) on histone acetylation and its role in the regulation of interleukin (IL)-8 expression.
Material: A human alveolar epithelial cell line A549 was used
in
vitro.
Methods: Histone H4 acetylation at the IL-8 promoter region was assessed by a chromatin immunoprecipitation (ChIP) assay. The expression and production of IL-8 were evaluated by quantitative polymerase chain reaction and specific immunoassay. Effects of a HDAC inhibitor, trichostatin A (TSA), and a HAT inhibitor, anacardic acid, were assessed.
Results:
Escherichia coli-derived LPS showed a dose- and time-dependent stimulatory effect on IL-8 protein production and mRNA expression in A549 cells
in vitro. LPS showed a significant stimulatory effect on histone H4 acetylation at the IL-8 promoter region by ChIP assay. Pretreatment with TSA showed a dose-dependent stimulatory effect on IL-8 release from A549 cells as compared to LPS alone. Conversely, pretreatment with anacardic acid inhibited IL-8 production and expression in A549 cells.
Conclusion: These data suggest that LPS-mediated proinflammatory responses in the lungs might be modulated via changing chromatin remodeling by HAT inhibition.
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