Melinjo (Gnetum gnemon) extract intake during lactation stimulates hepatic AMP-activated protein kinase in offspring of excessive fructose-fed pregnant rats.

Excessive maternal fructose intake during pregnancy and in early postnatal life has metabolic consequences for the offspring. We investigated the effects of melinjo (Gnetum gnemon) extract (MeE) intake during lactation on the expression and phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in the liver of offspring from excessive fructose-fed pregnant dams. Pregnant Wistar rats received a normal diet and 100g/L fructose solution during gestation ad libitum. At delivery, dams were divided into two groups: a control diet (FC) or a 0.1% MeE-containing diet (FM) fed during lactation. The dams that were not treated with fructose were fed a control diet (CC). At postnatal week 3, some pups were sacrificed, while the remaining continued to receive a normal diet and were sacrificed at week 17. Blood chemistry and phosphorylation levels of AMPK and acetyl-coenzyme A carboxylase (ACC) were evaluated. Plasma glucose levels in FC female offspring increased compared to that receiving CC at weeks 3 and 17; however, the levels in FM female offspring decreased at week 17. The insulin levels in FM female offspring decreased significantly compared to that in FC female offspring at week 3. Hepatic AMPK phosphorylation was upregulated in FM offspring at week 3 and in female, but not male, offspring at week 17. ACC phosphorylation in FM female offspring was upregulated at week 17. Our results suggest that maternal MeE intake during lactation may modulate the hepatic AMPK pathways in female offspring.

Oxidative stress induced interleukin-32 mRNA expression in human bronchial epithelial cells.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and persistent inflammation in the airways and lung parenchyma. Oxidative stress contributes to the pathogenesis of COPD. Interleukin (IL)-32 expression has been reported to increase in the lung tissue of patients with COPD. Here, we show that IFNγ upregulated IL-32 expression and that oxidative stress augmented IFNγ-induced-IL-32 expression in airway epithelial cells. We further investigated transcriptional regulation responsible for IFNγ induced IL-32 expression in human airway epithelial cells. METHODS: Human bronchial epithelial (HBE) cells were stimulated with H2O2 and IFNγ, and IL-32 expression was evaluated. The cell viability was confirmed by MTT assay. The intracellular signaling pathways regulating IL-32 expression were investigated by examining the regulatory effects of MAPK inhibitors and JAK inhibitor after treatment with H2O2 and IFNγ, and by using a ChIP assay to identify transcription factors (i.e. c-Jun, CREB) binding to the IL-32 promoter. Promoter activity assays were conducted after mutations were introduced into binding sites of c-Jun and CREB in the IL-32 promoter. IL-32 expression was also examined in HBE cells in which the expression of either c-Jun or CREB was knocked out by siRNA of indicated transcription factors. RESULTS: There were no significant differences of cell viability among groups. After stimulation with H2O2 or IFNγ for 48 hours, IL-32 expression in HBE cells was increased by IFNγ and synergistically upregulated by the addition of H2O2. The H2O2 augmented IFNγ induced IL-32 mRNA expression was suppressed by a JNK inhibitor, but not by MEK inhibitor, p38 inhibitor, and JAK inhibitor I. Significant binding of c-Jun and CREB to the IL-32 promoter was observed in the IFNγ + H2O2 stimulated HBE cells. Introducing mutations into the c-Jun/CREB binding sites in the IL-32 promoter prominently suppressed its transcriptional activity. Further, knocking down CREB expression by siRNA resulted in significant suppression of IL-32 induction by IFNγ and H2O2 in HBE cells. CONCLUSION: IL-32 expression in airway epithelium may be augmented by inflammation and oxidative stress, which may occur in COPD acute exacerbation. c-Jun and CREB are key transcriptional factors in IFNγ and H2O2 induced IL-32 expression.

Impact of COPD exacerbations on osteoporosis assessed by chest CT scan.

BACKGROUND: COPD pathology involves not only the lungs but also extrapulmonary abnormalities. Osteoporosis is one of the most important abnormalities because it may cause vertebral compression fractures and deteriorate pulmonary function. COPD patients have many risk factors for osteoporosis, such as low BMI, decreased activity, systemic inflammation, and use of corticosteroids. Some of these factors have been shown to deteriorate with COPD exacerbations. We previously demonstrated the correlation between emphysema and osteoporosis and between emphysema progression and COPD exacerbations. Thus, the hypothesis that exacerbation causes osteoporosis progression in COPD patients was investigated. METHODS: Forty-two COPD patients not on osteoporosis treatment for over 2 years were recruited. During follow-up, exacerbations had been prospectively recorded. Thoracic vertebral bone mineral density (BMD) was measured using chest CT, and the annual change in BMD was calculated. The change was compared between patients with and without a history of exacerbations. RESULTS: The decrease in thoracic vertebral BMD was greater in patients with than in those without a history of exacerbations (median ΔBMD mg/ml·year: -3.78 versus -0.30, p = 0.02). Moreover, multivariate regression analysis showed that exacerbations and baseline PaO2 were independent predictors of the BMD decrease (R² = 0.20, p = 0.007, and R² = 0.09, p = 0.03, respectively) after adjustment for baseline age, smoking status, and airflow limitation. CONCLUSIONS: This is the first longitudinal study to demonstrate that COPD exacerbations are independently associated with osteoporosis progression. Osteoporosis progression should be evaluated in COPD patients, especially in those with a history of frequent exacerbations.

A NOD2 gene polymorphism is associated with the prevalence and severity of chronic obstructive pulmonary disease in a Japanese population.

BACKGROUND AND OBJECTIVE: Genetic background is thought to be one of the risk factors for development of COPD. Recently, it has been proposed that the innate immune system is involved in the pathophysiology of COPD. We hypothesized that polymorphisms in the nucleotide-binding and oligomerization domain (NOD)1 and NOD2 genes would be associated with the pathogenesis of COPD. In addition, the associations between these single nucleotide polymorphisms (SNPs) and phenotypes of COPD were analysed. METHODS: Japanese COPD patients (n = 228) and non-COPD smokers (n = 101) were recruited from the outpatient clinic at Kyoto University Hospital, Kyoto, Japan. At entry into the study, a blood sample was taken and a pulmonary function test was performed. Genotyping was performed for 6 selected tag SNPs of NOD1 and 5 tag SNPs of NOD2. Further investigations were performed for SNP that were associated with COPD, including baseline gene expression, the relative proportions of splicing variants in whole blood, responses to ligand and enhancement of gene expression in peripheral blood neutrophils stimulated with pro-inflammatory cytokines. RESULTS: The distribution of NOD2 rs1077861 genotypes differed between Japanese COPD patients and non-COPD smokers (P = 0.036). This SNP was also associated with a lower FEV(1) % predicted (57.2 ± 1.8 for TT vs 50.8 ± 2.3 for TA/AA, P = 0.03) and DL(CO) /V(A) (2.89 ± 0.1 in TT vs 2.53 ± 0.14 in TA/AA, P = 0.036) in COPD patients. NOD2 gene expression after stimulation with 10 ng/mL of tumour necrosis factor-α for 4 h, was increased to a greater extent in TA/AA genotype than in TT genotype peripheral blood neutrophils (P = 0.015). CONCLUSIONS: The NOD2 rs1077861 SNP may influence the development and progression of COPD in Japanese subjects.

[An autopsy case of massive hemoptysis in systemic sarcoidosis with pulmonary granulomatous arteritis].

A 49-year-old female was admitted to our hospital because of worsening of congestive heart failure on November 2000 in a state after insertion of permanent pacemaker for complete atrioventricular block in 1986, followed by a clinical history of chronic heart failure due to dilated cardiomyopathy. After admission, her general condition had been improved, but, she had massive hemoptysis suddenly and died on February 2001. At autopsy, noncaseating granulomas were observed scattering in lungs, liver and spleen, not associated with any infectious lesions, therefore indicating systemic sarcoidosis. In lungs, granulomatous arteritis in small- and medium-sized muscular arteries associated with disputation of the media and elastic laminae were observed, suggesting the direct cause of hemoptysis. This is the extremely rare case of pulmonary arteritis with systemic sarcoidosis resulting the death from massive hemoptysis.