Mild endoplasmic reticulum stress augments the proinflammatory effect of IL-1β in pancreatic rat β-cells via the IRE1α/XBP1s pathway

The prevalence of obesity and type 1 diabetes in children is increasing worldwide. Insulin resistance and augmented circulating free fatty acids associated with obesity may cause pancreatic β-cell endoplasmic reticulum (ER) stress. We tested the hypothesis that mild ER stress predisposes β-cells to an exacerbated inflammatory response when exposed to IL-1β or TNF-α, cytokines that contribute to the pathogenesis of type 1 diabetes. INS-1E cells or primary rat β-cells were exposed to a low dose of the ER stressor cyclopiazonic acid (CPA) or free fatty acids, followed by low-dose IL-1β or TNF-α. ER stress signaling was inhibited by small interfering RNA. Cells were evaluated for proinflammatory gene expression by RT-PCR and ELISA, gene reporter activity, p65 activation by immunofluorescence, and apoptosis. CPA pretreatment enhanced IL-1β- induced, but not TNF-α-induced, expression of chemokine (C-C motif) ligand 2, chemokine (C-X-C motif) ligand 1, inducible nitric oxide synthase, and Fas via augmented nuclear factor κB (NF-κB) activation. X-box binding protein 1 (XBP1) and inositol-requiring enzyme 1, but not CCAAT/enhancer binding protein homologous protein, knockdown prevented the CPA-induced exacerbation of NF-κB-dependent genes and decreased IL-1β-induced NF-κB promoter activity. XBP1 modulated NF-κB activity via forkhead box O1 inhibition. In conclusion, rat β-cells facing mild ER stress are sensitized to IL-1β, generating a more intense and protracted inflammatory response through inositol-requiring enzyme 1/XBP1 activation. These observations link β-cell ER stress to the triggering of exacerbated local inflammation.     

Gastric dysmotility after liquid bolus ingestion in systemic sclerosis: an ultrasonographic study

Gastric involvement appears quite commonly in systemic sclerosis (SSc). The aim of this study was to evaluate gastric wall motility using ultrasonography, a noninvasive method able to track both filling and emptying of fundus and antrum. The study was performed in 20 SSc patients and 20 healthy control subjects. Gastric filling and emptying were evaluated by transabdominal ultrasonography, measuring changes in fundus and antral areas over a 1-h period after ingestion of a liquid bolus (500 ml of mineral water). Areas of both gastric fundus and antrum at basal evaluation were found to be smaller in SSc patients than in healthy controls. Gastric filling was significantly reduced after ingestion of liquid bolus. Gastric emptying was delayed both in fundus and antrum. No significant differences of gastric wall motility have been observed in different subsets of SSc patients. Our findings show that gastric dysmotility is frequent and severe in SSc patients, contributing to the gastrointestinal disturbances which are very common in this disease.     

L-citrulline Prevents Alveolar and Vascular Derangement in a Rat Model of Moderate Hyperoxia-induced Lung Injury

Background

Moderate normobaric hyperoxia causes alveolar and vascular lung derangement in the newborn rat. Endogenous nitric oxide (NO), which promotes lung growth, is produced from the metabolism of l-arginine to l-citrulline in endothelial cells. We investigated whether administering l-citrulline by raising the serum levels of l-arginine and enhancing NO endogenous synthesis attenuates moderate hyperoxia-induced lung injury.

Methods

Newborn rats were exposed to FiO₂?=?0.6 or room air for 14?days to induce lung derangement and then were administered l-citrulline or a vehicle (sham). Lung histopathology was studied with morphometric features. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected for analysis. Lung vascular endothelial growth factor (VEGF), nitric oxide synthase (eNOS), and matrix metalloproteinase 2 (MMP2) gene and protein expressions were assessed.

Results

Serum l-arginine rose in the L-citr?+?hyperoxia group (p?=?0.05), as well as the Von Willebrand factor stained vessels count (p?=?0.0008). Lung VEGF immune staining, localized on endothelial cells, was weaker in the sections under hyperoxia than the l-citr?+?hyperoxia and room air groups. This pattern was comparable with the VEGF gene and protein expression profiles. Mean alveolar size increased in the untreated hyperoxia and sham-treated groups compared with the groups reared in room air or treated with l-citrulline under exposure to hyperoxia (p?=?0.0001). Lung VEGF and eNOS increased in the l-citrulline-treated rats, though this treatment did not change MMP2 gene expression but regulated the MMP2 active protein, which rose in BALF (p?=?0.003).

Conclusions

We conclude that administering l-citrulline proved effective in improving alveolar and vascular growth in a model of oxygen-induced pulmonary damage, suggesting better lung growth and matrix regulation than in untreated groups.     

Reproductive factors and clinical features of Parkinson's disease

BackgroundLiterature suggests that sex steroid hormones may modify the risk for Parkinson's disease (PD). We investigated the potential effect of reproductive factors on the clinical features of idiopathic PD (IPD) patients.MethodsAll IPD female patients admitted to and evaluated at our Institute over a 12-month period were included in the present cross-sectional study. We investigated the effect of the following parameters by multivariate linear regression analysis: age at menarche, age at menopause, length of fertile life, duration of exposure to endogenous estrogens and cumulative length of pregnancies, use of contraceptives and hormonal replacement therapy.ResultsIn total, 579 patients were evaluated and 497 reported menopause before PD onset. In this population, age at PD onset was positively associated with age at menarche and at menopause, length of fertile life and duration of estrogen exposure. Moreover, UPDRS motor score was inversely associated with age at menopause, length of fertile life and duration of estrogen exposure. Increasing age at menarche was also associated with predominant resting tremor at PD onset. In models refitted on patients with early PD (disease duration <5 years; N = 226) all the associations found were confirmed. The relationship between surrogates of estrogen exposure and UPDRS motor score actually became more significant.ConclusionsOur observations support the concept that hormonal exposure of the nigro-striatal network during life may influence its susceptibility to degenerative stimuli in later life, but the association does not seem to be unique? unidirectional. In particular, increased severity of PD signs correlates with shorter duration of estrogen exposure. The underlying mechanisms need to be clarified.     

Efficacy of semantic–phonological treatment combined with tDCS for verb retrieval in a patient with aphasia

Recent studies reported enhanced performance on language tasks induced by transcranial direct current stimulation (tDCS) in patients with aphasia. One chronic patient with non-fluent aphasia received 20 sessions of a verb anomia training combined with off-line bihemispheric tDCS applied to the dorsolateral prefrontal cortex (DLPFC) – anodal tDCS over left DLPFC plus cathodal tDCS over right DLPFC. A significant improvement in verb naming was observed at all testing times (4, 12, 24, and 48 weeks from post-entry/baseline testing) for treated and untreated verbs. Our findings show beneficial effects of verb anomia training in combination with tDCS in chronic aphasic patient, suggesting a long-lasting effect of this treatment.