Silicosis is an occupational lung disease, characterized by irreversible and progressive fibrosis. Silica exposure leads to intense lung inflammation, reactive oxygen production, and extracellular ...ATP (eATP) release by macrophages. The P2X7 purinergic receptor is thought to be an important immunomodulator that responds to eATP in sites of inflammation and tissue damage. The present study investigates the role of P2X7 receptor in a murine model of silicosis. To that end wild-type (C57BL/6) and P2X7 receptor knockout mice received intratracheal injection of saline or silica particles. After 14 days, changes in lung mechanics were determined by the end-inflation occlusion method. Bronchoalveolar lavage and flow cytometry analyzes were performed. Lungs were harvested for histological and immunochemistry analysis of fibers content, inflammatory infiltration, apoptosis, as well as cytokine and oxidative stress expression. Silica particle effects on lung alveolar macrophages and fibroblasts were also evaluated in cell line cultures. Phagocytosis assay was performed in peritoneal macrophages. Silica exposure increased lung mechanical parameters in wild-type but not in P2X7 knockout mice. Inflammatory cell infiltration and collagen deposition in lung parenchyma, apoptosis, TGF-β and NF-κB activation, as well as nitric oxide, reactive oxygen species (ROS) and IL-1β secretion were higher in wild-type than knockout silica-exposed mice. In vitro studies suggested that P2X7 receptor participates in silica particle phagocytosis, IL-1β secretion, as well as reactive oxygen species and nitric oxide production. In conclusion, our data showed a significant role for P2X7 receptor in silica-induced lung changes, modulating lung inflammatory, fibrotic, and functional changes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Considerable evidence indicates that a signaling crosstalk between the brain and periphery plays important roles in neurological disorders, and that both acute and chronic peripheral inflammation can ...produce brain changes leading to cognitive impairments. Recent clinical and epidemiological studies have revealed an increased risk of cognitive impairment and dementia in individuals with impaired pulmonary function. However, the mechanistic underpinnings of this association remain unknown. Exposure to SiO
(silica) particles triggers lung inflammation, including infiltration by peripheral immune cells and upregulation of pro-inflammatory cytokines. We here utilized a mouse model of lung silicosis to investigate the crosstalk between lung inflammation and memory.
Silicosis was induced by intratracheal administration of a single dose of 2.5 mg SiO
/kg in mice
Molecular and behavioral measurements were conducted 24 h and 15 days after silica administration. Lung and hippocampal inflammation were investigated by histological analysis and by determination of pro-inflammatory cytokines. Hippocampal synapse damage, amyloid-β (Aβ) peptide content and phosphorylation of Akt, a proxy of hippocampal insulin signaling, were investigated by Western blotting and ELISA. Memory was assessed using the open field and novel object recognition tests.
Administration of silica induced alveolar collapse, lung infiltration by polymorphonuclear (PMN) cells, and increased lung pro-inflammatory cytokines. Lung inflammation was followed by upregulation of hippocampal pro-inflammatory cytokines, synapse damage, accumulation of the Aβ peptide, and memory impairment in mice.
The current study identified a crosstalk between lung and brain inflammatory responses leading to hippocampal synapse damage and memory impairment after exposure to a single low dose of silica in mice.
Display omitted
•BALB/c mice got saline (0.05 mL) or 10 μg of lipopolysaccharide into the trachea.•A dose-response curve for eugenol treatment (15–1500 mg/kg) was done 6 h after LPS.•Other mice (same ...protocol) received the lower effective eugenol dose (150 mg/kg).•Anti-inflammatory and anti-oxidant actions of eugenol were tested in these mice.•Eugenol improved LPS-triggered lung injury as anti-inflammatory and anti-oxidant.
Acute lung injury (ALI) remains a major cause of mortality. In lipopolysaccharide (LPS)-stimulated macrophages, eugenol reduces cyclooxygenase-2 expression, NF-κB activation, and inflammatory mediators. We examined the anti-inflammatory and anti-oxidative action of eugenol in an in vivo model of LPS-induced lung injury. Lung mechanics and histology were analyzed in mice 24 h after LPS exposure, with and without eugenol treatment at different doses. Additional animals, submited to the same protocol, were treated with eugenol at 150 mg/kg to determine its effect on inflammatory cytokines (ELISA) and oxidative markers. LPS-induced lung functional and histological changes were significantly improved by eugenol, in a dose-dependent way. Furthermore, eugenol (150 mg/kg) was able to inhibit the release of inflammatory cytokines (TNF-α, IL-1β and IL-6), NADPH oxidase activity, as well as antioxidant enzymes activity (superoxide dismutase, catalase and glutathione peroxidase). Finally, eugenol reduced LPS-induced protein oxidation. In conclusion, eugenol improved in vivo LPS-induced ALI through both anti-inflammatory and anti-oxidative effects, avoiding damage to lung structure.
Few studies have compared the clinical impact of multiple DNA‐virus infections in haploidentical hematopoietic stem cell transplantation (haplo‐HSCT) with posttransplant cyclophosphamide (PTCy) and ...unrelated donor allogeneic hematopoietic stem cell transplantation (UD‐HSCT) with thymoglobulin, so we retrospectively analyzed viral infections in the first 6 mo posttransplant in these scenarios. Fifty‐nine patients underwent to haplo‐HSCT, and 68 to UD‐HSCT. The most frequent infection was cytomegalovirus (CMV) (76.3% in haplo‐HSCT and 69.1% in UD‐HSCT) (P = .878) and in the group of patients with CMV reactivation, maximal CMV viral load over 2500 UI/ml correlated with worse overall survival‐hazard ratio (HR) 1.93 (95% confidence interval CI 1.04‐3.59) P = .03. The cumulative incidence of multiple DNA virus within 180 d of posttransplant was 78.7% for one virus and 28.4% for two or more viruses with no difference regarding the type of transplant. Viral infections, age, and acute graft versus host disease (GVHD) grades II–IV were risk factors for worse overall survival in multivariate analyses: one virus HR 2.53 (95% CI 1.03‐6.17) P = .04, two or more viruses HR 3.51 (95% CI 1.37‐9) P < .01, age HR 1.03 (95% CI 1.02‐1.05) P < .01 and acute GVHD II–IV HR 1.97 (95% CI 1.13‐3.43) P = .01. Also, age over 50 y HR 4.25 (95% CI 2.01‐8.97) P < .001, second CMV reactivation or having both CMV and BK polyomavirus (BKV) HR 2.65 (95% CI 1.26‐5.56) P = .01 and acute GVHD grades II–IV HR 2.23 (95% CI 1.12‐4.43) P = .022 were risk factors for nonrelapse mortality in the multivariate analyses. In conclusion, multiple DNA‐virus infections are frequent in both haplo‐HSCT and UD‐HSCT and a risk factor for worse overall survival.
Murine papain-induced emphysema is a model that reproduces many of the features found in patients. Bone marrow-derived mononuclear cells (BMMC) have already been used to repair the alveolar ...epithelium in respiratory diseases, but not in the papain model. Thus, we hypothesized that BMMC could prevent the pathophysiological processes in papain-induced experimental emphysema. Female BALB/c mice received intratracheal instillation of 50 μL of saline (S groups) or papain (P groups, 10 IU/50 μl of saline) on days 1 and 7 of the experimental protocol. On the 14th day, 2 × 10
BMMC of male BALB/c mice (SC21 and PC21) or saline (SS21 and PS21) were injected by the jugular vein. Analyses were done on days 14 (S14 and P14) and 21 (SS21, PS21, SC21, and PC21) of the protocol. qPCR evaluated the presence of the Y chromosome in the lungs of BMMC recipient animals. Functional residual capacity (FRC), alveolar diameter, cellularity, elastic fiber content, concentrations of TNF-α, IL-1β, IL-6, MIP-2, KC, IFN-γ, apoptosis, mRNA expression of the dual oxidase (DUOX1 and DUOX2), production of H
O
and DUOX activity were evaluated in lung tissue. We did not detect the Y chromosome in recipients' lungs. FRC, alveolar diameter, polymorphonuclear cells (PMN) and levels of KC, MIP-2, and IFN-γ increased in P14 and PS21 groups; the changes in the latter were reverted by BMMC. TNF-α, IL-1β e IL-6 were similar in all groups. The amount of elastic fibers was smaller in P14 and PS21 than in other groups, and BMMC did not increase it in PC21 mice. PS21 animals showed increased DUOX activity and mRNA expression for DUOX1 and 2. Cell therapy reverted the activity of DUOX and mRNA expression of DUOX1. BMMC reduced mRNA expression of DUOX2. Apoptosis index was elevated in PS21 mice, which was reduced by cell therapy in PC21. Static compliance, viscoelastic component of elastance and pressure to overcome viscoelasticity were increased in P14 and PS21 groups. These changes and the high resistive pressure found on day 21 were reverted by BMMC. In conclusion, BMMC showed potent anti-inflammatory, antiapoptotic, antioxidant, and restorative roles in papain-triggered pulmonary emphysema.
Zika virus (ZIKV) has been associated with serious health conditions, and an intense search to discover different ways to prevent and treat ZIKV infection is underway. Berberine and emodin possess ...several pharmacological properties and have been shown to be particularly effective against the entry and replication of several viruses. We show that emodin and berberine trigger a virucidal effect on ZIKV. When the virus was exposed to 160 µM of berberine, a reduction of 77.6% in the infectivity was observed; when emodin was used (40 µM), this reduction was approximately 83.3%. Dynamic light scattering data showed that both compounds significantly reduce the hydrodynamic radius of virus particle in solution. We report here that berberine and emodin, two natural compounds, have strong virucidal effect in Zika virus.
Cyanobacterial blooms that generate microcystins (MCYSTs) are increasingly recognized as an important health problem in aquatic ecosystems. We have previously reported the impairment of pulmonary ...structure and function by microcystin-LR (MCYST-LR) exposure as well as the pulmonary improvement by intraperitoneally injected (i.p.) LASSBio 596. In the present study, we aimed to evaluate the usefulness of LASSBio 596 per os on the treatment of pulmonary and hepatic injuries induced by MCYST-LR. Swiss mice received an intraperitoneal injection of 40 μl of saline (CTRL) or a sub-lethal dose of MCYST-LR (40 μg/kg). After 6 h the animals received either saline (TOX and CTRL groups) or LASSBio 596 (50 mg/kg, LASS group) by gavage. Eight hours after the first instillation, lung impedance (static elastance, elastic component of viscoelasticity and resistive, viscoelastic and total pressures) was determined by the end-inflation occlusion method. Left lung and liver were prepared for histology. In lung and hepatic homogenates MCYST-LR, TNF-α, IL-1β and IL-6 were determined by ELISA. LASSBio 596 per os (LASS mice) kept all lung mechanical parameters, polymorphonuclear (PMN) cells, pro-inflammatory mediators, and alveolar collapse similar to control mice (CTRL), whereas in TOX these findings were higher than CTRL. Likewise, liver structural deterioration (hepatocytes inflammation, necrosis and steatosis) and inflammatory process (high levels of pro-inflammatory mediators) were less evident in the LASS than TOX group. LASS and CTRL did not differ in any parameters studied. In conclusion, orally administered LASSBio 596 prevented lung and hepatic inflammation and completely blocked pulmonary functional and morphological changes induced by MCYST-LR.
► LASSBio 596 was tested for the first time by oral administration. ► LASSBio 596 per os avoided lung inflammation and pulmonary mechanical dysfunction. ► LASSBio 596 per os improved liver structure and inflammation.
Background
Previous research showed that mnemonic strategy training (MST) improves cognitive performance in people with MCI, and has been associated with increased brain activation consonant with the ...cognitive processes engaged by the training, such as, semantic memory, decision‐making, cognitive control, face processing and social cognition. Despite the growing body of literature on MST in MCI, we are not aware of any randomized controlled study that have examined the effect of MST on resting‐state functional connectivity (FC). Therefore, the aim of the present study was to investigate the effect of MST, focused on face‐name associations, on resting‐state FC in older adults with MCI.
Method
Twenty‐six amnestic MCI participants were randomized to one of two interventions: MST (N=14) or an Education Program (EP) (N=12). Both interventions were face‐to‐face, and occurred twice a week over two consecutive weeks (i.e., four sessions). Open‐eyes resting‐state functional magnetic resonance imaging (fMRI) was collected at pre‐ and post‐intervention. Nine regions of interest (ROIs) were selected a priori, based on areas that showed activation changes in a face‐name fMRI paradigm after MST (considering the contrast post>pre within the MST group, and in the comparison MST > EP). Changes in FC (post > pre, and pre > post) were examined through ROI‐to‐ROI analysis in the contrasts MST > EP and EP > MST. Analyses were conducted with CONN toolbox 17.f, and significant results were corrected for multiple comparison using false discovery rate (FDR).
Result
At post‐intervention, the MST group showed increased FC relative to the EP. Specifically, there was FC increase between the right inferior frontal gyrus (pars triangularis) and three ROIs in the left hemisphere: fusiform gyrus, temporal pole and orbitofrontal cortex. Within group analysis showed that FC increased after intervention only in the MST group, whereas the EP group showed decreased FC.
Conclusion
Our findings indicate that MST enhance FC in functionally relevant regions for the training; effects that support a general change in the innate connectivity that are not limited to a task‐specific condition. Our results extent the knowledge on the underlying mechanisms of MST, and may provide neurophysiological evidence of transfer.
Abstract
Background
Previous research showed that mnemonic strategy training (MST) improves cognitive performance in people with MCI, and has been associated with increased brain activation consonant ...with the cognitive processes engaged by the training, such as, semantic memory, decision‐making, cognitive control, face processing and social cognition. Despite the growing body of literature on MST in MCI, we are not aware of any randomized controlled study that have examined the effect of MST on resting‐state functional connectivity (FC). Therefore, the aim of the present study was to investigate the effect of MST, focused on face‐name associations, on resting‐state FC in older adults with MCI.
Method
Twenty‐six amnestic MCI participants were randomized to one of two interventions: MST (N=14) or an Education Program (EP) (N=12). Both interventions were face‐to‐face, and occurred twice a week over two consecutive weeks (i.e., four sessions). Open‐eyes resting‐state functional magnetic resonance imaging (fMRI) was collected at pre‐ and post‐intervention. Nine regions of interest (ROIs) were selected a priori, based on areas that showed activation changes in a face‐name fMRI paradigm after MST (considering the contrast post>pre within the MST group, and in the comparison MST > EP). Changes in FC (post > pre, and pre > post) were examined through ROI‐to‐ROI analysis in the contrasts MST > EP and EP > MST. Analyses were conducted with CONN toolbox 17.f, and significant results were corrected for multiple comparison using false discovery rate (FDR).
Result
At post‐intervention, the MST group showed increased FC relative to the EP. Specifically, there was FC increase between the right inferior frontal gyrus (pars triangularis) and three ROIs in the left hemisphere: fusiform gyrus, temporal pole and orbitofrontal cortex. Within group analysis showed that FC increased after intervention only in the MST group, whereas the EP group showed decreased FC.
Conclusion
Our findings indicate that MST enhance FC in functionally relevant regions for the training; effects that support a general change in the innate connectivity that are not limited to a task‐specific condition. Our results extent the knowledge on the underlying mechanisms of MST, and may provide neurophysiological evidence of transfer.
PDF
