Inflammasomes are immune complexes whose activation leads to the release of pro-inflammatory cytokines IL-18 and IL-1β. Type I IFNs play a role in fighting infection and stimulate the expression of ...IFN-stimulated genes (ISGs) involved in inflammation. Despite the importance of these cytokines in inflammation, the regulation of inflammasomes by type I IFNs remains poorly understood. Here, we analysed RNA-sequencing data from patients with monogenic interferonopathies and found an up-regulation of several inflammasome-related genes. To investigate the effect of type I IFN on the inflammasome, we treated human monocyte-derived macrophages with IFN-α and observed an increase in
and
mRNA levels over time, whereas
and
were not directly correlated to IFN-α exposure time. IFN-α treatment reduced the release of mature IL-1β and IL-18, but not caspase-1, in response to ATP-mediated NLRP3 inflammasome activation, suggesting regulation occurs at cytokine expression levels and not the inflammasome itself. However, more studies are required to investigate how regulation by IFN-α occurs and impacts NLRP3 and other inflammasomes at both transcriptional and post-translational levels.
Cytokine- and chemokine-mediated signalling is involved in the neuroinflammatory process that leads to retinal ganglion cell (RGC) damage in glaucoma. Substances with anti-inflammatory properties ...could decrease these cytokines and chemokines and thus prevent RGC death. The authors of this study analysed the anti-inflammatory effect of a hydrophilic saffron extract standardized to 3% crocin content, focusing on the regulation of cytokine and chemokine production, in a mouse model of unilateral laser-induced ocular hypertension (OHT). We demonstrated that following saffron treatment, most of the concentration of proinflammatory cytokines (IL-1β, IFN-γ, TNF-α, and IL-17), anti-inflammatory cytokines (IL-4 and IL-10), Brain-derived Neurotrophic Factor (BDNF), Vascular Endothelial Growth Factor (VEGF), and fractalkine were unaffected in response to laser-induced OHT in both the OHT eye and its contralateral eye. Only IL-6 levels were significantly increased in the OHT eye one day after laser induction compared with the control group. These results differed from those observed in animals subjected to unilateral OHT and not treated with saffron, where changes in cytokine levels occurred in both eyes. Therefore, saffron extract regulates the production of proinflammatory cytokines, VEGF, and fractalkine induced by increasing intraocular pressure (IOP), protecting the retina from inflammation. These results indicate that saffron could be beneficial in glaucoma by helping to reduce the inflammatory process.
Purpose: To analyse the anti‐inflammatory effect of saffron extract, by regulating the expression of cytokines and chemokines involved in the neuroinflammatory process leading to retinal ganglion ...cell (RGC) damage, in a mouse model of unilateral laser‐induced ocular hypertension (OHT).
Methods: Three groups of Albino Swiss mice treated with saffron extract were used; saffron naïve group (SNG), saffron laser group 1 day (SLG1d) and saffron laser group 3 days (SLG3d). Both eyes with OHT (treated with laser photocoagulation) and their contralateral were analysed. Retinal samples were processed and multiarray kits (MILLIPLEX MAP Mouse Cytokine/Myokine Magnetic Bead Panel) were used to quantify the expression of: IL‐1β, IL‐4, IL‐6, IL‐10, IL‐17, IFN‐ϒ, TNF‐α, Brain‐derived Neurotrophic Factor (BDNF), Vascular Endothelial Growth Factor (VEGF) and Fractalkine. Immunohistochemical analysis was performed to locate cells expressing the factors and cytokines detected in the multiplex assay.
Results: After saffron treatment, no significant differences were found, at 1 and 3 days after laser‐induced OHT, between the concentration of proinflammatory cytokines (IL‐1β, IFN‐γ, TNF‐α and IL‐17), anti‐inflammatory cytokines (IL‐4 and IL‐10), BDNF, VEGF, and fractalkine in both the OHT eye and its contralateral eye, compared to saffron naïve. IL‐6 levels increased significantly in the OHT eye in SLG1d, reaching normal values at SLG3d compared to SNG. These results are contrary to those found in OHT eyes and their contralateral not treated with saffron, in which changes in cytokine levels were observed.
Conclusions: Saffron is effective in regulating the production of proinflammatory cytokines, VEGF, and fractalkine induced by increased IOP, thus protecting the retina from its related damage. Saffron could be beneficial as coadjutant therapies in the treatment of glaucoma, thus helping to decrease the inflammatory process that occurs in this pathology.
Glaucoma is a neurodegenerative disease that causes blindness. In this study, we aimed to evaluate the protective role of cilastatin (CIL), generally used in the treatment of nephropathologies ...associated with inflammation, in an experimental mouse model based on unilateral (left) laser-induced ocular hypertension (OHT). Male Swiss mice were administered CIL daily (300 mg/kg, i.p.) two days before OHT surgery until sacrifice 3 or 7 days later. Intraocular Pressure (IOP), as well as retinal ganglion cell (RGC) survival, was registered, and the inflammatory responses of macroglial and microglial cells were studied via immunohistochemical techniques. Results from OHT eyes were compared to normotensive contralateral (CONTRA) and naïve control eyes considering nine retinal areas and all retinal layers. OHT successfully increased IOP values in OHT eyes but not in CONTRA eyes; CIL did not affect IOP values. Surgery induced a higher loss of RGCs in OHT eyes than in CONTRA eyes, while CIL attenuated this loss. Similarly, surgery increased macroglial and microglial activation in OHT eyes and to a lesser extent in CONTRA eyes; CIL prevented both macroglial and microglial activation in OHT and CONTRA eyes. Therefore, CIL arises as a potential effective strategy to reduce OHT-associated damage in the retina of experimental mice.
Abstract
Background and Aims
Hyponatremia is the most common electrolyte disturbance in clinical care. Even mild presentations are associated with poor prognosis and increased mortality, in spite of ...which there is a trend to minimize the importance of small variations in natremia, that have historically been dismissed as not having negative consequences despite growing evidence against it. In this regard, it has not been studied to date whether an intermittent but recurrent hyponatremia is relevant. There are clinical scenarios where this condition could occur and be overlooked, such as cirrhosis or heart failure.
Method
Different rat models have been used to study the effects of different hypotonic situations on the electrolyte balance and central nervous system: intermittent recurrent hyponatremia (intraperitoneal (i.p.) daily dose of desmopressin acetate (ddAVP) and a water dose equivalent to 2.5% of the animal's body weight in hyposodic diet fed animals), acute on intermittent recurrent hyponatremia (i.p. water overload equivalent to 10% of the animal's body weight in animals subjected to intermittent recurrent hyponatremia) and acute hyponatremia (i.p. administration of a 10% of the animal's body weight water overload in chow fed animals). Apparent diffusion coefficient (ADC) obtained from diffusion weighted images (DWI) acquired through magnetic resonance (7T Bruker Biospec) was used to study content and distribution of brain water, and immunohistochemistry was used to examine glial fibrillary acidic-protein (GFAP), astrocyte marker, and myelin basic protein (MBP), oligodendrocyte and myelin marker.
Results
In the intermittent recurrent hyponatremia model, mild and transient hyponatremia was induced (baseline Nap 136.50±1.73mEq/L vs 4h post-medication 129.44±1.20mEq/L, p<0.001), which was recovered 24h after treatment (141.25±0.96mEq/L, NS compared to baseline). However, this situation was repeated over a 7 day period. This translated into a lower ADC value in the whole brain (WB) compared to chow fed animals (25.07±1.71 vs 26.71±2.40*10−3mm2/s, p = 0.05) after this 7 day period, suggesting an increase in total brain water in this situation. There was also an increase in GFAP expression in the gray matter (GM) compared to chow fed animals (33.22±5.25 vs 25.07±2.31au, p = 0.031), although no significant changes in MBP’s expression were seen. Acute on intermittent recurrent hyponatremia induced hypotonic hyponatremia (116.00±1.16mEq/L, p<0.001 compared to baseline). In this situation, a progressive decrease in ADC values in the WB was seen, and it was less pronounced compared to chow fed animals (slope -0.11±0.02 vs -0.26±0.006, p = 0.014). When GM and white matter (WM) were analysed separately, they both showed a progressive increase in ADC values, more evident in the WM (slope WM 0.19±0.04, p<0.05; slope GM 0.05±0.02, p = 0.002). The water overload increased GFAP and MBP’s expression in the WM (GFAP 23.17±6.37 vs 16.83±5.17au, p = 0.001; MBP 45.20±8.32 vs 28.76±7.03au, p<0.001), but no changes were seen in the GM, similarly to what had been observed in the acute hyponatremia model.
Conclusion
Intermittent recurrent hyponatremia is a novel animal model that suggests there can be significant water retention after only a few hours of hyponatremia a day, provided this situation is repeated over time. Such water retention translates into greater brain water accumulation and astroglial activation in the GM. These animals's response to an additional water overload does not show big variations compared to what is observed in acute hyponatremia. This study highlights the importance of slight fluctuations in natremia, which, if maintained over time, can translate underlying water retention with consequences at the central nervous system level.
Wernicke-Korsakoff Syndrome (WKS) is a neuropsychiatric disorder whose etiology is a thiamine deficiency (TD), with alcoholism being the main underlying cause. Previous evidence suggests the presence ...of initial neuroinflammation and oxidative/nitrosative stress in the physiopathology, although the specific molecular mechanisms underlying TD-induced brain damage and behavioral disabilities are unknown.
We explored the specific role of the innate immune receptor TLR4 in three murine models of WKS, based on the combination of a thiamine-deficient diet and pyrithiamine injections (0.25 mg/kg, i.p.) over time. The Symptomatic Model (SM) allowed us to describe the complete neurological/neurobehavioral symptomatology over 16 days of TD. Animals showed an upregulation of the TLR4 signaling pathway both in the frontal cortex (FC) and cerebellum and clear motor impairments related with cerebellar dysfunction. However, in the Pre-Symptomatic Model (PSM), 12 days of TD induced the TLR4 pathway upregulation in the FC, which correlated with disinhibited-like behavior, but not in the cerebellum, and no motor impairments. In addition, we tested the effects of the biolipid oleoylethanolamide (OEA, 10 mg/kg, i.p., once daily, starting before any symptom of the pathology is manifested) through the Glucose-Precipitated Model (GPM), which was generated by glucose loading (5 g/kg, i.v., last day) in thiamine-deficient animals to accelerate damage. Pretreatment with OEA prevented the TLR4-induced signature in the FC, as well as an underlying incipient memory disability and disinhibited-like behavior.
This study suggests a key role for TLR4 in TD-induced neuroinflammation in the FC and cerebellum, and it reveals different vulnerability of these brain regions in WKS over time. Pre-treatment with OEA counteracts TD-induced TLR4-associated neuroinflammation and may serve as co-adjuvant therapy to prevent WKS-induced neurobehavioral alterations.
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•Pivotal role of TLR4 in thiamine deficiency-induced neuroinflammation in three animal models of Wernicke-Korsakoff Syndrome.•Different vulnerability of frontal cortex and cerebellum to thiamine deficiency-induced TLR4 cascade upregulation over time.•Changes in the frontal cortex and cerebellum correlate with disinhibited-like behavior and motor dysfunction, respectively.•OEA pretreatment prevents the TLR4 cascade in frontal cortex, a light memory impairment and the disinhibition-like behavior.
Vertical dispersion in vegetated shear flows Rubol, Simonetta; Battiato, Ilenia; de Barros, Felipe P. J.
Water resources research,
October 2016, Letnik:
52, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Canopy layers control momentum and solute transport to and from the overlying water surface layer. These transfer mechanisms strongly dependent on canopy geometry, affect the amount of solute in the ...river, the hydrological retention and availability of dissolved solutes to organisms located in the vegetated layers, and are critical to improve water quality. In this work, we consider steady state transport in a vegetated channel under fully developed flow conditions. Under the hypothesis that the canopy layer can be described as an effective porous medium with prescribed properties, i.e., porosity and permeability, we model solute transport above and within the vegetated layer with an advection‐dispersion equation with a spatially variable dispersion coefficient (diffusivity). By means of the Generalized Integral Transform Technique, we derive a semianalytical solution for the concentration field in submerged vegetated aquatic systems. We show that canopy layer's permeability affects the asymmetry of the concentration profile, the effective vertical spreading behavior, and the magnitude of the peak concentration. Due to its analytical features, the model has a low computational cost. The proposed solution successfully reproduces previously published experimental data.
Key Points
Solute transport in vegetated aquatic flows
Development of a computationally efficient semianalytical solution for the concentration
Vegetation permeability has a key role in regulating transport
Knowledge about the mechanism of action (MoA) of monoclonal antibodies (mAb) is required to understand which patients with multiple myeloma (MM) benefit the most from a given mAb, alone or in ...combination therapy. Although there is considerable research about daratumumab, knowledge about other anti-CD38 mAbs remains scarce.
We performed a comprehensive analysis of the MoA of isatuximab.
Isatuximab induces internalization of CD38 but not its significant release from MM cell surface. In addition, we uncovered an association between levels of CD38 expression and different MoA: (i) Isatuximab was unable to induce direct apoptosis on MM cells with CD38 levels closer to those in patients with MM, (ii) isatuximab sensitized CD38
MM cells to bortezomib plus dexamethasone in the presence of stroma, (iii) antibody-dependent cellular cytotoxicity (ADCC) was triggered by CD38
and CD38
tumor plasma cells (PC), (iv) antibody-dependent cellular phagocytosis (ADCP) was triggered only by CD38
MM cells, whereas (v) complement-dependent cytotoxicity could be triggered in less than half of the patient samples (those with elevated levels of CD38). Furthermore, we showed that isatuximab depletes CD38
B-lymphocyte precursors and natural killer (NK) lymphocytes
-the latter through activation followed by exhaustion and eventually phagocytosis.
This study provides a framework to understand response determinants in patients treated with isatuximab based on the number of MoA triggered by CD38 levels of expression, and for the design of effective combinations aimed at capitalizing disrupted tumor-stroma cell protection, augmenting NK lymphocyte-mediated ADCC, or facilitating ADCP in CD38
MM patients.
.
We put together a first-principles equation of state (FPEOS) database for matter at extreme conditions by combining results from path integral Monte Carlo and density functional molecular dynamics ...simulations of the elements H, He, B, C, N, O, Ne, Na, Mg, Al, and Si as well as the compounds LiF, B_{4}C, BN, CH_{4}, CH_{2}, C_{2}H_{3}, CH, C_{2}H, MgO, and MgSiO_{3}. For all these materials, we provide the pressure and internal energy over a density-temperature range from ∼0.5 to 50 g cm^{-3} and from ∼10^{4} to 10^{9} K, which are based on ∼5000 different first-principles simulations. We compute isobars, adiabats, and shock Hugoniot curves in the regime of L- and K-shell ionization. Invoking the linear mixing approximation, we study the properties of mixtures at high density and temperature. We derive the Hugoniot curves for water and alumina as well as for carbon-oxygen, helium-neon, and CH-silicon mixtures. We predict the maximal shock compression ratios of H_{2}O, H_{2}O_{2}, Al_{2}O_{3}, CO, and CO_{2} to be 4.61, 4.64, 4.64, 4.89, and 4.83, respectively. Finally we use the FPEOS database to determine the points of maximum shock compression for all available binary mixtures. We identify mixtures that reach higher shock compression ratios than their end members. We discuss trends common to all mixtures in pressure-temperature and particle-shock velocity spaces. In the Supplemental Material, we provide all FPEOS tables as well as computer codes for interpolation, Hugoniot calculations, and plots of various thermodynamic functions.
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