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•The aqueous ultrasound-assisted extraction (UAE) of polyphenols was optimized for H. rhamnoides L. fruits.•UAE, enzymatic treatment (E-UAE), and buffers were used for the assessment ...of phenolic yield.•Phytochemical analysis revealed a high recovery of flavonols, specifically isorhamnetin-O-glycosides.•Non-buffered E-UAE extraction induced the highest yield of compounds with in vitro bioactivity.
The main purpose of the present study was to determine the effect of associating an optimized ultrasound-assisted extraction (UAE) protocol with enzyme-assisted extraction (EAE) in aqueous media, using the dried berries of Hippophae rhamnoides L. (sea buckthorn) as plant material. A specialized software was used for the determination of potential optimal extraction parameters, leading to the development of four optimized extracts with different characteristics (UAE ± EAE). For these extracts, buffered or non-buffered solutions have been used, with the aim to determine the influence of adjustable pH on extractability. As enzymatic solution, a pectinase, cellulase, and hemicellulase mix (2:1:1) has been applied, acting as pre-treatment for the optimized protocol. The highest extractive yields have been identified for non-buffered extracts, and the E-UAE combination obtained extracts with the highest overall in vitro antioxidant activity. The HPLC-MSn analysis demonstrated a rich composition in different types of isorhamnetin-O-glycosides, as well as some quercetin-O-glycosides, showing a high recovery of specific flavonol-type polyphenolic species. Moreover, we have tentatively identified two flavanols (i.e., catechin and epigallocatechin) and one flavone derivative (i.e., luteolin).
Oligodendrocyte death and demyelination are hallmarks of multiple sclerosis (MS). Here we show that ATP signaling can trigger oligodendrocyte excitotoxicity via activation of calcium-permeable P2X
7
...purinergic receptors expressed by these cells. Sustained activation of P2X
7
receptors
in vivo
causes lesions that are reminiscent of the major features of MS plaques, i.e., demyelination, oligodendrocyte death, and axonal damage. In addition, treatment with P2X
7
antagonists of chronic experimental autoimmune encephalomyelitis (EAE), a model of MS, reduces demyelination and ameliorates the associated neurological symptoms. Together, these results indicate that ATP can kill oligodendrocytes via P2X
7
activation and that this cell death process contributes to EAE. Importantly, P2X
7
expression is elevated in normal-appearing axon tracts in MS patients, suggesting that signaling through this receptor in oligodendrocytes may be enhanced in this disease. Thus, P2X
7
receptor antagonists may be beneficial for the treatment of MS.
•Enhanced eosinophil numbers in the spinal cord in the course of EAE.•Absence of eosinophils has no impact on clinical development or severity of EAE.•Spinal cord inflammation and demyelination is ...not affected by eosinophil deficiency.
Experimental autoimmune encephalomyelitis (EAE) represents the mouse model of multiple sclerosis, a devastating neurological disorder. EAE development and progression involves the infiltration of different immune cells into the brain and spinal cord. However, less is known about a potential role of eosinophil granulocytes for EAE disease pathogenesis. In the present study, we found enhanced eosinophil abundance accompanied by increased concentration of the eosinophil chemoattractant eotaxin-1 in the spinal cord in the course of EAE induced in C57BL/6 mice by immunization with MOG35–55 peptide. However, the absence of eosinophils did not affect neuroinflammation, demyelination and clinical development or severity of EAE, as assessed in ∆dblGATA1 eosinophil-deficient mice. Taken together, despite their enhanced abundance in the inflamed spinal cord during disease progression, eosinophils were dispensable for EAE development.
•New amines(aq) solutions densities and isobaric heat capacities experimental data over a wide range of conditions.•Density and isobaric heat capacity decrease with amine mass fraction.•A modified ...Tammann-Tait Equation represents experimental density as a function of temperature, pressure, and molality.•Experimental data agrees with reported literature data within uncertainties.•Isobaric heat capacity is well-represented with an empirical correlation as a function of temperature and composition.
Densities and isobaric heat capacities of DEAE + H2O and EAE + H2O systems are presented in this paper. Density measurements were carried out at high pressure (up to 100 MPa) and temperatures from (293.15 to 393.15) K, with amine mass fractions of 0.1; 0.2; 0.3 and 0.4. These data were gathered using a vibrating tube densimeter (Anton Paar DMA HPM) with a relative expanded uncertainty of ±0.1 % (k = 2). A non-adiabatic quasi-isothermal flow calorimeter was used for isobaric heat capacity measurements with a relative expanded uncertainty better than 1 % (k = 2). Measurements reached pressures up to 25 MPa, and temperatures from (293.15 to 353.15) K, with amine mass fractions of 0.1; 0.2; 0.3 and 0.4. Both amine DEAE + H2O and EAE + H2O systems show a density and isobaric heat capacity decrease with amine mass fraction increase. Density data as a function of temperature, pressure and molality were fitted using a modified Tammann-Tait empirical equation of state. Furthermore, isobaric heat capacity data were correlated using an empirical function of temperature and amine mass fraction, but not pressure due to its lack of sensitivity in the measured data. Both correlations are in good agreement with the uncertainties. Comparison with experimental density data available in literature showed lower deviations than the associated uncertainties. Our isobaric heat capacity experimental data agree well with the scarce literature.
Abstract Multiple sclerosis (MS), a demyelinating disease of the central nervous system (CNS), presents as a complex disease with variable clinical and pathological manifestations, involving ...different pathogenic pathways. Animal models, particularly experimental autoimmune encephalomyelitis (EAE), have been key to deciphering the pathophysiology of MS, although no single model can recapitulate the complexity and diversity of MS, or can, to date, integrate the diverse pathogenic pathways. Since the first EAE model was introduced decades ago, multiple classic (induced), spontaneous, and humanized EAE models have been developed, each recapitulating particular aspects of MS pathogenesis. The advances in technologies of genetic ablation and transgenesis in mice of C57BL/6J background and the development of myelin-oligodendrocyte glycoprotein (MOG)-induced EAE in C57BL/6J mice yielded several spontaneous and humanized EAE models, and resulted in a plethora of EAE models in which the role of specific genes or cell populations could be precisely interrogated, towards modeling specific pathways of MS pathogenesis/regulation in MS. Collectively, the numerous studies on the different EAE models contributed immensely to our basic understanding of cellular and molecular pathways in MS pathogenesis as well as to the development of therapeutic agents: several drugs available today as disease modifying treatments were developed from direct studies on EAE models, and many others were tested or validated in EAE. In this review, we discuss the contribution of major classic, spontaneous, and humanized EAE models to our understanding of MS pathophysiology and to insights leading to devising current and future therapies for this disease.
Data-driven soft sensors have been widely used in industrial processes. Traditional soft sensors are mostly shallow networks, which cannot easily describe the complicated process data patterns. In ...this article, a new deep learning approach is proposed for soft sensors, which is based on the stacked enhanced auto-encoder (SEAE). The original stacked auto-encoder (SAE) learns the hierarchical features of the raw observed input data with unsupervised layerwise pretraining. In each layer, the features are learned from its low-level ones with an AE by minimizing the reconstruction error for them. This usually causes accumulation of information loss from the lowest layer to the highest layer. Hence, the learned features may not well represent the raw input data patterns. The new SEAE network is designed by adding the constraint of additional reconstruction for the raw input data at each layer. In this way, the learned features at each layer are a good representation for the raw input data. The effectiveness of the proposed SEAE-based soft sensor method is validated on an industrial sulfur recovery unit.
The sphingosine 1-phosphate (S1P) receptor 1 (S1P1) has emerged as a therapeutic target for the treatment of multiple sclerosis (MS). Fingolimod (FTY720) is the first functional antagonist of S1P1 ...that has been approved for oral treatment of MS. Previously, we have developed novel butterfly derivatives of FTY720 that acted similar to FTY720 in reducing disease symptoms in a mouse model of experimental autoimmune encephalomyelitis (EAE).
In this study, we have synthesized a piperidine derivative of the oxazolo-oxazole compounds, denoted ST-1505, and its ring-opened analogue ST-1478, and characterised their in-vitro and in-vivo functions. Notably, the 3-piperidinopropyloxy moiety resembles a structural motif of pitolisant, a drug with histamine H3R antagonistic/inverse agonist activity approved for the treatment of narcolepsy. Both novel compounds exerted H3R affinities, and in addition, ST-1505 was characterised as a dual S1P1+3 agonist, whereas ST-1478 was a dual S1P1+5 agonist. Both multitargeting compounds were also active in mice and reduced the lymphocyte numbers as well as diminished disease symptoms in the mouse model of MS. The effect of ST-1478 was dependent on SK-2 activity suggesting that it is a prodrug like FTY720, but with a more selective S1P receptor activation profile, whereas ST-1505 is a fully active drug even in the absence of SK-2.
In summary, these data suggest that the well soluble piperidine derivatives ST-1505 and ST-1478 hold promise as novel drugs for the treatment of MS and other autoimmune or inflammatory diseases, and by their H3R antagonist potency, they might additionally improve cognitive impairment during disease.
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•ST-1505 and ST-1478 are novel dual modulators, that act as S1P1 receptor functional antagonists and histamine H3R antagonists.•ST-1478 is a pro-drug that requires SK-2 for activation.•ST-1505 is a fully active drug acting independent of SK-2.•They act protective in a mouse model of multiple sclerosis.•The combined modulation of S1P1 and H3R may have an additional benefit in MS treatment as compared to S1P1 alone.
Microglial cell activation is the earliest biomarker of the inflammatory processes that cause central nervous system (CNS) lesions in multiple sclerosis. We hypothesized that 1,25-dihydroxyvitamin D3 ...(1,25-(OH)2D3) production by activated microglia and macrophages in the CNS inhibits these inflammatory processes. To test this hypothesis, we targeted the Cyp27b1 gene specifically in myeloid cells, then analyzed the influence of disrupted myeloid cell 1,25-(OH)2D3 synthesis on vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis (EAE). Myeloid cell 1,25-(OH)2D3 synthesis was essential for vitamin D3-mediated EAE resistance. Increased CTLA-4 expression in the CNS-infiltrating CD4+ Tconv and Treg cells and decreased splenic B cell CD86 expression correlated with resistance. These new data provide solid support for the view that vitamin D3 reduces MS risk in part through a mechanism involving myeloid cell 1,25-(OH)2D3 production and CTLA-4 upregulation in CNS-infiltrating CD4+ T cells. We suggest that CTLA-4 serves as a vitamin D3-regulated immunological checkpoint in multiple sclerosis prevention.
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•CYP27B1 (25-(OH)D3 hydroxylase) was specifically deleted in myeloid cells•Myeloid cell derived 1,25-(OH)2D3 is required for vitamin D3-mediated prevention of EAE.•Paracrine 1,25-(OH)2D3 signaling in the CNS led to enhanced CTLA-4 expression in effector and regulatory CD4+ T cells.
Multiple sclerosis (MS) is an autoimmune and neurodegenerative disorder characterized by chronic inflammation, demyelination, as well as axonal and neuronal loss in the central nervous system (CNS). ...Macrophages and microglia are important components of the innate immune system. They participate in the primary response to microorganisms and play a role in inflammatory responses, homeostasis, and tissue regeneration. In the initial phase of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, macrophages from peripheral tissues infiltrate into the CNS and, together with residential microglia, contribute to the pathogenesis of MS. In the early stages, microglia and macrophages are expressed as the M1 phenotype, which can release proinflammatory cytokines, leading to tissue damage in the CNS. However, in the later stage, the M2 phenotype, which is the phenotype that is associated with resolving inflammation and tissue repair, becomes predominant in the CNS. Therefore, it is hypothesized that the M1/M2 phenotype balance plays an important role in disease progression and that the transition from the proinflammatory M1 phenotype to the regulatory or anti-inflammatory M2 phenotype can lead to restoration of homeostasis and improved functional outcomes. This review of recent literature focuses on the discussion of the M1/M2 phenotypes of microglia and macrophages as well as their relevance in the pathophysiology and treatment of MS and EAE. Furthermore, the possibility of directing the polarization of microglia and macrophages toward the M2 phenotype as a therapeutic and preventative strategy for MS is discussed.
•MS is the most common cause of neurological disability in the young adults and lack effective treatment.•Microglia and macrophages are the key players in the development of EAE and MS, and exert two opposite effects.•The M1 and M2 subpopulations co-exist in the CNS and peripheral system during the disease progression.•Molecular interventions of M2 subpopulation may be a potential therapeutic approach for EAE and MS in the future.
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