Hybrid Nanoparticles as a Novel Tool for Regulating Psychosine-Induced Neuroinflammation and Demyelination In Vitro and Ex vivo

Polymeric nanoparticles are being extensively investigated as an approach for brain delivery of drugs, especially for their controlled release and targeting capacity. Nose-to-brain administration of nanoparticles, bypassing the blood brain barrier, offers a promising strategy to deliver drugs to the central nervous system. Here, we investigated the potential of hybrid nanoparticles as a therapeutic approach for demyelinating diseases, more specifically for Krabbe’s disease. This rare leukodystrophy is characterized by the lack of enzyme galactosylceramidase, leading to the accumulation of toxic psychosine in glial cells causing neuroinflammation, extensive demyelination and death. We present evidence that lecithin/chitosan nanoparticles prevent damage associated with psychosine by sequestering the neurotoxic sphingolipid via physicochemical hydrophobic interactions. We showed how nanoparticles prevented the cytotoxicity caused by psychosine in cultured human astrocytes in vitro, and how the nanoparticle size and PDI augmented while the electrostatic charges of the surface decreased, suggesting a direct interaction between psychosine and the nanoparticles. Moreover, we studied the effects of nanoparticles ex vivo using mouse cerebellar organotypic cultures, observing that nanoparticles prevented the demyelination and axonal damage caused by psychosine, as well as a moderate prevention of the astrocytic death. Taken together, these results suggest that lecithin-chitosan nanoparticles are a potential novel delivery system for drugs for certain demyelinating conditions such as Krabbe’s disease, due to their dual effect: not only are they an efficient platform for drug delivery, but they exert a protective effect themselves in tampering the levels of psychosine accumulation

Eco-friendly strategy for the joint valorization of invasive macroalgae and fast-growing wood to produce advanced biofuels

A novel sustainable scheme to jointly valorize Sargassum muticum (Sm) and Paulownia wood (PW) was proposed in this work, employing the advanced environmentally friendly microwave-assisted autohydrolysis (MA) as pretreatment. Sm is an invasive macroalga that has been drastically spread in the Atlantic coast of Europe, causing environmental damage. Conversely, Paulownia elongata x fortunei is a fast-growing biomass with a high biomass production and potential for biofuels production. Thus, the concomitant valorization of both biomasses may lead to benefits related to environmental protection and bioeconomy. A sequential approach was proposed: first stage of glucose production from Sm (treated by MA and enzymatic hydrolysis to obtain a glucose-rich liquor), and second stage with MA-pretreated PW followed by saccharification and fermentation, employing in this process the glucose rich solution obtained from algae, to obtain simultaneously second and third generation bioethanol. These approaches enabled to add the ethanol production from both biomasses, leading to up to 45.2 g ethanol/L (70% ethanol yield), boosting ethanol titers compared to using only one biomass (up to 27.8 g/L) and confirming the benefits of combining MA-processed biomass. Furthermore, up to 87% of the energy may be recovered, reflecting a suitable approach within an integrated strategy.Agencia Estatal de Investigación | Ref. PID2019-110031RB-I00Agencia Estatal de Investigación | Ref. CNS2022-136095Xunta de Galicia | Ref. ED431C 2017/62-GRCXunta de Galicia | Ref. ED481B-2022-020Agencia Estatal de Investigación | Ref. RYC2018-026177-IAgencia Estatal de Investigación | Ref. RYC2020-030690-IUniversidade de Vigo/CISU

Piezo1 regulates calcium oscillations and cytokine release from astrocytes

Astrocytes are important for information processing in the brain and they achieve this by fine‐tuning neuronal communication via continuous uptake and release of biochemical modulators of neurotransmission and synaptic plasticity. Often overlooked are their important functions in mechanosensation. Indeed, astrocytes can detect pathophysiological changes in the mechanical properties of injured, ageing, or degenerating brain tissue. We have recently shown that astrocytes surrounding mechanically‐stiff amyloid plaques upregulate the mechanosensitive ion channel, Piezo1. Moreover, ageing transgenic Alzheimer's rats harboring a chronic peripheral bacterial infection displayed enhanced Piezo1 expression in amyloid plaque‐reactive astrocytes of the hippocampus and cerebral cortex. Here, we have shown that the bacterial endotoxin, lipopolysaccharide (LPS), also upregulates Piezo1 in primary mouse cortical astrocyte cultures in vitro. Activation of Piezo1, via the small molecule agonist Yoda1, enhanced Ca2+ influx in both control and LPS‐stimulated astrocytes. Moreover, Yoda1 augmented intracellular Ca2+ oscillations but decreased subsequent Ca2+ influx in response to adenosine triphosphate (ATP) stimulation. Neither blocking nor activating Piezo1 affected cell viability. However, LPS‐stimulated astrocyte cultures exposed to the Piezo1 activator, Yoda1, migrated significantly slower than reactive astrocytes treated with the mechanosensitive channel‐blocking peptide, GsMTx4. Furthermore, our data show that activating Piezo1 channels inhibits the release of cytokines and chemokines, such as IL‐1β, TNFα, and fractalkine (CX3CL1), from LPS‐stimulated astrocyte cultures. Taken together, our results suggest that astrocytic Piezo1 upregulation may act to dampen neuroinflammation and could be a useful drug target for neuroinflammatory disorders of the brain

Synergetic effect of hydrothermal and deep eutectic solvents (DES) pretreatments on Robinia wood fractionation for the manufacture of bioethanol and cellulose nanocrystals

This study dealt with the use of environmentally friendly processes based on microwave-assisted autohydrolysis (MAA) and deep eutectic solvents (DES) for the selective fractionation of Robinia pseudoacacia wood (RW) within a biorefinery approach. MAA enabled the recovery of 76% of hemicelluloses in the form of oligomers. Afterwards, different conditions were assessed for the optimal delignification of RW with the DES choline chloride combined with lactic acid reaching delignification ratios up to 86%. Two different methods were accomplished to valorize the cellulosic-rich solid fraction after delignification: (i) bioethanol via enzymatic-fermentative pathway (attaining 53.3 g ethanol/L, about 83% of ethanol yield), and (ii) cellulose nanocrystals (length of 27–550 nm, width of 2–12 nm). Hence, this study presents a novel multiproduct biorefinery to selectively separate the main components of RW and valorize its cellulosic fraction using eco-friendly proceduresUniversidade de Vigo/CISUGMinisterio de Economía| Ref. PID2019-110031RB-I00Xunta de Galicia | Ref. ED431C 2017/62-GRCMinisterio de Ciencia, Innovación y Universidades | Ref. FPU21/02446Ministerio de Ciencia, Innovación y Universidades | Ref. PRE2020-093359Ministerio de Ciencia, Innovación y Universidades | Ref. RYC2018-026177-IXunta de Galicia | Ref. ED481B-2022-02

Microwave-assisted extraction of hemicellulosic oligosaccharides and phenolics from Robinia pseudoacacia wood

Financiaciado para publicación en acceso aberto: Universidade de Vigo/CISUGMicrowave-assisted autohydrolysis is an environmentally friendly intensification technology that permits the selective solubilization of hemicelluloses in form of oligosaccharides in a short time and with low energy consumption. The purpose of this work was to evaluate the suitability of microwave-assisted autohydrolysis to produce oligosaccharides and phenolics with potential prebiotic and antioxidant activities from Robinia pseudoacacia wood. The influence of treatment time (0–30 min) and temperature (200–230 ◦C) on oligosaccharide production was studied and conditions of 230 ◦C and 0.25 min resulted in maximum content of xylooligosaccharides (7.69 g XO/L) and more efficient energy consumption. Furthermore, under those conditions, liquors showed high contents of phenols (80.28 mg GAE/g of RW) and flavonoids (44.51 RE/g) with significant antioxidant activities (112.07 and 102.30 mg TE/g, measured by ABTS and FRAP tests, respectively). Additionally, the solubilized hemicelluloses were structurally characterized by HPAEC-PAD, MALDI-TOF-MS, FTIR and TGA/DSC, and HPLC-ESI-MS analysis allowed the tentative identification of 17 phytochemicals.Ministerio de Economía y Competitividad | Ref. PID2019-110031RB-I00Xunta de Galicia | Ref. ED431C 2017/62-GRCMinisterio de Ciencia e Innovación | Ref. FPU21/02446Ministerio de Ciencia e Innovación | Ref. PRE 2020 093359Ministerio de Ciencia e Innovación | Ref. RYC2018-026177-IXunta de Galicia | Ref. ED481B-2022-02

Inhibition of Piezo1 attenuates demyelination in the central nervous system

Piezo1 is a mechanosensitive ion channel that facilitates the translation of extracellular mechanical cues to intracellular molecular signaling cascades through a process termed, mechanotransduction. In the central nervous system (CNS), mechanically gated ion channels are important regulators of neurodevelopmental processes such as axon guidance, neural stem cell differentiation, and myelination of axons by oligodendrocytes. Here, we present evidence that pharmacologically mediated overactivation of Piezo1 channels negatively regulates CNS myelination. Moreover, we found that the peptide GsMTx4, an antagonist of mechanosensitive cation channels such as Piezo1, is neuroprotective and prevents chemically induced demyelination. In contrast, the positive modulator of Piezo1 channel opening, Yoda‐1, induces demyelination and neuronal damage. Using an ex vivo murine‐derived organotypic cerebellar slice culture model, we demonstrate that GsMTx4 attenuates demyelination induced by the cytotoxic lipid, psychosine. Importantly, we confirmed the potential therapeutic effects of GsMTx4 peptide in vivo by co‐administering it with lysophosphatidylcholine (LPC), via stereotactic injection, into the cerebral cortex of adult mice. GsMTx4 prevented both demyelination and neuronal damage usually caused by the intracortical injection of LPC in vivo; a well‐characterized model of focal demyelination. GsMTx4 also attenuated both LPC‐induced astrocyte toxicity and microglial reactivity within the lesion core. Overall, our data suggest that pharmacological activation of Piezo1 channels induces demyelination and that inhibition of mechanosensitive channels, using GsMTx4, may alleviate the secondary progressive neurodegeneration often present in the latter stages of demyelinating diseases

Recuperacion de compostos bioactivos procedentes de podas de vide mediante o uso de disolventes intelixentes

Neste traballo investigouse a obtención de compostos antioxidantes a partir de podas da vide mediante extracción sólido-líquido utilizando solventes eutécticos profundos (DES) como un medio para desenvolver procesos de separación sostibles. A partir dunha selección preliminar de sete Deep Eutectic Solvents (DES) diferentes, seleccionouse unha combinación a base de glicerina-glicina-auga como sistema máis efectivo para recuperar compostos fenólicos a partir desta biomasa residual. Posteriormente, avaliouse o efecto de diferentes parámetros operativos como a temperatura (T), tempo (t), contido en auga e relación líquido-sólido (RLS) para determinar as condicións óptimas de extracción para recuperar antioxidantes naturais en termos de contido fenolóxico total (TPC), flavonoides (TFC) e actividade antioxidante dos extractos. As condicións óptimas (T = 70 ºC, t = 45 min, 40 % de auga e RLS = 15 mL/g) permitiron a recuperación dun alto nivel de compostos fenólicos (TPC = 27,49 mg GAE/g biomasa) e de flavonoides (TFC = 40,74 mg RE/g biomasa); así como unha notable actividade antioxidante (29,76; 36,09 e 20,51 mg TE/g biomasa para os ensaios de DPPH, ABTS e FRAP, respectivamente)

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum

Trends and outcome of neoadjuvant treatment for rectal cancer: A retrospective analysis and critical assessment of a 10-year prospective national registry on behalf of the Spanish Rectal Cancer Project

Introduction: Preoperative treatment and adequate surgery increase local control in rectal cancer. However, modalities and indications for neoadjuvant treatment may be controversial. Aim of this study was to assess the trends of preoperative treatment and outcomes in patients with rectal cancer included in the Rectal Cancer Registry of the Spanish Associations of Surgeons. Method: This is a STROBE-compliant retrospective analysis of a prospective database. All patients operated on with curative intention included in the Rectal Cancer Registry were included. Analyses were performed to compare the use of neoadjuvant/adjuvant treatment in three timeframes: I)2006–2009; II)2010–2013; III)2014–2017. Survival analyses were run for 3-year survival in timeframes I-II. Results: Out of 14, 391 patients, 8871 (61.6%) received neoadjuvant treatment. Long-course chemo/radiotherapy was the most used approach (79.9%), followed by short-course radiotherapy ± chemotherapy (7.6%). The use of neoadjuvant treatment for cancer of the upper third (15-11 cm) increased over time (31.5%vs 34.5%vs 38.6%, p = 0.0018). The complete regression rate slightly increased over time (15.6% vs 16% vs 18.5%; p = 0.0093); the proportion of patients with involved circumferential resection margins (CRM) went down from 8.2% to 7.3%and 5.5% (p = 0.0004). Neoadjuvant treatment significantly decreased positive CRM in lower third tumors (OR 0.71, 0.59–0.87, Cochrane-Mantel-Haenszel P = 0.0008). Most ypN0 patients also received adjuvant therapy. In MR-defined stage III patients, preoperative treatment was associated with significantly longer local-recurrence-free survival (p < 0.0001), and cancer-specific survival (p < 0.0001). The survival benefit was smaller in upper third cancers. Conclusion: There was an increasing trend and a potential overuse of neoadjuvant treatment in cancer of the upper rectum. Most ypN0 patients received postoperative treatment. Involvement of CRM in lower third tumors was reduced after neoadjuvant treatment. Stage III and MRcN + benefited the most