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Extracellular soluble algal organic matter (AOM) significantly interferes with microalgae flocculation. This study investigated the effects of various AOM fractions on Chlorella sp. flocculation using ferric chloride (FeCl3), sodium hydroxide (NaOH), and chitosan. All flocculants achieved high separation efficiency (87-99 %), but higher dosages were required in the presence of AOM. High molecular weight (>50 kDa) AOM fraction was identified as the primary inhibitor of flocculation across different pH levels, whereas low/medium molecular weight (<3 and <50 kDa) AOM had minimal impact. Compositional analysis revealed that the inhibitory AOM fraction is a glycoprotein rich in carbohydrates, including neutral, amino, and acidic sugars. The significance of this study is in identifying carboxyl groups (-COOH) from acidic monomers in >50 kDa AOM that inhibit flocculation. Understanding AOM composition and the interaction dynamics between AOM, cells, and flocculants is crucial for enhancing the techno-economics and sustainability of flocculation-based microalgae harvesting.
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Chlorella , Floculación , Solubilidad , Chlorella/metabolismo , Floculación/efectos de los fármacos , Concentración de Iones de Hidrógeno , Compuestos Orgánicos/farmacología , Microalgas/metabolismo , Espacio Extracelular/química , Peso Molecular , Quitosano/química , Quitosano/farmacologíaRESUMEN
Infections caused by pathogenic Escherichia coli are a serious threat to human health, while conventional antibiotic susceptibility tests (AST) have a long turn-around time, and rapid antibiotic susceptibility methods are urgently needed to save lives in the clinic, reduce antibiotic misuse and prevent emergence of antibiotic-resistant bacteria. We optimized and validated the feasibility of a novel rapid AST based on SYBR Green I and Propidium Iodide (SGPI-AST) for E. coli drug susceptibility test. A total of 112 clinical isolates of E. coli were collected and four antibiotics (ceftriaxone, cefoxitin, imipenem, meropenem) were selected for testing. Bacterial survival rate of E. coli was remarkably linearly correlated with S value at different OD600 values. After optimizing the antibiotic concentrations, the sensitivity and specificity of SGPI-AST reached 100%/100%, 97.8%/100%, 100%/100% and 98.4%/99% for ceftriaxone, cefoxitin, imipenem and meropenem, respectively, and the corresponding concordances of the SGPI-AST with conventional AST were 1.000, 0.980, 1.000 and 0.979, respectively. The SGPI-AST can rapidly and accurately determine the susceptibility of E. coli clinical isolates to multiple antibiotics in 60 min, and has the potential to be applied to guide the precise selection of antibiotics for clinical management of infections caused by pathogenic E. coli.
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Antibacterianos , Benzotiazoles , Diaminas , Escherichia coli , Pruebas de Sensibilidad Microbiana , Compuestos Orgánicos , Propidio , Quinolinas , Escherichia coli/efectos de los fármacos , Escherichia coli/aislamiento & purificación , Pruebas de Sensibilidad Microbiana/métodos , Benzotiazoles/farmacología , Antibacterianos/farmacología , Humanos , Quinolinas/farmacología , Compuestos Orgánicos/farmacología , Diaminas/farmacología , Propidio/análogos & derivados , Propidio/farmacología , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/tratamiento farmacológicoRESUMEN
Viruses impose a significant public health burden globally, and one of the key elements in controlling their transmission is the ability to inactivate them using disinfectants. However, numerous challenges to inactivating foodborne viruses exist due to inherent viral characteristics (such as recalcitrance to commonly used inactivation agents) and external factors (such as improper cleaning before application of inactivation agent, improper contact time, etc.). Given the potential for improper application of disinfectants (such as shorter than recommended contact time, improper disinfectant concentration, etc.), understanding the performance of a disinfectant in the presence of an organic load is important. To accomplish this, the introduction of simulated organic loads is often used when studying the efficacy of a disinfectant against different viruses. However, the different types of simulated organic loads used in foodborne virus inactivation studies or their relative effects on inactivation have not been reviewed. The purpose of this review is to survey different simulated organic load formulations used in studying foodborne virus inactivation, as well as present and compare the influence of these different formulations on viral inactivation. The findings included in this review suggest that many simulated organic load formulations can reduce disinfectants' efficacy against viruses. Based on the findings in this review, blood, particularly serum or feces, are among the most commonly used and efficacious forms of simulated organic load in many tests.
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Desinfectantes , Inactivación de Virus , Virus , Inactivación de Virus/efectos de los fármacos , Desinfectantes/farmacología , Virus/efectos de los fármacos , Humanos , Microbiología de Alimentos , Desinfección/métodos , Enfermedades Transmitidas por los Alimentos/prevención & control , Enfermedades Transmitidas por los Alimentos/virología , Compuestos Orgánicos/farmacología , Compuestos Orgánicos/químicaRESUMEN
Broad cellular components-initiated efficient chemical reactions that occur in malignant cells may contribute to exploring emerging strategies for cancer treatment. Herein, an ozonated oleogel (OG(O)) was developed to achieve cancer ozone therapy (O3-T) based on intracellular Criegee's reaction. By integrating the chemo-drug, the ozone-loaded oleogel (Dox@OG(O)) was prepared as a chemotherapeutic agent for local O3-T, associated with chemotherapy (CT)/radiotherapy (RT)/immunotherapy and wound healing. The in vitro results showed that, Dox@OG(O) could achieve high ozone loading efficiency and ensure its stability. This Oleogel-mediated O3-T could directly destroy tumor cells via intracellular Criegee's reaction occurred on cell membranes, as well as the effects of tumor microenvironment (TME) regulation by the generation of oxygen/reactive oxygen species (ROS) and depletion of glutathione (GSH). Meanwhile, under the stimulation of X-ray, an accelerated free radical's production was observed, further combined with the radio-sensitivity after TME regulation, an effective anti-tumor effect would be achieved. Further on, in vivo results demonstrated that the locally implanted Dox@OG(O) could effectively inhibit the growth of both primary and secondary tumors. Considering these results above, it will serve as inspiration for future studies investigating of O3-T, especially for postoperative skin diseases.
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Doxorrubicina , Neoplasias , Compuestos Orgánicos , Ozono , Microambiente Tumoral , Ozono/química , Animales , Humanos , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Microambiente Tumoral/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Compuestos Orgánicos/química , Compuestos Orgánicos/farmacología , Compuestos Orgánicos/administración & dosificación , Ratones Endogámicos BALB C , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Ratones Desnudos , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Femenino , Glutatión/metabolismo , RatonesRESUMEN
BACKGROUND: Colony stimulating factor 1 receptor (CSF1R) signaling is crucial for the maintenance and function of various myeloid subsets. CSF1R antagonism was previously shown to mitigate clinical severity in experimental autoimmune encephalomyelitis (EAE). The associated mechanisms are still not well delineated. METHODS: To assess the effect of CSF1R signaling, we employed the CSF1R antagonist PLX5622 formulated in chow (PLX5622 diet, PD) and its control chow (control diet, CD). We examined the effect of PD in steady state and EAE by analyzing cells isolated from peripheral immune organs and from the CNS via flow cytometry. We determined CNS infiltration sites and assessed the extent of demyelination using immunohistochemistry of cerebella and spinal cords. Transcripts of genes associated with neuroinflammation were also analyzed in these tissues. RESULTS: In addition to microglial depletion, PD treatment reduced dendritic cells and macrophages in peripheral immune organs, both during steady state and during EAE. Furthermore, CSF1R antagonism modulated numbers and relative frequencies of T effector cells both in the periphery and in the CNS during the early stages of the disease. Classical neurological symptoms were milder in PD compared to CD mice. Interestingly, a subset of PD mice developed atypical EAE symptoms. Unlike previous studies, we observed that the CNS of PD mice was infiltrated by increased numbers of peripheral immune cells compared to that of CD mice. Immunohistochemical analysis showed that CNS infiltrates in PD mice were mainly localized in the cerebellum while in CD mice infiltrates were primarily localized in the spinal cords during the onset of neurological deficits. Accordingly, during the same timepoint, cerebella of PD but not of CD mice had extensive demyelinating lesions, while spinal cords of CD but not of PD mice were heavily demyelinated. CONCLUSIONS: Our findings suggest that CSF1R activity modulates the cellular composition of immune cells both in the periphery and within the CNS, and affects lesion localization during the early EAE stages.
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Encefalomielitis Autoinmune Experimental , Ratones , Animales , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Compuestos Orgánicos/farmacología , Médula Espinal/patología , Microglía , Receptores del Factor Estimulante de Colonias , Proteínas Tirosina Quinasas Receptoras , Ratones Endogámicos C57BLRESUMEN
The objective of this study was to evaluate the impact of dietary zinc supplementation in pre-weaned dairy calves on the phenotypic antimicrobial resistance (AMR) of fecal commensal bacteria. A repository of fecal specimens from a random sample of calves block-randomized into placebo (n = 39) and zinc sulfate (n = 28) groups collected over a zinc supplementation clinical trial at the onset of calf diarrhea, calf diarrheal cure, and the last day of 14 cumulative days of zinc or placebo treatment were analyzed. Antimicrobial susceptibility testing was conducted for Enterococcus spp. (n = 167) and E. coli (n = 44), with one representative isolate of each commensal bacteria tested per sample. Parametric survival interval regression models were constructed to evaluate the association between zinc treatment and phenotypic AMR, with exponentiated accelerated failure time (AFT) coefficients adapted for MIC instead of time representing the degree of change in AMR (MIC Ratio, MR). Findings from our study indicated that zinc supplementation did not significantly alter the MIC in Enterococcus spp. for 13 drugs: gentamicin, vancomycin, ciprofloxacin, erythromycin, penicillin, nitrofurantoin, linezolid, quinupristin/dalfopristin, tylosin tartrate, streptomycin, daptomycin, chloramphenicol, and tigecycline (MR = 0.96-2.94, p > 0.05). In E. coli, zinc supplementation was not associated with resistance to azithromycin (MR = 0.80, p > 0.05) and ceftriaxone (MR = 0.95, p > 0.05). However, a significant reduction in E. coli MIC values was observed for ciprofloxacin (MR = 0.17, 95% CI 0.03-0.97) and nalidixic acid (MR = 0.28, 95% CI 0.15-0.53) for zinc-treated compared to placebo-treated calves. Alongside predictions of MIC values generated from these 17 AFT models, findings from this study corroborate the influence of age and antimicrobial exposure on phenotypic AMR.
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Antibacterianos , Antiinfecciosos , Animales , Bovinos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Zinc/farmacología , Escherichia coli , Farmacorresistencia Bacteriana , Antiinfecciosos/farmacología , Enterococcus , Diarrea/tratamiento farmacológico , Diarrea/veterinaria , Diarrea/microbiología , Compuestos Orgánicos/farmacología , Suplementos Dietéticos , Ciprofloxacina/farmacologíaRESUMEN
Oxides of silicon (Si), manganese (Mn), and zinc (Zn) have been used as soil amendments to reduce As mobility and uptake in paddy soil systems. However, these amendments are hypothesized to be affected differently depending on the soil pH and their effect on As speciation in rice paddy systems is not fully understood. Herein, we used a microcosm experiment to investigate the effects of natural Si-rich fly ash and synthetic Mn and Zn oxides on the temporal development of porewater chemistry, including aqueous As speciation (As(III), As(V), MMA, DMA, and DMMTA) and solid-phase As solubility, in a naturally calcareous soil with or without soil acidification (with sulfuric acid) during 28 days of flooding and subsequent 14 days of drainage. We found that soil acidification to pH 4.5 considerably increased the solubility of Si, Fe, Mn, and Zn compared to the non-acidified soil. Additions of Mn and Zn oxides decreased the concentrations of dissolved arsenite and arsenate in the non-acidified soil whereas additions of Zn oxide and combined Si-Zn oxides increased them in the acidified soil. The Si-rich fly ash did not increase dissolved Si and As in the acidified and non-acidified soils. Dimethylated monothioarsenate (DMMTA) was mainly observed in the acidified soil during the later stage of soil flooding. The initial 28 days of soil flooding decreased the levels of soluble and exchangeable As and increased As associated with Mn oxides, whereas the subsequent 14 days of soil drainage reversed the trend. This study highlighted that soil acidification considerably controlled the solubilization of Ca and Fe, thus influencing the soil pH-Eh buffering capacity, the solubility of Si, Mn, and Zn oxides, and the mobility of different As species in carbonate-rich and acidic soils under redox fluctuations.
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Arsénico , Oryza , Contaminantes del Suelo , Óxido de Zinc , Arsénico/análisis , Manganeso/farmacología , Suelo , Silicio/farmacología , Ceniza del Carbón/farmacología , Óxido de Zinc/farmacología , Óxidos/farmacología , Compuestos Orgánicos/farmacología , Zinc/farmacología , Contaminantes del Suelo/análisisRESUMEN
Bletilla striata polysaccharide (BSP) is a naturally occurring polysaccharide that demonstrates notable biocompatibility and biodegradability. Additionally, BSP possesses therapeutic attributes, including anti-inflammatory and reparative actions. Herein, we report a novel BSP hydrogel prepared using 1,4-butanediol diglycidyl ether (BDDE) as a cross-linking agent. The hydrogel was synthesized via condensation of the hydroxyl group in the BSP molecule with the epoxy group in BDDE. This technique of preparation preserves BSP's natural properties while avoiding any potentially hazardous or adverse effects that may occur during the chemical alteration. Compared with BSP before crosslinking, BSP hydrogel has distinct advantages, such as a three-dimensional network structure, improved water retention, enhanced swelling capacity, greater thermal stability, and superior mechanical properties. Experiments on in vitro cytotoxicity, hemolysis, and degradation revealed that BSP hydrogel had good biocompatibility and biodegradability. Finally, we evaluated the in vivo wound repair effect of BSP hydrogel, and the results showed that BSP hydrogel had a significant wound-healing effect. Furthermore, the BSP hydrogel promoted the polarization of M1-type macrophages towards the M2-type and reduced the inflammatory response during the wound healing phase. Because of its ease of production, safety, efficacy, and environmental friendliness, BSP hydrogel is considered a highly promising material for wound dressings.
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Hidrogeles , Compuestos Orgánicos , Hidrogeles/farmacología , Compuestos Orgánicos/farmacología , Polisacáridos/química , Cicatrización de HeridasRESUMEN
Excess sodium intake poses health risks, prompting the exploration of taste modulators to reduce the salt content in low-sodium foods yet maintain salty perception. Previous research found a subthreshold synergistic effect among pyroglutamyl dipeptides on saltiness enhancement. This study investigated the subthreshold synergistic effect of pyroglutamyl peptides and organic acids on saltiness perception. Pyroglutamyl dipeptides (pgluE, pgluV), pyroglutamyl tripeptides (pgluVL and pgluVC), and organic acids (malic acid and succinic acid) were explored in a model system and subsequently in commercial brown onion sauce. The detection thresholds of peptides (pgluE, pgluV, pgluVL, and pgluVC) were determined to be 646, 77, 273, and 221 µmol/L, respectively, and the subthreshold synergistic effect of the pyroglutamyl tripeptides and organic acids was determined using the isobologram method. One of the eight combinations of pyroglutamyl tripeptides with pyroglutamyl dipeptide (pgluV) showed a subthreshold synergistic effect, whereas four combinations of tripeptides with malic acid and one combination with succinic acid exhibited a subthreshold synergistic effect. In commercial brown onion sauce, 25 and 30% salt reductions were achieved using the combinations of the tripeptides with malic acid and succinic acid, respectively. This research lays the foundation for future investigations into the potential combinations of pyroglutamyl peptides and organic acids for saltiness enhancement in low-sodium foods.
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Cloruro de Sodio , Gusto , Cloruro de Sodio/farmacología , Cloruro de Sodio Dietético , Compuestos Orgánicos/farmacología , Sodio , Péptidos/farmacología , Dipéptidos/farmacología , Succinatos/farmacologíaRESUMEN
Two triple interpenetrating Zn(II)-based MOFs were studied in this paper. Named [Zn6(1,4-bpeb)4(IPA)6(H2O)]n (MOF-1) and {[Zn3(1,4-bpeb)1.5(DDBA)3]n·2DMF} (MOF-2), {1,4-bpeb = 1,4-bis [2-(4-pyridy1) ethenyl]benze, IPA = Isophthalic acid, DDBA = 3,3'-Azodibenzoic acid}, they were synthesized by the hydrothermal method and were characterized and stability tested. The results showed that MOF-1 had good acid-base stability and solvent stability. Furthermore, MOF-1 had excellent green fluorescence and with different phenomena in different solvents, which was almost completely quenched in acetone. Based on this phenomenon, an acetone sensing test was carried out, where the detection limit of acetone was calculated to be 0.00365% (volume ratio). Excitingly, the MOF-1 could also be used as a proportional fluorescent probe to specifically detect tryptophan, with a calculated detection limit of 34.84 µM. Furthermore, the mechanism was explained through energy transfer and competitive absorption (fluorescence resonance energy transfer (FRET)) and internal filtration effect (IFE). For antibacterial purposes, the minimum inhibitory concentrations of MOF-1 against Escherichia coli and Staphylococcus aureus were 19.52 µg/mL and 39.06 µg/mL, respectively, and the minimum inhibitory concentrations of MOF-2 against Escherichia coli and Staphylococcus aureus were 68.36 µg/mL and 136.72 µg/mL, respectively.
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Acetona , Zinc , Zinc/farmacología , Triptófano/farmacología , Metales/farmacología , Antibacterianos/farmacología , Compuestos Orgánicos/farmacología , Solventes/farmacología , Escherichia coliRESUMEN
Polycyclic aromatic compounds (PACs) present in the water column are considered to be one of the primary contaminant groups contributing to the toxicity of a crude oil spill. Because crude oil is a complex mixture composed of thousands of different compounds, oil spill models rely on quantitative structure-activity relationships like the target lipid model to predict the effects of crude oil exposure on aquatic life. These models rely on input provided by single species toxicity studies, which remain insufficient. Although the toxicity of select PACs has been well studied, there is little data available for many, including transformation products such as oxidized hydrocarbons. In addition, the effect of environmental influencing factors such as temperature on PAC toxicity is a wide data gap. In response to these needs, in the present study, Stage I lobster larvae were exposed to six different understudied PACs (naphthalene, fluorenone, methylnaphthalene, phenanthrene, dibenzothiophene, and fluoranthene) at three different relevant temperatures (10, 15, and 20 °C) all within the biological norms for the species during summer when larval releases occur. Lobster larvae were assessed for immobilization as a sublethal effect and mortality following 3, 6, 12, 24, and 48 h of exposure. Higher temperatures increased the rate at which immobilization and mortality were observed for each of the compounds tested and also altered the predicted critical target lipid body burden, incipient median lethal concentration, and elimination rate. Our results demonstrate that temperature has an important influence on PAC toxicity for this species and provides critical data for oil spill modeling. More studies are needed so oil spill models can be appropriately calibrated and to improve their predictive ability. Environ Toxicol Chem 2023;42:2389-2399. © 2023 SETAC.
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Contaminación por Petróleo , Petróleo , Hidrocarburos Policíclicos Aromáticos , Compuestos Policíclicos , Contaminantes Químicos del Agua , Animales , Larva , Nephropidae , Temperatura , Compuestos Policíclicos/farmacología , Hidrocarburos Policíclicos Aromáticos/toxicidad , Contaminantes Químicos del Agua/toxicidad , Compuestos Orgánicos/farmacología , Petróleo/toxicidad , Contaminación por Petróleo/análisis , LípidosRESUMEN
Hair loss is a growing esthetic condition driven by complex mechanisms that has numerous psycho-social implications. Conventional drug applications usually focus on a single treatment target, and the penetration depth restricts the post-delivery effect. Method: We fabricated a curcumin-zinc framework (ZnMOF) encapsulated gamma-polyglutamic acid (γ-PGA) microneedle patch (ZnMOF-MN) as a multifunctional biosafe transdermal drug delivery system. ZnMOF was characterized with the field emission scanning electron microscope (FE-SEM), dynamic light scattering (DLS), elemental mapping, and X-ray diffraction (XRD). The topographical and hygroscopic features of ZnMOF-MN were characterized with SEM. The in vitro ZnMOF release profile and the in vivo penetration of ZnMOF-MN were also evaluated. The anti-oxidant, anti-apoptosis, and antiandrogen effects of ZnMOF solution and ZnMOF-MN extract were studied on mouse dermal papilla cells (DPCs). Two animal models (in C57BL/6 mice), including androgenic alopecia (AGA) model and wound healing model, were used to identify the therapeutic effect of ZnMOF-MN on hair regrowth and wound healing in vivo. Hair follicles, surrounding vessels (CD31+), and proliferating cells (Ki67+) were evaluated by histological staining. Results: ZnMOF crystals were cone-shaped nanoparticles with a size distribution of 424.9 ± 59.01 nm. ZnMOF-MN patch can create temporary holes in the skin to directly and evenly deliver bioactive ZnMOF particles to the targeted depth and achieve a steady and sustained release of Zn2+ and curcumin. In vitro, ZnMOF significantly improved the viability of DPCs against the excess reactive oxygen species (ROS) and inhibited the apoptosis induced by zinc deficiency. In addition, it also reversed the inhibitory effects of dihydrotestosterone (DHT) infiltration. Moreover, the ZnMOF-MN treatment has been proved to accelerate wound healing and increase hair follicles in wound healing models, and improved the hair regrowth in AGA animal models. Enhanced capillary density and cell proliferation observed in the CD31+ and Ki67+ staining of ZnMOF-MN group in both animal models also suggested that ZnMOF can facilitate angiogenesis and promote cell proliferation in the skin, respectively. Conclusion: The ZnMOF-MN treatment is a comprehensive solution with excellent therapeutic efficacy and patient-friendly features for promoting hair growth under various clinical conditions.
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Curcumina , Ratones , Animales , Curcumina/farmacología , Curcumina/uso terapéutico , Zinc/farmacología , Antígeno Ki-67 , Ratones Endogámicos C57BL , Cabello , Alopecia/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Compuestos Orgánicos/farmacologíaRESUMEN
BACKGROUND: Neonatal hydrocephalus is a congenital abnormality resulting in an inflammatory response and microglial cell activation both clinically and in animal models. Previously, we reported a mutation in a motile cilia gene, Ccdc39 that develops neonatal progressive hydrocephalus (prh) with inflammatory microglia. We discovered significantly increased amoeboid-shaped activated microglia in periventricular white matter edema, reduced mature homeostatic microglia in grey matter, and reduced myelination in the prh model. Recently, the role of microglia in animal models of adult brain disorders was examined using cell type-specific ablation by colony-stimulating factor-1 receptor (CSF1R) inhibitor, however, little information exists regarding the role of microglia in neonatal brain disorders such as hydrocephalus. Therefore, we aim to see if ablating pro-inflammatory microglia, and thus suppressing the inflammatory response, in a neonatal hydrocephalic mouse line could have beneficial effects. METHODS: In this study, Plexxikon 5622 (PLX5622), a CSF1R inhibitor, was subcutaneously administered to wild-type (WT) and prh mutant mice daily from postnatal day (P) 3 to P7. MRI-estimated brain volume was compared with untreated WT and prh mutants P7-9 and immunohistochemistry of the brain sections was performed at P8 and P18-21. RESULTS: PLX5622 injections successfully ablated IBA1-positive microglia in both the WT and prh mutants at P8. Of the microglia that are resistant to PLX5622 treatment, there was a higher percentage of amoeboid-shaped microglia, identified by morphology with retracted processes. In PLX-treated prh mutants, there was increased ventriculomegaly and no change in the total brain volume was observed. Also, the PLX5622 treatment significantly reduced myelination in WT mice at P8, although this was recovered after full microglia repopulation by P20. Microglia repopulation in the mutants worsened hypomyelination at P20. CONCLUSIONS: Microglia ablation in the neonatal hydrocephalic brain does not improve white matter edema, and actually worsens ventricular enlargement and hypomyelination, suggesting critical functions of homeostatic ramified microglia to better improve brain development with neonatal hydrocephalus. Future studies with detailed examination of microglial development and status may provide a clarification of the need for microglia in neonatal brain development.
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Hidrocefalia , Microglía , Ratones , Animales , Microglía/metabolismo , Hidrocefalia/etiología , Hidrocefalia/metabolismo , Encéfalo , Compuestos Orgánicos/metabolismo , Compuestos Orgánicos/farmacología , Modelos Animales de EnfermedadRESUMEN
Truncated transforming growth factor ß receptor type II (tTßRII) is a promising anti-liver fibrotic candidate because it serves as a trap for binding excessive TGF-ß1 by means of competing with wild type TßRII (wtTßRII). However, the widespread application of tTßRII for the treatment of liver fibrosis has been limited by its poor fibrotic liver-homing capacity. Herein, we designed a novel tTßRII variant Z-tTßRII by fusing the platelet-derived growth factor ß receptor (PDGFßR)-specific affibody ZPDGFßR to the N-terminus of tTßRII. The target protein Z-tTßRII was produced using Escherichia coli expression system. In vitro and in vivo studies showed that Z-tTßRII has a superior specific fibrotic liver-targeting potential via the engagement of PDGFßR-overexpressing activated hepatic stellate cells (aHSCs) in liver fibrosis. Moreover, Z-tTßRII significantly inhibited cell migration and invasion, and downregulated fibrosis- and TGF-ß1/Smad pathway-related protein levels in TGF-ß1-stimiluated HSC-T6 cells. Furthermore, Z-tTßRII remarkably ameliorated liver histopathology, mitigated the fibrosis responses and blocked TGF-ß1/Smad signaling pathway in CCl4-induced liver fibrotic mice. More importantly, Z-tTßRII exhibits a higher fibrotic liver-targeting potential and stronger anti-fibrotic effects than either its parent tTßRII or former variant BiPPB-tTßRII (PDGFßR-binding peptide BiPPB modified tTßRII). In addition, Z-tTßRII shows no significant sign of potential side effects in other vital organs in liver fibrotic mice. Taken together, we conclude that Z-tTßRII with its a high fibrotic liver-homing potential, holds a superior anti-fibrotic activity in liver fibrosis in vitro and in vivo, which may be a potential candidate for targeted therapy for liver fibrosis.
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Cirrosis Hepática , Factor de Crecimiento Transformador beta1 , Ratones , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Células Estrelladas Hepáticas/metabolismo , Transducción de Señal , Compuestos Orgánicos/farmacología , Factor de Crecimiento Transformador beta , Tetracloruro de Carbono/efectos adversos , Tetracloruro de Carbono/metabolismoRESUMEN
The assessment and prediction of the toxicity of engineered nanomaterials (NMs) present in mixtures is a challenging research issue. Herein, the toxicity of three advanced two-dimensional nanomaterials (TDNMs), in combination with an organic chemical (3,4-dichloroaniline, DCA) to two freshwater microalgae (Scenedesmus obliquus and Chlorella pyrenoidosa), was assessed and predicted not only from classical mixture theory but also from structure-activity relationships. The TDNMs included two layered double hydroxides (Mg-Al-LDH and Zn-Al-LDH) and a graphene nanoplatelet (GNP). The toxicity of DCA varied with the type and concentration of TDNMs, as well as the species. The combination of DCA and TDNMs exhibited additive, antagonistic, and synergistic effects. There is a linear relationship between the different levels (10, 50, and 90%) of effect concentrations and a Freundlich adsorption coefficient (KF) calculated by isotherm models and adsorption energy (Ea) obtained in molecular simulations, respectively. The prediction model incorporating both parameters KF and Ea had a higher predictive power for the combined toxicity than the classical mixture model. Our findings provide new insights for the development of strategies aimed at evaluating the ecotoxicological risk of NMs towards combined pollution situations.
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Chlorella , Contaminantes Químicos del Agua , Agua Dulce , Compuestos Orgánicos/farmacología , Hidróxidos , Contaminantes Químicos del Agua/farmacologíaRESUMEN
Current antiplatelet therapies have several clinical complications and are mostly irreversible in terms of suppressing platelet activity; hence, there is a need to develop improved therapeutic agents. Previous studies have implicated RhoA in platelet activation. Here, we further characterized the lead RhoA inhibitor, Rhosin/G04, in platelet function and present structure-activity relationship (SAR) analysis. A screening for Rhosin/G04 analogs in our chemical library by similarity and substructure searches revealed compounds that showed enhanced antiplatelet activity and suppressed RhoA activity and signaling. A screening for Rhosin/G04 analogs in our chemical library using similarity and substructure searches revealed compounds that showed enhanced antiplatelet activity and suppressed RhoA activity and signaling. SAR analysis revealed that the active compounds have a quinoline group optimally attached to the hydrazine at the 4-position and halogen substituents at the 7- or 8-position. Having indole, methylphenyl, or dichloro-phenyl substituents led to better potency. Rhosin/G04 contains a pair of enantiomers, and S-G04 is significantly more potent than R-G04 in inhibiting RhoA activation and platelet aggregation. Furthermore, the inhibitory effect is reversible, and S-G04 is capable of inhibiting diverse-agonist-stimulated platelet activation. This study identified a new generation of small-molecule RhoA inhibitors, including an enantiomer capable of broadly and reversibly modulating platelet activity.
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Inhibidores de Agregación Plaquetaria , Proteína de Unión al GTP rhoA , Inhibidores de Agregación Plaquetaria/farmacología , Proteína de Unión al GTP rhoA/metabolismo , Plaquetas/metabolismo , Compuestos Orgánicos/farmacología , Relación Estructura-ActividadRESUMEN
As the CNS-resident macrophages and member of the myeloid lineage, microglia fulfill manifold functions important for brain development and homeostasis. In the context of neurodegenerative diseases, they have been implicated in degenerative and regenerative processes. The discovery of distinct activation patterns, including increased phagocytosis, indicated a damaging role of myeloid cells in multiple system atrophy (MSA), a devastating, rapidly progressing atypical parkinsonian disorder. Here, we analyzed the gene expression profile of microglia in a mouse model of MSA (MBP29-hα-syn) and identified a disease-associated expression profile and upregulation of the colony-stimulating factor 1 (Csf1). Thus, we hypothesized that CSF1 receptor-mediated depletion of myeloid cells using PLX5622 modifies the disease progression and neuropathological phenotype in this mouse model. Intriguingly, sex-balanced analysis of myeloid cell depletion in MBP29-hα-syn mice revealed a two-faced outcome comprising an improved survival rate accompanied by a delayed onset of neurological symptoms in contrast to severely impaired motor functions. Furthermore, PLX5622 reversed gene expression profiles related to myeloid cell activation but reduced gene expression associated with transsynaptic signaling and signal release. While transcriptional changes were accompanied by a reduction of dopaminergic neurons in the SNpc, striatal neuritic density was increased upon myeloid cell depletion in MBP29-hα-syn mice. Together, our findings provide insight into the complex, two-faced role of myeloid cells in the context of MSA emphasizing the importance to carefully balance the beneficial and adverse effects of CSF1R inhibition in different models of neurodegenerative disorders before its clinical translation.SIGNIFICANCE STATEMENT Myeloid cells have been implicated as detrimental in the disease pathogenesis of multiple system atrophy. However, long-term CSF1R-dependent depletion of these cells in a mouse model of multiple system atrophy demonstrates a two-faced effect involving an improved survival associated with a delayed onset of disease and reduced inflammation which was contrasted by severely impaired motor functions, synaptic signaling, and neuronal circuitries. Thus, this study unraveled a complex role of myeloid cells in multiple system atrophy, which indicates important functions beyond the previously described disease-associated, destructive phenotype and emphasized the need of further investigation to carefully and individually fine-tune immunologic processes in different neurodegenerative diseases.
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Atrofia de Múltiples Sistemas , Animales , Ratones , Atrofia de Múltiples Sistemas/genética , Longevidad , Compuestos Orgánicos/farmacología , Microglía/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Modelos Animales de Enfermedad , Células Mieloides/metabolismo , Receptores del Factor Estimulante de ColoniasRESUMEN
Most regulatory ecological risk-assessment frameworks largely disregard discrepancies between the laboratory, where effects of single substances are assessed on individual organisms, and the real environment, where organisms live together in populations and are often exposed to multiple simultaneously occurring substances. We assessed the capability of individual-based models (IBMs) with a foundation in the dynamic energy budget (DEB) theory to predict combined effects of chemical mixtures on populations when they are calibrated on toxicity data of single substances at the individual level only. We calibrated a DEB-IBM for Daphnia magna for four compounds (pyrene, dicofol, α-hexachlorocyclohexane, and endosulfan), covering different physiological modes of action. We then performed a 17-week population experiment with D. magna (designed using the DEB-IBM), in which we tested mixture combinations of these chemicals at relevant concentrations, in a constant exposure phase (7-week exposure and recovery), followed by a pulsed exposure phase (3-day pulse exposure and recovery). The DEB-IBM was validated by comparing blind predictions of mixture toxicity effects with the population data. The DEB-IBM accurately predicted mixture toxicity effects on population abundance in both phases when assuming independent action at the effect mechanism level. The population recovery after the constant exposure was well predicted, but recovery after the pulse was not. The latter could be related to insufficient consideration of stochasticity in experimental design, model implementation, or both. Importantly, the mechanistic DEB-IBM performed better than conventional statistical mixture assessment methods. We conclude that the DEB-IBM, calibrated using only single-substance individual-level toxicity data, produces accurate predictions of population-level mixture effects and can therefore provide meaningful contributions to ecological risk assessment of environmentally realistic mixture exposure scenarios. Environ Toxicol Chem 2022;41:2240-2258. © 2022 SETAC.
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Daphnia , Contaminantes Químicos del Agua , Animales , Compuestos Orgánicos/farmacología , Medición de Riesgo , Contaminantes Químicos del Agua/químicaRESUMEN
During emission, TiO2 nanoparticles (NPs) might meet various chemicals, including metal ions and organic compounds in aquatic environments (e.g., surface water, sediments). At environmentally safe concentrations, combinations of both TiO2 NPs and those chemicals might cause cocktail effects (i.e., mixture toxicity) to aquatic organisms. Previous models such as concentration addition and independent action require dose-response curves of single components in the mixtures to predict the mixture toxicity. Structure-activity relationship (QSAR) models might predict the toxicity of nano-mixtures without dose-response curves of single components in the mixtures. However, current quantitative structure-activity relationship (QSAR) models are mainly focused on predicting cytotoxicity (i.e., cell viability) of heterogeneous metallic TiO2 nanoparticles (NPs) or mixtures of TiO2 NPs and four metal ions (Cu2+, Cd2+, Ni2+, and Zn2+). To minimize the experimental cost of nano-mixture risk assessment, in this study, we developed novel nano-mixture QSAR models to predict i) EC50 of 76 nano-mixtures containing TiO2 NPs and one of eight inorganic/organic compounds (i.e., AgNO3, Cd(NO3)2, Cu(NO3)2, CuSO4, Na2HAsO4, NaAsO2, Benzylparaben and Benzophenone-3), to Daphnia magna(D. magna), and ii) immobilization of D. magna exposed to one of 98 mixtures containing TiO2 NPs and one of eleven inorganic/organic compounds (i.e., AgNO3, Cd(NO3)2, Cu(NO3)2, CuSO4, Na2HAsO4, NaAsO2, Benzylparaben Benzophenone-3, Pirimicarb, Pentabromodiphenyl Ether and Triton X-100). The nano-mixture QSAR models were developed with mixture descriptors (Dmix) combing quantum descriptors of mixture components (e.g., TiO2 NPs and its partners) by using different machine learning techniques (i.e., random forest, neural network, support vector machine, and multiple linear regression). Nano-mixture QSAR models built with the random forest algorithm and proposed mixture descriptors exhibited good performance for predicting logEC50 (Adj.R2test = 0.955 ± 0.003, RMSEtest = 0.016 ± 0.002, and MAEtest = 0.008 ± 0.001) and immobilization (Adj.R2test = 0.888 ± 0.011, RMSEtest = 11.327 ± 0.730, and MAEtest = 5.933 ± 0.442). The models developed in this study were implemented in a user-friendly application for assessing the aquatic toxicity of TiO2 based nano-mixtures.
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Daphnia , Contaminantes Químicos del Agua , Animales , Cadmio/farmacología , Compuestos Orgánicos/farmacología , Relación Estructura-Actividad Cuantitativa , Titanio , Contaminantes Químicos del Agua/toxicidadRESUMEN
Robust biomarkers for anti-epileptic drugs (AEDs) activity in the human brain are essential to increase the probability of successful drug development. The frequency analysis of electroencephalographic (EEG) activity, either spontaneous or evoked by transcranial magnetic stimulation (TMS-EEG) can provide cortical readouts for AEDs. However, a systematic evaluation of the effect of AEDs on spontaneous oscillations and TMS-related spectral perturbation (TRSP) has not yet been provided. We studied the effects of Lamotrigine, Levetiracetam, and of a novel potassium channel opener (XEN1101) in two groups of healthy volunteers. Levetiracetam suppressed TRSP theta, alpha and beta power, whereas Lamotrigine decreased delta and theta but increased the alpha power. Finally, XEN1101 decreased TRSP delta, theta, alpha and beta power. Resting-state EEG showed a decrease of theta band power after Lamotrigine intake. Levetiracetam increased theta, beta and gamma power, while XEN1101 produced an increase of delta, theta, beta and gamma power. Spontaneous and TMS-related cortical oscillations represent a powerful tool to characterize the effect of AEDs on in vivo brain activity. Spectral fingerprints of specific AEDs should be further investigated to provide robust and objective biomarkers of biological effect in human clinical trials.