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OBJECTIVE: Triggering receptor expressed on myeloid cells-2 (TREM2) and progranulin (PGRN) are critical regulators of microglia activation and can be detected in cerebrospinal fluid (CSF). However, whether microglial reactivity is detrimental or neuroprotective for Alzheimer disease (AD) is still debatable. METHODS: We identified 663 participants with baseline ß-amyloid (Aß) positron emission tomography (PET) and CSF biomarker data, including phosphorylated tau181 (p-Tau181), soluble TREM2 (sTREM2), PGRN, and growth-associated protein-43 (GAP-43). Among them, 254 participants had concurrent longitudinal CSF biomarkers. We used multivariate regression analysis to study the associations of CSF microglial biomarkers with Aß PET, CSF p-Tau181, and CSF GAP-43 cross-sectionally and longitudinally. A Chinese aging cohort's independent CSF samples (n = 65) were analyzed as a validation. RESULTS: Higher baseline levels of CSF microglial biomarkers were related to faster rates of CSF sTREM2 increase and CSF PGRN decrease. Elevated CSF p-Tau181 was associated with higher levels of CSF microglial biomarkers and faster rates of CSF sTREM2 increase and CSF PGRN decrease. In both cohorts, higher Aß burden was associated with attenuated CSF p-Tau181 effects on CSF microglial biomarker increases. Independent of Aß PET and CSF p-Tau181 pathologies, higher levels of CSF sTREM2 but not CSF PGRN were related to elevated CSF GAP-43 levels and faster rates of CSF GAP-43 increase. INTERPRETATION: These findings suggest that higher Aß burden may attenuate the p-Tau-associated microglial responses, and TREM2-related microglial reactivity may independently correlate with GAP-43-related presynaptic loss. This study highlights the two-edged role of microglial reactivity in AD and other neurodegenerative diseases. ANN NEUROL 2024;95:917-928.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Glicoproteínas de Membrana , Microglía , Tomografía de Emisión de Positrones , Progranulinas , Receptores Inmunológicos , Proteínas tau , Humanos , Microglía/metabolismo , Masculino , Femenino , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Anciano , Proteínas tau/líquido cefalorraquídeo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Persona de Mediana Edad , Receptores Inmunológicos/metabolismo , Progranulinas/líquido cefalorraquídeo , Glicoproteínas de Membrana/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Anciano de 80 o más Años , Estudios Longitudinales , Estudios TransversalesRESUMEN
INTRODUCTION: The spatial and temporal patterns of cortical mean diffusivity (cMD), as well as its association with Alzheimer's disease (AD) and suspected non-Alzheimer's pathophysiology (SNAP), are not yet fully understood. METHODS: We compared baseline (n = 617) and longitudinal changes (n = 421) of cMD, cortical thickness, and gray matter volume and their relations to vascular risk factors, amyloid beta (Aß), and tau positron emission tomography (PET), and longitudinal cognitive decline in Aß PET negative and positive older adults. RESULTS: cMD increases were more sensitive to detecting brain structural alterations than cortical thinning and gray matter atrophy. Tau-related cMD increases partially mediated Aß-related cognitive decline in AD, whereas vascular disease-related increased cMD levels substantially mediated age-related cognitive decline in SNAP. DISCUSSION: These findings revealed the dynamic changes of microstructural and macrostructural indicators and their associations with AD and SNAP, providing novel insights into understanding upstream and downstream events of cMD in neurodegenerative disease. HIGHLIGHTS: Cortical mean diffusivity (cMD) was more sensitive to detecting structural changes than macrostructural factors. Tau-related cMD increases partially mediated amyloid beta-related cognitive decline in Alzheimer's disease (AD). White matter hyperintensity-related higher cMD mainly explained the age-related cognitive decline in suspected non-Alzheimer's pathophysiology (SNAP). cMD may assist in tracking earlier neurodegenerative signs in AD and SNAP.
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OBJECTIVE: Increased presynaptic dysfunction measured by cerebrospinal fluid (CSF) growth-associated protein-43 (GAP43) may be observed in Alzheimer's disease (AD), but how CSF GAP43 increases relate to AD-core pathologies, neurodegeneration, and cognitive decline in AD requires further investigation. METHODS: We analyzed 731 older adults with baseline ß-amyloid (Aß) positron emission tomography (PET), CSF GAP43, CSF phosphorylated tau181 (p-Tau181 ), and 18 F-fluorodeoxyglucose PET, and longitudinal residual hippocampal volume and cognitive assessments. Among them, 377 individuals had longitudinal 18 F-fluorodeoxyglucose PET, and 326 individuals had simultaneous longitudinal CSF GAP43, Aß PET, and CSF p-Tau181 data. We compared baseline and slopes of CSF GAP43 among different stages of AD, as well as their associations with Aß PET, CSF p-Tau181 , residual hippocampal volume, 18 F-fluorodeoxyglucose PET, and cognition cross-sectionally and longitudinally. RESULTS: Regardless of Aß positivity and clinical diagnosis, CSF p-Tau181 -positive individuals showed higher CSF GAP43 concentrations (p < 0.001) and faster rates of CSF GAP43 increases (p < 0.001) compared with the CSF p-Tau181 -negative individuals. Moreover, higher CSF GAP43 concentrations and faster rates of CSF GAP43 increases were strongly related to CSF p-Tau181 independent of Aß PET. They were related to more rapid hippocampal atrophy, hypometabolism, and cognitive decline (p < 0.001), and predicted the progression from MCI to dementia (area under the curve for baseline 0.704; area under the curve for slope 0.717) over a median 4 years of follow up. INTERPRETATION: Tau aggregations rather than Aß plaques primarily drive presynaptic dysfunction measured by CSF GAP43, which may lead to sequential neurodegeneration and cognitive impairment in AD or neurodegenerative diseases. ANN NEUROL 2022;92:1001-1015.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/patología , Proteínas tau/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Tomografía de Emisión de Positrones/métodosRESUMEN
Objective: This study aimed to validate FANCI as a potential marker for both prognosis and therapy in liver hepatocellular carcinoma. Method: FANCI expression data were acquired from GEPIA, HPA, TCGA, and GEO databases. The impact of clinicopathological features was analyzed by UALCAN. The prognosis of Liver Hepatocellular Carcinoma (LIHC) patients with highly expressed FANCI was constructed utilizing Kaplan-Meier Plotter. GEO2R was employed to identify differentially expressed genes (DEGs). Metascape was used to analyze functional pathways correlations. Protein-Protein interaction (PPI) networks were generated by Cytoscape. Furthermore, molecular complex detection (MCODE) was utilized to recognize Hub genes, which were selected to establish a prognostic model. Lastly, the relationship between FANCI and immune cell infiltration in LIHC was examined. Results: Compared to adjacent tissues, FANCI expression levels were significantly higher in LIHC tissues and were positively correlated to the cancer grade, stage, and prior hepatitis B virus (HBV) infection. High expression of FANCI was found to be associated with poor prognosis in LIHC (HR=1.89, p<0.001). DEGs that were positively correlated with FANCI were involved in various processes, including the cell cycle, VEGF pathway, immune system processes, and biogenesis of ribonucleoproteins. MCM10, TPX2, PRC1, and KIF11 were identified as key genes closely related to FANCI and poor prognosis. A reliable five-variable prognostic model was constructed with strong predictive capability. Lastly, a positive correlation was observed between FANCI expression and tumor-infiltration levels of CD8+ T cells, B cells, regulatory T (Tregs), CD4+ T helper 2 (Th2), and macrophage M2 cells. Conclusion: FANCI may hold promise as a potential biomarker for predicting prognostic outcomes, and a valuable therapeutic target for LIHC patients, with a focus on anti-proliferation, anti-chemoresistance, and combination with immunotherapy.
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Carcinoma Hepatocelular , Anemia de Fanconi , Hepatitis B , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Pronóstico , Proteínas del Grupo de Complementación de la Anemia de FanconiRESUMEN
INTRODUCTION: Although presynaptic loss measured by cerebrospinal fluid (CSF) growth-associated protein-43 (GAP-43) is significantly involved in Alzheimer's disease (AD), the sequential association between CSF GAP-43 and AD-typical neurodegeneration is poorly understood. METHODS: We compared baseline CSF GAP-43 levels (n = 730) and longitudinal CSF GAP-43 changes (n = 327) in various biological stages of AD, and investigated their relationships with cross-sectional and longitudinal measures of residual hippocampal volume, 18 F-fluorodeoxyglucose PET, regional gray matter volume and cortical thickness, and cognition. RESULTS: Elevated CSF GAP43 levels were significantly associated with faster rates of hippocampal atrophy, AD-signature hypometabolism and cortical thinning, and middle temporal gray matter atrophy-related and AD-signature hypometabolism-related cognitive decline. In contrast, baseline levels of all these neurodegeneration biomarkers did not predict longitudinal CSF GAP-43 increases. DISCUSSION: These findings suggest that presynaptic loss may occur prior to neurodegeneration, highlighting the importance of lowing tau aggregation and tau-related synaptic dysfunction in elderly adults and AD patients.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Adulto , Humanos , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Estudios Transversales , Proteína GAP-43 , Enfermedad de Alzheimer/metabolismo , Disfunción Cognitiva/metabolismo , Biomarcadores/líquido cefalorraquídeo , AtrofiaRESUMEN
Mucosa-associated invariant T (MAIT) cells are unconventional innate-like T cells that recognize microbial riboflavin-related metabolites presented by the evolutionarily conserved MHC class I-related (MR1) molecule. MAIT cells are abundant in circulation and mucosal tissues and are poised to mount rapid effector responses against diverse microbial organisms. Despite the absence of virally encoded riboflavin-related metabolite antigens, MAIT cells can respond to viral infections in an MR1-independent and cytokine-dependent manner. In chronic HIV-1 infection, MAIT cells are persistently depleted and functionally exhausted. Long-term effective combination antiretroviral therapy can only partially rescue MAIT cell numbers and dysfunction. Our understanding of the mechanisms underlying MAIT cell loss in HIV-1 infection is still incomplete, and to date, few effective strategies to recover their loss in humans are available. Here, we review current knowledge concerning the mechanisms of MAIT cell responses and loss in different stages of HIV-1 infection and how we may potentially develop strategies to restore these cells in the clinical setting. We further discuss novel strategies that may aid future investigations into MAIT cell immunobiology in HIV-1 infection, including the potential use of three-dimensional organoid models to dissect the mechanisms of MAIT cell depletion and to explore interventions that may restore their numbers and functionality.
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Acquired drug resistance decreases the efficacy of gefitinib after approximately 1 year of treatment in non-small-cell lung cancer (NSCLC). Autophagy is a process that could lead to cell death when it is prolonged. Thus, we investigated a drug combination therapy of gefitinib with rapamycin-a cell autophagy activator-in gefitinib-resistant NSCLC cell line H1975 to improve the therapeutic efficacy of gefitinib in advanced NSCLC cells through acute cell autophagy induction. Cell viability and tumor formation assays indicated that rapamycin is strongly synergistic with gefitinib inhibition, both in vitro and in vivo. Mechanistic studies demonstrated that EGFR expression and cell autophagy decreased under gefitinib treatment and were restored after the drug combination therapy, indicating a potential cell autophagy-EGFR positive feedback regulation. To further optimize the delivery efficiency of the combinational agents, we constructed an anti-EGFR aptamer-functionalized nanoparticle (NP-Apt) carrier system. The microscopic observation and cell proliferation assays suggested that NP-Apt achieved remarkably targeted delivery and cytotoxicity in the cancer cells. Taken together, our results suggest that combining rapamycin and gefitinib can be an efficacious therapy to overcome gefitinib resistance in NSCLC, and targeted delivery of the drugs using the aptamer-nanoparticle carrier system further enhances the therapeutic efficacy of gefitinib.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Nanopartículas , Autofagia , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Combinación de Medicamentos , Resistencia a Antineoplásicos , Receptores ErbB/metabolismo , Gefitinib/farmacología , Gefitinib/uso terapéutico , Humanos , Neoplasias Pulmonares/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/uso terapéutico , Sirolimus/farmacología , Sirolimus/uso terapéuticoRESUMEN
Chiral semiconductor nanostructures have received enormous attention due to their emerging circularly polarized luminescence (CPL) properties. However, compared with well-studied photoluminescence (PL), the reported CPL is much weaker and more challenging to be modulated. Herein, we describe a new approach for acquiring the intense and tunable CPL from inorganic chiral photonic crystals (CPCs) doped with semiconductor quantum dots (QDs). Unprecedentedly, the sign, position and intensity of CPL peaks can be precisely controlled by manipulating either the photonic band gap of CPCs or luminescence wavelength of QDs and a giant absolute dissymmetry factor |glum | up to 0.25 is obtained. More importantly, the origin of the CPL modulation is clearly elucidated by both experiment and theory. This work lays the foundation for the construction of next-generation high-performance CPL-based devices.
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Quantum dots (QDs) have numerous potential applications in lighting, engineering, and biomedicine. QDs are mainly excreted through the kidney due to their ultrasmall sizes; thus, the kidneys are target organs of QD toxicity. Here, an organoid screening platform is established and used to study the nephrotoxicity of QDs. Organoids are templated from monodisperse microfluidic Matrigel droplets and found to be homogeneous in both tissue structure and functional recapitulation within a population and suitable for the quantitative screening of toxic doses. Kidney organoids are proved displaying higher sensitivity than 2D-cultured cell lines. Similar to metal-containing QDs, black phosphorus (BP)-QDs are found to have moderate toxicity in the kidney organoids. The nephrotoxicity of BP-QDs are validated in both mice and human renal tubular epithelial cells. BP-QDs are also found to cause insulin insensitivity and endoplasmic reticulum (ER) stress in the kidney. Furthermore, ER stress-related IRE1α signaling is shown to mediate renal toxicity and insulin insensitivity caused by BP-QDs. In summary, this work demonstrates the use of constructed kidney organoids as 3D high-throughput screening tools to assess nanosafety and further illuminates the effects and molecular mechanisms of BP-QD nephrotoxicity. The findings will hopefully enable improvement of the safety of BP-QD applications.
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Puntos Cuánticos , Animales , Endorribonucleasas , Humanos , Ratones , Organoides , Fósforo , Proteínas Serina-Treonina Quinasas , Puntos Cuánticos/toxicidadRESUMEN
Astrocytes migration is essential in the formation of the glial scar during the injury response process of the central nervous system (CNS) especially during inflammation. Integrin ß1 is part of the extracellular matrix receptors in the CNS and it has been reported that integrin ß-deficient astrocytes randomly migrate into wounds. Previous studies have found that ß-1,4 Galactosyltransferase-I (ß-1,4-GalT-I) enhanced the ß-1,4-galactosylation of integrin ß1. Src-suppressed C kinase substrate (SSeCKS) is an inflammatory response protein which functionally interacts with ß-1,4 Galactosyltransferase-I (ß-1,4-GalT-I). In this study we aim to investigate the role of SSeCKS and ß-1,4-GalT-I in the migration of astrocytes during lipopolysaccharide (LPS)-induced inflammation. Coimmunoprecipitation and immunofluorescence assays have demonstrated that SSeCKS and ß-1,4-GalT-I were significantly enhanced in LPS-treated astrocytes and their interactions may occur in the Trans-Golgi Network. Lectin blot showed that the knockdown of ß-1,4-GalT-I could inhibit the ß-1,4-galactosylation of glycoproteins including integrin ß1 with and without LPS, and that SSeCKS knockdown inhibits the ß-1,4-galactosylation of glycoproteins including integrin ß1 only in LPS-induced astrocytes. Additionally, wound healing assays indicated that ß-1,4-GalT-I knockdown could inhibit astrocytes migration with and without LPS but SSeCKS inhibited cell migration only when LPS was present. Therefore our findings suggest that SSeCKS affects astrocytes migration by regulating the ß-1,4-galactosylation of glycoproteins including integrin ß1, via ß-1,4-GalT-I expression in LPS-sensitized astrocytes.
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Proteínas de Anclaje a la Quinasa A/metabolismo , Astrocitos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Movimiento Celular/fisiología , Galactosiltransferasas/metabolismo , Lipopolisacáridos/farmacología , Animales , Animales Recién Nacidos , Astrocitos/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Ordered microgel networks have undergone extensive research and shown translational promise in tissue engineering, precision and regenerative medicine, controlled delivery, optics and electronics, etc. Here, we introduce a new low-cost and efficient synthesizer for ordered microgel networks. The gel precursor microdroplets are formulated and incubated in a microfluidics tubing system to obtain tailorable and reproducible microgels, which are then patterned into networks under the precise spatiotemporal control of the tubing system and integrated either by crosslinking the microgel interfaces or by forming lipid bilayers at the interfaces. The system can synthesize ordered networks out of heterogeneous microgels by withdrawing multi-phase cell-laden or acellular gel precursors into the tubing and gelation, or out of homogeneous microgels by simultaneously injecting gel precursors and immiscible oil into the tubing and gelation. The ordered gel networks are synthesized at the tubing outlet or within a piece of enlarging tubing, where the microgels are collided and glued in defined sequences.
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Selenite (Se4+) has been found to counteract the neurotoxicity of methylmercury (MeHg) in MeHg-poisoned rats. However, Se4+ has narrow range between its toxic and beneficial effects. Nanoelemental selenium (SeNPs) was found to be less toxic than other forms of Se such as Se4+. In this study, the effects of SeNPs on the load of mercury (Hg) in rats were investigated. Hyphenated technique based on size-exclusion chromatography coupled with UV and inductively coupled plasma mass spectrometry (SEC-ICP-MS) detection and synchrotron radiation X-ray fluorescence spectroscopy (SR-XRF) were used to analyze the Hg-Se-containing proteins in the serum from MeHg-poisoned rats. The Hg-Se-containing fractions monitored by UV and ICP-MS were further characterized by MALDI-TOF-MS. Elevated serum Hg and Se levels were found in MeHg-poisoned rats after SeNPs treatment. Three main Hg-containing bands with molecular weights (MWs) of 25, 62 and 140â¯kDa were detected in the control samples. Treatment with SeNPs increased the Hg content in proteins at 62 and 170â¯kDa and decreased the Hg content at 25â¯kDa. The fraction with 25â¯kDa was assigned to metallothioneins (MTs), and fractions with 40 and 75â¯kDa were assigned to albumin. This study showed that the low-toxicity SeNPs could reduce the Hg load in the tissues and promote the formation of high molecular weight Hg- and Se-containing proteins in MeHg-poisoned rats.
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Intoxicación del Sistema Nervioso por Mercurio/prevención & control , Mercurio/sangre , Metaloproteínas/sangre , Compuestos de Metilmercurio/toxicidad , Nanopartículas , Proteínas de Unión al Selenio/sangre , Selenio/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Masculino , Espectrometría de Masas , Intoxicación del Sistema Nervioso por Mercurio/sangre , Unión Proteica , Ratas , Ratas Sprague-Dawley , Selenio/sangre , Espectrometría por Rayos XRESUMEN
Circulating tumor cells (CTCs) played a significant role in early diagnosis and prognosis of carcinomas, and efficient capture of CTCs was highly desired to provide important and reliable evidence for clinical diagnosis. In present work, we successfully synthesized functional magnetic Fe3O4/P(MMA-AA) composite nanoparticles (FCNPs) inspired by a counterbalance concept for recognition and capture of CTCs. This counterbalance, composed of polyethylene glycol (PEG) suppressing cell adhesion and anti-epithelial-cell-adhesion-molecule (anti-EpCAM) antibody targeting tumor cells, could both enhance the specific capture of tumor cells and reduce unspecific adhesion of normal cells. The study showed that the PEG density on the surface of the FCNPs affected the specificity of the materials, and a density of ca. 15% was efficient for reducing the unspecific adhesion. After incubation with the mixture of HepG2 cells and Jurkat T cells, the FCNPs reached a capture efficiency as high as about 86.5% of the cancer cells, suggesting great potential on detection of CTCs in the diagnoses and prognoses of cancer metastasis.
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Nanopartículas , Células Neoplásicas Circulantes , Polietilenglicoles , Moléculas de Adhesión Celular , Línea Celular Tumoral , Humanos , MagnetismoRESUMEN
The easy and effective capture of a single protein from a complex mixture is of great significance in proteomics and diagnostics. However, adsorbing nanomaterials are commonly decorated with specific ligands through a complicated and arduous process. Fe3 O4 /carboxymethylated chitosan (Fe3 O4 /CMCS) nanoclusters are developed as a new nonligand modified strategy to selectively capture bovine hemoglogin (BHB) and other structurally similar proteins (i.e., lysozyme (LYZ) and chymotrypsin (CTP)). The ligand-free Fe3 O4 /CMCS nanoclusters, in addition to their simple and economical two-step preparation process, possess many merits, including uniform morphology, high negative charges (-27 mV), high saturation magnetization (60 emu g(-1) ), and high magnetic content (85%). Additionally, the ligand-free Fe3 O4 /CMCS nanoclusters are found to selectively capture BHB in a model protein mixture even within biological samples. The reason for selective protein capture is further investigated from nanomaterials and protein structure. In terms of nanomaterials, it is found that high negative charges are conducive to selectively adsorb BHB. In consideration of protein structure, interestingly, the ligand-free magnetic nanoclusters display a structure-selective protein adsorption capacity to efficiently capture other proteins structurally similar to BHB, such as LYZ and CTP, showing great potential of the ligand-free strategy in biomedical field.
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Quitosano/química , Nanopartículas de Magnetita/química , Proteínas/química , Adsorción , Electroforesis en Gel de Poliacrilamida , Ligandos , Microscopía Electrónica de Transmisión , Conformación ProteicaRESUMEN
In this study, uniform superparamagnetic Fe3O4/carboxymethyl chitosan composite nanospheres with high saturation magnetization were successfully synthesized via a modified inverse emulsion crosslinking approach, using genipin as a cross-linking agent. These nanospheres were then characterized, and their protein adsorption capacity was further investigated under various conditions. The implementation of a sonication treatment of a mixture containing Fe3O4 nanoparticles and carboxymethyl chitosan before the emulsion process significantly promoted the homogeneity of Fe3O4 nanoparticles in an aqueous phase system. The Fe3O4/carboxymethyl chitosan composite nanospheres were of uniform spherical structure, were approximately 230 nm in size, and possessed superparamagnetic characteristics with a mean saturation magnetization as high as 35 emu g(-1), corresponding to a magnetite content of 43%. Lysozyme was then employed as a model protein to investigate the effects of pH, incubation time and ion strength on the protein adsorption capacity of the as-synthesized composite nanospheres. The as-obtained composite nanospheres could serve as a promising candidate for fast and efficient protein adsorption.
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Quitosano/análogos & derivados , Óxido Ferrosoférrico/química , Muramidasa/química , Nanosferas , Adsorción , Microscopía Electrónica de Rastreo , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
Uniform hollow superparamagnetic poly(lactic-co-glycolic acid) (PLGA)/Fe(3)O(4) composite microspheres composed of an inner cavity, PLGA inner shell and Fe(3)O(4) outer shell have been synthesized by a modified oil-in-water (O/W) emulsion-solvent evaporation method using Fe(3)O(4) nanoparticles as a particulate emulsifier. The obtained composite microspheres with an average diameter of 2.5 µm showed excellent monodispersity and stability in aqueous medium, strong magnetic responsiveness, high magnetite content (>68%), high saturation magnetization (58 emu g(-1)) and high efficiency in lysozyme adsorption.
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Óxido Ferrosoférrico , Ácido Láctico , Microesferas , Muramidasa/química , Ácido Poliglicólico , Adsorción , Copolímero de Ácido Poliláctico-Ácido PoliglicólicoRESUMEN
As heavy metal industrial wastewater increases in volume and complexity, we need more efficient, cheaper, and renewable technologies to curb its environmental impact. Compared to advection electrosorption, through-flow electrosorption is a hotspot technique that makes more efficient use of the adsorption capacity of activated carbon fiber mats. A cascade flow-through electrosorption assembly based on activated carbon fiber was used to obtain the best adsorption of Zn2+ in water at a voltage of 2 V, pH value of 8, plate spacing of 3 mm, and temperature of 15°C. The process is more closely fitted to the secondary adsorption kinetic equation and the Langmuir equation. The adsorption capacity of the module decreases at a progressively slower rate with the number of cycles and will eventually retain 75% of its peak value with significant regenerability. The study of this module can provide technical support for treating heavy metal wastewater.
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BACKGROUND: Parkinson's disease (PD) is a neurodegenerative condition characterized by the progressive loss of dopaminergic neurons within the substantia nigra. Neuroinflammation plays a pivotal role in the pathogenesis of PD, involving the activation of microglia cells, heightened production of proinflammatory cytokines, and perturbations in the composition of the gut microbiota. Rubusoside (Ru), the principal steviol bisglucoside present in Rubus chingii var. suavissimus (S.K.Lee) L.T.Lu (Rosaceae), has been documented for its anti-inflammatory properties in diverse disease models. Nonetheless, there is an imperative need to comprehensively assess and elucidate the protective and anti-inflammatory attributes of Ru concerning PD, as well as to uncover the underlying mechanism involved. OBJECTIVE: The aim of this study is to evaluate the neuroprotective and anti-inflammatory effects of Ru on PD and investigate its potential mechanisms associated with microbes. RESEARCH DESIGN AND METHODS: We pre-treated mice and cell lines with Ru in order to simulate the progression of PD and the neuroinflammatory state. The mouse model was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), SN4741 cells were induced by 1-methyl-4-phenylpyridine (mpp+), and BV-2 cells were induced by lipopolysaccharide (LPS). We assessed the impact of Ru on motor function, neuroinflammation, neuron apoptosis, the composition of gut microbes, and their metabolites. RESULTS: Ru treatment reduces the release of pro-inflammatory mediators by inhibiting microglia activation. It also prevents neuronal apoptosis, thereby safeguarding dopaminergic neurons and ameliorating motor dysfunction. Furthermore, it induces alterations in the fecal microbiota composition and metabolites profile in PD mice. In vitro experiments have demonstrated that Ru inhibits neuronal apoptosis in SN4741 cells induced by mpp+, suppresses the production of pro-inflammatory mediators, and activates the c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase (p38 MAPK), and nuclear factor kappa-B (NF-κB) signaling pathways. CONCLUSION: Ru exhibits inhibitory effects on the MPTP-induced PD model by mitigating neuroinflammation and neuronal apoptosis while also inducing changes in the gut microbiota and metabolite composition.
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Diterpenos de Tipo Kaurano , Microbioma Gastrointestinal , Glucósidos , Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratones , Animales , Enfermedad de Parkinson/metabolismo , Enfermedades Neuroinflamatorias , Antiinflamatorios/uso terapéutico , 1-Metil-4-fenilpiridinio , Apoptosis , Mediadores de Inflamación/metabolismo , Neuronas Dopaminérgicas , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Microglía , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
In vitro organoids, including cerebral organoids, are usually developed without mechanical compression, which may contribute to a delay in maturation. Here, we present a protocol for encapsulating cerebral organoids with a thin shell of low-concentration alginate hydrogel. We describe steps for organoid generation, microfluidic chip culture, Matrigel coating, expansion culture, and alginate encapsulation. We then detail procedures for maturation culture and organoid characterization. The moderate compressive stimulation that the shell provides promotes cell proliferation and neuronal maturation. For complete details on the use and execution of this protocol, please refer to Tang et al.1.
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Alginatos , Hidrogeles , Organoides , Alginatos/química , Alginatos/farmacología , Organoides/citología , Organoides/efectos de los fármacos , Hidrogeles/química , Animales , Ratones , Humanos , Proliferación Celular/efectos de los fármacos , Técnicas de Cultivo de Célula/métodos , Encéfalo/citología , Encéfalo/efectos de los fármacosRESUMEN
BACKGROUND: Sphingolipids not only serve as structural components for maintaining cell membrane fluidity but also function as bioactive molecules involved in cell signaling and the regulation of various biological processes. Their pivotal role in cancer cell development, encompassing cancer cell proliferation, migration, angiogenesis, and metastasis, has been a focal point for decades. However, the contribution of sphingolipids to the complexity of tumor microenvironment promoting cancer progression has been rarely investigated. METHODS: Through the integration of publicly available bulk RNA-seq and single-cell RNA-seq data, we conducted a comprehensive analysis to compare the transcriptomic features between tumors and adjacent normal tissues, thus elucidating the intricacies of the tumor microenvironment (TME). RESULTS: Disparities in sphingolipid metabolism (SLM)-associated genes were observed between normal and cancerous tissues, with the TME characterized by the enrichment of sphingolipid signaling in macrophages. Cellular interaction analysis revealed robust communication between macrophages and cancer cells exhibiting low SLM, identifying the crucial ligand-receptor pair, macrophage inhibitory factor (MIF)-CD74. Pseudo-time analysis unveiled the involvement of SLM in modulating macrophage polarization towards either M1 or M2 phenotypes. Categorizing macrophages into six subclusters based on gene expression patterns and function, the SPP1+ cluster, RGS1+ cluster, and CXCL10+ cluster were likely implicated in sphingolipid-induced M2 macrophage polarization. Additionally, the CXCL10+, AGER+, and FABP4+ clusters were likely to be involved in angiogenesis through their interaction with endothelial cells. CONCLUSION: Based on multiple scRNA-seq datasets, we propose that a MIF-targeted strategy could potentially impede the polarization from M1 to M2 and impair tumor angiogenesis in low-SLM non-small cell lung cancer (NSCLC), demonstrating its potent antitumor efficacy.