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1.
Org Biomol Chem ; 22(37): 7702-7706, 2024 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-39224970

RESUMEN

The development of facile and convenient atom-economical methods for the preparation of organosulfur compounds from CS2 is a challenging endeavor. Herein, a one-pot, environmentally friendly method to access S-aryl/alkyl dithiocarbamates has been demonstrated by a three-component coupling involving aryl/alkyl thiols, CS2 and amines in the presence of a common base K2CO3. The transformation process can proceed in an H2O-DMAc (3 : 1) mixed solvent without requiring any catalysts or extensive prefunctionalization of reactants. The protocol is operationally simple and affords dithiocarbamates with various moieties (including aryl, aliphatic, heteroaryl and alkenyl) in good yields.

2.
Can Respir J ; 2024: 5812829, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39188353

RESUMEN

Objective: This study aims to evaluate a novel prone position ventilation device designed to enhance patient safety, improve comfort, and reduce adverse events, facilitating prolonged tolerance in critically ill patients. Methods: A randomized controlled trial was conducted on 60 critically ill patients from January 2020 to June 2023. Of which, one self-discharged during treatment and another was terminated due to decreased oxygenation, leaving an effective sample of 58 patients. Patients were allocated to either a control group receiving traditional prone positioning aids (ordinary sponge pads and pillows) or an intervention group using a newly developed adjustable prone positioning device. A subset of patients in each group also received life support technologies such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). We assessed prone position ventilation tolerance, oxygen saturation increments postintervention, duration of prone positioning, CRRT filter lifespan, and the incidence of adverse events. Results: The intervention group exhibited significantly longer average tolerance to prone positioning (16.6 hours vs. 8.3 hours, P < 0.001 with a difference of 8.3 (4.4, 12.2) hours), higher increases in oxygen saturation postventilation (9% vs. 6%, P < 0.001 with a difference of 3.0 (1.5, 4.5)), and reduced time required for medical staff to position patients (11.7 min vs. 21.8 min, P < 0.001 with a difference of -10.1 (-11.9, -8.3)). Adverse events, including catheter displacement or blockage, facial edema, pressure injuries, and vomiting or aspiration, were markedly lower in the intervention group, with statistical significance (P < 0.05). In patients receiving combined life support, the intervention group demonstrated improved catheter blood drainage and extended CRRT filter longevity. Conclusion: The newly developed adjustable prone ventilation device significantly improves tolerance to prone positioning, enhances oxygenation, and minimizes adverse events in critically ill patients, thereby also facilitating the effective application of life support technologies.


Asunto(s)
Enfermedad Crítica , Posicionamiento del Paciente , Respiración Artificial , Humanos , Posición Prona , Masculino , Femenino , Persona de Mediana Edad , Enfermedad Crítica/terapia , Respiración Artificial/métodos , Respiración Artificial/instrumentación , Posicionamiento del Paciente/métodos , Anciano , Oxigenación por Membrana Extracorpórea/métodos , Oxigenación por Membrana Extracorpórea/instrumentación , Oxigenación por Membrana Extracorpórea/efectos adversos , Adulto , Terapia de Reemplazo Renal Continuo/métodos , Terapia de Reemplazo Renal Continuo/instrumentación , Diseño de Equipo
3.
Clin Kidney J ; 17(8): sfae209, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39145144

RESUMEN

Background: This study investigates the link between genetic variants associated with kidney function and immunoglobulin A (IgA) nephropathy (IgAN) progression. Methods: We recruited 961 biopsy-proven IgAN patients and 651 non-IgAN end-stage renal disease (ESRD) patients from Ruijin Hospital. Clinical and renal pathological data were collected. The primary outcome was the time to ESRD. A healthy population was defined as estimated glomerular filtration rate >60 mL/min/1.73 m2 without albuminuria or hematuria. Fifteen single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of kidney function and genotyped by the SNaPshot. Immunohistochemistry in renal tissue and ELISA in urine samples were performed to explore the potential functions of genetic variations. Results: The rs77924615-G was independently associated with an increased risk for ESRD in IgAN patients after adjustments for clinical and pathologic indices, and treatment (adjusted hazard ratio 2.10; 95% confidence interval 1.14-3.88). No significant differences in ESRD-free survival time were found among different genotypes in non-IgAN ESRD patients (log-rank, P = .480). Moreover, rs77924615 exhibited allele-specific enhancer activity by dual-luciferase reporter assay. Accordingly, the urinary uromodulin-creatinine ratio (uUCR) was significantly higher in healthy individuals with rs77924615 AG or GG than in individuals with AA. Furthermore, uromodulin expression in tubular epithelial cells was higher in patients with rs77924615 AG or GG. Finally, we confirmed that an increased uUCR (P = .009) was associated with faster IgAN progression. Conclusion: The SNP rs77924615, which modulates the enhancer activity of the UMOD gene, is associated with renal function deterioration in IgAN patients by increasing uromodulin levels in both the renal tubular epithelium and urine.

4.
Cell Death Discov ; 10(1): 369, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39164252

RESUMEN

The linear ubiquitin chain assembly complex (LUBAC) mediates the linear ubiquitination of various proteins and is involved in NF-κB signaling and immune regulation. However, the function and mechanism of linear ubiquitination in regulating oncogenic signaling and tumor growth have remained poorly understood. Herein, we identified Gli proteins, key transcription factors in the Hedgehog (Hh) signaling pathway, as novel substrates of LUBAC. Linear ubiquitination stabilizes Gli proteins, leading to the noncanonical activation of Hh signaling in CRC cells. Furthermore, LUBAC facilitates tumor growth in CRC cells. Additionally, elevated expression of LUBAC components in CRC tissues was observed, and higher expression levels of these components correlated with poor prognosis in CRC patients. Interestingly, inhibition of LUBAC using either a small molecule agonist or RNA silencing specifically suppressed cell growth in CRC cells but had no effect on normal intestinal cells. Taken together, aberrant expression of LUBAC components activates Hh signaling noncanonically by mediating linear ubiquitination, promoting tumor growth in CRC, demonstrating the novel function of linear ubiquitination in regulating the protein stability of its substrates and highlighting the potential of targeting LUBAC as a therapeutic strategy in CRC.

5.
Adv Sci (Weinh) ; 11(36): e2404350, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39052888

RESUMEN

Effective water management is crucial for the optimal operation of low-temperature polymer electrolyte membrane fuel cells (PEMFCs). Excessive liquid water production can cause flooding in the gas diffusion electrodes and flow channels, limiting mass transfer and reducing PEMFC performance. To tackle this issue, a nature-inspired chemical engineering (NICE) approach has been adopted that takes cues from the integument structure of desert-dwelling lizards for passive water transport. By incorporating engraved, capillary microchannels into conventional flow fields, PEMFC performance improves significantly, including a 15% increase in maximum power density for a 25 cm2 cell and 13% for a 100 cm2 cell. Electro-thermal maps of the lizard-inspired flow field demonstrate a more uniform spatial distribution of current density and temperature than the conventional design. Neutron radiography provides evidence that capillary microchannels in the lizard-inspired flow field facilitate the efficient transport and removal of generated liquid water, thereby preventing blockages in the reactant channels. These findings present a universally applicable and highly efficient water management strategy for PEMFCs, with the potential for widespread practical implementation for other electrochemical devices.

6.
Odontology ; 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38995322

RESUMEN

The roles and molecular mechanisms of Delta-like 1 (DLK1) in periodontitis remain largely unknown. Here, we investigated the expression of DLK1 and NF-κB p65 in Porphyromonas gingivalis (Pg.)-induced periodontitis in vivo. Periodontal inflammation and alveolar bone resorption were analyzed using western blotting, micro-computed tomography, TRAP staining, immunohistochemistry, and immunofluorescence. Raw246.7 cells were stimulated with 1 µg/ml Porphyromonas gingivalis lipopolysaccharide (Pg.LPS) to assess DLK1 expression in vitro. DLK1 overexpression was achieved, and transfection efficiency was confirmed using western blotting and immunofluorescence. The NF-κB and MAPK pathways were activated by treating cells with 1 µg/ml Pg.LPS to explore related mechanisms. Compared with normal tissues, both DLK1 and NF-κB p65 expression increased in periodontitis gingival tissues. DLK1-positive expression was observed in inflammatory infiltrating cells and osteoclasts in the marginal lacunae of the alveolar bone. DLK1 expression in CD68-positive macrophages was detected by immunofluorescence. However, DLK1 expression in Raw246.7 cells decreased after Pg.LPS stimulation and during osteoclast differentiation. DLK1 levels negatively correlated with TNF-α, IL-1ß, and NFATC1. Increased DLK1 in Raw246.7 cells further inhibited COX2 and iNOS expressions. Mechanistically, DLK1 overexpression down-regulated NF-κB p65 and JNK levels. In summary, these findings suggest that DLK1 overexpression inhibits periodontal inflammation through the NF-κB p65 and JNK pathways. Interventions targeting increased DLK1 levels may have therapeutic implications for periodontitis.

7.
Food Chem X ; 23: 101547, 2024 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-38974194

RESUMEN

Taiping Houkui (TPHK) is prevalent green tea in China, its flavor quality is significantly influenced by different production regions. However, the key flavor compounds responsible for these discrepancies remain unclearly. Here, TPHK samples were produced from fresh leaves of 'Shidacha 2' cultivar planted in 14 distinct production regions. In 14 TPHK samples, a total of 33 non-volatile compounds were identified and quantified. Partial least-squares discriminant analysis (PLS-DA) reveal that theanine and glutamate were the main umami compounds, caffeine imparted with bitterness, which collectively contributed to the variation in the taste flavor of TPHK across different production regions. Furthermore, the profiles of 51 volatile compounds were determined, integrated PLS-DA with odor activity values of volatiles indicated that linalool (165.7-888.5) and geraniol (11.9-141.4) affecting the floral aroma of TPHK among different production regions. Our findings revealed the critical compounds that contributed to the effect of production regions on flavor quality of TPHK.

8.
Kidney Dis (Basel) ; 10(3): 167-180, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38835407

RESUMEN

Introduction: IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the (immuno)proteasome probably plays an important role in IgAN. Methods: We firstly analyzed the association of variants in the UBE2L3 region with susceptibility to IgAN in 3,495 patients and 9,101 controls, and then analyzed the association between lead variant and clinical phenotypes in 1,803 patients with regular follow-up data. The blood mRNA levels of members of the ubiquitin-proteasome system including UBE2L3 were analyzed in peripheral blood mononuclear cells from 53 patients and 28 healthy controls. The associations between UBE2L3 and the expression levels of genes involved in Gd-IgA1 production were also explored. Results: The rs131654 showed the most significant association signal in UBE2L3 region (OR: 1.10, 95% CI: 1.04-1.16, p = 2.29 × 10-3), whose genotypes were also associated with the levels of Gd-IgA1 (p = 0.04). The rs131654 was observed to exert cis-eQTL effects on UBE2L3 in various tissues and cell types, particularly in immune cell types in multiple databases. The UBE2L3, LUBAC, and proteasome subunits were highly expressed in patients compared with healthy controls. High expression levels of UBE2L3 were not only associated with higher proteinuria (r = 0.34, p = 0.01) and lower eGFR (r = -0.28, p = 0.04), but also positively correlated with the gene expression of LUBAC and other proteasome subunits. Additionally, mRNA expression levels of UBE2L3 were also positively correlated with IL-6 and RELA, but negatively correlated with the expression levels of the key enzyme in the process of glycosylation including C1GALT1 and C1GALT1C1. Conclusion: In conclusion, by combined genetic association and differed expression analysis of UBE2L3, our data support a role of genetically conferred dysregulation of the (immuno)proteasome in regulating galactose-deficient IgA1 in the development of IgAN.

9.
Heliyon ; 10(11): e31619, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38845857

RESUMEN

Exploring the symbiotic potential between fungal and yeast species, this study investigates the co-cultivation dynamics of Monascus, a prolific producer of pharmacologically relevant secondary metabolites, and Wickerhamomyce anomalous. The collaborative interaction between these microorganisms catalyzed a substantial elevation in the biosynthesis of secondary metabolites, prominently Monacolin K and natural pigments. Central to our discoveries was the identification and enhanced production of oxylipins (13S-hydroxyoctadecadienoic acid,13S-HODE), putative quorum-sensing molecules, within the co-culture environment. Augmentation with exogenous oxylipins not only boosted Monacolin K production by over half but also mirrored morphological adaptations in Monascus, affecting both spores and mycelial structures. This augmentation was paralleled by a significant upregulation in the transcriptional activity of genes integral to the Monacolin K biosynthetic pathway, as well as genes implicated in pigment and spore formation. Through elucidating the interconnected roles of quorum sensing, G-protein-coupled receptors, and the G-protein-mediate signaling pathway, this study provides a comprehensive view of the molecular underpinnings facilitating these metabolic enhancements. Collectively, our findings illuminate the profound influence of Wickerhamomyces anomalous co-culture on Monascus purpureus, advocating for oxylipins as a pivotal quorum-sensing mechanism driving the observed symbiotic benefits.

10.
Phenomics ; 4(2): 146-157, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38884057

RESUMEN

Genome-wide association studies (GWASs) have identified 30 independent genetic variants associated with IgA nephropathy (IgAN). A genetic risk score (GRS) represents the number of risk alleles carried and thus captures an individual's genetic risk. However, whether and which polygenic risk score crucial for the evaluation of any potential personal or clinical utility on risk and prognosis are still obscure. We constructed different GRS models based on different sets of variants, which were top single nucleotide polymorphisms (SNPs) reported in the previous GWASs. The case-control GRS analysis included 3365 IgAN patients and 8842 healthy individuals. The association between GRS and clinical variability, including age at diagnosis, clinical parameters, Oxford pathology classification, and kidney prognosis was further evaluated in a prospective cohort of 1747 patients. Three GRS models (15 SNPs, 21 SNPs, and 55 SNPs) were constructed after quality control. The patients with the top 20% GRS had 2.42-(15 SNPs, p = 8.12 × 10-40), 3.89-(21 SNPs, p = 3.40 × 10-80) and 3.73-(55 SNPs, p = 6.86 × 10-81) fold of risk to develop IgAN compared to the patients with the bottom 20% GRS, with area under the receiver operating characteristic curve (AUC) of 0.59, 0.63, and 0.63 in group discriminations, respectively. A positive correlation between GRS and microhematuria, mesangial hypercellularity, segmental glomerulosclerosis and a negative correlation on the age at diagnosis, body mass index (BMI), mean arterial pressure (MAP), serum C3, triglycerides can be observed. Patients with the top 20% GRS also showed a higher risk of worse prognosis for all three models (1.36, 1.42, and 1.36 fold of risk) compared to the remaining 80%, whereas 21 SNPs model seemed to show a slightly better fit in prediction. Collectively, a higher burden of risk variants is associated with earlier disease onset and a higher risk of a worse prognosis. This may be informational in translating knowledge on IgAN genetics into disease risk prediction and patient stratification. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00138-6.

11.
Talanta ; 278: 126451, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-38917549

RESUMEN

Developing water-soluble nanomaterials with high photoluminescence emission and high yield for biological analysis and imaging is urgently needed. Herein, water-soluble blue emitting silicon and nitrogen co-doped carbon dots (abbreviated as Si-CDs) of a high photoluminescence quantum yield of 80 % were effectively prepared with high yield rate (59.1 %) via one-step hydrothermal treatment of N-[3-(trimethoxysilyl)propyl]ethylenediamine (DAMO) and trans-aconitic acid. Furthermore, the Si-CDs demonstrate environmental robustness, photo-stability and biocompatibility. Given the importance of the potentially abnormal levels of acid phosphatase (ACP) in cancer diagnosis, developing a reliable and sensitive ACP measurement method is of significance for clinical research. The Si-CDs unexpectedly promote the catalytic oxidation of ACP on dopamine (DA) to polydopamine under acidic conditions through the produced reactive oxygen species (ROS). Correspondingly, a fluorescence response strategy using Si-CDs as the dual functions of probes and promoting enzyme activity of ACP on catalyzing DA was constructed to sensitively determine ACP. The quantitative analysis of ACP displayed a linear range of 0.1-60 U/L with a detection limit of 0.056 U/L. The accurate detection of ACP was successfully achieved in human serum through recovery tests. As a satisfactory fluorescent probe, Si-CDs were successfully applied to fluorescent imaging of A549 cells in cytoplasmic with long-term and safe staining. The Si-CDs have the dual properties of outstanding fluorescent probes and auxiliary oxidase activity, indicating their great potential in multifunctional applications.


Asunto(s)
Fosfatasa Ácida , Carbono , Dopamina , Nitrógeno , Puntos Cuánticos , Silicio , Fosfatasa Ácida/metabolismo , Fosfatasa Ácida/análisis , Humanos , Silicio/química , Dopamina/análisis , Dopamina/química , Puntos Cuánticos/química , Carbono/química , Nitrógeno/química , Imagen Óptica
12.
Foods ; 13(10)2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38790823

RESUMEN

Histamine, a bioactive component in certain foods such as Huangjiu has been associated with liver injury and disrupted intestinal balance. This study explored the potential therapeutic effects of fucoidan (FCD) in mitigating histamine-induced imbalances in mice. We found that FCD mitigated liver injury, reducing transaminases, oxidative stress, and inflammation. Histological improvements included decreased cell infiltration and necrosis. FCD restored tight junction proteins and suppressed inflammation-related genes. Western blot analysis revealed FCD's impact on TGF-ß1, p-AKT, AKT, CYP2E1, Grp78, NLRP3, Cas-1, and GSDMD. Gut LPS levels decreased with FCD. Gut microbiota analysis showed FCD's modulation effect, reducing Firmicutes and increasing Bacteroides. FCD demonstrates potential in alleviating histamine-induced liver injury, regulating inflammation, and influencing gut microbiota. Further research exploring higher dosages and additional parameters is warranted.

13.
PLoS One ; 19(5): e0304143, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38781281

RESUMEN

This study addressed enamel demineralization, a common complication in fixed orthodontic treatment, by evaluating a novel orthodontic adhesive with DMAHDM-PCL composite fibers. These fibers, produced through electrospinning, were incorporated into orthodontic adhesive to create experimental formulations at different concentrations and a control group. The study assessed antimicrobial properties, biosafety, and mechanical characteristics. New orthodontic adhesive exhibited significant bacteriostatic effects, reducing bacterial biofilm activity and concentrations. Incorporating 1% and 3% DMAHDM-PCL did not affect cytocompatibility. Animal tests confirmed no inflammatory irritation. Shear bond strength and adhesive residual index results indicated that antimicrobial fibers didn't impact bonding ability. In conclusion, orthodontic adhesives with 3% DMAHDM-PCL fibers are potential antimicrobial bonding materials, offering a comprehensive solution to enamel demineralization in orthodontic patients.


Asunto(s)
Cementos Dentales , Poliésteres , Poliésteres/química , Cementos Dentales/química , Cementos Dentales/farmacología , Animales , Biopelículas/efectos de los fármacos , Metacrilatos/química , Metacrilatos/farmacología , Humanos , Ensayo de Materiales
14.
J Colloid Interface Sci ; 669: 228-235, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38713961

RESUMEN

The development of heterogeneous supported nanocatalysts with a high kinetics combined with low cost is off importance but remains still challenged for hydrazine hydrate served as a promising hydrogen storage material. Herein, by virtue of surficial functional groups, ultrafine NiRh NPs were monodispersed on the two-dimensional V2C surface via a conventional wet chemical co-reduction. The optimized NiRh/V2C system demonstrates an excellent catalytic performance toward selectively catalyzing dehydrogenation of hydrazine hydrate, affording 100% H2 selectivity with the turnover frequency (TOF) value of 987.5 h-1 at 323 K. Such an enhancement is mainly attributed to synergistic effect of nanosystem, which will optimize local surface energy and promote electron transfer in NiRh/V2C system, thereby improving the kinetic selectivity of catalytic hydrazine hydrate decomposition. This work has provided a facile strategy for developing nanocatalysts with high kinetics that could enable huge industrial applications in the future.

15.
Kidney Int Rep ; 9(4): 1057-1066, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38765575

RESUMEN

Introduction: Immunoglobulin A nephropathy (IgAN) has been reported to coexist with hepatitis B virus (HBV) infection. Despite the clinical significance of this association, there is a lack of comprehensive research investigating the impact of various common conditions following HBV infection and the potential influence of anti-HBV therapy on the progression of IgAN. Methods: We investigated 3 distinct states of HBV infection, including chronic HBV infection, resolved HBV infection, and the deposition of hepatitis B antigens in renal tissue, in a follow-up database of 1961 patients with IgAN. IgAN progression was defined as a loss of estimated glomerular filtration rate (eGFR) >40%. Multivariable cause-specific hazards models to analyze the relationship between HBV states and IgAN progression. Results: Chronic HBV infection was identified as an independent risk factor for IgAN progression, supported by both prematching analysis (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.06-2.44; P = 0.024) and propensity-score matching analysis (HR, 1.74; 95% CI 1.28-2.37; P < 0.001). Conversely, resolved HBV infection showed no significant association with IgAN progression (HR, 1.01; 95% CI 0.67-1.52; P = 0.969). Moreover, the presence of HBV deposition in the kidneys and the utilization of anti-HBV therapy did not appear to be significant risk factors for renal outcomes (P > 0.05). Conclusion: Chronic HBV infection is an independent risk factor for IgAN progression, whereas resolved HBV infection is not. In patients with IgAN, management of concurrent chronic HBV infection should be enhanced. The presence of HBV deposition in the kidneys and the use of anti-HBV medications do not impact the kidney disease progression in patients with IgAN with concurrent HBV infection.

17.
Adv Mater ; 36(28): e2401918, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38662940

RESUMEN

The complex pathologies in Alzheimer's disease (AD) severely limit the effectiveness of single-target pharmic interventions, thus necessitating multi-pronged therapeutic strategies. While flexibility is essentially demanded in constructing such multi-target systems, for achieving optimal synergies and also accommodating the inherent heterogeneity within AD. Utilizing the dynamic reversibility of supramolecular strategy for conferring sufficient tunability in component substitution and proportion adjustment, amphiphilic calixarenes are poised to be a privileged molecular tool for facilely achieving function integration. Herein, taking ß-amyloid (Aß) fibrillation and oxidative stress as model combination pattern, a supramolecular multifunctional integration is proposed by co-assembling guanidinium-modified calixarene with ascorbyl palmitate and loading dipotassium phytate within calixarene cavity. Serial pivotal events can be simultaneously addressed by this versatile system, including 1) inhibition of Aß production and aggregation, 2) disintegration of Aß fibrils, 3) acceleration of Aß metabolic clearance, and 4) regulation of oxidative stress, which is verified to significantly ameliorate the cognitive impairment of 5×FAD mice, with reduced Aß plaque content, neuroinflammation, and neuronal apoptosis. Confronted with the extremely intricate clinical realities of AD, the strategy presented here exhibits ample adaptability for necessary alterations on combinations, thereby may immensely expedite the advancement of AD combinational therapy through providing an exceptionally convenient platform.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Calixarenos , Nanopartículas , Estrés Oxidativo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/química , Nanopartículas/química , Ratones , Calixarenos/química , Estrés Oxidativo/efectos de los fármacos , Humanos
18.
Adv Mater ; : e2313869, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38688523

RESUMEN

Accumulation of pathological tau is a hallmark of Alzheimer's disease (AD), which correlates more closely with cognitive impairment than does the amyloid-ß (Aß) burden. Autophagy is a powerful process for the clearance of toxic proteins including aberrant tau. However, compromised autophagy is demonstrated in neurodegeneration including AD, and current autophagy inducers remain enormously challenging due to inability of restoring autophagy pathway and lack of targeting specificity. Here, pathogenic tau-specific autophagy based on customized nanochaperone is developed for AD treatment. In this strategy, the nanochaperone can selectively bind to pathogenic tau and maintain tau homeostasis, thereby ensuring microtubule stability which is important for autophagy pathway. Meanwhile, the bound pathogenic tau can be sequestered in autophagosomes by in situ autophagy activation of nanochaperone. Consequently, autophagosomes wrapping with pathogenic tau are able to be trafficked along the stabilized microtubule to achieve successful fusion with lysosomes, resulting in the enhancement of autophagic flux and pathologic tau clearance. After treatment with this nanochaperone-mediated autophagy strategy, the tau burden, neuron damages, and cognitive deficits of AD mice are significantly alleviated in the brain. Therefore, this work represents a promising candidate for AD-targeted therapy and provides new insights into future design of anti-neurodegeneration drugs.

19.
Langmuir ; 40(13): 7178-7191, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38506447

RESUMEN

The interaction of cyclodextrins (CDs) with structure-controlled polymers is expected to provide significant insights into macromolecular recognition. However, the interaction of CDs with structure-controlled polymers has been an underexamined issue of investigation. Herein, alternating amphiphilic cooligomers (oligoCnAH, where n denotes the carbon number of alkyl groups; n = 4, 8, and 12) were synthesized by copper(I)-catalyzed azide-alkyne cycloaddition polymerization of heterodimers of 4-azido-5-hexynoic acid (AH) derivatives carrying N-alkylamide and t-butyl (tBu) ester side chains, followed by hydrolysis of the tBu ester, to study the interaction of CDs with oligoCnAH by 1H NMR, nuclear Overhauser effect spectroscopy, and pulse-field-gradient spin-echo NMR. These NMR studies indicated that αCD interacted with oligoC4AH, αCD and ßCD interacted with oligoC8AH, and all CDs interacted with oligoC12AH. Based on the equilibrium models proposed, the binding constants were evaluated for the binary mixtures, which showed interaction. Comparing the interactions of the CDs/oligoC12AH binary mixtures with those of the binary mixtures of CDs and alternating copolymers of sodium maleate and dodecyl vinyl ether (polyC12M), it is concluded that oligoC12AH forms less stable micelles than does polyC12M presumably because of the lower molecular weight, the hydrophilic amide groups in the side chain, and the longer interval between neighboring C12 groups in oligoC12AH.

20.
J Cancer ; 15(8): 2229-2244, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38495507

RESUMEN

Background: Keratin 80(KRT80) encodes a type II intermediate filament protein, known for maintaining cell integrity of cells and its involvement in the tumorigenesis and progression of various cancers. However, comprehensive research on its relevance to lung adenocarcinoma remains limited. Methods: In this study, we utilized multiple databases to investigate the transcriptional expression of KRT80 and its correlation with clinicopathological features. A range of assays, including the Cell Counting Kit 8 assay, colony formation assay, cell migration assay, and flow cytometry, were employed to elucidate the impact of KRT80 on the malignant behavior of lung adenocarcinoma. Immunoprecipitation and mass spectrometry were also used to identify putative genes interacting with KRT80. Results: The expression of KRT80 was elevated in lung adenocarcinoma and patients with high levels of KRT80 expression had poor clinical outcomes. Silencing KRT80 suppressed cell viability, and migration, while overexpression had the opposite effect. In addition, Immunoprecipitation and mass spectrometry revealed an interaction between KRT80 and valosin-containing protein (VCP), with VCP knockdown reducing the stability of KRT80 protein. Overexpression of KRT80 mitigated the inhibitory effect of VCP knockdown to some extent. Conclusion: Our findings collectively suggest that KRT80 is a promising diagnostic and prognostic indicator for lung adenocarcinoma. Additionally, the interaction between KRT80 and VCP plays a crucial role in the progression of lung adenocarcinoma, which implies that KRT80 is a promising therapeutic target.

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