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1.
Heliyon ; 10(17): e36588, 2024 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-39263185

RESUMEN

Purpose: Primary surgery failure of macular holes causes poor visual acuity outcomes. Several studies indicate that small-medium idiopathic full-thickness macular holes (iFTMH) have consistent and high anatomical closure rates after vitrectomy and internal limiting membrane (ILM) peeling, regardless of iFTMH diameters. However, there is no systematic analysis examining the relationship between iFTMH diameters and anatomical closure rates. Methods: In this systematic review and meta-regression, we searched PubMed, Embase, and Web of Science databases on October 24th, 2022. We included studies regarding iFTMH, with ILM peeling/inverted flap technique, long-lasting gas tamponade, and face-down position after surgery. Univariable meta-regression with a restricted cubic spline model and component-plus-residual plot after covariables adjustment were used to explore non-linear association. Results: A total of 7257 participants from 19 randomized controlled trials and 49 observational studies were included in this meta-analysis. In ILM peeling group, every 100-µm increment in diameter was associated with a 3.8 % (95 % confidence interval [CI], 1.8%-5.7 %, P < 0.001) relatively lower anatomical closure rate. Yet, among studies using the inverted flap technique, baseline iFTMH diameter was not associated with a lower anatomical closure rate (0.2 %, 95%CI, -4.2 %-4.5 %, P > 0.9). The restricted cubic spline model and component-plus-residual plot controlling for age, sex, and symptom duration prior to surgery showed no evident non-linearity in both surgical techniques. Conclusions: The iFTMH diameter is linear and inversely associated with the anatomical closure rate after the ILM peeling technique, but not with the inverted flap technique. The present study supports the use of advanced techniques, e.g., inverted flap technique, in small-medium iFTMH to improve anatomical closure rates.

2.
Mol Cell Biochem ; 2024 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-39231894

RESUMEN

The degradation of proteasomes or lysosomes is emerging as a principal determinant of programmed death ligand 1 (PDL1) expression, which affects the efficacy of immunotherapy in various malignancies. Intracellular cholesterol plays a central role in maintaining the expression of membrane receptors; however, the specific effect of cholesterol on PDL1 expression in cancer cells remains poorly understood. Cholesterol starvation and stimulation were used to modulate the cellular cholesterol levels. Immunohistochemistry and western blotting were used to analyze the protein levels in the samples and cells. Quantitative real-time PCR, co-immunoprecipitation, and confocal co-localization assays were used for mechanistic investigation. A xenograft tumor model was constructed to verify these results in vivo. Our results showed that cholesterol suppressed the ubiquitination and degradation of PDL1 in hepatocellular carcinoma (HCC) cells. Further mechanistic studies revealed that the autocrine motility factor receptor (AMFR) is an E3 ligase that mediated the ubiquitination and degradation of PDL1, which was regulated by the cholesterol/p38 mitogenic activated protein kinase axis. Moreover, lowering cholesterol levels using statins improved the efficacy of programmed death 1 (PD1) inhibition in vivo. Our findings indicate that cholesterol serves as a signal to inhibit AMFR-mediated ubiquitination and degradation of PDL1 and suggest that lowering cholesterol by statins may be a promising combination strategy to improve the efficiency of PD1 inhibition in HCC.

3.
Ecotoxicol Environ Saf ; 283: 116828, 2024 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-39094458

RESUMEN

The neonicotinoid pesticide acetamiprid has been widely used in agricultural pest control and was frequently detected in the water environment. There have been some studies of the toxic effects of acetamiprid on fish, but studies on aquatic lower vertebrates are still very limited. As a primitive jawless vertebrate, Lethenteron reissneri has a special position in evolution and is now listed as a national second level protected animal in China. The present study aimed to investigate the toxic effect of acetamiprid on the liver of L. reissneri larvae. A conjoint analysis of the transcriptomics and metabolomics was performed to determine the responses of L. reissneri larvae liver to acetamiprid at different concentrations (L for low concentration 25 mg/L and H for high concentration 100 mg/L). Even low concentrations of acetamiprid can cause significant liver damage to L. reissneri larvae in a short period. In omics analyses, 2141 differentially expressed genes (DEGs) and 183 differentially abundant metabolites (DAMs) were identified in the H/Control group, and 229 DEGs and 144 DAMs were identified in the L/C group. Correlation analyses revealed acetamiprid affected the metabolic pathways of L. reissneri larvae liver such as the glycerophospholipid metabolism and arachidonic acid metabolism. This study not only enriches the basis for understanding the toxic effect of acetamiprid exposure to L. reissneri larvae liver and provides more information on the breeding and conservation of L. reissneri, but also further causes attention on toxicity risk from acetamiprid to aquatic lower vertebrate species.


Asunto(s)
Larva , Metabolómica , Neonicotinoides , Transcriptoma , Contaminantes Químicos del Agua , Animales , Neonicotinoides/toxicidad , Larva/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Transcriptoma/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Insecticidas/toxicidad , China , Peces/genética
4.
Eur J Pharm Biopharm ; 203: 114473, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39186959

RESUMEN

Hydroxychloroquine sulfate (HCQ) is currently being repurposed for cancer treatment. The antitumor mechanism of HCQ is inhibition of cellular autophagy, but its therapeutic potential is severely limited by poor solubility, lack of tumor targeting and lower cellular uptake. Therefore, utilization of human H-chain apoferritin (HFn) composed only of heavy subunits is an attractive approach for tumor targeting drug delivery. This study focused on pH-triggered encapsulation of HCQ within the inner cavity of HFn to form HFn@HCQ nanoparticles for tumor-targeted drug delivery. Characterization using a range of techniques has been used to confirm the successful establishment of HFn@HCQ. HFn@HCQ exhibited pH-responsive release behavior, with almost no drug release at pH 7.4, but 80% release at pH 5.0. Owing to its intrinsic binding to transferrin receptor 1 (TfR1), HFn@HCQ was significantly internalized through TfR1-mediated endocytosis, with a 4.4-fold difference of internalization amount across cell lines. Additionally, HFn@HCQ enhanced the antitumor effect against four different cancer cell lines when compared against HCQ alone, especially in TfR1 high-expressing cells, where the inhibitory effect was 3-fold higher than free HCQ. The autophagy inhibition of HFn@HCQ has been demonstrated, which is a major pathway to induce cancer cell death. According to current findings, HFn based drug delivery is a promising strategy to target and kill TfR1 overexpressing tumor cells.


Asunto(s)
Antineoplásicos , Apoferritinas , Autofagia , Liberación de Fármacos , Reposicionamiento de Medicamentos , Hidroxicloroquina , Nanopartículas , Humanos , Hidroxicloroquina/farmacología , Hidroxicloroquina/química , Hidroxicloroquina/administración & dosificación , Autofagia/efectos de los fármacos , Reposicionamiento de Medicamentos/métodos , Apoferritinas/química , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Nanopartículas/química , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Concentración de Iones de Hidrógeno , Receptores de Transferrina/metabolismo , Neoplasias/tratamiento farmacológico , Portadores de Fármacos/química , Endocitosis/efectos de los fármacos
5.
Int J Biol Macromol ; 278(Pt 1): 134672, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39134199

RESUMEN

A hyperbranched poly (titanium oxide) (HBPTi) with hydroxyl terminal groups was synthesized via polycondensation reaction as a synergistic modifier with tannin to promote performance of casein-based composite film. The synergistic effects of HBPTis, acquiring different hyperbranched structures, with tannin on the microstructure, mechanical characteristics, barrier against water vapor, and thermal stability of casein-based film were investigated in this work. The tensile strength of the composite films increased from 7.6 MPa to 22.1 MPa, which accounts for 190.79 % increase after the addition of HBPTi compared to casein-tannin films modified with glycerol. The casein-tannin films with the help of HBPTi presented excellent water vapor permeation, thermal stability, and showed nearly 100 % UV absorption in the range 200-400 nm. Additionally, the microstructure of HBPTi modified casein-tannin films tend to be more compact due to the promoted interaction of casein-tannin composite aided by covalent bonding and/or other types of bonding between casein, tannin and HBPTi. Therefore, associative modification using such hyperbranched polymers and tannins provides extendable application value for casein-based films especially as food packaging materials and for other fields as well.


Asunto(s)
Caseínas , Taninos , Caseínas/química , Taninos/química , Embalaje de Alimentos/métodos , Polímeros/química , Resistencia a la Tracción , Vapor , Permeabilidad
6.
J Immunother Cancer ; 12(8)2024 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-39174053

RESUMEN

BACKGROUND: Immune escape is an important feature of hepatocellular carcinoma (HCC). The overall response rate of immune checkpoint inhibitors (ICIs) in HCC is still limited. Revealing the immune regulation mechanisms and finding new immune targets are expected to further improve the efficacy of immunotherapy. Our study aims to use CRISPR screening mice models to identify potential targets that play a critical role in HCC immune evasion and further explore their value in improving immunotherapy. METHODS: We performed CRISPR screening in two mice models with different immune backgrounds (C57BL/6 and NPG mice) and identified the immunosuppressive gene Gsk3a as a candidate for further investigation. Flow cytometry was used to analyze the impact of Gsk3a on immune cell infiltration and T-cell function. RNA sequencing was used to identify the changes in neutrophil gene expression induced by Gsk3a and alterations in downstream molecules. The therapeutic value of the combination of Gsk3a inhibitors and anti-programmed cell death protein-1 (PD-1) antibody was also explored. RESULTS: Gsk3a, as an immune inhibitory target, significantly promoted tumor growth in immunocompetent mice rather than immune-deficient mice. Gsk3a inhibited cytotoxic T lymphocytes (CTLs) function by inducing neutrophil chemotaxis. Gsk3a promoted self-chemotaxis of neutrophil expression profiles and neutrophil extracellular traps (NETs) formation to block T-cell activity through leucine-rich α-2-glycoprotein 1 (LRG1). A significant synergistic effect was observed when Gsk3a inhibitor was in combination with anti-PD-1 antibody. CONCLUSIONS: We identified a potential HCC immune evasion target, Gsk3a, through CRISPR screening. Gsk3a induces neutrophil recruitment and NETs formation through the intermediate molecule LRG1, leading to the inhibition of CTLs function. Targeting Gsk3a can enhance CTLs function and improve the efficacy of ICIs.


Asunto(s)
Carcinoma Hepatocelular , Inmunoterapia , Neoplasias Hepáticas , Animales , Humanos , Ratones , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/terapia , Línea Celular Tumoral , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Evasión Inmune , Inmunoterapia/métodos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Ratones Endogámicos C57BL , Escape del Tumor/efectos de los fármacos
7.
Neuroendocrinology ; 2024 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-39182479

RESUMEN

INTRODUCTION: Empathy is the ability of an individual to present and respond to the emotions of others and is thought to originate from parental behavior. Testosterone could promote aggression and inhibit biparental behavior and vasopressin (AVP) could promote aggression. Given levels of aggression and parental care are closely associated with levels of empathy, we hypothesized that testosterone may influence empathetic behavior via the AVP system. METHODS: We examined testosterone levels and tested social, empathic, and anxiety-like behaviors after castration surgery to pubertal mice, and subsequently examined the molecular levels of AVP, V1aR in different brain regions. Finally, pharmacological experiments were used to test the effects on empathic behavior by injecting testosterone in combination with V1aR antagonist. RESULTS: Here, we show that pubertal castration reduced serum testosterone levels, increased empathetic behavior and sociality, and reduced anxiety-like behaviors in male C57 mice. The pubertal castration also reduced AVP and vasopressin receptor (V1aR) protein levels, and AVP mRNA levels in the PVN. It also reduced the number of AVP-positive neurons in the PVN. In addition, pubertal subcutaneous injection of testosterone reduced emotional contagion and consolation of castrated mice, while concomitant injection of V1aR antagonists into the ACC reversed the downregulation of emotional contagion and consolation induced by testosterone. CONCLUSION: It is suggested that testosterone in puberty regulates empathetic behavior in C57 mice possibly via the AVP system in the ACC. These findings help us to understand the neuroendocrine mechanisms underlying empathetic behavior and provide potential targets for the treatment of psychiatric disorders associated with low empathy.

8.
Sci Rep ; 14(1): 18970, 2024 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-39152139

RESUMEN

Mitochondrial dysfunction, characterized by elevated oxidative stress, impaired energy balance, and dysregulated mitochondrial dynamics, is a hallmark of metabolic syndrome (MetS) and its comorbidities. Ferulic acid (FA), a principal phenolic compound found in whole grains, has demonstrated potential in ameliorating oxidative stress and preserving energy homeostasis. However, the influence of FA on mitochondrial health within the context of MetS remains unexplored. Moreover, the impact of FA on autophagy, which is essential for maintaining energy homeostasis and mitochondrial integrity, is not fully understood. Here, we aimed to study the mechanisms of action of FA in regulating mitochondrial health and autophagy using palmitate-treated HepG2 hepatocytes as a MetS cell model. We found that FA improved mitochondrial health by restoring redox balance and optimizing mitochondrial dynamics, including biogenesis and the fusion/fission ratio. Additionally, FA was shown to recover autophagy and activate AMPK-related cell signaling. Our results provide new insights into the therapeutic potential of FA as a mitochondria-targeting agent for the prevention and treatment of MetS.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Autofagia , Ácidos Cumáricos , Hepatocitos , Síndrome Metabólico , Dinámicas Mitocondriales , Transducción de Señal , Ácidos Cumáricos/farmacología , Autofagia/efectos de los fármacos , Humanos , Síndrome Metabólico/metabolismo , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/patología , Dinámicas Mitocondriales/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Células Hep G2 , Palmitatos/farmacología , Palmitatos/toxicidad , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos
9.
Quant Imaging Med Surg ; 14(8): 5891-5901, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39144009

RESUMEN

Background: The musculoskeletal system participates in the pathology of metabolic disorders. Several studies have focused on body composition changes; however, the adipose tissue between muscle bundles with different metabolic statuses has rarely been studied. This study sought to explore the association between body compositions and metabolic disorders in Asians, and identify whether these body compositions can be used to detect metabolic disorders with different waist circumferences (WCs) by computed tomography (CT). Methods: A total of 116 subjects were included in the study and categorized into the following four groups according to WC and metabolic syndrome (MS): (I) the healthy control group; (II) the normal WC with metabolic disorder group; (III) the normal WC with MS group; and (IV) the larger WC with MS group. The International Diabetes Federation (IDF) criteria based on WC, laboratory tests, body mass index (BMI), and medical history was used to diagnose MS. Body composition parameters, such as muscle attenuation, the cross-sectional area of subcutaneous adipose tissue (SAT), muscle, extramyocellular lipid (EMCL), visceral adipose tissue (VAT), and the ratios between different compositions [e.g., the SMR (SAT/muscle), EMR (EMCL/muscle), and VMR (VAT/muscle)] were calculated for the thigh and abdomen. The areas under the curve (AUCs) of the receiver operating characteristic (ROC) curves adjusted for multiple comparisons were used to discriminate among metabolic disorders. Results: The groups with metabolic disorders had more SAT (P=0.001) and EMCL (P=0.040) in the thigh, and more VAT (P=0.001) and a higher SMR (P<0.001) in the abdomen. EMCL and muscle attenuation in the thigh (AUCs =0.790 and 0.791), and the VMR and SMR in the abdomen were better able to diagnose metabolic disorders (AUCs =0.752 and 0.746) than other body composition parameters. While SAT and EMCL in the thigh (AUCs =0.768 and 0.760), and VAT and the VMR in the abdomen (AUCs =0.788 and 0.775) were better able to diagnose MS than other parameters. Conclusions: Body composition parameters for the thigh and abdomen could assist in detecting patients with an increased risk of MS.

10.
Nutrients ; 16(13)2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38999760

RESUMEN

Toddlerhood (aged 13~36 months) is a period of dietary transition, with water intake being significantly influenced by parental feeding patterns, cultural traditions, and the availability of beverages and food. Nevertheless, given the lack of applicable data, it is challenging to guide and evaluate the water intake of toddlers in China. In this study, our objectives were to assess the daily total water intake (TWI), evaluate the consumption patterns of various beverages and food sources contributing to the TWI, determine the conformity of participants to the adequate intake (AI) recommendation of water released by the Chinese Nutrition Society, and analyze the various contributors to the daily total energy intake (TEI). The data for the assessment of water and dietary intake were obtained from the cross-sectional dietary intake survey of infants and young children (DSIYC, 2018-2019). A total of 1360 eligible toddlers were recruited in the analysis. The differences in related variables between two age groups were compared by Mann-Whitney U test and Chi-Square test. The potential correlation between water and energy intake was examined utilizing age-adjusted partial correlation. Toddlers consumed a median daily TWI of 1079 mL, with 670 mL (62.3%, r = 0.752) derived from beverages and 393 mL (37.7%, r = 0.716) from foods. Plain water was the primary beverage source, contributing 300 mL (52.2%, r = 0.823), followed by milk and milk derivatives (MMDs) at 291 mL (45.6%, r = 0.595). Notably, only 28.4% of toddlers managed to reach the recommended AI value. Among these, toddlers obtain more water from beverages than from foods. The median daily TEI of toddlers was 762 kcal, including 272 kcal from beverages (36.4%, r = 0.534) and 492 kcal from foods (63.6%, r = 0.894). Among these, the median daily energy intake from MMDs was 260 kcal, making up 94.6% of the energy intake from beverages (r = 0.959). As the pioneer survey on TWI of toddlers in China based on nationally representative data, attention to the quality and quantity of water intake and actions to better guide parents by both individuals and authorities are eagerly anticipated. Additionally, the revision of the reference value of TWI for Chinese toddlers is urgently required.


Asunto(s)
Bebidas , Ingestión de Líquidos , Ingestión de Energía , Humanos , Lactante , China , Masculino , Preescolar , Femenino , Estudios Transversales , Encuestas Nutricionales , Agua , Dieta/estadística & datos numéricos , Encuestas sobre Dietas , Conducta Alimentaria , Ingesta Diaria Recomendada , Pueblos del Este de Asia
11.
J Med Chem ; 67(14): 12068-12084, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-39012838

RESUMEN

Hsp70-Bim protein-protein interaction (PPI) is the most recently identified specific target in chronic myeloid leukemia (CML) therapy. Herein, we developed a new class of Hsp70-Bim PPI inhibitors via scaffold hopping of S1g-10, the most potent Hsp70-Bim PPI inhibitor thus far. Through structure-activity relationship (SAR) study, we obtained a biphenyl scaffold compound JL-15 with a 5.6-fold improvement in Hsp70-Bim PPI suppression (Kd = 123 vs 688 nM) and a 4-fold improvement in water solubility (29.42 vs 7.19 µg/mL) compared to S1g-10. It maintains comparable apoptosis induction capability with S1g-10 against both TKI-sensitive and TKI-resistant CML cell lines in an Hsp70-Bim-dependent manner. Additionally, through SAR, 1H-15N TRSOY-NMR, and molecular docking, we revealed that Lys319 is a "hot spot" in the Hsp70-Bim PPI interface. Collectively, these results provide a novel chemical scaffold and structural insights for the rational design of Hsp70-Bim PPI inhibitors.


Asunto(s)
Compuestos de Bifenilo , Proteínas HSP70 de Choque Térmico , Leucemia Mielógena Crónica BCR-ABL Positiva , Simulación del Acoplamiento Molecular , Humanos , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP70 de Choque Térmico/química , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/química , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proteína 11 Similar a Bcl2/metabolismo , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Unión Proteica , Descubrimiento de Drogas
12.
Int J Biol Macromol ; 274(Pt 2): 133345, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38944066

RESUMEN

Engineering biocatalysts with enhanced stereoselectivity is highly desirable, and active-site loop dynamics play an important role in its regulation. However, knowledge of their precise roles in catalysis and evolution is limited. Here, we used the strategy of Rosetta enzyme design combined molecular dynamic simulations (MDs) to reprogram the landscapes of the key active-site loop dynamics of the carbonyl reductase LfSDR1 to improve stereoselectivity. The key flexible loop in the active site showed the potential to regulate the catalytic properties. A library of virtual variants was produced using the Rosetta design and assessed dynamic effect of the loop with the aid of MDs. A potential candidate was obtained with significant stereoselectivity (ee > 99 %) compared to the wild-type (ee = 42 %) without loss of catalytic activity or thermostability. The molecular basis of the catalytic property enhancement was flanked by MDs, which revealed the role of the G92L mutation in regulating loop dynamics to stabilize the environment of the active site. Finally, a series of the challenge bulky substrate derivatives were assessed using the G92L variant, and all showed improved stereoselectivity ee > 99 %. This study provides novel insights for improving stereoselectivity through rational engineering of the loop dynamics of biocatalysts.


Asunto(s)
Oxidorreductasas de Alcohol , Alcoholes , Dominio Catalítico , Simulación de Dinámica Molecular , Estereoisomerismo , Alcoholes/química , Alcoholes/metabolismo , Oxidorreductasas de Alcohol/química , Oxidorreductasas de Alcohol/genética , Oxidorreductasas de Alcohol/metabolismo , Especificidad por Sustrato , Biocatálisis , Ingeniería de Proteínas/métodos , Mutación
13.
J Cardiovasc Pharmacol ; 84(1): 71-80, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38922574

RESUMEN

ABSTRACT: Clinical practice shows that a critical unmet need in the field of thrombosis prevention is the availability of anticoagulant therapy without bleeding risk. Inhibitors against FXIa or FXIIa have been extensively studied because of their low bleeding risk. However, whether these compounds produce synergistic effects has not yet been explored. In this study, analyses of activated partial thromboplastin time in combination with the FXIa inhibitor PN2KPI and the FXIIa inhibitor Infestin4 at different proportions were performed using the SynergyFinder tool identifying synergistic anticoagulation effects. Both an FeCl 3 -induced carotid artery thrombosis mouse model and a transient occlusion of the middle cerebral artery mouse model showed that the combination of PN2KPI and Infestin4, which are 28.57% and 6.25% of the effective dose, respectively, significantly prevents coagulation, and furthermore, dual inhibition does not cause bleeding risk.


Asunto(s)
Anticoagulantes , Coagulación Sanguínea , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Factor XIIa , Factor XIa , Animales , Factor XIa/antagonistas & inhibidores , Factor XIa/metabolismo , Anticoagulantes/farmacología , Coagulación Sanguínea/efectos de los fármacos , Masculino , Factor XIIa/antagonistas & inhibidores , Factor XIIa/metabolismo , Trombosis de las Arterias Carótidas/prevención & control , Trombosis de las Arterias Carótidas/inducido químicamente , Trombosis de las Arterias Carótidas/tratamiento farmacológico , Ratones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Hemorragia/inducido químicamente , Ratones Endogámicos C57BL , Tiempo de Tromboplastina Parcial
14.
Int J Biol Macromol ; 272(Pt 1): 132624, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38838594

RESUMEN

In this work, the interaction of chondroitin sulfate (CS) and dermatan sulfate (DS) with plant lectins was studied by affinity capillary electrophoresis (ACE), surface plasmon resonance (SPR) technology, molecular docking simulation, and circular dichroism spectroscopy. The ACE method was used for the first time to study the interaction of Ricinus Communis Agglutinin I (RCA I), Wisteria Floribunda Lectin (WFA), and Soybean Agglutinin (SBA) with CS and DS, and the results were in good agreement with those of the SPR method. The results of experiments indicate that RCA I has a strong binding affinity with CS, and the sulfated position does not affect the relationship, but the degree of sulfation can affect the combination of RCA I with CS to some extent. However, the binding affinity with DS is very weak. This study lays the foundation for developing more specialized analysis methods for CS and DS based on RCA I.


Asunto(s)
Sulfatos de Condroitina , Dermatán Sulfato , Simulación del Acoplamiento Molecular , Lectinas de Plantas , Unión Proteica , Sulfatos de Condroitina/química , Dermatán Sulfato/química , Dermatán Sulfato/metabolismo , Lectinas de Plantas/química , Lectinas de Plantas/metabolismo , Resonancia por Plasmón de Superficie , Aglutininas/química , Aglutininas/metabolismo , Dicroismo Circular , Electroforesis Capilar
15.
Biochem Pharmacol ; 224: 116261, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38705534

RESUMEN

Delayed neurocognitive recovery (dNCR) is a common complication in geriatric surgical patients. The impact of anesthesia and surgery on patients with neurodegenerative diseases, such as Parkinson's disease (PD) or prion disease, has not yet been reported. In this study, we aimed to determine the association between a pre-existing A53T genetic background, which involves a PD-related point mutation, and the development of postoperative dNCR. We observed that partial hepatectomy induced hippocampus-dependent cognitive deficits in 5-month-old A53T transgenic mice, a model of early-stage PD without cognitive deficits, unlike in age-matched wild-type (WT) mice. We respectively examined molecular changes at 6 h, 1 day, and 2 days after partial hepatectomy and observed that cognitive changes were accompanied by weakened angiotensin-(1-7)/Mas receptor [Ang-(1-7)/MasR] axis, increased alpha-synuclein (α-syn) expression and phosphorylation, decreased methylated protein phosphatase-2A (Me-PP2A), and prompted microglia M1 polarization and neuronal apoptosis in the hippocampus at 1 day after surgery. Nevertheless, no changes in blood-brain barrier (BBB) integrity or plasma α-syn levels in either A53T or WT mice. Furthermore, intranasal administration of selective MasR agonist AVE 0991, reversed the mentioned cognitive deficits in A53T mice, enhanced MasR expression, reduced α-syn accumulation and phosphorylation, and attenuated microglia activation and apoptotic response. Our findings suggest that individuals with the A53T genetic background may be more susceptible to developing postoperative dNCR. This susceptibility could be linked to central α-syn accumulation mediated by the weakened Ang-(1-7)/MasR/methyl-PP2A signaling pathway in the hippocampus following surgery, independent of plasma α-syn level and BBB.


Asunto(s)
Angiotensina I , Hipocampo , Ratones Transgénicos , Fragmentos de Péptidos , Receptores Acoplados a Proteínas G , alfa-Sinucleína , Animales , Humanos , Masculino , Ratones , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Angiotensina I/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Mutación , Fragmentos de Péptidos/metabolismo , Complicaciones Cognitivas Postoperatorias/metabolismo , Complicaciones Cognitivas Postoperatorias/genética , Complicaciones Posoperatorias/metabolismo , Complicaciones Posoperatorias/genética , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética
16.
Polymers (Basel) ; 16(9)2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38732688

RESUMEN

This study evaluated the effect of simulated pulpal pressure (SPP) conditions and storage time on contemporary adhesive systems' microtensile bond strength (µTBS) to dentin. Extracted human molars were prepared and randomly divided into four groups according to the adhesives: Clearfil Megabond 2 (CSE), Beautibond Xtreme Universal (BXU), G2-Bond (G2B), and Scotchbond Universal Plus (SBP). Each adhesive group was further divided following the SPP conditions: control with no simulation (SPP-CTR), SPP with distilled water (SPP-DTW), and SPP with fetal bovine serum (SPP-FBS). Resin composite build-ups were prepared, and teeth were stored in water (37 °C) for 24 h (24 h) and 3 months (3 m). Then, teeth were sectioned to obtain resin-dentin bonded beams and tested to determine the µTBS. Data were analyzed using three-way ANOVA, Tukey post hoc tests (=0.05), and Weibull failure analysis. Failure mode was observed using scanning electron microscopy. The µTBS response was affected by adhesive systems, simulated pulpal pressure conditions, and storage time. SPP-CTR groups presented a higher overall bond strength than SPP-DTW and SPP-FBS, which were not significantly different from each other. Only for SBP, the SPP-FBS group showed higher µTBS than the SPP-DTW group. The Weibull analysis showed that the bonding reliability and durability under SPP-DTW and SPP-FBS were inferior to SPP-CTR, and the 24 h bonding quality of adhesives to dentin was superior to that of 3 m. SPP drastically reduced the µTBS of all adhesives to dentin regardless of solution (distilled water or fetal bovine serum). Storage after 3 m also decreased µTBS despite the SPP condition.

17.
Cells ; 13(9)2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38727267

RESUMEN

The unique prolyl isomerase Pin1 binds to and catalyzes cis-trans conformational changes of specific Ser/Thr-Pro motifs after phosphorylation, thereby playing a pivotal role in regulating the structure and function of its protein substrates. In particular, Pin1 activity regulates the affinity of a substrate for E3 ubiquitin ligases, thereby modulating the turnover of a subset of proteins and coordinating their activities after phosphorylation in both physiological and disease states. In this review, we highlight recent advancements in Pin1-regulated ubiquitination in the context of cancer and neurodegenerative disease. Specifically, Pin1 promotes cancer progression by increasing the stabilities of numerous oncoproteins and decreasing the stabilities of many tumor suppressors. Meanwhile, Pin1 plays a critical role in different neurodegenerative disorders via the regulation of protein turnover. Finally, we propose a novel therapeutic approach wherein the ubiquitin-proteasome system can be leveraged for therapy by targeting pathogenic intracellular targets for TRIM21-dependent degradation using stereospecific antibodies.


Asunto(s)
Peptidilprolil Isomerasa de Interacción con NIMA , Proteolisis , Ubiquitinación , Humanos , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Conformación Proteica , Animales , Neoplasias/metabolismo , Neoplasias/patología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Ubiquitina-Proteína Ligasas/metabolismo
18.
Micromachines (Basel) ; 15(4)2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38675346

RESUMEN

A compact Ka-band antenna array has been proposed to realize broadband and high gain for millimeter-wave applications. The antenna array is divided into a multilayer composed of a driven slot patch layer and a parasitic patch array layer, which is excited by a mixed CPW-Slot-Couple feeding network layer. According to characteristic mode analysis, a pair of narrow coupling slots are introduced in the driven patch to move the resonant frequency of characteristic mode 3 to the resonant frequency of characteristic mode 2 for enhanced bandwidth. In this article, a 1to4 CPW-Slot-Couple feeding network for a 2 × 2 driven slot patch array is implemented, and then each driven slot patch excites a 2 × 2 parasitic patch array. Finally, a proposed 4 × 4 × 3 (row × column × layer) Ka-band antenna array is fabricated to verify the design concepts. The measured results show that the frequency bandwidth of the antenna array is 25 GHz to 32 GHz, and the relative bandwidth is 24.5%. The peak gain is 20.1 dBi. Due to its attractive properties of miniaturization, broadband, and high gain, the proposed antenna array could be applied to millimeter-wave wireless communication systems.

19.
Org Lett ; 26(16): 3375-3379, 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38629756

RESUMEN

The synthesis and structural revision of the dimerized cyclic hexapeptides antatollamides A (1) and B (2) are reported. These are unique peptides with two proline residues and bicyclic peptides combined by a disulfide bond. Cyclization and disulfide bond formation of the linear peptide led to antatollamide A (1). However, the 1H and 13C NMR spectra of synthetic antatollamide A (1) were not consistent with those of isolated antatollamide A (1). Meanwhile, the NMR spectra of the monomeric cyclic hexapeptide cyclo(Pro-Pro-Phe-dCys-Ile-Val) (3) and the isolated antatollamide A (1) were identified completely. In addition, we found that isolated antatollamide B (2) is cyclo(Pro-Pro-dPhe-dCys-Ile-Val) (4).


Asunto(s)
Péptidos Cíclicos , Péptidos Cíclicos/química , Péptidos Cíclicos/síntesis química , Estructura Molecular , Ciclización , Dimerización
20.
Transl Vis Sci Technol ; 13(4): 28, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38648051

RESUMEN

Purpose: Retinal and optic nerve diseases have become the primary cause of irreversible vision loss and blindness. However, there is still a lack of thorough evaluation regarding their prevalence in China. Methods: This artificial intelligence-based national screening study applied a previously developed deep learning algorithm, named the Retinal Artificial Intelligence Diagnosis System (RAIDS). De-identified personal medical records from January 2019 to December 2021 were extracted from 65 examination centers in 19 provinces of China. Crude prevalence and age-sex-adjusted prevalence were calculated by mapping to the standard population in the seventh national census. Results: In 2021, adjusted referral possible glaucoma (63.29, 95% confidence interval [CI] = 57.12-68.90 cases per 1000), epiretinal macular membrane (21.84, 95% CI = 15.64-29.22), age-related macular degeneration (13.93, 95% CI = 11.09-17.17), and diabetic retinopathy (11.33, 95% CI = 8.89-13.77) ranked the highest among 10 diseases. Female participants had significantly higher adjusted prevalence of pathologic myopia, yet a lower adjusted prevalence of diabetic retinopathy, referral possible glaucoma, and hypertensive retinopathy than male participants. From 2019 to 2021, the adjusted prevalence of retinal vein occlusion (0.99, 95% CI = 0.73-1.26 to 1.88, 95% CI = 1.42-2.44), macular hole (0.59, 95% CI = 0.41-0.82 to 1.12, 95% CI = 0.76-1.51), and hypertensive retinopathy (0.53, 95% CI = 0.40-0.67 to 0.77, 95% CI = 0.60-0.95) significantly increased. The prevalence of diabetic retinopathy in participants under 50 years old significant increased. Conclusions: Retinal and optic nerve diseases are an important public health concern in China. Further well-conceived epidemiological studies are required to validate the observed increased prevalence of diabetic retinopathy, hypertensive retinopathy, retinal vein occlusion, and macular hole nationwide. Translational Relevance: This artificial intelligence system can be a potential tool to monitor the prevalence of major retinal and optic nerve diseases over a wide geographic area.


Asunto(s)
Inteligencia Artificial , Enfermedades del Nervio Óptico , Enfermedades de la Retina , Humanos , China/epidemiología , Prevalencia , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Enfermedades de la Retina/epidemiología , Enfermedades de la Retina/diagnóstico , Enfermedades del Nervio Óptico/epidemiología , Enfermedades del Nervio Óptico/diagnóstico , Adulto Joven , Adolescente , Tamizaje Masivo/métodos , Anciano de 80 o más Años
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