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1.
J Exp Clin Cancer Res ; 43(1): 277, 2024 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-39358777

RESUMEN

BACKGROUND: Early dissemination to distant organs accounts for the dismal prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Chronic, dysregulated, persistent and unresolved inflammation provides a preferred tumor microenvironment (TME) for tumorigenesis, development, and metastasis. A better understanding of the key regulators that maintain inflammatory TME and the development of predictive biomarkers to identify patients who are most likely to benefit from specific inflammatory-targeted therapies is crucial for advancing personalized cancer treatment. METHODS: This study identified cell-specific expression of CALB2 in human PDAC through single-cell RNA sequencing analysis and assessed its clinicopathological correlations in tissue microarray using multi-color immunofluorescence. Co-culture systems containing cancer-associated fibroblasts (CAFs) and patient-derived organoids (PDOs) in vitro and in vivo were employed to elucidate the effects of CALB2-activated CAFs on PDAC malignancy. Furthermore, CUT&RUN assays, luciferase reporter assays, RNA sequencing, and gain- or loss-of-function assays were used to unravel the molecular mechanisms of CALB2-mediated inflammatory reprogramming and metastasis. Additionally, immunocompetent KPC organoid allograft models were constructed to evaluate CALB2-induced immunosuppression and PDAC metastasis, as well as the efficacy of inflammation-targeted therapy. RESULTS: CALB2 was highly expressed both in CAFs and cancer cells and correlated with an unfavorable prognosis and immunosuppressive TME in PDAC patients. CALB2 collaborated with hypoxia to activate an inflammatory fibroblast phenotype, which promoted PDAC cell migration and PDO growth in vitro and in vivo. In turn, CALB2-activated CAFs upregulated CALB2 expression in cancer cells through IL6-STAT3 signaling-mediated direct transcription. In cancer cells, CALB2 further activated Ca2+-CXCL14 inflammatory axis to facilitate PDAC metastatic outgrowth and immunosuppression. Genetic or pharmaceutical inhibition of CXCL14 significantly suppressed CALB2-mediated metastatic colonization of PDAC cells in vivo and extended mouse survival. CONCLUSIONS: These findings identify CALB2 as a key regulator of inflammatory reprogramming to promote PDAC metastatic progression. Combination therapy with αCXCL14 monoclonal antibody and gemcitabine emerges as a promising strategy to suppress distant metastasis and improve survival outcomes in PDAC with CALB2 overexpression.


Asunto(s)
Metástasis de la Neoplasia , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Ratones , Animales , Inflamación/patología , Inflamación/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Femenino , Masculino , Pronóstico
2.
J Clin Pharmacol ; 2024 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-39404139

RESUMEN

Risperidone extended-release injectable suspension (R-ERIS; marketed as RYKINDO) is a novel immediate-release version of risperidone formulated as extended-release microspheres for biweekly intramuscular injection to treat schizophrenia in adults. The pharmacokinetics (PK) and safety of R-ERIS were evaluated in a multicenter, randomized, open-label, multiple-dose study in patients with stable schizophrenia or schizoaffective disorder. Eligible patients (N = 108) 18 to 65 years old were randomized (1:1) to receive IM injections of R-ERIS 25 mg or the comparator, a biweekly risperidone long-acting injectable (BW-RLAI; marketed as RISPERDAL CONSTA) 25 mg for a total of 5 injections. The primary objective was to evaluate the relative bioavailability of active moiety (risperidone plus 9-hydroxyrisperidone) at steady state. Blood samples were analyzed for risperidone and 9-hydroxyrisperidone using a validated, specific, and sensitive liquid chromatography with tandem mass spectrometry method. Plasma concentration-time data were analyzed using non-compartmental methods. Pharmacokinetic parameters were calculated based on individual patient PK profiles. Safety was assessed using standard measures. At steady state, mean plasma concentrations of the active moiety were similar for R-ERIS and BW-RLAI. R-ERIS rapidly released risperidone after the injection without apparent lag time. Plasma active moiety levels reached steady state after the second injection of R-ERIS. The elimination of the drug was completed approximately 2 weeks earlier for R-ERIS as compared to that for BW-RLAI. R-ERIS was safe and well tolerated. Overall, R-ERIS exhibited a faster onset and offset than BW-RLAI and statistical analysis of exposure parameters demonstrated bioequivalence at steady state.

3.
AAPS J ; 26(5): 102, 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39266802

RESUMEN

Oral administration of peptide represents a promising delivery route, however, it is hindered by the harsh gastrointestinal environment, leading to low in vivo absorption. In this study, auto-adaptive protein corona-AT 1002-cationic liposomes (Pc-AT-CLs) are constructed with the characteristic of hydrophilic and electrically neutral surface properties for the encapsulation of liraglutide. BSA protein corona is used to coat AT-CLs reducing the adherence of mucus, and may fall off after penetrating the mucus layer. Transmucus transport experiment demonstrated that the mucus penetration amount of Pc-AT-CLs are 1.45 times that of AT-CLs. After penetrating the mucus layer, AT-CLs complete transmembrane transport by the dual action of AT and cationic surface properties. Transmembrane transport experiment demonstrated that the apparent permeability coefficient (Papp) of AT-CLs is 2.03 times that of CLs. In vivo tests demonstrated that Pc-AT-CLs exhibited a significant hypoglycemic effect and enhanced the relative bioavailability comparing to free liraglutide. Pc-AT-CLs protect liraglutide from degradation, facilitate its absorption, and ultimately improve its oral bioavailability.


Asunto(s)
Sistemas de Liberación de Medicamentos , Hipoglucemiantes , Liposomas , Liraglutida , Moco , Animales , Liraglutida/administración & dosificación , Liraglutida/farmacocinética , Liraglutida/farmacología , Moco/metabolismo , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/química , Humanos , Disponibilidad Biológica , Administración Oral , Masculino , Ratas Sprague-Dawley , Ratas , Absorción Intestinal/efectos de los fármacos
4.
Chem Commun (Camb) ; 60(76): 10548-10551, 2024 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-39229778

RESUMEN

Manipulating the conjugated backbone of small molecule acceptors (SMAs) is of particular importance in developing efficient organic solar cells (OSCs). Recently, trimers and other multi-arm SMAs have been found to be able to provide more intermolecular interaction, demonstrating excellent molecular stacking and device performance. However, the synthesis of this type of SMA usually relies on tristin or polystin compounds. Instead, expanding multiple arms in the central cores of SMAs is relatively simple and not restricted by tin compounds. Based on the quinoxaline core, two kinds of multi-arm SMAs, FQx-IC and TQx-IC with 4 and 3 arms, have been developed in this work. Compared to FQx-IC, TQx-IC exhibits an ordered face-on molecular orientation, appropriate film-forming process, and more favorable phase separation morphology and balanced charge transport. When blended with the polymer donor D18, OSCs based on TQx-IC achieve a power conversion efficiency (PCE) of 17.36%, which is superior to the device based on D18:FQx-IC (16.24%). In addition, using the ternary strategy of incorporating the TQx-IC into the D18:Y6 system, an excellent PCE of 18.82% is achieved. Therefore, this multi-arm molecular design strategy has great potential for regulating molecular stacking, absorption, and the corresponding device performance.

5.
Am J Transl Res ; 16(8): 3832-3841, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39262754

RESUMEN

OBJECTIVE: To explore the risk factors for refractory peritonitis in patients undergoing peritoneal dialysis. METHODS: We retrospectively collected data from 130 patients who underwent peritoneal dialysis (PD) and received peritonitis treatment at the Renal Disease Center of Beijing Luhe Hospital affiliated with Capital Medical University from January 1, 2016 to January 30, 2023. According to clinical treatment results, patients with refractory peritonitis were classified as the refractory group (n=52 cases), and those with non-refractory peritonitis were classified as the non-refractory group (n=78 cases). Baseline information and laboratory indicators of patients in each group were collected, and Logistic regression model was used to identify the risk factors for the poor prognosis of peritonitis patients. RESULTS: There were statistically significant differences in dialysis time, dialysate sugar concentration and inducement type between the refractory group and the non-refractory group (P<0.05). The values of peripheral white blood cells (pWBC), T helper 2 cell (Th2), T regulatory cell (Treg), Treg/Th17 and C-reactive protein (CRP) in the refractory group were significantly higher than those in the non-refractory group, while the values of T helper 17 cell (Th17) and albumin (ALB) were significantly lower (all P<0.05). There were no significant differences in serum creatinine, blood urea, Th1, hemoglobin (Hb) and blood calcium levels between the two groups (all P>0.05). Gram-positive bacteria were the main pathogenic bacteria of peritonitis in all groups. The proportion of enterococcus/streptococcal peritonitis in the refractory group was higher than that in the non-refractory group (P<0.05). Logistic regression identified elevated pWBC, higher dialysate sugar concentration, exit-site infection and gram-negative bacteria infection as independent risk factors for refractory peritonitis in patients undergoing PD (all P<0.05). CONCLUSION: Elevated pWBC, high glucose dialysate concentration, exit-site infection, and gram-negative bacteria infection are risk factors for refractory peritonitis in patients undergoing PD.

6.
Adv Mater ; 36(39): e2409436, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39120050

RESUMEN

Dual-atom catalysts (DACs) originate unprecedented reactivity and maximize resource efficiency. The fundamental difficulty lies in the high complexity and instability of DACs, making the rational design and targeted performance optimization a grand challenge. Here, an atomically dispersed Pd2 DAC with an in situ generated Pd─Pd bond is constructed by a dynamic strategy, which achieves high activity and selectivity for semi-hydrogenation of alkynes and functional internal acetylene, twice higher than commercial Lindlar catalyst. Density functional theory calculations and systematic experiments confirms the ultrahigh properties of Pd2 DAC originates from the synergistic effect of the dynamically generated Pd─Pd bonds. This discovery highlights the potential for dynamic strategies and opens unprecedented possibilities for the preparation of robust DACs on an industrial scale.

7.
Shanghai Kou Qiang Yi Xue ; 33(3): 269-272, 2024 Jun.
Artículo en Chino | MEDLINE | ID: mdl-39104342

RESUMEN

PURPOSE: To investigate the feasibility and effect of free latissimus dorsi myocutaneous flap in the reconstruction of giant head and neck defects. METHODS: Free latissimus dorsi myocutaneous flap on the cadaver was simulated dissected, and measured by Image-Pro Plus 6.0 to assess the feasibility of repairing giant head and neck defects. Between May 2011 and September 2022, seven patients with giant head and neck defects of different causes repaired with the latissimus dorsi myocutaneous flap were retrospectively analyzed. RESULTS: The diameter of the initiating thoracodorsal artery was (4.03±0.56) mm, and the mean lengths of the arteriolar and venous pedicles of the latissimus dorsi myocutaneous flaps obtained from human specimens were (85.5±10.5) mm and (104±4.2) mm, respectively. Among 7 patients, 5 cases had scalp defects, the remaining 2 cases had neck defects. There were no substantial postoperative problems in the donor site, and all seven latissimus dorsi myocutaneous flaps were successfully transplanted. CONCLUSIONS: For the treatment of considerable head and neck deformities, the latissimus dorsi myocutaneous flap is an optimal muscle flap due to its abundance of tissue, enough length of vascular pedicles, and sufficient venous drainage.


Asunto(s)
Colgajo Miocutáneo , Procedimientos de Cirugía Plástica , Músculos Superficiales de la Espalda , Humanos , Músculos Superficiales de la Espalda/trasplante , Colgajo Miocutáneo/trasplante , Procedimientos de Cirugía Plástica/métodos , Estudios Retrospectivos , Cuello/cirugía , Cuello/anatomía & histología , Cabeza/cirugía , Cabeza/anatomía & histología , Neoplasias de Cabeza y Cuello/cirugía , Cadáver , Cuero Cabelludo/cirugía , Masculino
8.
Int J Nanomedicine ; 19: 7817-7830, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39099790

RESUMEN

Background: Photothermal therapy (PTT) guided by photoacoustic imaging (PAI) using nanoplatforms has emerged as a promising strategy for cancer treatment due to its efficiency and accuracy. This study aimed to develop and synthesize novel second near-infrared region (NIR-II) absorption-conjugated polymer acceptor acrylate-substituted thiadiazoloquinoxaline-diketopyrrolopyrrole polymers (PATQ-DPP) designed specifically as photothermal and imaging contrast agents for nasopharyngeal carcinoma (NPC). Methods: The PATQ-DPP nanoparticles were synthesized and characterized for their optical properties, including low optical band gaps. Their potential as PTT agents and imaging contrast agents for NPC was evaluated both in vitro and in vivo. The accumulation of nanoparticles at tumor sites was assessed post-injection, and the efficacy of PTT under near-infrared laser irradiation was investigated in a mouse model of NPC. Results: Experimental results indicated that the PATQ-DPP nanoparticles exhibited significant photoacoustic contrast enhancement and favorable PTT performance. Safety and non-toxicity evaluations confirmed the biocompatibility of these nanoparticles. In vivo studies showed that PATQ-DPP nanoparticles effectively accumulated at NPC tumor sites and demonstrated excellent tumor growth inhibition upon exposure to near-infrared laser irradiation. Notably, complete elimination of nasopharyngeal tumors was observed within 18 days following PTT. Discussion: The findings suggest that PATQ-DPP nanoparticles are a promising theranostic agent for NIR-II PAI and PTT of tumors. This innovative approach utilizing PATQ-DPP nanoparticles provides a powerful tool for the early diagnosis and precise treatment of NPC, offering a new avenue in the management of this challenging malignancy.


Asunto(s)
Nanopartículas , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Técnicas Fotoacústicas , Terapia Fototérmica , Animales , Técnicas Fotoacústicas/métodos , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/diagnóstico por imagen , Terapia Fototérmica/métodos , Ratones , Línea Celular Tumoral , Humanos , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/diagnóstico por imagen , Nanopartículas/química , Rayos Infrarrojos , Ratones Desnudos , Medios de Contraste/química , Ratones Endogámicos BALB C , Polímeros/química , Femenino
9.
Biosens Bioelectron ; 263: 116621, 2024 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-39098283

RESUMEN

Constructing label-free bivariate fluorescence biosensor would be intriguing and desired for the recognizable and accurate detection of two specific DNA segments, yet the design of functional DNA structures with low overlapped interference might be challenging. Herein in this work, a double-faced Janus DNA nanoarchitecture (JDNA) with bi-responsive recognition regions on opposite sides was assembled, which consisted of two substrate strands and two template strands for loading green-/red-emissive Ag nanoclusters (gAgNC and rAgNC) as bivariate signaling reporters. Of note, the hybridized double helix in the middle rationally oriented two flank faces and stabilized the rigid conformation of JDNA, while the template sequences of bicolor clusters were blocked to minimize non-specific background leakage. Upon inputting two targets, the discernible hairpins lost their hairpin structures due to forming two dsDNA complexes. They were executed to simultaneously invade JDNA for activating two individual target-recycled strand displacement (TRSD) events, guiding signal transduction and efficient amplification. Consequently, the clustering templates were unlocked via the tailored conformation switch of JDNA, in which gAgNC and rAgNC were in situ synthesized in two diagonal positions, thereby significantly emitting bi-responsive signal without cross interference. Benefited from the logic integration of double-faced JDNA and TRSD, a label-free, sensitive and specific bivariate fluorescence approach was developed, which would open a new avenue for the potential application in biosensing and bioanalysis.


Asunto(s)
Técnicas Biosensibles , ADN , Nanopartículas del Metal , Plata , Técnicas Biosensibles/métodos , Plata/química , ADN/química , Nanopartículas del Metal/química , Humanos , Espectrometría de Fluorescencia/métodos , Nanoestructuras/química , Hibridación de Ácido Nucleico , Límite de Detección , Fluorescencia , Colorantes Fluorescentes/química
10.
Medicine (Baltimore) ; 103(28): e38374, 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38996170

RESUMEN

The objective of this study is to investigate the associated risk factors and their effects on cognitive impairment (CI) in patients undergoing peritoneal dialysis. A retrospective analysis was conducted on the basic information of 268 patients who underwent continuous ambulatory peritoneal dialysis (CAPD) at our hospital from January 2020 to September 2023. Cognitive function was assessed using the Montreal Cognitive Assessment Scale during their subsequent dialysis visits. Participants were categorized into a CI group and a cognitively normal group. Blood and other biological samples were collected for relevant biomarker analysis. Subsequently, we analyzed and compared the factors influencing CI between the 2 groups. The prevalence of CI among CAPD patients was 58.2%. Compared to the cognitively normal group, the CI group had a higher prevalence of alcohol consumption, lower levels of education, and reduced serum uric acid levels (P < .05). There was also a higher incidence of autoimmune diseases such as systemic lupus erythematosus in the CI group (P < .05). In terms of dialysis efficacy, the residual kidney Kt/V and residual kidney Ccr were significantly lower in the CI group compared to the cognitively normal group. In blood parameters, the CI group showed elevated total cholesterol levels and lower serum calcium concentrations (P < .05). Logistic regression analysis identified male gender, older age, lower educational attainment, hypercholesterolemia, and elevated high-sensitivity C-reactive protein levels as independent risk factors for CI in CAPD patients (P < .05). Additionally, in this patient cohort, dialysis duration and residual renal function were protective factors against CI (P < .05). CI is prevalent among PD patients. Elevated high-sensitivity C-reactive protein levels, male gender, older age, lower educational attainment, and hypercholesterolemia constitute an independent risk factor for CI in CAPD patients, whereas residual renal function acts as a protective element.


Asunto(s)
Disfunción Cognitiva , Diálisis Peritoneal Ambulatoria Continua , Humanos , Masculino , Femenino , Persona de Mediana Edad , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Factores de Riesgo , Estudios Retrospectivos , Diálisis Peritoneal Ambulatoria Continua/efectos adversos , Anciano , Adulto , Prevalencia , Factores Sexuales , Factores de Edad , Escolaridad , Proteína C-Reactiva/análisis , Fallo Renal Crónico/terapia
11.
Acta Biomater ; 185: 203-214, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-39053817

RESUMEN

Vaccines play a critical role in combating infectious diseases and cancers, yet improving their efficacy remains challenging. Here, we introduce a separable nanocomposite hydrogel microneedle (NHMN) patch designed for intradermal and sustained delivery of ovalbumin (OVA), a model antigen, to enhance adaptive immune responses. The NHMN patch consists of an array of OVA-loaded microneedles made from photo-cross-linked methacrylated hyaluronic acid and laponite (LAP), supported by a hyaluronic acid backing. The incorporation of LAP not only enhances the mechanical strength of the pure hydrogel microneedles but also significantly prolongs OVA release. Furthermore, in vitro cell experiments demonstrate that NHMNs effectively activate dendritic cells without compromising cell viability. Upon skin penetration, NHMNs detach from the backing as the hyaluronic acid rapidly dissolves upon contact with the skin interstitial fluid, thereby acting as antigen reservoirs to release antigens to abundant skin dendritic cells. NHMNs containing 0.5% w/v LAP achieved a 15-day OVA release in vivo. Immunization studies demonstrate that the intradermal and sustained release of OVA via NHMNs elicited stronger and longer-lasting adaptive immune responses compared to conventional bolus injection. Given its easy to use, painless and minimally invasive features, the NHMN patch shows promise in improving vaccination accessibility and efficacy against a range of diseases. STATEMENT OF SIGNIFICANCE: The study introduces a separable nanocomposite hydrogel microneedle (NHMN) patch. This patch consists of an array of ovalbumin (OVA, a model antigen)-loaded microneedles made from photo-cross-linked methacrylated hyaluronic acid and laponite, with a hyaluronic acid backing, designed for intradermal and sustained delivery of antigens. This patch addresses several key challenges in traditional vaccination methods, including poor antigen uptake and presentation, and rapid systematic clearance. The incorporation of laponite enhances mechanical strength of microneedles, promotes dendritic cell activation, and significantly slows down antigen release. NHMN-based vaccination elicits stronger and longer-lasting adaptive immune responses compared to conventional bolus injection. This NHMN patch holds great potential for improving the efficacy, accessibility, and patient comfort of vaccinations against a range of diseases.


Asunto(s)
Inmunidad Adaptativa , Hidrogeles , Nanocompuestos , Agujas , Ovalbúmina , Animales , Ovalbúmina/inmunología , Ovalbúmina/administración & dosificación , Inmunidad Adaptativa/efectos de los fármacos , Hidrogeles/química , Nanocompuestos/química , Antígenos/administración & dosificación , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Femenino , Inyecciones Intradérmicas , Ácido Hialurónico/química , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacología , Silicatos
12.
Food Chem ; 458: 140235, 2024 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-38964105

RESUMEN

The mechanism of goat milk (GM) flavor improvement based on lipid changes requires understanding. According to sensory evaluation results, the texture, taste, appearance, aroma, and overall acceptability score of Guishan fermented goat milk (GMF) were higher than those of GM. In total, 779 lipid molecules and 121 volatile compounds were formed from the metabolite-lipid level in the GM and GMF, as determined through lipidomics and gas chromatography-mass spectrometry. The key volatile flavor compounds in the GMF were (E,E)-2,4-decadienal, ethyl acetate, acetoin, 2,3-pentanedione, acetic acid, and 2,3-butanedione. Of them, 60 lipids significantly contributed to the flavor profiles of the GMF, based on the correlation analysis. The triacylglycerides (TAGs) 12:0_14:0_16:0 and 13:0_13:0_18:2 contributed to aroma retention, while TAG and phosphatidylethanolamine were identified as key substrates for flavor compound formation during fermentation. Lipids associated with glycerophospholipid and linoleic acid metabolism pathways significantly affected volatile compound formation in the GMF. This study provides an in-depth understanding of the lipids and flavors of the GMF, and this information will be useful for the development of specific GMF products.


Asunto(s)
Fermentación , Aromatizantes , Cabras , Lípidos , Leche , Gusto , Compuestos Orgánicos Volátiles , Animales , Compuestos Orgánicos Volátiles/química , Compuestos Orgánicos Volátiles/metabolismo , Compuestos Orgánicos Volátiles/análisis , Aromatizantes/química , Aromatizantes/metabolismo , Lípidos/química , Lípidos/análisis , Leche/química , Leche/metabolismo , Humanos , Productos Lácteos Cultivados/análisis , Masculino , Femenino , Cromatografía de Gases y Espectrometría de Masas , Adulto , Adulto Joven
13.
J Nanobiotechnology ; 22(1): 434, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39044233

RESUMEN

Pulmonary Fibrosis (PF) is a fatal disease in the interstitial lung associated with high mortality, morbidity, and poor prognosis. Transforming growth factor-ß1 (TGF-ß1) is a fibroblast-activating protein that promotes fibrous diseases. Herein, an inhalable system was first developed using milk exosomes (M-Exos) encapsulating siRNA against TGF-ß1 (MsiTGF-ß1), and their therapeutic potential for bleomycin (BLM)-induced PF was investigated. M-siTGF-ß1 was introduced into the lungs of mice with PF through nebulization. The collagen penetration effect and lysosomal escape ability were verified in vitro. Inhaled MsiTGF-ß1 notably alleviated inflammatory infiltration, attenuated extracellular matrix (ECM) deposition, and increased the survival rate of PF mice by 4.7-fold. M-siTGF-ß1 protected lung tissue from BLM toxicity by efficiently delivering specific siRNA to the lungs, leading to TGF-ß1 mRNA silencing and epithelial mesenchymal transition pathway inhibition. Therefore, M-siTGF-ß1 offers a promising avenue for therapeutic intervention in fibrosis-related disorders.


Asunto(s)
Bleomicina , Colágeno , Transición Epitelial-Mesenquimal , Exosomas , Pulmón , Leche , Fibrosis Pulmonar , ARN Interferente Pequeño , Factor de Crecimiento Transformador beta1 , Animales , Exosomas/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Ratones , Colágeno/metabolismo , Bleomicina/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Pulmón/efectos de los fármacos , Leche/química , Ratones Endogámicos C57BL , Humanos , Permeabilidad , Masculino , Nebulizadores y Vaporizadores
14.
BMC Microbiol ; 24(1): 283, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39085808

RESUMEN

BACKGROUND: The guts of mammals are home to trillions of microbes, forming a complex and dynamic ecosystem. Gut microbiota is an important biological barrier for maintaining immune homeostasis. Recently, the use of antibiotics to clear gut microbiota has gained popularity as a low cost and easy-to-use alternative to germ-free animals. However, the effect of the duration of the antibiotic cocktail on the gut microbiome is unclear, and more importantly, the effect of dramatic changes in the gut microbiota on intestinal tissue morphology and local immune response is rarely reported. RESULTS: We observed a significant reduction in fecal microbiota species and abundance after 1 week of exposure to an antibiotic cocktail, gavage twice daily by intragastric administration. In terms of composition, Bacteroidetes and Firmicutes were replaced by Proteobacteria. Extending antibiotic exposure to 2-3 weeks did not significantly improve the overall efficiency of microbiotal consumption. No significant histomorphological changes were observed in the first 2 weeks of antibiotic cocktail exposure, but the expression of inflammatory mediators in intestinal tissue was increased after 3 weeks of antibiotic cocktail exposure. Mendelian randomization analysis showed that Actinobacteria had a significant causal association with the increase of IL-1ß (OR = 1.65, 95% CI = 1.23 to 2.21, P = 0.007) and TNF-α (OR = 1.81, 95% CI = 1.26 to 2.61, P = 0.001). CONCLUSIONS: Our data suggest that treatment with an antibiotic cocktail lasting 1 week is sufficient to induce a significant reduction in gut microbes. 3 weeks of antibiotic exposure can lead to the colonization of persistant microbiota and cause changes in intestinal tissue and local immune responses.


Asunto(s)
Antibacterianos , Heces , Microbioma Gastrointestinal , Antibacterianos/farmacología , Animales , Heces/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Interleucina-1beta/genética , Ratones , Bacterias/efectos de los fármacos , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Ratones Endogámicos C57BL , Bacteroidetes/efectos de los fármacos , Firmicutes/efectos de los fármacos
15.
BMC Nephrol ; 25(1): 157, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38714960

RESUMEN

BACKGROUND: This study aims to investigate the influencing factors of vascular calcification in peritoneal dialysis (PD) patients and its relationship with long-term prognosis. METHODS: This retrospective cohort study included chronic kidney disease patients undergoing peritoneal dialysis at the Peritoneal Dialysis Center of Beijing Luhu Hospital, Capital Medical University, from January 2019 to March 2019. Demographic and clinical laboratory data, including serum sclerostin (SOST), calcium (Ca), phosphate (P), serum albumin (ALB), and intact parathyroid hormone (iPTH) levels, were collected. Abdominal aortic calcification (AAC) was assessed using abdominal lateral X-ray examination to determine the occurrence of vascular calcification, and patients were divided into the AAC group and Non-AAC group based on the results. RESULTS: A total of 91 patients were included in the study. The AAC group consisted of 46 patients, while the Non-AAC group consisted of 45 patients. The AAC group had significantly older patients compared to the non-AAC group (P < 0.001) and longer dialysis time (P = 0.004). Multivariable logistic regression analysis indicated that risk factors for vascular calcification in PD patients included dialysis time, diabetes, hypertension, and SOST. Kaplan-Meier survival analysis showed that the AAC group had a significantly higher mortality rate than the non-AAC group (χ2 = 35.993, P < 0.001). Multivariable Cox regression analysis revealed that dialysis time, diabetes and AAC were risk factors for all-cause mortality in peritoneal dialysis patients. CONCLUSION: Longer dialysis time, comorbid diabetes, comorbid hypertension, and SOST are risk factors for vascular calcification in PD patients. Additionally, AAC, longer dialysis time, and comorbid diabetes are associated with increased risk of all-cause mortality in peritoneal dialysis patients.


Asunto(s)
Diálisis Peritoneal , Insuficiencia Renal Crónica , Calcificación Vascular , Calcificación Vascular/diagnóstico , Calcificación Vascular/etiología , Diálisis Peritoneal/efectos adversos , Pronóstico , Estudios Retrospectivos , Insuficiencia Renal Crónica/terapia , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano
16.
Food Chem X ; 22: 101384, 2024 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-38681228

RESUMEN

This study identified characteristic whey proteins from Zhongdian Yak (ZY), Diqing Yellow Cattle (DYC), and Cattle Yak (CY), revealing insights into their potential functions and released peptides. A total of 118 whey proteins were quantified in milk obtained from the three breeds of cattle, including seven characteristic proteins (IGL@ protein, 40S ribosomal protein S9, calreticulin, etc.) in CY milk and two characteristic proteins (RNA helicase and uncharacterized protein (A0A3Q1LFQ2)) in ZY milk. These characteristic proteins are involved in the phagosome and Fc gamma R-mediated phagocytosis pathways, exhibiting immunoprotective activities, verified through molecular docking. Furthermore, the molecular docking results showed five whey proteins (IGL@ protein, rho GDP-dissociation inhibitor 1, small monomeric GTPase, action-like protein 3, and adenylyl cyclase-associated protein) interacted with TLR4 through multiple hydrogen and hydrophobic bonds. Therefore, these proteins may exert immunomodulatory functions by inhibiting TLR4. Meanwhile, whey proteins produced bioactive peptides, such as antioxidant peptides and ACE inhibitory peptides after simulated gastrointestinal digestion (SGID). The whey proteins and bioactive peptides from CY exhibited more types and activities than the ZY and DYC whey proteins. This study provides a theoretical basis for promoting formula milk powder production.

17.
Cyberpsychol Behav Soc Netw ; 27(6): 420-425, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38511278

RESUMEN

Extensive research has documented bully victimization as a pivotal risk factor contributing to aggressive behaviors among adolescents. Particularly, the negative outcome of increased aggressive behaviors may be exacerbated when the aggressive actions are novel and difficult to detect. The present study aims to explore the complex relationships between cyberbullying and school bullying victimization and malevolent creativity and the potential mediating role of hostile attribution using two-wave longitudinal data. The present study analyzed data from 262 rural adolescents. The results revealed that cyberbullying victimization significantly predicted malevolent creativity, whereas school bullying victimization did not. Hostile attribution served as a mediator in the relationship between cyberbullying victimization and malevolent creativity in the longitudinal models. These findings provide significant implications for mitigating the negative influence of bullying victimization on the emergence of malevolent creativity in rural adolescents.


Asunto(s)
Creatividad , Víctimas de Crimen , Ciberacoso , Hostilidad , Población Rural , Humanos , Adolescente , Masculino , Femenino , Población Rural/estadística & datos numéricos , Víctimas de Crimen/psicología , Víctimas de Crimen/estadística & datos numéricos , Estudios Longitudinales , Ciberacoso/psicología , Ciberacoso/estadística & datos numéricos , Acoso Escolar/psicología , Acoso Escolar/estadística & datos numéricos , Conducta del Adolescente/psicología , Agresión/psicología
18.
Proc Natl Acad Sci U S A ; 121(12): e2320054121, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38470921

RESUMEN

Delamination of the continental lithospheric mantle is well recorded beneath several continents. However, the fate of the removed continental lithosphere has been rarely noted, unlike subducted slabs reasonably well imaged in the upper and mid mantle. Beneath former Gondwana, recent seismic tomographic models indicate the presence of at least 5 horizontal fast-wavespeed anomalies at ~600 km depths that do not appear to be related to slab subduction, including fast structures in locations consistent with delamination associated with the Paraná Flood Basalt event at ~134 Ma and the Deccan Traps event at ~66 Ma. These fast-wavespeed anomalies often lie above broad slow seismic wavespeed trunks at 500 to 700 km depths beneath former Gondwana, with slow wavespeed anomalies branching around them. Numerical experiments indicate that delaminated lithosphere tends to stagnate in the transition zone and mid-mantle above a mantle plume where it shapes subsequent plume upwelling. For hot plumes, the melt volume generated during plume-influenced delamination can easily reach ~2 to 4 × 106 km3, consistent with the basalt eruption volume at the Deccan Traps. This seismic and numerical evidence suggests that observed high-wavespeed mid-mantle anomalies beneath the locations of former flood basalts are delaminated fragments of former continental lithosphere, and that lithospheric delamination events in the presence of subcontinental plumes induced several of the continental flood basalts associated with the multiple breakup stages of Gondwanaland. Continued upwelling in these plumes can also have entrained subcontinental lithosphere in the mid-mantle to bring its distinctive geochemical signal to the modern mid-ocean spreading centers that surround southern and western Africa.

19.
Support Care Cancer ; 32(3): 146, 2024 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-38326575

RESUMEN

OBJECTIVES: The purpose of this study was to explore the experience of financial toxicity among caregivers of cancer patients and to provide recommendations for subsequent intervention strategies. METHODS: Computer searches of PubMed, EmBase, The Cochrane Library, Web of Science, CINAHL (EBSCO), CNKI, Wanfang database, and SinoMed for qualitative studies experience of financial toxicity among caregivers cancer patients. The search time frame was from the establishment of the database to May 2023. The quality of included studies was assessed using the Qualitative Research Checklist from the Joanna Briggs Institute (JBI) Reviewer's Manual. The meta-synthesis was integrated following the meta-aggregation method proposed by the Joanna Briggs Institute (JBI) and reported following the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) guidelines. RESULTS: A total of nine studies were included, distilling 25 qualitative findings into nine new categories and synthesizing three synthesized findings: caregivers have strong negative experiences that affect their family relationships, daily work and life; caregivers use different strategies to cope with financial toxicity; needs and expectations of caregivers coping with financial toxicity. CONCLUSIONS: Financial toxicity among caregivers of cancer patients affects their daily lives. Receiving timely recognition of this financial burden and providing assistance to enhance their coping skills are crucial in mitigating its impact. Healthcare professionals should focus on the financial toxicity experienced by caregivers of people with cancer, address their supportive needs, and develop a comprehensive support system to improve caregivers' coping abilities and quality of life.


Asunto(s)
Cuidadores , Neoplasias , Humanos , Adaptación Psicológica , Cuidadores/psicología , Cuidadores/economía , Costo de Enfermedad , Neoplasias/psicología , Neoplasias/economía , Investigación Cualitativa , Calidad de Vida
20.
Medicine (Baltimore) ; 103(6): e37111, 2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38335417

RESUMEN

BACKGROUND: Pregnancy in patients with nephrotic syndrome presents enormous challenges to both the mother and fetus, and there are no treatment guidelines for these patients. METHODS: We show a case of a woman with anti-PLA2R antibody-positive membranous nephropathy who did not have a kidney biopsy. Her clinical course during both pregnancies was closely followed and her medications were guided. RESULTS: She gave birth to 2 healthy babies and her condition was very well controlled with the help of medication. CONCLUSION: Patients with nephrotic syndrome can have successful pregnancies after drug treatment. In addition, similar to the non-pregnant population, percutaneous kidney biopsy is not required for the diagnosis of idiopathic membranous nephropathy (IMN) in pregnant nephrotic syndrome patients with anti-PLA2R antibody positive, but the etiology of secondary MN should be excluded.


Asunto(s)
Glomerulonefritis Membranosa , Síndrome Nefrótico , Humanos , Femenino , Embarazo , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/tratamiento farmacológico , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/etiología , Autoanticuerpos , Receptores de Fosfolipasa A2 , Madres
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