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Naturally derived compounds show promise as treatments for microbial infections. Polyphenols, abundantly found in various plants, fruits, and vegetables, are noted for their physiological benefits including antimicrobial effects. This study introduced a new set of acylated phloroglucinol derivatives, synthesized and tested for their antifungal activity in vitro against seven different pathogenic fungi. The standout compound, 3-methyl-1-(2,4,6-trihydroxyphenyl) butan-1-one (2b), exhibited remarkable fungicidal strength, with EC50 values of 1.39 µg/mL against Botrytis cinerea and 1.18 µg/mL against Monilinia fructicola, outperforming previously screened phenolic compounds. When tested in vivo, 2b demonstrated effective antifungal properties, with cure rates of 76.26% for brown rot and 83.35% for gray mold at a concentration of 200 µg/mL, rivaling the commercial fungicide Pyrimethanil in its efficacy against B. cinerea. Preliminary research suggests that 2b's antifungal mechanism may involve the disruption of spore germination, damage to the fungal cell membrane, and leakage of cellular contents. These results indicate that compound 2b has excellent fungicidal properties against B. cinerea and holds potential as a treatment for gray mold.
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Chemical investigation of the acid hydrolysate of Cynanchum bungei roots led to the isolation of eleven undescribed steroids, namely cynbungenins A-K (1-11), and seven previously described analogues (12-18). The complete structures of these compounds were elucidated using the comprehensive spectroscopic analyses and reference data. Structurally, compounds 1 and 2 represent the first example of androstane-type steroids found in the Cynanchum plants, and compounds 3-6 and 12 are characterized as pregnane-type steroids with a rare 8,14-seco-steroid core. In the cytotoxic activity assay, compound 16 displayed the strongest cytotoxic effect against MCF-7, HCT-116, HeLa, and HepG2 cancer cell lines, with IC50 values of 9.98-16.42 µM, and further research indicated that it induced both apoptosis and cell cycle arrest in the G0/G1 phase in a dose-dependent manner toward HepG2 cells.
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BACKGROUND: Minimally invasive surgery (MIS) and craniotomy (CI) are the current treatments for spontaneous supratentorial cerebral haemorrhage (SSTICH). AIM: To compare the efficacy and safety of MIS and CI for the treatment of SSTICH. METHODS: Clinical and imaging data of 557 consecutive patients with SSTICH who underwent MIS or CI between January 2017 and December 2022 were retrospectively analysed. The patients were divided into two subgroups: The MIS group and CI group. Propensity score matching was performed to minimise case selection bias. The primary outcome was a dichotomous prognostic (favourable or unfavourable) outcome based on the modified Rankin Scale (mRS) score at 3 months; an mRS score of 0-2 was considered favourable. RESULTS: In both conventional statistical and binary logistic regression analyses, the MIS group had a better outcome. The outcome of propensity score matching was unexpected (odds ratio: 0.582; 95%CI: 0.281-1.204; P = 0.144), which indicated that, after excluding the interference of each confounder, different surgical modalities were more effective, and there was no significant difference in their prognosis. CONCLUSION: Deciding between MIS and CI should be made based on the individual patient, considering the hematoma size, degree of midline shift, cerebral swelling, and preoperative Glasgow Coma Scale score.
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Amlexanox (ALX) is a small molecule drug for the treatment of inflammatory, autoimmune, metabolic and tumor diseases. At present, there are no studies on whether ALX has a therapeutic effect on inflammatory bowel disease (IBD). In this study, we used a mouse model of dextran sulfate sodium (DSS)-induced colitis to investigate the effect of ALX targeted inhibition of TBK1 on colitis. We found that the severity of colitis in mice was correlated with TBK1 expression. Notably, although ALX inhibited the activation of the TBK1-NF-κB/TBK1-IRF3 pro-inflammatory signaling pathway, it exacerbated colitis and reduced survival in mice. The results of drug safety experiments ruled out a relationship between this exacerbating effect and drug toxicity. In addition, ELISA results showed that ALX promoted the secretion of IL-1ß and IFN-α, and inhibited the production of cytokines IL-6, TNF-α, IL-10, TGF-ß and secretory IgA. Flow cytometry results further showed that ALX promoted T cell proliferation, activation and differentiation, and thus played a pro-inflammatory role; Also, ALX inhibited the generation of dendritic cells and the polarization of macrophages to M1 type, thus exerting anti-inflammatory effect. These data suggest that the regulation of ALX on the function of different immune cells is different, so the effect on the inflammatory response is bidirectional. In conclusion, our study demonstrates that simply inhibiting TBK1 in all immune cells is not effective for the treatment of colitis. Further investigation the anti-inflammatory mechanism of ALX on dendritic cells and macrophages may provide a new strategy for the treatment of IBD.
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BACKGROUND: Complications associated with cardiovascular implantable electronic devices may necessitate device and lead removal. An open approach to removal may be electively chosen in cases with high risk of complications or those requiring additional concomitant cardiac surgery. This study aimed to investigate outcomes of patients who underwent elective open lead extractions (OLE) at two large tertiary care centers. METHODS: The records of 29 patients undergoing elective OLE were analyzed through retrospective chart review. RESULTS: 69 total leads were extracted from 29 patients (77% completely, 23% partially). The average age of the oldest leads was 13.3 ± 11.3 years. Infective endocarditis with severe valvular insufficiency requiring valvular intervention (41%)-an infectious etiology, and tricuspid valve intervention to correct RV lead-related severe TR (38%)-a noninfectious etiology, were the most common reasons for OLE. 38% of the patients had additional co-primary or secondary indications for open extraction, such as CABG and pericardiectomies. The rate of major complications and procedural failure was 3% each (1/29). 30-day survival was 100%, and 1-year survival was 92%. The average length of hospital stay was 15 days and higher among those undergoing OLE for infectious indications. CONCLUSION: Open lead extractions offered a similar clinical success rate (97%) to transvenous extractions in this cohort and may be a viable alternative for those necessitating valvular intervention or when the risk of complications from TLE is considered very high.
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Background: Conduction disease is an important and common complication post-transcatheter aortic valve replacement (TAVR). Previously, we developed a conduction disease risk stratification and management protocol post-TAVR. This study aims to evaluate high-grade aortic valve block (HAVB) incidence and risk factors in a large cohort undergoing ambulatory cardiac monitoring post-TAVR according to conduction risk grouping. Methods: This single-center, retrospective study evaluated all patients discharged on ambulatory cardiac monitoring between 2016 and 2021 and stratified them into 3 groups based on electrocardiogram predictors of HAVB risk (group 1 [low], group 2 [intermediate], and group 3 [high]). HAVB was defined as ≥2 consecutive nonconducted P waves in sinus rhythm or bradycardia <50 beats/minute with a fixed rate for atrial fibrillation/flutter. Descriptive statistics were used to show the incidence and timeline, while logistic regression was utilized to evaluate predictors of HAVB. Results: Five hundred twenty-eight patients were included (median age 80 years [74-85]; 43.8% female). Forty-one patients (7.8%) developed HAVB during ambulatory monitoring (68% were asymptomatic). Over a median follow-up of 2 years (1.3-2.7), the overall mortality rate was 15.0% (30-day mortality rate of 0.57%, n = 3). Risk factors for HAVB were male sex (odds ratio [OR] = 2.46, p = 0.02, 95% CI = 1.21-5.43), baseline right bundle branch block (OR = 2.80, p = 0.01, 95% CI = 1.17-6.19), and post-TAVR QRS >150 âms (OR = 2.16, p = 0.03, 95% CI = 1.01-4.40). The negative predictive value for patients in groups 1 and 2 for 30-day HAVB was 95.0 and 93.8%, respectively. Conclusions: The risk of 30-day HAVB post-TAVR on ambulatory monitoring post-TAVR varies according to post-TAVR electrocardiogram findings, and a 3-group algorithm effectively identifies groups with a low negative predictive value for HAVB.
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BACKGROUND: Patients with stroke frequently experience pulmonary dysfunction. AIM: To explore the effects of information-motivation-behavioral (IMB) skills model-based nursing care on pulmonary function, blood gas indices, complication rates, and quality of life (QoL) in stroke patients with pulmonary dysfunction. METHODS: We conducted a controlled study involving 120 stroke patients with pulmonary dysfunction. The control group received routine care, whereas the intervention group received IMB-model-based nursing care. Various parameters including pulmonary function, blood gas indices, complication rates, and QoL were assessed before and after the intervention. RESULTS: Baseline data of the control and intervention groups were comparable. Post-intervention, the IMB model-based care group showed significant improvements in pulmonary function indicators, forced expiratory volume in 1 sec, forced vital capacity, and peak expiratory flow compared with the control group. Blood gas indices, such as arterial oxygen pressure and arterial oxygen saturation, increased significantly, and arterial carbon dioxide partial. pressure decreased significantly in the IMB model-based care group compared with the control group. The intervention group also had a lower complication rate (6.67% vs 23.33%) and higher QoL scores across all domains than the control group. CONCLUSION: IMB model-based nursing care significantly enhanced pulmonary function, improved blood gas indices, reduced complication rates, and improved the QoL of stroke patients with pulmonary dysfunction. Further research is needed to validate these results and to assess the long-term efficacy and broader applicability of the model.
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Objective: This retrospective cohort study aimed to investigate the composition and diversity of lung microbiota in patients with severe pneumonia and explore its association with short-term prognosis. Methods: A total of 301 patients diagnosed with severe pneumonia underwent bronchoalveolar lavage fluid metagenomic next-generation sequencing (mNGS) testing from February 2022 to January 2024. After applying exclusion criteria, 236 patients were included in the study. Baseline demographic and clinical characteristics were compared between survival and non-survival groups. Microbial composition and diversity were analyzed using alpha and beta diversity metrics. Additionally, LEfSe analysis and machine learning methods were employed to identify key pathogenic microorganism associated with short-term mortality. Microbial interaction modes were assessed through network co-occurrence analysis. Results: The overall 28-day mortality rate was 37.7% in severe pneumonia. Non-survival patients had a higher prevalence of hypertension and exhibited higher APACHE II and SOFA scores, higher procalcitonin (PCT), and shorter hospitalization duration. Microbial α and ß diversity analysis showed no significant differences between the two groups. However, distinct species diversity patterns were observed, with the non-survival group showing a higher abundance of Acinetobacter baumannii, Klebsiella pneumoniae, and Enterococcus faecium, while the survival group had a higher prevalence of Corynebacterium striatum and Enterobacter. LEfSe analysis identified 29 distinct terms, with 10 potential markers in the non-survival group, including Pseudomonas sp. and Enterococcus durans. Machine learning models selected 16 key pathogenic bacteria, such as Klebsiella pneumoniae, significantly contributing to predicting short-term mortality. Network co-occurrence analysis revealed greater complexity in the non-survival group compared to the survival group, with differences in central genera. Conclusion: Our study highlights the potential significance of lung microbiota composition in predicting short-term prognosis in severe pneumonia patients. Differences in microbial diversity and composition, along with distinct microbial interaction modes, may contribute to variations in short-term outcomes. Further research is warranted to elucidate the clinical implications and underlying mechanisms of these findings.
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Líquido del Lavado Bronquioalveolar , Microbiota , Humanos , Masculino , Femenino , Pronóstico , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Líquido del Lavado Bronquioalveolar/microbiología , Neumonía/microbiología , Neumonía/mortalidad , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Secuenciación de Nucleótidos de Alto Rendimiento , Pulmón/microbiología , Pulmón/patología , Metagenómica , Aprendizaje AutomáticoRESUMEN
BACKGROUND: The aim of this study was to investigate the epidemiological characteristics and antibiotic resistance patterns of Ureaplasma urealyticum (UU) infection among women and children in southwest China. METHODS: A total of 8,934 specimens, including urogenital swabs and throat swabs were analyzed in this study. All samples were tested using RNA-based Simultaneous Amplification and Testing (SAT) methods. Culture and drug susceptibility tests were performed on UU positive patients. RESULTS: Among the 8,934 patients, the overall positive rate for UU was 47.92%, with a higher prevalence observed among women of reproductive age and neonates. The majority of UU positive outpatients were women of reproductive age (88.03%), while the majority of UU positive inpatients were neonates (93.99%). Overall, hospitalization rates due to UU infection were significantly higher in neonates than in women. Further analysis among neonatal inpatients revealed a higher incidence of preterm birth and low birth weight in UU positive inpatients (52.75% and 3.65%, respectively) than in UU negative inpatients (44.64% and 2.89%, respectively), especially in very preterm and extremely preterm neonates. Moreover, the incidence rate of bronchopulmonary dysplasia (BPD) among hospitalized neonatal patients was significantly higher in the UU positive group (6.89%) than in the UU negative group (4.18%). The drug susceptibility tests of UU in the neonatology, gynecology and obstetrics departments exhibited consistent sensitivity patterns to antibiotics, with high sensitivity to tetracyclines and macrolides, and low sensitivity to fluoroquinolones. Notably, UU samples collected from the neonatology department exhibited significantly higher sensitivity to azithromycin and erythromycin (93.8% and 92.9%, respectively) than those collected from the gynecology and obstetrics departments. CONCLUSIONS: This study enhances our understanding of the current epidemiological characteristics and antibiotic resistance patterns of UU infection among women and children in southwest China. These findings can aid in the development of more effective intervention, prevention and treatment strategies for UU infection.
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Antibacterianos , Farmacorresistencia Bacteriana , Pruebas de Sensibilidad Microbiana , Infecciones por Ureaplasma , Ureaplasma urealyticum , Humanos , Infecciones por Ureaplasma/epidemiología , Infecciones por Ureaplasma/microbiología , Infecciones por Ureaplasma/tratamiento farmacológico , Ureaplasma urealyticum/efectos de los fármacos , Ureaplasma urealyticum/aislamiento & purificación , Ureaplasma urealyticum/genética , Femenino , China/epidemiología , Recién Nacido , Antibacterianos/farmacología , Adulto , Masculino , Adolescente , Lactante , Persona de Mediana Edad , Adulto Joven , Preescolar , Niño , PrevalenciaRESUMEN
Human respiratory syncytial virus (HRSV) is the most prevalent pathogen contributing to acute respiratory tract infections (ARTI) in infants and young children and can lead to significant financial and medical costs. Here, we developed a simultaneous, dual-gene and ultrasensitive detection system for typing HRSV within 60 minutes that needs only minimum laboratory support. Briefly, multiplex integrating reverse transcription-recombinase polymerase amplification (RT-RPA) was performed with viral RNA extracted from nasopharyngeal swabs as a template for the amplification of the specific regions of subtypes A (HRSVA) and B (HRSVB) of HRSV. Next, the Pyrococcus furiosus Argonaute (PfAgo) protein utilizes small 5'-phosphorylated DNA guides to cleave target sequences and produce fluorophore signals (FAM and ROX). Compared with the traditional gold standard (RT-qPCR) and direct immunofluorescence assay (DFA), this method has the additional advantages of easy operation, efficiency and sensitivity, with a limit of detection (LOD) of 1 copy/µL. In terms of clinical sample validation, the diagnostic accuracy of the method for determining the HRSVA and HRSVB infection was greater than 95%. This technique provides a reliable point-of-care (POC) testing for the diagnosis of HRSV-induced ARTI in children and for outbreak management, especially in resource-limited settings.
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ARN Viral , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Sensibilidad y Especificidad , Humanos , Virus Sincitial Respiratorio Humano/genética , Virus Sincitial Respiratorio Humano/aislamiento & purificación , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Infecciones por Virus Sincitial Respiratorio/virología , ARN Viral/genética , Lactante , Pyrococcus furiosus/genética , Pyrococcus furiosus/aislamiento & purificación , Proteínas Argonautas/genética , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificación de Ácido Nucleico/métodos , Límite de Detección , Nasofaringe/virología , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/virología , PreescolarRESUMEN
This work includes a novel approach for synthesis/fabrication of AuNRs of varied aspect ratios leading to investigation on the kinetics of their growth mechanism. The synthesized AuNRs were further functionalized with MWCNTs (AuNRs@MWCNTs) by one-pot synthesis. The synthesized AuNRs and AuNRs@MWCNTs were characterized by employing UV-vis spectroscopy. Red shifts in the spectra of AuNRs confirmed the formation of nanorods of higher aspect ratios. Morphology of AuNRs and functionalized AuNRs was confirmed by high-resolution scanning electron microscopy. Biological studies were carried out by fabricating efficient nonenzymatic glucose sensors for optical and electrochemical sensing via UV and cyclic voltammetry in the detection ranges of 0.7-28 mM glucose (UV) and 5.5 µM-0.33 mM (CV). An electrochemical sensing study was carried out via AuNR- and AuNRs@MWCNT-modified GCEs in a 0.1 M NaOH electrolyte solution. The modified electrodes exhibited very high sensitivity with a broad linear range. The order of sensitivity (via CV) was found to be AuNRX0@MWCNTs > AuNRD5@MWCNTs > AuNRD5 > AuNRX0.
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Flavonoids play an important role in forming wine grapes and wine quality characteristics. The flavonoids of three winter red wine grapes, Yeniang No. 2 (YN2), Marselan (Mar), and Guipu No. 6 (GP6), were analyzed by ultra-high-performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-QQQ-MS). Furthermore, the flavonoids in GP6 grapevines using two types of training systems, namely, trellis (T) and espaliers (E), were also compared in this study. Overall, 196 flavonoid metabolites, including 96 flavones, 38 flavonols, 19 flavanones, 18 polyphenols, 15 anthocyanins, 7 isoflavones, and 3 proanthocyanidins, were identified. The flavonoid profiles were remarkably different among these three grape varieties, while they did not change much in the GP6 managed on trellis and espaliers. Grape varieties with different genetic backgrounds have their own unique flavonoid profiles. Compared with Mar-T, isoflavones and flavonols presented higher contents in GP6-T and YN2-T, which mainly contain glycitein, genistin, calycosin, kaempferide, isotrifoliin, and ayanin. The anthocyanin content was significantly higher in YN2-T than in the other two varieties. YN2 and GP6-T present a more stable color, with significantly more acetylated diglucosides and methylated anthocyanins in YN2-T and GP6-T than in Mar-T. Notably, GP6 had more varied flavonoids and the better characteristics to its flavonoid profile out of these three varieties, due to it containing a higher number of anthocyanins, flavone, and flavonols and the greatest number of different flavonoid metabolites (DFMs), with higher contents than YN2 and Mar. Compared with the trellis training system, the espaliers training system increased the content of flavonoids detected in GP6 grape berries; however, the composition of flavonoids strictly depends on the grape variety.
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Flavonoides , Metabolómica , Vitis , Vino , Vitis/química , Vitis/metabolismo , Flavonoides/análisis , Flavonoides/metabolismo , Vino/análisis , Metabolómica/métodos , China , Cromatografía Líquida de Alta Presión , Antocianinas/análisis , Antocianinas/metabolismo , MetabolomaRESUMEN
Dynamic hydrogels with the features of injection, self-healing, and remodeling at the target site have been developed as smart multifunctional biomaterials for drug delivery. However, most self-healing injectable hydrogels are difficult to control protein release after implantation, owing to the deficiency of pH responsiveness, which reduces the bioavailability of proteins. Herein, we propose a facile strategy to endow pH responsiveness into a dynamic hydrogel with both self-healing and injectable capabilities, by crosslinking biomacromolecular backbones via dual pH sensitive dynamic covalent bond. Particularly, oxidized konjac glucomannan (OKGM) can be crosslinked with poly (aspartic hydrazide) (PAHy) and N-carboxyethyl chitosan (CEC) to form dynamic acylhydrazone bonds and imide bonds, respectively, endowing the hydrogel with pH responsiveness and dynamic behaviors. Specifically, PAHy facilitates the formation of acylhydrazone bonds, improving the mechanical properties and pH sensitivity while reducing the degradation behavior of the hydrogels under physiological conditions. Kinetics indicate that the release of bovine serum albumin follows Fick diffusion under different pH conditions. The pH responsive hydrogel with self-healing injectable capabilities has the potential to be used as a controllable and sustain release carrier for protein drugs.
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Quitosano , Hidrogeles , Mananos , Albúmina Sérica Bovina , Quitosano/química , Hidrogeles/química , Concentración de Iones de Hidrógeno , Mananos/química , Albúmina Sérica Bovina/química , Animales , Liberación de Fármacos , Preparaciones de Acción Retardada/química , Bovinos , InyeccionesRESUMEN
INTRODUCTION: The impact of mRNA-based coronavirus disease-2019 (COVID-19) vaccines on atrial arrhythmias (AA) and ventricular arrhythmias incidence is unknown. METHODS: BIOTRONIK Home Monitoring data and Medicare Claims data were utilized to identify individuals implanted with a cardiac implantable electronic device (CIED) between 2010 and 2020 who received one or more doses of COVID-19 vaccine in 2021. The burden of AA (%) in the 3 months postvaccination was compared to those noted in the preceding 3 months using the Wilcoxon signed rank test. Sub-analyses comparing the effects of the influenza vaccine against the COVID-19 vaccine were also evaluated for individuals who received the influenza vaccine in 2020. A 1:1 propensity score match comparison between COVID-19 vaccine and non-vaccinated patients was also performed. RESULTS: First and second doses of the COVID-19 vaccine were administered to 7757 and 6579 individuals with a CIED (age 76.2 ± 9.0 years, 49% males), respectively. While a small but statistically significant increase in the burden of AA was noted in the 3 months postvaccination compared to the preceding 3 months after the first dose of the COVID-19 vaccine (0.43 ± 9.04%, p = .028) a similar rise in AA was found following the influenza vaccine and for matched patients who did not receive the COVID-19 vaccine. No significant difference in device therapies was seen pre- and postvaccination. CONCLUSIONS: Though we report a small but significant increase in the number of CIED-detected AAs following vaccination for COVID-19 over a 3-month window, we believe these results correlate more with time and the progressive nature of AF rather than the vaccine itself. While these data should not dissuade from the use of these vaccines, increased vigilance and prompt treatment of AF is required for high-risk groups, specifically males over 70 years of age, following vaccination.
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Sarcoid myositis is a rare and often debilitating extrapulmonary manifestation of sarcoidosis that can be difficult to recognize without a prior sarcoidosis diagnosis. Sarcoidosis with muscle nodules or masses as the first symptom is the least common form, occurring in approximately 0.5%-2.3% of cases. This article presents four middle-aged female patients who initially sought medical attention for a lower limb mass. Ultrasound examinations revealed consistent characteristic changes indicative of myositis. All patients underwent ultrasound-guided muscle biopsy and were diagnosed with sarcoidosis. Therefore, ultrasonography plays a pivotal role as the primary diagnostic tool for the early detection of sarcoid myositis.
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Red fluorescent hydrogels possessing injectable and self-healing properties have widespread potential in biomedical field. It is still a challenge to achieve a biomacromolecules based dynamic hydrogels simultaneously combining with excellent red fluorescence, good mechanical properties, and biocompatibility. Here we first explore hydrophilic inclusion complex of (R-CDs@α-CD) derived from hydrophobic red fluorescent carbon dots (R-CDs) and α-cyclodextrin (α-CD), and then achieved a red fluorescent and dynamic polysaccharide R-CDs@α-CD/CEC-l-OSA hydrogel. The nanocomposite hydrogel can be fabricated through controlled doping of red fluorescent R-CDs@α-CD into dynamic polymer networks, taking reversibly crosslinked N-carboxyethyl chitosan (CEC) and oxidized sodium alginate (OSA) as an example. The versatile red fluorescent hydrogel simultaneously combines the features of injection, biocompatibility, and augmented mechanical properties and self-healing behavior, especially in rapid self-recovery even after integration. The R-CDs@α-CD uniformly dispersed into dynamic hydrogel played the role of killing two birds with one stone, that is, endowing red emission of a hydrophilic fluorescent substance, and improving mechanical and self-healing properties as a dynamic nano-crosslinker, via forming hydrogen bonds as reversible crosslinkings. The novel red fluorescent and dynamic hydrogel based on polysaccharides is promising for using as biomaterials in biomedical field.
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Alginatos , Carbono , Quitosano , Hidrogeles , Nanocompuestos , Puntos Cuánticos , Alginatos/química , Quitosano/química , Carbono/química , Nanocompuestos/química , Hidrogeles/química , Puntos Cuánticos/química , Puntos Cuánticos/toxicidad , Colorantes Fluorescentes/química , alfa-Ciclodextrinas/química , Materiales Biocompatibles/química , Animales , Interacciones Hidrofóbicas e HidrofílicasRESUMEN
Colorectal cancer (CRC) is one of the most common tumors of the digestive system worldwide. KRAS mutations limit the use of anti-EGFR antibodies in combination with chemotherapy for the treatment of CRC. Therefore, novel targeted therapies are needed to overcome the KRAS-induced oncogenesis. Recent evidence suggests that inhibition of PI3K led to ferroptosis, a nonapoptotic cell death closely related to KRAS-mutant cells. Here, we showed that a selective PI3Kδ inhibitor TYM-3-98 can suppress the AKT/mTOR signaling and activate the ferroptosis pathway in KRAS-mutant CRC cells in a concentration-dependent manner. This was evidenced by the lipid peroxidation, iron accumulation, and depletion of GSH. Moreover, the overexpression of the sterol regulatory element-binding protein 1 (SREBP1), a downstream transcription factor regulating lipid metabolism, conferred CRC cells greater resistance to ferroptosis induced by TYM-3-98. In addition, the effect of TYM-3-98 was confirmed in a xenograft mouse model, which demonstrated significant tumor suppression without obvious hepatoxicity or renal toxicity. Taken together, our work demonstrated that the induction of ferroptosis contributed to the PI3Kδ inhibitor-induced cell death via the suppression of AKT/mTOR/SREBP1-mediated lipogenesis, thus displaying a promising therapeutic effect of TYM-3-98 in CRC treatment.
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Neoplasias Colorrectales , Ferroptosis , Lipogénesis , Proteínas Proto-Oncogénicas c-akt , Proteínas Proto-Oncogénicas p21(ras) , Transducción de Señal , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Serina-Treonina Quinasas TOR , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Humanos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Serina-Treonina Quinasas TOR/metabolismo , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Lipogénesis/efectos de los fármacos , Lipogénesis/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Ratones , Transducción de Señal/efectos de los fármacos , Ratones Desnudos , Línea Celular Tumoral , Mutación/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos BALB C , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Fosfatidilinositol 3-Quinasa Clase I/genética , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacologíaRESUMEN
Objective: In this study, we evaluated the effectiveness of health education based on the transtheoretical model in reducing symptoms of kinesiophobia and enhancing rehabilitation outcomes among elderly patients post-total knee arthroplasty. Methods: Elderly patients post-knee replacement surgery were randomly divided into a control group, which received standard health education, and an experimental group, which received transtheoretical model-based health education. The intervention commenced on the day after surgery and continued for a duration of six months. Assessments of kinesiophobia scores, rehabilitation self-efficacy, and knee function were conducted before the intervention, and then at one, three, and six months postoperatively. Results: Between January 2022 and December 2022, 130 elderly patients who met the eligibility criteria were enrolled and subsequently randomly assigned into two groups of equal size. Comparable baseline characteristics were observed between the two groups The experimental group demonstrated lower kinesiophobia scores and higher scores in rehabilitation self-efficacy and knee function at one, three, and six months following surgery, compared to the control group. Conclusion: Health education based on a transtheoretical model reduces the symptoms of kinesiophobia and enhances rehabilitation self-efficacy and knee functions in elderly patients after knee replacement surgery.