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Candesartan cilexetil (CC) is one of well-tolerated antihypertensive drugs, while its poor solubility and low bioavailability limit its use. Herein, two mesoporous silica (Syloid XDP 3150 and Syloid AL-1 FP) and the corresponding amino-modified products (N-XDP 3150 and N-AL-1 FP) have been selected as the carriers of Candesartan cilexetil to prepare solid dispersion through solvent immersion, and characterized through using powder X-ray diffraction analysis, infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy, and solid-state nuclear magnetic resonance spectroscopy, etc. The state of CC changed from crystalline to amorphous after loading onto the silica carriers, in which no interactions between CC and silica existed. Then, the dissolution behaviors in vitro were studied through using flow-through cell dissolution method. CC-XDP 3150 sample exhibited the most extensive dissolution, and the cumulative release of CC from it was 1.88-fold larger than that of CC. Moreover, the pharmacokinetic results in rats revealed that the relative bioavailability of CC-XDP 3150 and CC-N-XDP 3150 solid dispersions were estimated to be 326 % % and 238 % % in comparison with CC, respectively. Clearly, pore size, pore volume, and surface properties of silica carrier have remarkable effect on loading, dissolution and bioavailability of CC. In brief, this work will provide valuable information in construction of mesoporous silica-based delivery system toward poorly water-soluble drugs.
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Background: Diabetic nephropathy (DN) and diabetic retinopathy (DR) are common microvascular complications of diabetes. The purpose of this study was to investigate the correlation between retinal vascular geometric parameters and pathologically diagnosed type 2 DN and to determine the capacity of retinal vascular geometric parameters in differentiating DN from non-diabetic renal disease (NDRD). Methods: The study participants were adult patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease who underwent a renal biopsy. Univariate and multivariable regression analyses were performed to evaluate associations between retinal vessel geometry parameters and pathologically diagnosed DN. Multivariate binary logistic regression analyses were performed to establish a differential diagnostic model for DN. Results: In total, 403 patients were examined in this cross-sectional study, including 152 (37.7%) with DN, 157 (39.0%) with NDRD and 94 (23.3%) with DN combined with NDRD. After univariate logistic regression, total vessel fractal dimension, arteriolar fractal dimension and venular fractal dimension were all found to be associated with DN. In multivariate analyses adjusting for age, sex, blood pressure, diabetes, DR and other factors, smaller retinal vascular fractal dimensions were significantly associated with DN (P < .05). We developed a differential diagnostic model for DN combining traditional clinical indicators and retinal vascular geometric parameters. The area under the curve of the model established by multivariate logistic regression was 0.930. Conclusions: Retinal vessel fractal dimension is of great significance for the rapid and non-invasive differentiation of DN. Incorporating retinal vessel fractal dimension into the diagnostic model for DN and NDRD can improve the diagnostic efficiency.
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Red mud (RM), a hazardous solid waste generated in the alumina production process, of which the mineral composition is mainly hematite, is unable to be applied directly in the cement industry due to its high alkalinity. With the rise of geopolymers, RM-based grouting materials play an essential role in disaster prevention and underground engineering. To adequately reduce the land-based stockpiling of solid wastes, ultrafine calcium oxide, red mud, and slag were utilized as the main raw materials to prepare geopolymers, the C-R-S (calcium oxide-red mud-slag) grouting cementitious materials. The direct impact of red mud addition on the setting time, fluidity, water secretion, mechanical properties, and rheological properties of C-R-S were also investigated. In addition, a scanning electron microscope (SEM), X-ray diffraction (XRD), three-dimensional CT (3D-CT), Fourier transform infrared spectroscopy (FT-IR), and other characterization techniques were used to analyze the microstructure and polymerization mechanism. The related results reveal that the increase in red mud addition leads to an enhanced setting time, and the C-R-S-40 grouting cementitious material (40% red mud addition) exhibits the best fluidity of 27.5 cm, the lowest water secretion rate of 5.7%, and a high mechanical strength of 57.7 MPa. The C-R-S polymer grout conforms to the Herschel-Bulkley model, and the fitted value of R2 is above 0.99. All analyses confirm that the preparation process of C-R-S grouting cementitious material not only substantially improves the utilization rate of red mud, but also provides a theoretical basis for the high-volume application of red mud in the field of grouting.
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Efficient cutaneous wound healing requires a coordinated transition between inflammatory phases mediated by dynamic changes in leukocyte subset populations. Here, we identify STING as a key innate immune mediator governing timely resolution of inflammation by regulating macrophage dynamics during skin repair. Using a mouse model, we show STING deficiency caused delayed wound closure associated with abnormal persistence of TNF-α+ leukocytes. This resulted from the impaired macrophage recruitment. STING controlled the trafficking of bone marrow myeloid cells into blood and wounds, intrinsically enhancing macrophage migratory capacity through STAT3 activation. Specifically, STING modulated the production of monocyte chemokines and their receptors CCR2/CCR5 to enable efficient egress and wound infiltration. Consequently, disrupted systemic and local STING-STAT3-chemokine signaling combine to delay macrophage influx. This study elucidates STING as a critical rheostat tuning macrophage responses through STAT3 to orchestrate inflammatory resolution necessary for efficient wound healing. Our findings have broad implications for targeting STING therapeutically in both regenerative medicine and inflammatory disease contexts. STING regulates the macrophage trafficking through STAT3 in wound healing.
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BACKGROUND: Lupus nephritis (LN) is the most common cause of kidney injury in systemic lupus erythematosus (SLE) patients and is associated with increased mortality. DNA methylation, one of the most important epigenetic modifications, has been reported as a key player in the pathogenesis of SLE. Hence, our article aimed to explore DNA methylation in CD4+ T cells from LNs to identify additional potential biomarkers and pathogenic genes involved in the progression of LN. METHODS: Our study enrolled 46 SLE patients with or without kidney injury and 23 healthy controls from 2019 to 2022. CD4+ T cells were sorted for DNA methylation genotyping and RNA-seq. Through bioinformatics analysis, we identified the significant differentially methylated CpG positions (DMPs) only in the LN group and validated them by Bisulfite PCR. Integration analysis was used to screen for differentially methylated and expressed genes that might be involved in the progression of LN, and the results were analyzed via cell experiments and flow cytometry. RESULTS: We identified 243 hypomethylated sites and 778 hypermethylated sites only in the LN cohort. Three of these DMPs, cg08332381, cg03297029, and cg16797344, were validated by Bisulfite PCR and could be potential biomarkers for LN. Integrated analysis revealed that the expression of BCL2L14 and IFI27 was regulated by DNA methylation, which was validated by azacytidine (5-aza) treatment. The overexpression of BCL2L14 in CD4+ T cells might induce renal fibrosis and inflammation by regulating the differentiation and function of Tfh cells. CONCLUSION: Our study identified novel aberrant DMPs in CD4+ T cells only in LN patients and DNA methylation-regulated genes that could be potential LN biomarkers. BCL2L14 is likely involved in the progression of LN and might be a treatment target.
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Linfocitos T CD4-Positivos , Metilación de ADN , Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Metilación de ADN/genética , Linfocitos T CD4-Positivos/metabolismo , Femenino , Masculino , Adulto , Nefritis Lúpica/genética , Lupus Eritematoso Sistémico/genética , Epigénesis Genética/genética , Islas de CpG/genética , Estudios de Casos y Controles , Persona de Mediana Edad , BiomarcadoresRESUMEN
OBJECTIVES: To investigate PET/CT registration and quantification accuracy of thoracic lesions of a single 30-second deep-inspiration breath-hold (DIBH) technique with a total-body PET (TB-PET) scanner, and compared with free-breathing (FB) PET/CT. METHODS: 137 of the 145 prospectively enrolled patients finished a routine FB-300 s PET/CT exam and a 30-second DIBH TB-PET with chest to pelvis low dose CT. The total-body FB-300 s, FB-30 s, and DIBH-30 s PET images were reconstructed. Quantitative assessment (SUVmax and SUVmean of lung and other organs), PET/CT registration assessment and lesion analysis (SUVmax, SUVpeak, SUVmean and tumor-background ratio) were compared with Wilcoxon signed-rank tests. RESULTS: The SUVmax and SUVmean of the lung with DIBH-30 s were significantly lower than those with FB. The distances of the liver dome between PET and CT were significantly smaller with DIBH-30 s than with FB. 195 assessable lesions in 106 patients were included, and the detection sensitivity was 97.9 % and 99.0 % in FB-300 s, and DIBH-30 s, respectively. For both small co-identified lesions (n = 86) and larger co-identified lesions with a diameter ≥ 1 cm (n = 91), the lesion SUVs were significantly greater with DIBH-30 s than with FB-300 s. Regarding lesion location, the differences of the SUVs for the lesions in the lower thorax area (n = 97, p < 0.001) were significant between DIBH-30 s and FB-300 s, while these differences were not statistically significant in the upper thorax (n = 80, p > 0.05). The lesion tumor-to-surrounding-background ratio (TsBR) was significantly increased, both in the upper and lower thorax. CONCLUSION: The TB DIBH PET/CT technique is feasible in clinical practice. It reduces the background lung uptake and achieves better registration and lesion quantification, especially in the lower thorax.
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Contencion de la Respiración , Fluorodesoxiglucosa F18 , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Sensibilidad y Especificidad , Imagen de Cuerpo Entero , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Imagen de Cuerpo Entero/métodos , Adulto , Estudios Prospectivos , Anciano de 80 o más Años , Reproducibilidad de los Resultados , Neoplasias Torácicas/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , InhalaciónRESUMEN
The glymphatic system plays a key role in the clearance of waste from the parenchyma, and its dysfunction has been associated with the pathogenesis of Alzheimer's disease (AD). However, questions remain regarding its complete mechanisms. Here, we report that efflux of cerebrospinal fluid (CSF)/interstitial fluid (ISF) solutes occurs through a triphasic process that cannot be explained by the current model, but rather hints at the possibility of other, previously undiscovered routes from paravenous spaces to the blood. Using real-time, in vivo observation of efflux, a novel drainage pathway was discovered, in which CSF molecules enter the bloodstream directly through dynamically assembled, trumpet-shaped pores (basolateral Ï<8 µm; apical Ï < 2 µm) on the walls of brain venules. As Zn2+ could facilitate the brain clearance of macromolecular ISF solutes, Zn2+-induced reconstruction of the tight junctions (TJs) in vascular endothelial cells may participate in pore formation. Thus, an updated model for glymphatic clearance of brain metabolites and potential regulation is postulated. In addition, deficient clearance of Aß through these asymmetric venule pores was observed in AD model mice, supporting the notion that impaired brain drainage function contributes to Aß accumulation and pathogenic dilation of the perivascular space in AD.
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Background: Tarsal tunnel syndrome (TTS) is a condition in which the tibial nerve (TN) (or its terminal branches) is compressed by the flexor retinaculum (FR) and the deep fascia of the abductor hallucis muscle at the tarsal tunnel, causing symptoms that negatively impact the patient's quality of life, including numbness, a sensation of a foreign object, coldness, and pain. FR release via microtrauma using needle-knife has proven to be effective in China and is widely used by clinicians. The traditional acupotomy, however, is the "blind knife" treatment, which cannot guarantee patient safety due to risk of injury to important structures, particularly the neurovascular bundle. Compared with the conventional treatments, ultrasound-guided percutaneous FR release possesses noteworthy advantages including high efficacy and safety. Methods: Percutaneous release of the FR was performed on 51 formalin-fixed specimens. The specimens were divided into two groups: an ultrasound-guided acupotomy pushing group comprising 20 legs (group U) and a nonultrasound-guided acupotomy pushing group comprising 31 legs (group N). After high-frequency ultrasound exploration, those with clear vascular imaging were included in group U; otherwise, they were included in group N. The FR was released percutaneously, soft tissue was dissected layer by layer, and anatomical data were recorded. Results: There no cases of injury in group U (0%) and four in group N (12.9%). Among the different intervention methods, there were no significant differences in tissue injury types (χ2=2.80; P=0.09). The percentage of released FR in group U was 80.00% while that in group N was 61.29% (χ2=1.977; P=0.16), which did not represent a significant difference between the two groups. However, group U had a significantly greater release length than that in the group N (t=3.359; P=0.002), indicating that the flexor release length guided by ultrasound is significantly greater than the unguided one. Conclusions: Ultrasound-guided percutaneous release of the FR using a needle-knife can provide greater length and percentage of released FR while maintaining a comparable safety rate to the unguided procedure.
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Introduction: Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). This study aimed to develop CVD risk prediction models using machine learning to support clinical decision making and improve patient prognosis. Methods: Electronic medical records from patients with CKD at a single center from 2015 to 2020 were used to develop machine learning models for the prediction of CVD. Least absolute shrinkage and selection operator (LASSO) regression was used to select important features predicting the risk of developing CVD. Seven machine learning classification algorithms were used to build models, which were evaluated by receiver operating characteristic curves, accuracy, sensitivity, specificity, and F1-score, and Shapley Additive explanations was used to interpret the model results. CVD was defined as composite cardiovascular events including coronary heart disease (coronary artery disease, myocardial infarction, angina pectoris, and coronary artery revascularization), cerebrovascular disease (hemorrhagic stroke and ischemic stroke), deaths from all causes (cardiovascular deaths, non-cardiovascular deaths, unknown cause of death), congestive heart failure, and peripheral artery disease (aortic aneurysm, aortic or other peripheral arterial revascularization). A cardiovascular event was a composite outcome of multiple cardiovascular events, as determined by reviewing medical records. Results: This study included 8,894 patients with CKD, with a composite CVD event incidence of 25.9%; a total of 2,304 patients reached this outcome. LASSO regression identified eight important features for predicting the risk of CKD developing into CVD: age, history of hypertension, sex, antiplatelet drugs, high-density lipoprotein, sodium ions, 24-h urinary protein, and estimated glomerular filtration rate. The model developed using Extreme Gradient Boosting in the test set had an area under the curve of 0.89, outperforming the other models, indicating that it had the best CVD predictive performance. Conclusion: This study established a CVD risk prediction model for patients with CKD, based on routine clinical diagnostic and treatment data, with good predictive accuracy. This model is expected to provide a scientific basis for the management and treatment of patients with CKD.
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Enfermedades Cardiovasculares , Aprendizaje Automático , Insuficiencia Renal Crónica , Humanos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Masculino , Femenino , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/epidemiología , Persona de Mediana Edad , Pronóstico , Anciano , Medición de Riesgo/métodos , Factores de Riesgo , Adulto , Estudios RetrospectivosRESUMEN
BACKGROUND: Currently, the diagnosis of postneurosurgical intracranial infection is mainly dependent on cerebrospinal fluid (CSF) bacterial culture, which has the disadvantages of being time-consuming, having a low detection rate, and being easily affected by other factors. These disadvantages bring some difficulties to early diagnosis. Therefore, it is very important to construct a nomogram model to predict the risk of infection and provide a basis for early diagnosis and treatment. METHODS: This retrospective study analyzed postneurosurgical patient data from the Fourth Affiliated Hospital of Harbin Medical University between January 2019 and September 2023. The patients were randomly assigned in an 8:2 ratio into the training cohort and the internal validation cohort. In the training cohort, initial screening of relevant indices was conducted via univariate analysis. Subsequently, the least absolute shrinkage and selection operator logistic regression identified significant potential risk factors for inclusion in the nomogram model. The model's discriminative ability was assessed using the area under the receiver operating characteristic curve, and its calibration was evaluated through calibration plots. The clinical utility of the model was determined using decision curve analysis and further validated by the internal validation cohort. RESULTS: Multivariate logistic regression analysis of the training cohort identified 7 independent risk factors for postoperative intracranial infection: duration of postoperative external drainage (odds ratio [OR] 1.19, P = 0.005), continued fever (OR 2.11, P = 0.036), CSF turbidity (OR 2.73, P = 0.014), CSF pressure (OR 1.01, P = 0.018), CSF total protein level (OR 1.26, P = 0.026), CSF glucose concentration (OR 0.74, P = 0.029), and postoperative serum albumin level (OR 0.84, P < 0.001). Using these variables to construct the final model. The area under the receiver operating characteristic curve value of the model was 0.868 in the training cohort and 0.900 in the internal validation cohort. Calibration and the decision curve analysis indicated high accuracy and clinical benefit of the nomogram, findings that were corroborated in the validation cohort. CONCLUSIONS: This study successfully developed a novel nomogram for predicting postoperative intracranial infection, demonstrating excellent predictive performance. It offers a pragmatic tool for the early diagnosis of intracranial infection.
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Macrophages undertake pivotal yet dichotomous functions during skin wound healing, mediating both early proinflammatory immune activation and late anti-inflammatory tissue remodeling processes. The timely phenotypic transition of macrophages from inflammatory M1 to proresolving M2 activation states is essential for efficient healing. However, the endogenous mechanisms calibrating macrophage polarization in accordance with the evolving tissue milieu remain undefined. In this study, we reveal an indispensable immunomodulatory role for fibroblast-secreted exosomes in directing macrophage activation dynamics. Fibroblast-derived exosomes permitted spatiotemporal coordination of macrophage phenotypes independent of direct intercellular contact. Exosomes enhanced macrophage sensitivity to both M1 and M2 polarizing stimuli, yet they also accelerated timely switching from M1 to M2 phenotypes. Exosome inhibition dysregulated macrophage responses, resulting in aberrant inflammation and impaired healing, whereas provision of exogenous fibroblast-derived exosomes corrected defects. Topical application of fibroblast-derived exosomes onto chronic diabetic wounds normalized dysregulated macrophage activation to resolve inflammation and restore productive healing. Our findings elucidate fibroblast-secreted exosomes as remote programmers of macrophage polarization that calibrate immunological transitions essential for tissue repair. Harnessing exosomes represents a previously unreported approach to steer productive macrophage activation states with immense therapeutic potential for promoting healing in chronic inflammatory disorders.
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For the first time, hierarchical porous amorphous metal-organic frameworks (HP-aMOFs) containing ultramicropores, micropores, and mesopores were synthesized by etching a composite of MOF glass (agZIF-76) and ZnO using ammonia. These materials show potential applications in the adsorption of C2 hydrocarbons.
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Lung cancer, a global mortality leader, often necessitates Video-Assisted Thoracoscopic (VATS) surgery. However, post-operative nausea and vomiting (PONV) is common, highlighting a need for effective management and prevention strategies in this context. A retrospective case-control study at Fujian Medical University Union Hospital evaluated patients undergoing VATS radical resection of lung cancer between May and September 2022. Patients were categorized based on PONV prevention methods, and data encompassing demographics, surgical history, and postoperative adverse events s were analyzed to assess the association between prophylactic protocols and PONV incidence. The Netupitant and Palonosetron Hydrochloride (NEPA) group showed a significant reduction in PONV occurrences post-surgery compared to Ondansetron (ONDA) and Control groups, emphasizing NEPA's efficacy in alleviating PONV symptoms (P < 0.05). Furthermore, following VATS radical resection of lung cancer, NEPA markedly reduced the intensity of PONV symptoms in patients. Both univariate and multivariate logistic analyses corroborated that NEPA independently reduces PONV risk, with its protective effect also apparent in susceptible populations like females and non-smokers. NEPA utilization markedly reduced both the incidence and severity of PONV in patients undergoing VATS radical resection of lung cancer, serving as an independent protective factor in mitigating PONV risk post-surgery.
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Neoplasias Pulmonares , Náusea y Vómito Posoperatorios , Cirugía Torácica Asistida por Video , Humanos , Femenino , Cirugía Torácica Asistida por Video/métodos , Cirugía Torácica Asistida por Video/efectos adversos , Masculino , Neoplasias Pulmonares/cirugía , Náusea y Vómito Posoperatorios/prevención & control , Náusea y Vómito Posoperatorios/etiología , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Estudios de Casos y Controles , Antieméticos/uso terapéutico , Antieméticos/administración & dosificación , Ondansetrón/uso terapéutico , Ondansetrón/administración & dosificación , Palonosetrón/uso terapéutico , Palonosetrón/administración & dosificaciónRESUMEN
Esophageal cancer ranks among the most prevalent malignant tumors, and esophageal squamous cell carcinoma (ESCC) constitutes its predominant histological form. Despite its impact, a thorough insight into the molecular intricacies of ESCC's development is still incomplete, which hampers the advancement of targeted molecular diagnostics and treatments. Recently, B-cell lymphoma-2-associated transcription factor 1 (BCLAF1) has come under investigation for its potential involvement in tumor biology, yet its specific role and mechanism in ESCC remain unclear. In this study, we observed a marked increase in BCLAF1 expression in ESCC tissues, correlating with advanced tumor stages and inferior patient outcomes. Our comprehensive in vitro and in vivo studies show that BCLAF1 augments glycolytic activity and the proliferation, invasion, and spread of ESCC cells. By employing mass spectrometry, we identified YTHDF2 as a key protein interacting with BCLAF1 in ESCC, with further validation provided by colocalization, co-immunoprecipitation, and GST pull-down assay. Further investigations involving MeRIP-seq and RIP-seq, alongside transcriptomic analysis, highlighted SIX1 mRNA as a molecule significantly upregulated and modified by N6-methyladenosine (m6A) in BCLAF1 overexpressing cells. BCLAF1 was found to reduce the tumor-suppressive activities of YTHDF2, and its effects on promoting glycolysis and cancer progression were shown to hinge on SIX1 expression. This research establishes that BCLAF1 fosters glycolysis and tumor progression in ESCC through the YTHDF2-SIX1 pathway in an m6A-specific manner, suggesting a potential target for future therapeutic intervention.
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Proliferación Celular , Progresión de la Enfermedad , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio , Estabilidad del ARN , Proteínas de Unión al ARN , Proteínas Represoras , Animales , Femenino , Humanos , Masculino , Ratones , Adenosina/análogos & derivados , Adenosina/metabolismo , Línea Celular Tumoral , Movimiento Celular , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Glucólisis/genética , Ratones Desnudos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismoRESUMEN
Matching the thickness of the graphitic carbon nitride (CN) nanolayer with the charge diffusion length is expected to compensate for the poor intrinsic conductivity and charge recombination in CN for photoelectrochemical cells (PEC). Herein, the compact CN nanolayer with tunable thickness is in situ coated on carbon fibers. The compact packing along with good contact with the substrate improves the electron transport and alleviates the charge recombination. The PEC investigation shows CN nanolayer of 93 nm-thick yields an optimum photocurrent of 116 µA cm-2 at 1.23 V versus RHE, comparable to most micrometer-thick CN layers, with a low onset potential of 0.2 V in 1 m KOH under 1 sun illumination. This optimum performance suggests the electron diffusion length matches with the thickness of the CN nanolayer. Further deposition of NiFe-layered double hydroxide enhanced the surface water oxidation kinetics, delivering an improved photocurrent of 210 µA cm-2 with IPCE of 12.8% at 400 nm. The CN nanolayer also shows extended potential in PEC organic synthesis. This work experimentally reveals the PEC behavior of the nanometer-thick CN layer, providing new insights into CN in the application of energy and environment-related fields.
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Aging-associated renal dysfunction promotes the pathogenesis of chronic kidney disease. Mitochondrial dysfunction in renal tubular epithelial cells is a hallmark of senescence and leads to accelerated progression of renal disorders. Dysregulated calcium profiles in mitochondria contribute to aging-associated disorders, but the detailed mechanism of this process is not clear. In this study, modulation of the sirtuin 1/angiotensin II type 1 receptor (Sirt1/AT1R) pathway partially attenuated renal glomerular sclerosis, tubular atrophy, and interstitial fibrosis in D-galactose (D-gal)-induced accelerated aging mice. Moreover, modulation of the Sirt1/AT1R pathway improved mitochondrial dysfunction induced by D-gal treatment. Transient receptor potential channel, subtype C, member 3 (TRPC3) upregulation mediated dysregulated cellular and mitochondrial calcium homeostasis during aging. Furthermore, knockdown or knockout (KO) of Trpc3 in mice ameliorated D-gal-induced mitochondrial reactive oxygen species production, membrane potential deterioration, and energy metabolism disorder. Mechanistically, activation of the AT1R/PKA pathway promoted CREB phosphorylation and nucleation of CRE2 binding to the Trpc3 promoter (-1659 to -1648 bp) to enhance transcription. Trpc3 KO significantly improved the renal disorder and cell senescence in D-gal-induced mice. Taken together, these results indicate that TRPC3 upregulation mediates age-related renal disorder and is associated with mitochondrial calcium overload and dysfunction. TRPC3 is a promising therapeutic target for aging-associated renal disorders.
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Células Epiteliales , Galactosa , Túbulos Renales , Mitocondrias , Transducción de Señal , Canales Catiónicos TRPC , Animales , Ratones , Envejecimiento/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Túbulos Renales/metabolismo , Túbulos Renales/patología , Ratones Noqueados , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Canales Catiónicos TRPC/metabolismo , Canales Catiónicos TRPC/genéticaRESUMEN
Chiral covalent organic frameworks (COFs) hold considerable promise in the realm of heterogeneous asymmetric catalysis. However, fine-tuning the pore environment to enhance both the activity and stereoselectivity of chiral COFs in such applications remains a formidable challenge. In this study, we have successfully designed and synthesized a series of clover-shaped, hydrazone-linked chiral COFs, each with a varying number of accessible chiral pyrrolidine catalytic sites. Remarkably, the catalytic efficiencies of these COFs in the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde correlate well with the number of accessible pyrrolidine sites within the frameworks. The COF featuring nearly one pyrrolidine moiety at each nodal point demonstrated excellent reaction yields and enantiomeric excess (ee) values, reaching up to 97 and 83%, respectively. The findings not only underscore the profound impact of a deliberately controlled chiral pore environment on the catalytic efficiencies of COFs but also offer a new perspective for the design and synthesis of advanced chiral COFs for efficient asymmetric catalysis.
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Posttreatment of pristine metal-organic frameworks (MOFs) with suitable vapor may be an effective way to regulate their structures and properties but has been less explored. Herein, we report an interesting example in which a crystalline nonporous Eu(III)-MOF was transferred to a porous amorphous MOF (aMOF) via iodine vapor adsorption-desorption posttreatment, and the resulting aMOF showed improved turn-on sensing properties with respect to Ag+ ions. The crystalline Eu-MOF, namely, Eu-IPDA, was assembled from Eu(III) and 4,4'-{4-[4-(1H-imidazol-1-yl)phenyl]pyridine-2,6-diyl}dibenzoic acid (H2IPDA) and exhibited a two-dimensional (2D) coordination network based on one-dimensional secondary building blocks. The close packing of the 2D networks gives rise to a three-dimensional supramolecular framework without any significant pores. Interestingly, the nonporous Eu-IPDA could absorb iodine molecules when Eu-IPDA crystals were placed in iodine vapor at 85 °C, and the adsorption capacity was 1.90 g/g, which is comparable to those of many MOFs with large BET surfaces. The adsorption of iodine is attributed to the strong interactions among the iodine molecule, the carboxy group, and the N-containing group and leads to the amorphization of the framework. After immersion of the iodine-loaded Eu-IPDA in EtOH, approximately 89.7% of the iodine was removed, resulting in a porous amorphous MOF, denoted as a-Eu-IPDA. In addition, the remaining iodine in the a-Eu-IPDA framework causes strong luminescent quenching in the fluorescence emission region of the Eu(III) center when compared with that in Eu-IPDA. The luminescence intensity of a-Eu-IPDA in water suspensions was significantly enhanced when Ag+ ions were added, with a detection limit of 4.76 × 10-6 M, which is 1000 times that of pristine Eu-IPDA. It also showed strong anti-interference ability over many common competitive metal ions and has the potential to sense Ag+ in natural water bodies and traditional Chinese medicine preparations. A mechanistic study showed that the interactions between Ag+ and the absorbed iodine, the carboxylate group, and the N atoms all contribute to the sensing performance of a-Eu-IPDA.
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The use of human aging markers, which are physiological, biochemical and molecular indicators of structural or functional degeneration associated with aging, is the fundamental basis of individualized aging assessments. Identifying methods for selecting markers has become a primary and vital aspect of aging research. However, there is no clear consensus or uniform principle on the criteria for screening aging markers. Therefore, we combine previous research from our center and summarize the criteria for screening aging markers in previous population studies, which are discussed in three aspects: functional perspective, operational implementation perspective and methodological perspective. Finally, an evaluation framework has been established, and the criteria are categorized into three levels based on their importance, which can help assess the extent to which a candidate biomarker may be feasible, valid, and useful for a specific use context.