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1.
Artículo en Inglés | MEDLINE | ID: mdl-39269917

RESUMEN

Copper phenylacetylide (PACu) is a promising photocatalyst due to its unique copper ladder (CL) electron transport channel, which facilitates efficient charge transfer. However, the structure-activity relationship between the CL spacing and its catalytic performance has yet to be revealed. In this study, we skillfully selected multiple substituents to regulate the CL spacing of the PACu photocatalyst. Our findings indicate that reducing the CL spacing significantly enhances carrier separation and transport efficiency, leading to improved oxygen adsorption and activation. Specifically, PACu-F demonstrated superior photocatalytic activity, achieving a 99% conversion rate in benzylamine oxidation and maintaining an excellent stability over multiple cycles. This study confirms the feasibility of tuning the CL spacing in PACu using donor/acceptor substituents to achieve a high-efficiency photocatalytic performance, offering crucial insights into the rational design of advanced photocatalysts.

2.
Open Med (Wars) ; 19(1): 20241012, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39176252

RESUMEN

Background: Empagliflozin has been shown in clinical studies to lower the risk of adverse cardiovascular events. Using proteomics, the current study aims to determine whether empagliflozin reduces aortic alterations in obese mice and to investigate its molecular mechanism of action. Methods: We constructed obese mice and then treated them with empagliflozin. Changes in the weight of the mice were recorded. Blood glucose and lipid levels were measured in each group of mice, and changes in pulse wave velocity and aortic structure were recorded. In addition, changes in aortic protein expression were detected by proteomics and analyzed bioinformatically. Results: Proteomics results showed that 507 differentially expressed proteins (DEPs) were identified in the comparison of normal and obese mice, while 90 DEPs were identified in the comparison of obese and empagliflozin-treated mice. Examination of these three groups revealed that DEPs were largely associated with the digestion of unsaturated fats. Among them, empagliflozin significantly reduced the expression of fatty acid synthase (FASN), acyl-CoA desaturase 3 (SCD3), ACSL1. and ACSL5 in the aorta of obesity-induced mice, and there was a close relationship between the four. Conclusion: Empagliflozin reduced the protein expression of FASN, SCD3, ACSL1, and ACSL5 in the aorta of obese mice and improved aortic fatty acid metabolism and reduced vascular stiffness for vasoprotective effects.

3.
Sci Total Environ ; 948: 174977, 2024 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-39053535

RESUMEN

OBJECTIVE: To identify the potential metabolic biomarkers of fluorosis and the pathogenesis of fluorosis. METHODS: Sprague Dawley rats in this study were randomly divided into fluoride exposure and control groups. In the fluoride exposure group, six offspring rats without dental fluorosis were defined as group A, and six offspring rats with dental fluorosis were defined as group C. Eight offspring rats in the control group were defined as group B. The metabolites in plasma were determined using GC-MS, with differential metabolites (DMs) identified using VIP > 1, and P < 0.05. Cluster analysis, KEGG pathway enrichment analysis and Receiver Operating Characteristic (ROC) analysis were subsequently performed. The DMs which were caused by fluoride exposure in the previous study were used to verify our results. The GSE70719 from GEO database were used to support this research at the mRNA level and in vitro experiment were selected to verify above results. RESULTS: The 13 up-regulated and 4 down-regulated DMs were identified in the group A + C, the 18 up-regulated and 4 down-regulated DMs were identified in group A, and the 12 up-regulated and 2 down-regulated DMs were identified in group C. All groups showed enrichment in Aminoacyl-tRNA synthesis, D-glutamine and D-glutamate metabolism, Nitrogen metabolism, and Purine metabolism pathways. ROC analysis revealed that L-glutamine had excellent diagnostic ability for fluorosis (AUC > 0.85, P < 0.05). Changes in major DMs (L-glutamine, 4-hydroxyproline and L-alanine) were consistent with previous findings. Transcriptomic results showed the significant alteration of GLS gene in the fluoride exposure group. In vitro experiments confirmed decreased GLS and SLC1A5 genes expression. CONCLUSION: L-glutamine emerges as a potential biomarker for fluorosis. Glutamine metabolism was involved in the pathogenesis of fluorosis.


Asunto(s)
Fluoruros , Fluorosis Dental , Glutamina , Metabolómica , Ratas Sprague-Dawley , Animales , Glutamina/metabolismo , Fluorosis Dental/metabolismo , Ratas , Transcriptoma , Biomarcadores/metabolismo , Perfilación de la Expresión Génica
4.
Hu Li Za Zhi ; 71(4): 19-24, 2024 Aug.
Artículo en Chino | MEDLINE | ID: mdl-39084889

RESUMEN

The effectiveness of game-based learning strategies lies in the ability of these strategies to engage learners and enhance their motivation to learn. This is particularly important for today's younger generations, which are known to respond better to visual rather than textual information. Gamified education provides stimulating, realistic, and enjoyable learning experiences, helping students understand complex nursing knowledge and skills. The diversity of game-based learning tools, including based board games, escape room games, digital games, simulation games, mobile serious games, and virtual reality games, not only enhances students' learning effectiveness and skills but also improves their problem-solving abilities, communication skills, and ability to cope with various challenges in clinical care. In general, game-based learning is a strategy with great potential and importance. This strategy not only has profound implications for modern nursing education and clinical practice but also, through its promotion of innovative thinking and diversified applications, can effectively promote the learning motivation of nursing professionals, improve teaching effectiveness, and enhance professional abilities and self-directed learning capabilities. In an era in which medical knowledge is constantly evolving, game-based learning should be promoted and utilized to cultivate nursing professionals' capabilities effectively.


Asunto(s)
Educación en Enfermería , Humanos , Educación en Enfermería/métodos , Juegos de Video , Aprendizaje , Aprendizaje Basado en Problemas/métodos
5.
J Glob Health ; 14: 04123, 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38939961

RESUMEN

Background: Emotion-oriented approaches have demonstrated effectiveness in the care of the elderly. However, related studies have reported conflicting results. We aimed to explore the pooled effect of emotion-oriented approaches on the psychological outcomes and cognitive function of older adults through a meta-analysis of randomised controlled trials (RCTs). Methods: We searched eight databases - CINAHL, Cochrane, Embase, Ovid MEDLINE, PsycINFO, PubMed, Scopus, and Web of Science - for RCTs from inception to 11 January 2024. Participants aged 60 years or older who received emotion-oriented approaches as the intervention, and reported outcomes of interest in the studies were included. The primary outcome was psychological outcomes (depression, self-esteem, life satisfaction and loneliness), and the secondary outcome was global cognitive function. The pooled effect size was computed in comprehensive meta-analysis 3.0 software using Hedges' g (g) with random-effects model. Furthermore, heterogeneity was assessed through Cochrane's Q and I2 tests. The quality of the included studies was evaluated using the Cochrane Risk of Bias tool. To explore potential sources of heterogeneity, moderator analyses were conducted. Results: We included 37 RCTs and found that emotion-oriented approaches improve depression (g = -0.82, 95% CI = -1.08, -0.56), self-esteem (g = 0.98, 95% CI = 0.31, 1.64), life satisfaction (g = 0.63, 95% CI = 0.37, 0.88), loneliness (g = -2.22, 95% CI = -3.80, -0.64) and global cognitive function (g = 0.34, 95% CI = 0.19, 0.49) in older adults. We also observed significant follow-up effects on depression (g = -1.40, 95% CI = -2.45, -0.34) and loneliness (g = -3.48, 95% CI = 6.02, -0.94). Conclusions: Emotion-oriented approaches are promising interventions in improving psychological outcomes and global cognitive function in older adults. Health care workers should receive training to promote and integrate emotion-oriented approaches into routine care of older adults emphasising the importance of collaborative efforts among health care professionals and caregivers to ensure holistic care delivery.


Asunto(s)
Cognición , Emociones , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Anciano , Depresión , Persona de Mediana Edad , Soledad/psicología , Autoimagen , Anciano de 80 o más Años , Satisfacción Personal
6.
Clin Pharmacol Drug Dev ; 13(7): 716-728, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38757550

RESUMEN

Cofrogliptin (HSK7653) is a long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus with a twice-monthly dosing regimen. This study included 62 participants (48 without food effect, 14 with food effect) receiving single doses of HSK7653 (5, 10, 25, 50, 100, and 150 mg) or placebo. Pharmacokinetic samples were collected over 24 hours postdosing and sampling times are aligned with 12-lead electrocardiograms (ECGs) which were derived from continuous ECG recordings. For the concentration-QT interval corrected for heart rate (C-QTc) analysis, we used linear mixed-effects modeling to characterize the correlation between plasma concentrations of HSK7653 and the change from baseline in the QT interval which was corrected by Fridericia's formula (ΔQTcF). The result showed that a placebo-corrected Fridericia corrected QT interval (ΔΔQTcF) prolongation higher than 10 milliseconds is unlikely at the mean maximum observed concentration (Cmax) (411 ng/mL) associated with the recommended therapeutic doses (25 mg twice-monthly), even at the highest supratherapeutic concentration (2425 ng/mL). Thus, HSK7653 does not significantly affect QT prolongation at either recommended doses or the highest supratherapeutic concentration.


Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Relación Dosis-Respuesta a Droga , Electrocardiografía , Voluntarios Sanos , Frecuencia Cardíaca , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Método Doble Ciego , Electrocardiografía/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Síndrome de QT Prolongado/inducido químicamente , Pueblos del Este de Asia
7.
Ecotoxicol Environ Saf ; 278: 116432, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38728947

RESUMEN

Cadmium (Cd) pollution is a serious global environmental problem, which requires a global concern and practical solutions. Microbial remediation has received widespread attention owing to advantages, such as environmental friendliness and soil amelioration. However, Cd toxicity also severely deteriorates the remediation performance of functional microorganisms. Analyzing the mechanism of bacterial resistance to Cd stress will be beneficial for the application of Cd remediation. In this study, the bacteria strain, up to 1400 mg/L Cd resistance, was employed and identified as Proteus mirabilis Ch8 (Ch8) through whole genome sequence analyses. The results indicated that the multiple pathways of immobilizing and detoxifying Cd maintained the growth of Ch8 under Cd stress, which also possessed high Cd extracellular adsorption. Firstly, the changes in surface morphology and functional groups of Ch8 cells were observed under different Cd conditions through SEM-EDS and FTIR analyses. Under 100 mg/L Cd, Ch8 cells exhibited aggregation and less flagella; the Cd biosorption of Ch8 was predominately by secreting exopolysaccharides (EPS) and no significant change of functional groups. Under 500 mg/L Cd, Ch8 were present irregular polymers on the cell surface, some cells with wrapping around; the Cd biosorption capacity exhibited outstanding effects (38.80 mg/g), which was mainly immobilizing Cd by secreting and interacting with EPS. Then, Ch8 also significantly enhanced the antioxidant enzyme activity and the antioxidant substance content under different Cd conditions. The activities of SOD and CAT, GSH content of Ch8 under 500 mg/L Cd were significantly increased by 245.47%, 179.52%, and 241.81%, compared to normal condition. Additionally, Ch8 significantly induced the expression of Acr A and Tol C (the resistance-nodulation-division (RND) efflux pump), and some antioxidant genes (SodB, SodC, and Tpx) to reduce Cd damage. In particular, the markedly higher expression levels of SodB under Cd stress. The mechanism of Ch8 lays a foundation for its application in solving soil remediation.


Asunto(s)
Cadmio , Proteus mirabilis , Contaminantes del Suelo , Cadmio/toxicidad , Contaminantes del Suelo/toxicidad , Biodegradación Ambiental
8.
Front Pharmacol ; 15: 1197651, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38595918

RESUMEN

Primary membranous nephropathy (PMN) is the most common cause for adult nephrotic syndrome. Rituximab has demonstrated promising clinical efficacy by random controlled trials and the off-label use is widely adopted in PMN. However, the standard dosage is borrowed from B cell lymphoma treatment with far more antigens and is oversaturated for PMN treatment, accompanied with additional safety risk and unnecessary medical cost. More than 15% serious adverse events were observed under standard dosage and low dose therapies were explored recently. Dose optimization by clinical trials is extremely time- and cost-consuming and can be significantly accelerated with the aid of model-informed drug development. Here, we aim to establish the first population pharmacokinetic and pharmacodynamic (PPK/PD) model for rituximab in PMN to guide its dosage optimization. Rituximab pharmacokinetic and pharmacodynamic data from 41 PMN patients in a retrospective study under a newly proposed monthly mini-dose were used to construct quantitative dose-exposure-response relationship via mechanistic target-mediated drug disposition (TMDD) model followed by regression between the reduction of anti-PLA2R titer and time after the treatment. The final model, validated by goodness-of-fit plots, visual predictive checks and bootstrap, was used to recommend the optimized dosing regimen by simulations. The model was well validated for PK/PD prediction. The systemic clearance and half-life are 0.54 L/h and 14.7 days, respectively. Simulation of a novel regimen (6 monthly doses of 100 mg) indicated the comparable ability and superior duration time of CD20+ B cell depletion compared with standard dosage, while the cumulative dosage and safety risk was significantly decreased. We established the first PPK/PD model and provide evidence to support the dosage optimization based on monthly mini-dose. Our study can also efficiently accelerate dosage optimization of novel anti-CD20 antibodies in PMN and other indications.

9.
Artículo en Inglés | MEDLINE | ID: mdl-38651215

RESUMEN

Patients with long-term disease experience low resilience, emphasising the importance of psychological interventions to improve resilience. However, there is no comprehensive evidence on the efficacy of resilience-related psychological interventions (RRPIs) in this population. Therefore, we performed a meta-analysis to evaluate and extend knowledge from previous meta-analyses on the efficacy of RRPIs on resilience, stress, anxiety, depression and quality of life among patients with long-term disease. Cochrane Library, Embase, Ovid-MEDLINE, PubMed, Scopus, Web of Science and CINAHL electronic databases were searched until 3 February 2023. The pooled effect size of the efficacy of RRPIs was calculated using the Hedges' g (g) with random-effects model, while Cochrane Q-statistics and I2 tests assessed heterogeneity in Comprehensive Meta-Analysis 3.0 software. The Cochrane Risk of Bias 2.0 tool evaluated the quality of studies. Moderator analysis was used to explore sources of heterogeneity. Twenty randomised controlled trial studies were identified, representing a total of 1388 individuals with long-term disease. RRPIs significantly enhance resilience (g = 0.79), alleviate stress (g = -0.78), decrease anxiety (g = -1.14), mitigate depression (g = -0.96) and improve quality of life (g = 0.48). Positive psychology, mindfulness, cognitive behavioural therapy, acceptance and commitment-based intervention exhibited medium effects in strengthening resilience. Short-term effects of RRPIs on enhancing resilience were observed at 3-month follow-up period (g = 0.50). The incorporation of RRPIs into the management of patients with long-term disease shows a positive impact on their resilience, stress, anxiety, depression and quality of life. The results offer an evidence-based foundation for nurses in promoting resilience among patients with long-term disease.

10.
J Pharm Pharmacol ; 2024 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-38521537

RESUMEN

OBJECTIVES: The effects of wild Cordyceps proteins (WCPs) on the gut microbiota and the immune system of MRL/lpr mice were studied. METHODS: The effects of WCP on serum metabolic indexes (total triglyceride, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol) content was measured by a biochemical analyzer. CD4+, CD8+ cells, intestinal inflammation, and intestinal barrier function in MRL/lpr mice were measured by flow cytometry, 16S ribosomal RNA, western blot, and quantitative real-time polymerase chain reaction RT-PCR. KEY FINDINGS: The results showed that after the intervention of WCP, the content of CD4+ cells in lupus mice increased, and the levels of proinflammatory cytokines were down-regulated, such as tumor necrosis factor-α and interleukin-6. Secondly, WCP up-regulated the proteins and mRNA levels of ZO-1, Claudin-1, and Occludin. Thirdly, it also increased the Firmicutes/Bacteroidetes ratio and the abundance of Oscillospirales, Lachnospirales, Lachnospiraceae, and Clostridia, as well as negatively regulated the MAPK/NF-кB signaling pathway in lupus nephritis (LN) mice. CONCLUSIONS: These findings suggested that WCP may improve the symptoms of LN by altering immune factors and the intestinal barrier.

11.
Age Ageing ; 53(3)2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38536471

RESUMEN

BACKGROUND: Ageing process and abnormal protein accumulation in dementia damage neural pathways affecting the swallowing process and leading to swallowing disorder. OBJECTIVE: To estimate the prevalence of swallowing disorder among older adults with different dementia subtypes. METHODS: We conducted a systematic search across multiple databases, including PubMed, Embase, Scopus, Web of Science and OVID Medline. The meta-analysis employed R (version 4.0.2) and utilised a generalised linear mixed model with a random-effect approach to estimate the pooled prevalence of swallowing disorder among older adults, considering various dementia subtypes. The quality of included studies was assessed using Hoy's criteria. Heterogeneity was identified through Cochrane's Q and I2 statistics. To further explore heterogeneity, moderator analysis was performed to identify the contributing variables among the included studies. RESULTS: Eighteen studies with 12,532 older adults with different dementia subtypes were enrolled in our meta-analysis. The pooled prevalence of swallowing disorder among older adults with dementia was 58%, with 46.5% for Alzheimer's dementia, 34.9% for Parkinson's dementia, 18.8% for vascular dementia, 16.3% for mixed dementia and 12.2% for Lewy body dementia. According to assessment tools, Alzheimer's dementia had the highest prevalence, with 58% in instrumental assessments and 39% in clinical assessments. Medical history, Alzheimer's dementia, moderate-to-severe Clinical Dementia Rating, delayed oral phase, delayed pharyngeal phase and poor tongue motility contributed to the heterogeneity of the included studies. CONCLUSIONS: More than half of older adults with dementia demonstrate to have swallowing disorder. Our findings offer valuable insights to healthcare professionals for the identification of swallowing disorder in ageing population with dementia.


Asunto(s)
Trastornos de Deglución , Deglución , Demencia , Humanos , Trastornos de Deglución/epidemiología , Trastornos de Deglución/fisiopatología , Trastornos de Deglución/diagnóstico , Prevalencia , Demencia/epidemiología , Demencia/diagnóstico , Anciano , Femenino , Masculino , Anciano de 80 o más Años , Factores de Edad , Factores de Riesgo
12.
Hum Gene Ther ; 35(11-12): 365-373, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38526393

RESUMEN

Cell and gene therapy (CGT) innovations have provided several significant breakthroughs in recent years. However, CGTs often come with a high upfront cost, raising questions about patient access, affordability, and long-term value. This study reviewed cost-effectiveness analysis (CEA) studies that have attempted to assess the long-term value of Food and Drug Administration (FDA)-approved CGTs. Two reviewers independently searched the Tufts Medical Center CEA Registry to identify all studies for FDA-approved CGTs, per January 2023. A data extraction template was used to summarize the evidence in terms of the incremental cost-effectiveness ratio expressed as the cost per quality-adjusted life year (QALY) and essential modeling assumptions, combined with a template to extract the adherence to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. The review identified 26 CEA studies for seven CGTs. Around half of the base-case cost-effectiveness results indicated that the cost per QALY was below $100,000-$150,000, often used as a threshold for reasonable cost-effectiveness in the United States. However, the results varied substantially across studies for the same treatment, ranging from being considered very cost-effective to far from cost-effective. Most models were based on data from single-arm trials with relatively short follow-ups, and different long-term extrapolations between studies caused large differences in the modeled cost-effectiveness results. In sum, this review showed that, despite the high upfront costs, many CGTs have cost-effectiveness evidence that can support long-term value. Nonetheless, substantial uncertainty regarding long-term value exists because so much of the modeling results are driven by uncertain extrapolations beyond the clinical trial data.


Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos , Análisis Costo-Beneficio , Terapia Genética , United States Food and Drug Administration , Humanos , Terapia Genética/economía , Estados Unidos , Tratamiento Basado en Trasplante de Células y Tejidos/economía , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Años de Vida Ajustados por Calidad de Vida
13.
J Hazard Mater ; : 133749, 2024 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-38383276

RESUMEN

The superoxide radical (•O2-)-mediated peroxymonosulfate (PMS)-based photo-Fenton-like reaction enables highly selective water decontamination. Nevertheless, the targeted construction of •O2--mediated photo-Fenton-like system has been challenging. Herein, we developed an electron-rich/-poor dual sites driven •O2--mediated cascade photo-Fenton-like system by modulating electron density. Experimental and theoretical results demonstrated that PMS was preferentially adsorbed on electron-poor Co site. This adsorption promoted O-O bond cleavage of PMS to generate hydrogen peroxide (H2O2), which then migrated to electron-rich O site to extract eg electrons for O-H bond cleavage, rather than competing with PMS for Co site. The developed versatile cascade reaction system could selectively eliminate contaminants with low n-octanol/water partition constants (KOW) and dissociation constants (pKa) and remarkably resist inorganics (Cl-, H2PO4- and NO3-), humic acid (HA) and even real water matrices (tap water and secondary effluent). This finding provided a novel and plausible strategy to accurately and efficiently generate •O2- for the selective water decontamination.

14.
Cell Metab ; 36(3): 557-574.e10, 2024 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-38237601

RESUMEN

Augmented CD4+ T cell response in autoimmunity is characterized by extensive metabolic reprogramming. However, the epigenetic molecule that drives the metabolic adaptation of CD4+ T cells remains largely unknown. Here, we show that lysine acetyltransferase 6A (KAT6A), an epigenetic modulator that is clinically associated with autoimmunity, orchestrates the metabolic reprogramming of glucose in CD4+ T cells. KAT6A is required for the proliferation and differentiation of proinflammatory CD4+ T cell subsets in vitro, and mice with KAT6A-deficient CD4+ T cells are less susceptible to experimental autoimmune encephalomyelitis and colitis. Mechanistically, KAT6A orchestrates the abundance of histone acetylation at the chromatin where several glycolytic genes are located, thus affecting glucose metabolic reprogramming and subsequent CD4+ T cell responses. Treatment with KAT6A small-molecule inhibitors in mouse models shows high therapeutic value for targeting KAT6A in autoimmunity. Our study provides novel insights into the epigenetic programming of immunometabolism and suggests potential therapeutic targets for patients with autoimmunity.


Asunto(s)
Lisina Acetiltransferasas , Linfocitos T , Animales , Humanos , Ratones , Autoinmunidad/genética , Linfocitos T CD4-Positivos/metabolismo , Epigénesis Genética , Glucosa/metabolismo , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Lisina Acetiltransferasas/genética , Lisina Acetiltransferasas/metabolismo , Linfocitos T/metabolismo
15.
Diabetes Obes Metab ; 26(2): 463-472, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37867175

RESUMEN

AIM: This study compared the 5-year incidence rate of macrovascular and microvascular complications for tirzepatide, semaglutide and insulin glargine in individuals with type 2 diabetes, using the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes simulation model. RESEARCH DESIGN AND METHODS: This study was a 5-year SURPASS-2 trial extrapolation, with an insulin glargine arm added as an additional comparator. The 1-year treatment effects of tirzepatide (5, 10 or 15 mg), semaglutide (1 mg) and insulin glargine on glycated haemoglobin, systolic blood pressure, low-density lipoprotein and body weights were obtained from the SUSTAIN-4 and SURPASS-2 trials. We used the BRAVO model to predict 5-year complications for each study arm under two scenarios: the 1-year treatment effects persisted (optimistic) or diminished to none in 5 years (conservative). RESULTS: When compared with insulin glargine, we projected a 5-year risk reduction in cardiovascular adverse events [rate ratio (RR) 0.64, 95% confidence interval (CI) 0.61-0.67] and microvascular composite (RR 0.67, 95% CI 0.64-0.70) with 15 mg tirzepatide, and 5-year risk reduction in cardiovascular adverse events (RR 0.75, 95% CI 0.72-0.79) and microvascular composite (RR 0.79, 95% CI 0.76-0.82) with semaglutide (1 mg) under an optimistic scenario. Lower doses of tirzepatide also had similar, albeit smaller benefits. Treatment effects for tirzepatide and semaglutide were smaller but still significantly higher than insulin glargine under a conservative scenario. The 5-year risk reduction in diabetes-related complication events and mortality for the 15 mg tirzepatide compared with insulin glargine ranged from 49% to 10% under an optimistic scenario, which was reduced by 17%-33% when a conservative scenario was assumed. CONCLUSION: With the use of the BRAVO diabetes model, tirzepatide and semaglutide exhibited potential to reduce the risk of macrovascular and microvascular complications among individuals with type 2 diabetes, compared with insulin glargine in a 5-year window. Based on the current modelling assumptions, tirzepatide (15 mg) may potentially outperform semaglutide (1 mg). While the BRAVO model offered insights, the long-term cardiovascular benefit of tirzepatide should be further validated in a prospective clinical trial.


Asunto(s)
Complicaciones de la Diabetes , Diabetes Mellitus Tipo 2 , Humanos , Complicaciones de la Diabetes/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/efectos adversos , Insulina Glargina/efectos adversos , Estudios Prospectivos
16.
Small ; 20(10): e2306713, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37919863

RESUMEN

Luminescent metal clusters have attracted great interest in current research; however, the design synthesis of Al clusters with color-tunable luminescence remains challenging. Herein, an [Al8 (OH)8 (NA)16 ] (Al8 , HNA = nicotinic acid) molecular cluster with dual luminescence properties of fluorescence and room-temperature phosphorescence (RTP) is synthesized by choosing HNA ligand as phosphor. Its prompt photoluminescence (PL) spectrum exhibits approximately white light emission at room temperature. Considering that halogen atoms can be used to regulate the RTP property by balancing the singlet and triplet excitons, different CdX2 (X- = Cl- , Br- , I- ) are introduced into the reactive system of the Al8 cluster, and three new Al8 cluster-based metal-organic frameworks, {[Al8 Cd3 Cl5 (OH)8 (NA)17 H2 O]·2HNA}n (CdCl2 -Al8 ), {[Al8 Cd4 Br7 (OH)8 (NA)16 CH3 CN]·NA·HNA}n (CdBr2 -Al8 ) and {[Al8 Cd8 I16 (OH)8 (NA)16 ]}n (CdI2 -Al8 ) are successfully obtained. They realize the color tunability from blue to yellow at room temperature. The origination of fluorescence and phosphorescence has also been illustrated by structure-property analysis and theoretical calculation. This work provides new insights into the design of multicolor luminescent metal cluster-based materials and develops advanced photo-functional materials for multicolor display, anti-counterfeiting, and encryption applications.

17.
Clin Pharmacokinet ; 63(1): 93-108, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37985591

RESUMEN

PB201 is an orally active, partial glucokinase activator targeting both pancreatic and hepatic glucokinase. As the second glucokinase activator studied beyond phase I, PB201 has demonstrated promising glycemic effects as well as favorable pharmacokinetic (PK) and safety profiles in patients with type 2 diabetes mellitus (T2DM). This study aims to develop a population PK/pharmacodynamic (PD) model for PB201 using the pooled data from nine phase I/II clinical trials conducted in non-Chinese healthy volunteers and a T2DM population and to predict the PK/PD profile of PB201 in a Chinese T2DM population. We developed the PK/PD model using the non-linear mixed-effects modeling approach. All runs were performed using the first-order conditional estimation method with interaction. The pharmacokinetics of PB201 were well fitted by a one-compartment model with saturable absorption and linear elimination. The PD effects of PB201 on reducing the fasting plasma glucose and glycosylated hemoglobin levels in the T2DM population were described by indirect response models as stimulating the elimination of fasting plasma glucose, where the production of glycosylated hemoglobin was assumed to be stimulated by fasting plasma glucose. Covariate analyses revealed enhanced absorption of PB201 by food and decreased systemic clearance with ketoconazole co-administration, while no significant covariate was identified for the pharmacodynamics. The population PK model established for non-Chinese populations was shown to be applicable to the Chinese T2DM population as verified by the PK data from the Chinese phase I study. The final population PK/PD model predicted persistent and dose-dependent reductions in fasting plasma glucose and glycosylated hemoglobin levels in the Chinese T2DM population receiving 50/50 mg, 100/50 mg, and 100/100 mg PB201 twice daily for 24 weeks independent of co-administration of metformin. Overall, the proposed population PK/PD model quantitatively characterized the PK/PD properties of PB201 and the impact of covariates on its target populations, which allows the leveraging of extensive data in non-Chinese populations with the limited data in the Chinese T2DM population to successfully supported the waiver of the clinical phase II trial and facilitate the optimal dose regimen design of a pivotal phase III study of PB201 in China.


Asunto(s)
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucoquinasa , Hemoglobina Glucada , Glucemia , Voluntarios Sanos , Modelos Biológicos , Relación Dosis-Respuesta a Droga
18.
Diabetes Metab Syndr Obes ; 16: 2549-2560, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37645238

RESUMEN

Purpose: Among chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) is one of the commonest. Although empagliflozin has several therapeutic uses in treating cardiovascular and renal disorders, its impacts and mechanisms on NAFLD are poorly understood. This research aimed to examine the metabolic regulatory mechanism through which empagliflozin protects against NAFLD. Methods: Equal grouping of twenty-seven male C57BL/6J mice into those fed a normal diet (NCD), those fed a high-fat diet (HFD), and those fed an HFD with empagliflozin (Empa) was approached. HE, oil red O staining, and Masson staining were utilized for evaluating the pathological damage to the liver and the mice's liver and body weights. Lipids, blood glucose, and inflammation index were compared across the three groups. Liquid chromatography/mass spectrometry (LC-MS) has been employed for identifying liver metabolomics. Results: The findings suggested that empagliflozin mitigated the inflammatory and oxidative stress response associated with the buildup of lipids caused by HFD. Differentially expressed metabolites (DEMs) were identified by metabonomics analysis as present in both the HFD/NCD and Empa/HFD groups. These DEMs were primarily found in lipids and organic acids like lysophosphatidylcholine (lysoPC), lecithin (PC), triglyceride (TG), palmitic acid, and L-isoleucine. Among the enriched pathways that were shown to be important were those involved in the metabolism of histidine, arachidonic acid, the control of lipolysis in adipocytes, and insulin resistance. There was a strong correlation between inflammation and oxidative stress in most of the metabolites. The inflammation and oxidative stress unbalance were ameliorated by empagliflozin. Conclusion: NAFLD mice model showed considerable improvement in metabolic abnormalities and liver protection after treatment with empagliflozin. The process may include the overexpression of L-isoleucine and the downregulation of lysoPC, PC, TG, and palmitic acid to reduce liver harm caused by lipotoxicity.

19.
J Mol Cell Biol ; 2023 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-37634084

RESUMEN

Interleukin-1ß (IL-1ß)-induced signaling is one of the most important pathways in regulating inflammation and immunity. The assembly of the receptor complex, consisting of the ligand IL-1ß, the IL-1 receptor (IL-1R) type 1 (IL1R1), and the IL-1R accessory protein (IL1RAP), initiates this signaling. However, how the IL1R1-associated complex is regulated remains elusive. Angiopoietin like 3 (ANGPTL3), a key inhibitor of plasma triglyceride clearance, is mainly expressed in the liver and exists in both intracellular and extracellular secreted forms. Presently, ANGPTL3 has emerged as a highly promising drug target for hypertriglyceridemia and associated cardiovascular diseases. However, most studies have focused on the secreted form of ANGPTL3, while its intracellular role is still largely unknown. Here, we report that intracellular ANGPTL3 acts as a negative regulator of IL-1ß-triggered signaling. Overexpression of ANGPTL3 inhibited IL-1ß-induced NF-κB activation and the transcription of inflammatory genes in HepG2, THP1, and HEK293T cells, while knockdown or knockout of ANGPTL3 resulted in opposite effects. Mechanistically, ANGPTL3 interacted with IL1R1 and IL1RAP through its intracellular C-terminal fibrinogen-like domain (FLD) and disrupted the assembly of the IL1R1-associated complex. Taken together, our study reveals a novel role for ANGPTL3 in inflammation, whereby it inhibits the physiological interaction between IL1R1 and IL1RAP to maintain immune tolerance and homeostasis in the liver.

20.
Lasers Med Sci ; 38(1): 184, 2023 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-37578665

RESUMEN

The aim of this study is to systematically summarize the available evidence regarding low-level laser therapy (LLLT) speed-up effect on dental alignment in comprehensive orthodontic treatment. An extensive electronic search was conducted in PubMed, ScienceDirect, Cochrane, Web of Science, and Scopus up to February 20, 2023. The Cochrane risk of bias tool and the Newcastle-Ottawa Quality Assessment Form were used by two authors independently to assess the risk of bias (RoB). Statistical analysis was performed by Review Manager 5.3. The eight eligible trials were reviewed and included in qualitative synthesis. Four studies reported the overall time of leveling and alignment (OLAT, days), enabling a synthesizing of the data. The meta-analysis results showed that LLLT significantly reduced the overall time of leveling and alignment compared to control group (MD=-30.36, 95% CI range -41.50 to -19.22, P<0.0001), with moderate heterogeneity (χ2=4.10, P=0.25, I2=27%). Based on the data available, statistically significant evidence with moderate risk of bias suggests that LLLT may have a positive effect on accelerating dental alignment. However, due to the differences in intervention strategy and evaluating method, the conclusions should be interpreted with caution.


Asunto(s)
Terapia por Luz de Baja Intensidad , Técnicas de Movimiento Dental , Factores de Tiempo , Técnicas de Movimiento Dental/métodos
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