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A carbazolide-bis(NHC) NiII catalyst (1; NHC, N-heterocyclic carbene) for selective CO2 photoreduction was designed herein by a one-stone-two-birds strategy. The extended π-conjugation and the strong σ/π electron-donation characteristics (two birds) of the carbazolide fragment (one stone) lead to significantly enhanced activity for photoreduction of CO2 to CO. The turnover number (TON) and turnover frequency (TOF) of 1 were ninefold and eightfold higher than those of the reported pyridinol-bis(NHC) NiII complex at the same catalyst concentration using an identical Ir photosensitizer, respectively, with a selectivity of â¼100%. More importantly, an organic dye was applied to displace the Ir photosensitizer to develop a noble-metal-free photocatalytic system, which maintained excellent performance and obtained an outstanding quantum yield of 11.2%. Detailed investigations combining experimental and computational studies revealed the catalytic mechanism, which highlights the potential of the one-stone-two-birds effect.
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BACKGROUND: Studies examining the potential association between cooking oil and frailty risk in older adults have produced conflicting outcomes. Therefore, our objective was to explore the relationship between cooking oil (vegetable and animal fat oils), changes in oil usage, and the risk of frailty in older adults. METHODS: We included 4,838 participants aged ≥ 65 years without frailty (frailty index < 0.25) from the 2011 wave of the Chinese Longitudinal Healthy Longevity Survey. Follow-up occurred in the 2014 and 2018 waves. Cox proportional hazard models were utilized to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) to examine the association between cooking oil and frailty. Additionally, we evaluated the effect of switching cooking oil on frailty during the follow-up period. RESULTS: During a median follow-up of 3.0 (2.8-6.9) years, 1,348 individuals (27.9%) developed frailty. Compared to those using vegetable oil, users of animal fat oil had a lower risk of frailty (HR = 0.72, 95% CI: 0.61-0.85). Participants who switched from vegetable oil to animal fat oil, as well as those consistently using animal fat oil, had lower risks of frailty with HRs of 0.70 (0.52-0.95) and 0.63 (0.51-0.77) respectively, compared to those who consistently used vegetable oil. Conversely, individuals who switched from animal fat oil to vegetable oil experienced an increased risk of frailty (HR: 1.41, 95% CI: 1.01-1.97). CONCLUSIONS: The utilization of animal fat oil in cooking exhibited a reduced frailty risk among older adults. Conversely, transitioning from animal fat oil to vegetable oil may elevate the risk. These findings propose that substituting vegetable oil with animal fat oil in the diet may safeguard against frailty.
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Culinária , Fragilidade , Humanos , Idoso , Masculino , Feminino , Fragilidade/epidemiologia , Fragilidade/prevenção & controle , Culinária/métodos , Estudos de Coortes , China/epidemiologia , Idoso Fragilizado , Idoso de 80 Anos ou mais , Estudos Longitudinais , Incidência , Óleos de Plantas , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Psychological resilience has been associated with increased longevity in the oldest old; however, its significance in the broader older adult population has not been thoroughly explored. There is a lack of understanding regarding its relationship with cause-specific mortality in older adults. This study aims to address these gaps by investigating the association between psychological resilience and both overall mortality and cause-specific mortality in individuals aged 65 and older. METHODS: We enrolled 4,935 participants aged 65 and older in the Chinese Longitudinal Healthy Longevity Survey, with baseline assessments conducted in 2014 and follow-up surveys in 2018. To evaluate the associations between psychological resilience and mortality, we used Cox proportional hazards models. Additionally, we employed restricted cubic spline plots to illustrate the dose-response relationships between these variables. RESULTS: During a mean (Standard Deviation) follow-up of 3.2 years (1.2), 1726 participants died. Higher psychological resilience was independently associated with lower all-cause mortality risk (Hazard ratio [HR] 0.74, 95% confidence interval [CI]: 0.67-0.82) and cause-specific mortality from cardiovascular disease (HR 0.74, 95% CI: 0.59-0.93), respiratory diseases (HR 0.63, 95% CI:0.45-0.87), and other causes (HR 0.69, 95% CI: 0.60-0.78), excluding cancer-related mortality. Similar effects were evident when examining the psychological resilience score. The dose-response analysis further indicated a gradual decrease in mortality risk corresponding to higher psychological resilience scores. Interaction analyses revealed that psychological resilience has a more pronounced effect on mortality from other causes among economically independent older adults (P-interaction = 0.02). CONCLUSIONS: Enhanced psychological resilience is independently associated with reduced all-cause and some cause-specific mortality in older adults. These findings underscore the importance of addressing psychological factors in the promotion of healthy aging and longevity.
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Causas de Morte , Resiliência Psicológica , Humanos , Masculino , Idoso , Feminino , Estudos Longitudinais , Idoso de 80 Anos ou mais , China/epidemiologia , Modelos de Riscos Proporcionais , Mortalidade/tendências , Estudos de CoortesRESUMO
BACKGROUND: The waist-calf circumference ratio (WCR) has been suggested as a potential indicator of visceral adiposity. Nevertheless, the relationship between WCR and the risk of frailty remains unclear. Therefore, our study aimed to investigate the association between WCR and longitudinal changes in WCR with frailty risk in older adults. METHODS: We included 2359 participants aged ≥ 65 years without frailty (frailty index [FI] ≤ 0.21) from the Chinese Longitudinal Healthy Longevity Survey in the 2014 wave. The follow-up was conducted in 2018. We investigated the relationship of WCR, waist circumference (WC), and calf circumference (CC) with frailty using both the Cox proportional hazards model and the generalized estimating equation (GEE). RESULTS: During a median follow-up of 4.0 years, 668 (28.2%) frailty occurred. Those with higher WCR and WC had a significantly increased risk of frailty (fifth quintile compared with first quintile: hazard ratio [HR] = 1.59, 95% confidence interval [CI] 1.24-2.04 for WCR; HR = 1.69, 95% CI 1.27-2.24 for WC), whereas those in the fourth quintile of CC had a lower likelihood of developing frailty compared to those in the first quintile (HR = 0.67, 95% CI 0.50-0.89). Interaction analyses showed that the effects of WCR on frailty were more pronounced in females (P-interaction = 0.016). GEE analyses revealed that increased WCR and WC were associated with a higher risk of frailty (odds ratio [OR] = 1.74, 95% CI 1.43-2.12 for WCR; OR = 1.03, 95% CI 1.02-1.04 for WC), while CC showed opposite results (OR = 0.95, 95% CI 0.93-0.97). CONCLUSIONS: A higher WCR and WC, as well as a lower CC, were significantly associated with higher frailty. Of these measures, WCR demonstrated the strongest association with frailty, suggesting that having a combination of high central fat and low lean body mass may increase the risk of developing frailty.
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Fragilidade , Feminino , Humanos , Idoso , Circunferência da Cintura , Estudos de Coortes , Fragilidade/diagnóstico , Fragilidade/epidemiologia , Estudos Longitudinais , Obesidade Abdominal , Índice de Massa Corporal , Fatores de RiscoRESUMO
BACKGROUND: Waist circumference (WC), calf circumference (CC), and body mass index (BMI) have been independently linked to mortality. However, it's not yet clear how the waist-calf circumference ratio (WCR) relates to mortality. This study aims to investigate the relationship between WCR, WC, CC, and BMI with all-cause and cause-specific mortality in older adults. METHODS: In the 2014 Chinese Longitudinal Healthy Longevity Survey, 4627 participants aged 65 years and older were included, and they were subsequently followed up in 2018. Cox proportional hazards models were utilized to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality, based on WCR, WC, CC, and BMI. RESULTS: During a median follow-up of 3.4 years, 1671 deaths (36.1%) occurred. Compared to the second quartile of WCR, the highest quartile had a higher risk of mortality from all causes (HR 1.42, 95%CI 1.24-1.64), cardiovascular disease (CVD) (HR 1.88, 95%CI 1.38-2.56), and other causes (HR 1.37, 95%CI 1.15-1.63). The first and fourth quartiles of WC had HRs of 2.19 (1.00-4.79) and 2.69 (1.23-5.89), respectively, for cancer mortality. The highest quartile of CC was associated with a lower risk of all-cause and other-cause mortality, whereas the lowest quartile was associated with a higher risk of all-cause, CVD, and other-cause mortality compared to the second CC quartile. Additionally, the lowest quartile of BMI was associated with a higher risk of all-cause and respiratory disease mortality. Interaction analyses showed that the effects of CC on all-cause and CVD mortality were more pronounced in adults aged ≥ 80 years (P-interaction < .05). CONCLUSIONS: Higher WCR and lower CC increased the risk of all-cause, CVD, and other-cause mortality. Lower BMI was associated with higher all-cause and respiratory disease mortality risk, while WC only predicted cancer mortality.
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Doenças Cardiovasculares , Neoplasias , Humanos , Idoso , Estudos de Coortes , Índice de Massa Corporal , Causas de Morte , Circunferência da CinturaRESUMO
Commercial vehicles are important within the context of global warming, since they exhibit greenhouse gas (GHG) emissions that are disproportionate to their quantity. The aim of this study was to create a bottom-up GHG emissions assessment model which considers GHG emissions of newly produced commercial vehicles and those in current use. Through this study, the number of future commercial vehicles were predicted, thereby facilitating a simulation of future GHG emissions. Our results show that the total GHG emissions of commercial vehicles in 2019 was 580 million t CO2-eq.. Among them, the GHG emissions stemming from the production of new commercial vehicles accounted for â¼0.3% of the emissions, whereas the use stage accounted for more than 99.0%. Moreover, the future ownership of commercial vehicles depends on GDP and the demand of freight and passenger transport. The ownership of commercial vehicles was predicted about 36.61 million in 2025, 45.44 million in 2030 and 55.85 million in 2035. The carbon peak of commercial vehicles varies across different scenarios, peaking around 2031-2034, at 680-780 million t CO2-eq.. This study systematically simulated the carbon peak of commercial vehicles, contributing toward a deeper understanding of commercial vehicles within the context of GHG emissions. These results can be applied toward creating quantitatively-driven pathways for carbon peak or neutrality targets in the commercial vehicle sector.
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Gases de Efeito Estufa , Efeito Estufa , China , Aquecimento Global , Carbono , Emissões de Veículos/análiseRESUMO
BACKGROUND: Sarcopenia is defined as age-related loss of muscle mass, strength, and/or function in the context of aging. Mechanical ventilation (MV) is one of the most frequently used critical care technologies in critically ill patients. The prevalence of preexisting sarcopenia and the clinical impact of its prognostic value on patients with MV are unclear. This review sought to identify the prevalence and prognostic value of preexisting sarcopenia on MV patient health outcomes. METHODS: Relevant studies were identified by searching MEDLINE, Embase, and the Cochrane library and were searched for all articles published as of December 2021. The prevalence of sarcopenia was determined using the authors' definitions from the original studies. Comparisons were made between patients who did and did not have sarcopenia for prognostic outcomes, including mortality, the number of days of MV, the length of intensive care unit stay, and the length of hospital stay. Odds ratios (ORs) and weighted mean differences with 95% confidence intervals (CIs) were used for pooled analyses of the relationships between sarcopenia and prognostic outcomes. RESULTS: The initial search identified 1333 studies, 17 of which met the eligibility criteria for the quantitative analysis, including 3582 patients. The pooled prevalence was 43.0% (95% CI 34.0-51.0%; I2 = 96.7%). The pooled analyses showed that sarcopenia was related to increased mortality (OR 2.13; 95% CI 1.70, 2.67; I2 = 45.0%), longer duration of MV (MD = 1.22; 95% CI 0.39, 2.05; I2 = 97.0%), longer days of ICU stay (MD = 1.31; 95% CI 0.43, 2.19; I2 = 97.0%), and hospital stay (MD 2.73; 95% CI 0.58, 4.88; I2 = 98.0%) in patients with MV. CONCLUSION: The prevalence of sarcopenia is relatively high in patients with MV, and it will have a negative impact on the prognosis of patients. However, further, large-scale, high-quality prospective cohort studies are required.
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Respiração Artificial , Sarcopenia , Estado Terminal/epidemiologia , Estado Terminal/terapia , Humanos , Unidades de Terapia Intensiva , Tempo de Internação , Prevalência , Prognóstico , Estudos Prospectivos , Respiração Artificial/efeitos adversos , Sarcopenia/diagnóstico , Sarcopenia/epidemiologiaRESUMO
BACKGROUND: It remains unclear whether stress hyperglycemia is associated with delirium. We performed this cohort study to determine the association between stress hyperglycemia and delirium. METHODS: We consecutively enrolled patients aged ≥70 years who were admitted to the Geriatric Department of West China Hospital between March 2016 and July 2017. Stress hyperglycemia ratio (SHR) was calculated as fasting blood glucose divided by estimated average glucose derived from glycosylated hemoglobin (HbA1c) and was classified into three tertiles. Delirium was screened within 24 h of admission and three times daily thereafter, using the confusion assessment method. The Cox proportional hazards models were used to assess the association of SHR with delirium. RESULTS: Among 487 included patients (mean age 83.0 years, 72.0% male), 50 (10.3%) patients experienced delirium during hospitalization. Compared to the second tertile, both the lowest and the highest SHR tertiles were independently associated with delirium (hazard ratio [HR] 3.71, 95% confidence interval [CI] 1.45-9.51; and HR 2.97, 95% CI 1.29-6.81, respectively). Similar results were found after further adjusting for statin comedication. Multiple-adjusted restricted cubic splines revealed a nonlinear relationship between SHR and delirium (Pnonlinearity=0.04). Adding SHR to conventional risk factors improved the risk prediction of delirium (net reclassification index 0.39, P=0.01; integrated discrimination improvement 0.07, P=0.03). Subgroup analyses indicated that the relationship between SHR and delirium was more apparent in patients with HbA1c <6.5%, with significantly higher HR in the first (3.65, 95% CI 1.11-11.97) and third (3.13, 95% CI 1.13-8.72) SHR tertiles compared to the second tertile, while there was no significant association between SHR and delirium in those with HbA1c ≥6.5%. CONCLUSIONS: Both lower and higher SHR were associated with increased risk of delirium but only in patients with HbA1c <6.5%. Admission SHR may serve as a promising predictor of delirium, and incorporating this biomarker into prediction algorithms might have potential clinical utility in aiding delirium risk stratification, especially in those with HbA1c <6.5%.
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Delírio , Hiperglicemia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Delírio/diagnóstico , Delírio/epidemiologia , Feminino , Hemoglobinas Glicadas , Hospitalização , Humanos , Hiperglicemia/diagnóstico , Hiperglicemia/epidemiologia , MasculinoRESUMO
BACKGROUNDS: Although vitamin D and dentition status are each associated with frailty, their combined effects on frailty have not been studied. This study aimed to evaluate the combined effects of vitamin D and dentition status on frailty in old Chinese adults. METHODS: Baseline data were obtained from the 2011-2012 wave of the Chinese Longitudinal Healthy Longevity Survey. A total of 1074 participants ≥65 years who were non-frail or prefrail at baseline were included; follow-up was conducted in the 2014 wave. Frailty was assessed by a 40-item frailty index (FI) and classified into frail (FI > 0.21), prefrail (FI: 0.1-0.21), and non-frail (FI ≤0.1). Vitamin D was assessed by 25-Hydroxyvitamin D (25(OH)D) and categorized into quartiles and dichotomies (normal: ≥50 nmol/L vs. low: < 50 nmol/L). The presence of ≥20 natural teeth was defined as functional dentition, otherwise as non-functional dentition. We used bivariate logistic regression and restricted cubic splines to examine the association between vitamin D, dentition status, and frailty. We created a multiplicative interaction between vitamin D and dentition status to test for their combined effect. RESULTS: A total of 205 (19.1%) incident frailty were identified during the 3-year follow-up. Participants with the lowest quartile of plasma 25(OH) D were more likely to be frail (odds ratio [OR] 2.45, 95% confidence interval [CI]: 1.38 to 4.35) than those in the highest quartile. Older adults with the lowest quartile of 25(OH) D and non-functional dentition had the highest odds of frailty (OR = 3.67, 95% CI: 1.02 to 13.12). We also observed that a lower vitamin D level was associated with an increased risk of frailty with a threshold of 40.37 nmol/L using restricted cubic spline models. However, vitamin D levels were not significantly associated with frailty among participants with functional dentition. CONCLUSIONS: Low vitamin D levels were associated with an increased risk of frailty in older adults. Functional dentition modified the association of vitamin D with frailty.
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Fragilidade , Idoso , China/epidemiologia , Dentição , Idoso Fragilizado , Fragilidade/diagnóstico , Fragilidade/epidemiologia , Humanos , Estudos Longitudinais , Vitamina DRESUMO
BACKGROUND: COVID-19 has become a global pandemic, and close contacts and asymptomatic patients are worthy of attention. METHODS: A total of 1844 people in close contacts with 76 COVID-19 patients were investigated, and nasopharyngeal swabs and venous blood were collected for centralized medical quarantine observation. Real-time fluorescence was used to detect SARS-CoV-2 nucleic acid in nasopharyngeal swabs of all close contacts, and the colloidal gold method was used to detect serum-specific antibodies. Levels of IgM- and IgG-specific antibodies were detected quantitatively through chemiluminescence from the first nucleic acid turned negative date (0 week) and on weekly intervals of ≤1 week, 1-2 weeks, 2-3 weeks, 3-4 weeks, 4-5 weeks, 5-6 weeks, and 6-7 weeks. RESULTS: The total positive rate of the colloidal gold method (88.5%, 23/26) was significantly higher (χ2 = 59.182, p < 0.001) than that of the healthy control group (2.0%, 1/50). There was significant difference in IgG concentration at different time points (0-7 weeks) after negative nucleic acid conversion (χ2 = 14.034, p = 0.029). Serum IgG levels were significantly higher at weekly time points of 4-5 weeks (Z = -2.399, p = 0.016), 5-6 weeks (Z = -2.049, p = 0.040), and 6-7 weeks (Z = -2.197, p = 0.028) compared with 1-2 weeks after negative nucleic acid conversion. However, there was no significant difference (χ2 = 4.936, p = 0.552) in IgM concentration between time points tested (0-7 weeks) after negative nucleic acid conversion. The positive rates of IgM and IgG in asymptomatic patients (χ2 = 84.660, p < 0.001) were significantly higher than those in the healthy control group (χ2 = 9.201, p = 0.002) within 7 weeks of negative nucleic acid conversion. CONCLUSIONS: The IgG concentration in asymptomatic cases remained at a high level after nucleic acid turned negative. Nucleic acid detection combined with IgM and IgG antibody detection is an effective way to screen asymptomatic infections.
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Teste Sorológico para COVID-19/métodos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Adulto , Idoso , COVID-19/epidemiologia , Portador Sadio/sangue , China/epidemiologia , Feminino , Coloide de Ouro , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis. METHODS: The Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism. RESULTS: GABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce Ca2+ entry, which leads to activation of nuclear factor κB signalling and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression. CONCLUSIONS: Overexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.
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Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Quimiocinas/metabolismo , Modelos Animais de Doenças , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Macrófagos/fisiologia , Camundongos , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: The aim of this study was to determine the plasma level of soluble receptors for advanced glycation end-products (sRAGE) and aquaporin 5 (AQP5) in preterm infants with acute respiratory distress syndrome (RDS). METHODS: Forty-three preterm infants diagnosed with RDS were the experimental group. Ten apparently healthy preterm neonate infants were as normal controls. The experimental group was further divided into three subgroups based on PaO2/FiO2 (P/F): the mild group (200
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Aquaporina 5/sangue , Receptor para Produtos Finais de Glicação Avançada/sangue , Síndrome do Desconforto Respiratório do Recém-Nascido/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Síndrome do Desconforto Respiratório do Recém-Nascido/fisiopatologia , Índice de Gravidade de Doença , Fatores de TempoRESUMO
Multi-sensor sonar tracking has many advantages, such as the potential to reduce the overall measurement uncertainty and the possibility to hide the receiver. However, the use of multi-target multi-sensor sonar tracking is challenging because of the complexity of the underwater environment, especially the low target detection probability and extremely large number of false alarms caused by reverberation. In this work, to solve the problem of multi-target multi-sensor sonar tracking in the presence of clutter, a novel probabilistic multi-hypothesis tracker (PMHT) approach based on the extended Kalman filter (EKF) and unscented Kalman filter (UKF) is proposed. The PMHT can efficiently handle the unknown measurements-to-targets and measurements-to-transmitters data association ambiguity. The EKF and UKF are used to deal with the high degree of nonlinearity in the measurement model. The simulation results show that the proposed algorithm can improve the target tracking performance in a cluttered environment greatly, and its computational load is low.
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This study was aimed to establish an experimental mouse model of combined transgenic inhibition of both multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and inward rectifier potassium current (Ik1), and to observe whether the specific inhibition of both CaMKII and Ik1 can bring about any effects on cardiac remodeling. Mice were divided into 4 groups: wild type (WT), CaMKII inhibited (AC3-I), Ik1 inhibited (Kir2.1-AAA) and combined inhibition of both CaMKII and Ik1 (AC3-I+Kir2.1-AAA). Mice in each group received electrocardiogram (ECG) and echocardiography examination. ECG in the condition of isoproterenol (ISO) injection was also checked. The whole cell patch clamp technique was used to measure Ik1 and the transient outward potassium current (Ito) from enzymatically isolated myocytes of left ventricle. In the condition of basal status, no significant changes of heart rate, PR interval and QRS interval were observed. No mouse showed ventricular arrhythmias in all of the 4 groups. After ISO injection, each group presented no significant ventricular arrhythmias either. The indexes measured by M-mode (motion-mode) and two-dimensional echocardiography had no significant differences among the four groups. Ik1 in AC3-I group was significantly higher than those in other three groups (P < 0.01) because of the results brought about by CaMKII inhibition. Among the latter three groups, both Kir2.1-AAA group and AC3-I+Kir2.1-AAA group had a significant reduced Ik1 compared with that of WT group, which was due to the Ik1 inhibition (P < 0.01). Ito in AC3-I group was higher than that of the other three groups (P < 0.01), but there were no significant differences in Ito among WT, Kir2.1-AAA and AC3-I+Kir2.1-AAA groups. Thus, combined transgenic myocardial CaMKII and Ik1 inhibition eliminated the up-regulation of Ik1 in CaMKII inhibited mice, and had no effects on cardiac remodeling including heart structure and function as well as arrhythmias at the basic and ISO conditions. The results of this study may provide a basis for the further investigation of combined inhibition of CaMKII and Ik1 in pathogenic cardiac remodeling.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Coração/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Remodelação Ventricular , Animais , Arritmias Cardíacas , Síndrome de Brugada , Doença do Sistema de Condução Cardíaco , Modelos Animais de Doenças , Eletrocardiografia , Sistema de Condução Cardíaco/anormalidades , Ventrículos do Coração , Isoproterenol , Camundongos , Camundongos Transgênicos , Técnicas de Patch-Clamp , Regulação para CimaRESUMO
PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is essential for maturation of ribosomes, may have a role in lipogenesis, and is implicated in several diseases. A potent, selective, and cell-active PRMT3 inhibitor would be a valuable tool for further investigating PRMT3 biology. Here we report the discovery of the first PRMT3 chemical probe, SGC707, by structure-based optimization of the allosteric PRMT3 inhibitors we reported previously, and thorough characterization of this probe in biochemical, biophysical, and cellular assays. SGC707 is a potent PRMT3 inhibitor (IC50 =31±2â nM, KD =53±2â nM) with outstanding selectivity (selective against 31 other methyltransferases and more than 250 non-epigenetic targets). The mechanism of action studies and crystal structure of the PRMT3-SGC707 complex confirm the allosteric inhibition mode. Importantly, SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies. This well-characterized chemical probe is an excellent tool to further study the role of PRMT3 in health and disease.
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Inibidores Enzimáticos/química , Isoquinolinas/química , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Regulação Alostérica , Sítios de Ligação , Calorimetria , Linhagem Celular Tumoral , Inibidores Enzimáticos/metabolismo , Células HEK293 , Histonas , Humanos , Isoquinolinas/metabolismo , Metilação , Simulação de Dinâmica Molecular , Mutagênese , Ligação Proteica , Estrutura Terciária de Proteína , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Ressonância de Plasmônio de SuperfícieRESUMO
BACKGROUND: Single-cell sequencing was employed to analyze the tumor immune microenvironment in ovarian cancer (OC) patients, exploring the evolutionary roles of various macrophage subgroups in OC progression and their correlation with fatty acid metabolism-related genes in contributing to drug resistance. METHODS: This study aimed to decipher the mechanisms underlying OC chemoresistance (OC-CR) and carboplatin resistance by integrating and analyzing multiple single-cell RNA sequencing datasets from OC patients. The tumor immune microenvironment in OC-CR patients exhibited notable alterations in cellular interactions and the proportions of different immune cell populations, in contrast to the cohort sensitive to OC chemotherapy. RESULTS: The study demonstrates that the fatty acid-associated gene HEBP2 not only accelerates OC progression but also modifies the immune landscape of OC, driving the polarization from M0_TAM to M2_TAM. This shift results in a diminished efficacy of chemotherapy in OC. Furthermore, both in vitro and in vivo experiments underscored HEBP2's role in boosting the proliferation of OC-resistant cell lines and suppressing apoptosis, thereby facilitating carboplatin resistance. CONCLUSION: In conclusion, the immune microenvironments of OC-CR significantly differ from those sensitive to chemotherapy, underscoring HEBP2's role in fostering OC resistance. This establishes HEBP2 as a promising prognostic marker and a novel target for therapeutic strategies against OC resistance.
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Sarcopenia is a significant geriatric syndrome that involves the loss of skeletal muscle mass and strength. Due to its substantial endocrine role, the metabolic microenvironment of skeletal muscle undergoes changes with age. Examining the pathogenesis of sarcopenia through focusing on metabolic dysregulation could offer insights for developing more effective intervention strategies. In this study, we analyzed the transcriptomics data to identify specific genes involved in the regulation of metabolism in skeletal muscle during the development of sarcopenia. Three machine learning algorithms were employed to screen key target genes exhibiting strong correlations with metabolism, which were further validated using RNA-sequencing data and publicly accessible datasets. Among them, the metabolic enzyme nicotinamide N-methyltransferase (NNMT) was elevated in sarcopenia, and predicted sarcopenia with an area under the curve exceeding 0.7, suggesting it as a potential therapeutic target for sarcopenia. As expected, inhibition of NNMT improved the grip strength in aging mice and alleviated age-related decline in the mass index of the quadriceps femoris muscles and whole-body lean mass index. Additionally, the NNMTi treatment increased the levels of nicotinamide adenine dinucleotide (NAD+) content, as well as PGC1α and p-AMPK expression in the muscles of both the D-galactose-treated mouse model and naturally aging mouse model. Overall, this work demonstrates NNMT as a promising target for preventing age-related decline in muscle mass and strength.
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Zinc (Zn) alloys have demonstrated significant potential in healing critical-sized bone defects. However, the clinical application of Zn alloys implants is still hindered by challenges including excessive release of zinc ions (Zn2+), particularly in the early stage of implantation, and absence of bio-functions related to complex bone repair processes. Herein, a biodegradable aliphatic polycarbonate drug-eluting coating was fabricated on zinc-lithium (Zn-Li) alloys to inhibit Zn2+ release and enhance the osteogenesis, angiogenesis, and bacteriostasis of Zn alloys. Specifically, the photo-curable aliphatic polycarbonates were co-assembled with simvastatin and deposited onto Zn alloys to produce a drug-loaded coating, which was crosslinked by subsequent UV light irradiation. During the 60 days long-term immersion test, the coating showed distinguished stable drug release and Zn2+ release inhibition properties. Benefiting from the regulated release of Zn2+ and simvastatin, the coating facilitated the adhesion, proliferation, and differentiation of MC3T3-E1 cells, as well as the migration and tube formation of EA.hy926 cells. Astonishingly, the coating also showed remarkable antibacterial properties against both S. aureus and E. coli. The in vivo rabbit critical-size femur bone defects model demonstrated that the drug-eluting coating could efficiently promote new bone formation and the expression of platelet endothelial cell adhesion molecule-1 (CD31) and osteocalcin (OCN). The enhancement of osteogenesis, angiogenesis, and bacteriostasis is achieved by precisely controlling of the released Zn2+ at an appropriate level, as well as the stable release profile of simvastatin. This tailored aliphatic polycarbonate drug-eluting coating provides significant potential for clinical applications of Zn alloys implants.
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OBJECTIVE: Reliable identification of high-risk older adults who are likely to develop sarcopenia is essential to implement targeted preventive measures and follow-up. However, no sarcopenia prediction model is currently available for community use. Our objective was to develop and validate a risk prediction model for calculating the 1-year absolute risk of developing sarcopenia in an aging population. METHODS: One prospective population-based cohort of non-sarcopenic individuals aged 60 years or older were used for the development of a sarcopenia risk prediction model and model validation. Sarcopenia was defined according to the 2019 Asian Working Group for Sarcopenia consensus. Stepwise logistic regression was used to identify risk factors for sarcopenia incidence within a 1-year follow-up. Model performance was evaluated using the area under the receiver operating characteristics curve (AUROC) and calibration plot, respectively. RESULTS: The development cohort included 1042 older adults, among whom 87 participants developed sarcopenia during a 1-year follow-up. The PRE-SARC (PREdiction of SARCopenia Risk in community older adults) model can accurately predict the 1-year risk of sarcopenia by using 7 easily accessible community-based predictors. The PRE-SARC model performed well in predicting sarcopenia, with an AUROC of 87% (95% CI, 0.83-0.90) and good calibration. Internal validation showed minimal optimism, with an adjusted AUROC of 0.85. The prediction score was categorized into 4 risk groups: low (0%-10%), moderate (>10%-20%), high (>20%-40%), and very high (>40%). The PRE-SARC model has been incorporated into an online risk calculator, which is freely accessible for daily clinical applications (https://sarcopeniariskprediction.shinyapps.io/dynnomapp/). CONCLUSIONS: In community-dwelling individuals, the PRE-SARC model can accurately predict 1-year sarcopenia incidence. This model serves as a readily available and free accessible tool to identify older adults at high risk of sarcopenia, thereby facilitating personalized early preventive approaches and optimizing the utilization of health care resources.
RESUMO
HuaFu Shengji is the primary traditional Chinese medicine (TCM) therapy for treating chronic skin ulcer. The high activities of the protein enzyme in the wound fluids is one of the main cause of healing delay. In order to investigate the effect of TCM Zhuhong ointment for promoting wound healing. This research focused on its influence on matrix metalloproteinase (MMP) activities in wound fluids with TCM Yang syndromes, directly on the activated MMP-1,2 activities in vitro and on MMP-1,-2,-9 production by HSF. 8 wound fluid samples were collected, which were diagnosed Yang Syndromes in TCM. Wound fluid activities of MMP-2 and MMP-9 were measured by gelatin zymogram assay. MMP-1 and MMP-2 activities in vitro were measured by substrate cleavage. CCK-8 was used to observe the toxicity of Zhuhong ointment on HSF. MMP-1,-2,-9 production by HSF were detected by confocal microscope. Zhuhong ointment from 1 to 25 g x L(-1) obviously inhibited MMP-2 activity in wound fluid. When Zhuhong ointment was over 5 g x L(-1), it showed significantly inhibitory effect on wound fluid MMP-9 activity. In vitro study, when the mercury concentration was 320 mg x L(-1), Zhuhong ointment solution directly inhibited both MMP-1 activity and MMP-2. But mercury concentration from 0.51-2.56 mg x L(-1), it could activate MMP-1 activity, and from 0.51-64 mg x L(-1), activate MMP-2 activity instead. The mercury concentration when Zhuhong ointment saturated in DMEM was 39.6 mg x L(-1). When the mercury concentration was over 1.23 mg x L(-1), Zhuhong ointment showed toxicity to HSF. At 1.23, 0.62, 0.31 mg x L(-1) of mercury concentration, it increased MMP-1 expression by HSF, and at 1.23, 0.62 mg x L(-1), decreased MMP-2 expression. However, at 1.23, 0.62, 0.31 mg x L(-1), it decreased MMP-9 expression. At higher concentration, Zhuhong ointment can inhibit MMP-2, MMP-9 activities in wound fluid with dose-dependent way and show a direct inhibitory effect on activated MMP-1 and MMP-2 in vitro. But at a lower concentration, it showed two-way adjustment, with increased MMP-1, MMP-2 activities and its expression by HSF and decreased MMP-9 activity.