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Inflammation plays a critical role in the development of numerous diseases. Cannabidiol (CBD), found in hemp, exhibits significant pharmacological activities. Accumulating evidence suggests that CBD has anti-inflammatory and cardiovascular protection effects, but the potential mechanisms require further exploration. In this study, we aimed to reveal the mechanisms of CBD against high-fat, high-cholesterol (HFC) diet-induced inflammation combining metabolomics with network pharmacology. First, plasma lipidomics results indicated that oxidized lipids could serve as potential biomarkers for HFC diet-induced inflammation, and CBD reversed the elevated levels of oxidized lipids. The HFC diet was also found to enhance intestinal permeability, facilitating the entry of lipopolysaccharides (LPSs) into the circulatory system and subsequently increasing systemic inflammation. Additionally, cell metabolomic results indicated that CBD could reverse 10 important differential metabolites in LPS-induced RAW 264.7 cells. Using network pharmacology, we identified 49 core targets, and enrichment analysis revealed that arachidonic acid was the most significantly affected by CBD, which was closely associated with inflammation. Further integrated analysis focused on three key targets, including PTGS2, ALOX5, and ALOX15. Molecular docking showed high affinities between key targets and CBD, and qPCR further demonstrated that CBD could reverse the mRNA expression of these key targets in RAW 264.7 cells. Collectively, this finding integrates lipidomics and metabolomics with network pharmacology to elucidate the anti-inflammatory effects of CBD and validates key therapeutic targets.
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Climate change is raising concerns about how forests will respond to extreme droughts, heat waves, and their co-occurrence. In this greenhouse study, we tested how carbon and water relations relate to seedling growth and mortality of northeastern US trees during and after extreme drought, warming, and combined drought and warming. We compared the response of our focal species red spruce (Picea rubens Sarg.) to a common associate (paper birch, Betula papyrifera Marsh.) and a species expected to increase abundance in this region with climate change (northern red oak, Quercus rubra L.). We tracked growth and mortality, photosynthesis, and water use of 216 seedlings of these species through a treatment and a recovery year. Each red spruce seedling was planted in containers either alone or with another seedling to simulate potential competition and seedlings were exposed to combinations of drought (irrigated, 15-day 'short', or 30-day 'long') and temperature (ambient or 16 days at +3.5 °C daily maximum) treatments. We found dominant effects of the drought reducing photosynthesis, midday water potential, and growth of spruce and birch, but that oak showed considerable resistance to drought stress. The effects of planting seedlings together were moderate and likely due to competition for limited water. Despite high temperatures reducing photosynthesis for all species, the warming imposed in this study minorly impacted growth only for oak in the recovery year. Overall, we found that the diverse water-use strategies employed by the species in our study related to their growth and recovery following drought stress. This study provides physiological evidence to support the prediction that native species to this region like red spruce and paper birch are susceptible to future climate extremes that may favor other species like northern red oak, leading to potential impacts on tree community dynamics under climate change.
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Cd ions are absorbed and transported from the soil by crop roots, which are the first organ to be exposed to Cd. This results in an increase in cadmium ions in crops, significantly affecting crop growth and yield. Exogenous melatonin (MT) can help reduce cadmium (Cd) stress in cotton, but the specific contribution of roots to this process remains unclear. In order to address this knowledge gap, an in-situ root phenotyping study was conducted to investigate the the phenotype and lifespan of roots under cadmium stress (Cd) and melatonin treatment (Cd + MT). The results showed that MT alleviated the decreases in plant height, leaf area, SPAD value, stem diameter, stomatal conductance and net photosynthetic rate under Cd stress, which further promoted the biomass accumulation in various cotton organs. What is more, the Cd + MT treatment increased root volume, surface area, and length under Cd stress by 25.63â¯%, 10.58â¯%, and 21.89â¯%, respectively, compared with Cd treatment. Interestingly, compared to Cd treatment, Cd + MT treatment also significantly extended the lifespan of roots and root hairs by 6.68 days and 2.18 days, respectively. In addition, Cd + MT treatment reduced the transport of Cd from roots to shoots, particularly to bolls, and decreased the Cd bioconcentration factor in bolls by 61.17â¯%, compared to Cd treatment. In conclusion, these findings show that applying MT externally helps reduce Cd stress by delaying root senescence, promoting root development and regulating Cd transport. This method can be an effective approach to managing Cd stress in cotton.
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Background and Objective: The issue of falls poses a significant threat to the health of the elderly population. Although statins can cause myopathy, which implies that they may cause balance problems and increase the risk of falling, this has not been tested. Our objective was to assess whether the use of statins is linked to a higher risk of falls. Methods: A cross-sectional survey study and Mendelian randomization (MR) study were conducted to examine whether the use of statins was associated with an increased risk of falling and balance problems. The cross-sectional study included 2,656 participants from the US population (NHANES) who reported information on balance and falling problems in the past year and their use of statins. Univariate and multivariate logistic regression models were used to investigate the association between statin use and the likelihood of falling or experiencing balance problems. The MR study identified five Single Nucleotide Polymorphisms (SNPs) that predict statin use across five ancestry groups: Admixed African or African, East Asian, European, Hispanic, and South Asian. Additionally, SNPs predicting the risk of falls were acquired from the UK Biobank population. A two-sample MR analysis was performed to examine whether genetically predicted statin use increased the risk of falls. Results: The use of statins was found to be associated with an increased likelihood of balance and falling problems (balance problem, OR 1.25, 95%CI 1.02 to 1.55; falling problem, OR 1.27, 95%CI 1.03-1.27). Subgroup analysis revealed that patients under the age of 65 were more susceptible to these issues when taking statins (balance problem, OR 3.42, 95%CI 1.40 to 9.30; falling problem, OR 5.58, 95%CI 2.04-15.40). The MR analysis indicated that the use of statins, as genetically proxied, resulted in an increased risk of falling problems (OR 1.21, 95% CI 1.1-1.33). Conclusion: Our study found an association between the use of statins and an increased risk of balance problems and falls in adults over 40 years old, and the MR study result suggested statin use increased risk of falls. The risk was higher in participants under 65 years old compared to those over 65 years old.
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BACKGROUND: Areca nut polyphenols (AP) that extracted from areca nut, have been demonstrated for their potential of anti-fatigue effects. However, the underlying mechanisms for the anti-fatigue properties of AP has not been fully elucidated to date. Previous studies have predominantly concentrated on single aspects, such as antioxidation and anti-inflammation, yet have lacked comprehensive multi-dimensional analyses. PURPOSE: To explore the underlying mechanism of AP in exerting anti-fatigue effects. METHODS: In this study, we developed a chronic sleep deprivation-induced fatigue model and used physiological, hematological, and biochemical indicators to evaluate the anti- fatigue efficacy of AP. Additionally, a multi-omics approach was employed to reveal the anti-fatigue mechanisms of AP from the perspective of microbiome, metabolome, and proteome. RESULTS: The detection of physiology, hematology and biochemistry index indicated that AP markedly alleviate mice fatigue state induced by sleep deprivation. The 16S rRNA sequencing showed the AP promoted the abundance of probiotics (Odoribacter, Dubosiella, Marvinbryantia, and Eubacterium) and suppressed harmful bacteria (Ruminococcus). On the other hand, AP was found to regulate the expression of colonic proteins, such as increases of adenosine triphosphate (ATP) synthesis and mitochondrial function related proteins, including ATP5A1, ATP5O, ATP5L, ATP5H, NDUFA, NDUFB, NDUFS, and NDUFV. Serum metabolomic analysis revealed AP upregulated the levels of anti-fatigue amino acids, such as taurine, leucine, arginine, glutamine, lysine, and l-proline. Hepatic proteins express levels, especially tricarboxylic acid (TCA) cycle (CS, SDHB, MDH2, and DLST) and redox-related proteins (SOD1, SOD2, GPX4, and PRDX3), were significantly recovered by AP administration. Spearman correlation analysis uncovered the strong correlation between microbiome, metabolome and proteome, suggesting the anti-fatigue effects of AP is attribute to the energy homeostasis and redox balance through gut-liver axis. CONCLUSION: AP increased colonic ATP production and improve mitochondrial function by regulating gut microbiota, and further upregulated anti-fatigue amino acid levels in the blood. Based on the gut-liver axis, AP upregulated the hepatic tricarboxylic acid cycle and oxidoreductase-related protein expression, regulating energy homeostasis and redox balance, and ultimately exerting anti-fatigue effects. This study provides insights into the anti-fatigue mechanisms of AP, highlighting its potential as a therapeutic agent.
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Areca , Fadiga , Polifenóis , Polifenóis/farmacologia , Animais , Camundongos , Masculino , Fadiga/tratamento farmacológico , Areca/química , Microbioma Gastrointestinal/efeitos dos fármacos , Privação do Sono/tratamento farmacológico , Nozes/química , Modelos Animais de Doenças , Extratos Vegetais/farmacologia , Extratos Vegetais/química , MultiômicaRESUMO
The contractile function of vascular smooth muscle cells (VSMCs) typically undergoes significant changes with advancing age, leading to severe vascular aging-related diseases. The precise role and mechanism of stromal interaction molecule-1 (STIM1) in age-mediated Ca2+ signaling and vasocontraction remain unclear. The connection between STIM1 and age-related vascular dysfunction was investigated using a multi-myograph system, immunohistochemical analysis, protein blotting, and SA-ß-gal staining. Results showed that vasoconstrictor responses in the thoracic aorta, intrarenal artery, and coronary artery decreased with age. STIM1 knockdown in the intrarenal and coronary arteries reduced vascular tone in young mice, while no change was observed in the thoracic aorta. A significant reduction in vascular tone occurred in the STIM1 knockout group with nifedipine. In the thoracic aorta, vasoconstriction significantly decreased with age following the use of nifedipine and thapsigargin and almost disappeared after STIM1 knockdown. The proportion of senescent VSMCs increased significantly in aged mice and further increased in sm-STIM1 KO aged mice. Moreover, the expression of senescence markers p21, p16, and IL-6 significantly increased with age, with p21 expression further increased in the STIM1 knockdown aged group, but not p16 or IL-6. These findings indicate that different arteries exhibit distinct organ-specific features and that STIM1 downregulation may contribute to age-related vasoconstrictive dysfunction through activation of the p21 pathway.
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Envelhecimento , Vasos Coronários , Regulação para Baixo , Molécula 1 de Interação Estromal , Vasoconstrição , Animais , Molécula 1 de Interação Estromal/metabolismo , Molécula 1 de Interação Estromal/genética , Vasoconstrição/efeitos dos fármacos , Camundongos , Vasos Coronários/metabolismo , Vasos Coronários/fisiopatologia , Envelhecimento/metabolismo , Masculino , Camundongos Knockout , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Artéria Renal/metabolismo , Senescência Celular/efeitos dos fármacos , Interleucina-6/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Aorta/metabolismo , Aorta/efeitos dos fármacosRESUMO
The androgen receptor signaling inhibitor (ARSI) enzalutamide (Enz) has shown critical efficacy in the treatment of advanced prostate cancer (PCa). However, the development of drug resistance is a significant factor contributing to mortality in PCa patients. We aimed to explore the key mechanisms of Enz-resistance. Through analysis of GEO databases, we identified SLC4A4 as a novel driver in Enz resistance. Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-κB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo. Hence, our results suggest that targeting SLC4A4 could be a promising therapeutic strategy for Enz resistance. STATEMENT OF SIGNIFICANCE: SLC4A4 is a novel driver of enzalutamide resistance.
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Benzamidas , Resistencia a Medicamentos Antineoplásicos , Nitrilas , Feniltioidantoína , Neoplasias da Próstata , Simportadores de Sódio-Bicarbonato , Animais , Humanos , Masculino , Camundongos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , NF-kappa B/metabolismo , NF-kappa B/genética , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Simportadores de Sódio-Bicarbonato/genéticaRESUMO
SCOPE: The cannabidiol (CBD) in hemp oil has important pharmacological activities. Accumulating evidence suggests that CBD is beneficial in the cardiovascular system and has been applied as a health supplement for atherosclerosis. However, the mechanism remains unclear. METHODS AND RESULTS: This study investigates the impact of CBD on foam cell formation, cholesterol homeostasis, and lipid metabolism in macrophages. CBD elevates the levels of peroxisome proliferator-activated receptor gamma (PPARγ) and its associated targets, such as ATP binding transporter A1/G1 (ABCA1/ABCG1), thus reducing foam cell formation, and increasing cholesterol efflux within macrophages. Notably, the upregulation of ABCA1 and ABCG1 expression induced by CBD is found to be attenuated by both a PPARγ inhibitor and PPARγ small interfering RNA (siRNA). Moreover, transfection of PPARγ siRNA results in a decrease in the inhibitory effect of CBD on foam cell formation and promotion of cholesterol efflux. Through lipidomics analysis, the study finds that CBD significantly reverses the enhancement of ceramide (Cer). Correlation analysis indicates a negative association between Cer level and the expression of ABCA1/ABCG1. CONCLUSION: This study confirms that CBD can be an effective therapeutic candidate for atherosclerosis treatment by activating PPARγ, up-regulating ABCA1/ABCG1 expression, and down-regulating Cer level.
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Transportador 1 de Cassete de Ligação de ATP , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Canabidiol , Colesterol , Células Espumosas , Homeostase , Metabolismo dos Lipídeos , PPAR gama , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Canabidiol/farmacologia , Colesterol/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , PPAR gama/metabolismo , PPAR gama/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Homeostase/efeitos dos fármacos , Camundongos , Células RAW 264.7 , Ceramidas/metabolismoRESUMO
Branched fatty acid esters of hydroxy fatty acids (FAHFAs) represent trace lipids with significant natural biological functions. While exogenous FAHFAs have been extensively studied, research on FAHFAs in milk remains limited, constraining our grasp of their nutritional roles. This study introduces a non-targeted mass spectrometry approach combined with chemical networking of spectral fragmentation patterns to uncover FAHFAs. Through meticulous sample handling and comparisons of various data acquisition and processing modes, we validate the method's superiority, identifying twice as many FAHFAs compared to alternative techniques. This validated method was then applied to different milk samples, revealing 45 chemical signals associated with known and potential FAHFAs, alongside findings of 66 ceramide/hexosylceramide (Cer/HexCer), 48 phosphatidyl ethanolamine/lyso phosphatidyl ethanolamine (PE/LPE), 21 phosphatidylcholine/lysophosphatidylcholine (PC/LPC), 16 phosphatidylinositol (PI), 7 phosphatidylserine (PS), and 11 sphingomyelin (SM) compounds. This study expands our understanding of the FAHFA family in milk and provides a fast and convenient method for identifying FAHFAs.
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Ésteres , Ácidos Graxos , Espectrometria de Massas , Leite , Animais , Leite/química , Ácidos Graxos/análise , Ácidos Graxos/química , Ésteres/análise , Ésteres/química , Espectrometria de Massas/métodosRESUMO
Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous group of pathophysiological bases of airway inflammation and its anti-inflammatory response. Aberrant mitochondrial signaling and mitochondrial dysfunction underlie the pathomechanisms leading to COPD. This study aims to investigate the effects of the Yiqigubiao (YQGB) pill, a traditional Chinese medicine (TCM), on Sirtuin 5 (SIRT5) and mitochondrial function in patients with COPD. Methods: Thirty-four patients with COPD were randomized into oral YQGB or placebo groups concurrent with a 24-week routine treatment. The pulmonary function was assessed by examining the levels of forced expiratory volume in one second (FEV1)/forced vital capacity (FVC), FEV1, and FVC. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to detect SIRT5 expression in mitochondria isolated from peripheral blood. Flow cytometry was used to detect changes in mitochondrial membrane potential and reactive oxygen species (ROS) in peripheral blood lymphocytes. Human bronchial epithelial (HBE) cells stimulated by cigarette smoke extract (CSE) were treated with YQGB. After SIRT5 was knocked down in cells, the changes in mitochondrial membrane potential, levels of adenosine triphosphate (ATP), and ROS were detected. Results: YQGB treatment significantly improved lung function in patients with COPD. The expression of SIRT5 and the mitochondrial membrane potential significantly increased and ROS decreased in patients with COPD after YQGB treatment. The CSE decreased cell proliferation and SIRT5 expression, which was alleviated after YQGB treatment. Furthermore, SIRT5 was knocked down in CSE-stimulated HBE cells, and its expression was elevated upon YQGB treatment. The knockdown of SIRT5 significantly altered the CSE-stimulation-induced dysregulation of mitochondrial membrane potential, ATP levels, and ROS. This was also restored after YQGB treatment. Conclusions: YQGB treatment can elevate SIRT5 expression, restore mitochondrial function in COPD, and exert protective effects.
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Bamboo plants are an essential component of tropical ecosystems, yet their vulnerability to climate extremes, such as drought, is poorly understood due to limited knowledge of their hydraulic properties. Cephalostachyum pergracile, a commonly used tropical bamboo species, exhibited a substantially higher mortality rate than other co-occurring bamboos during a severe drought event in 2019, but the underlying mechanisms remain unclear. This study investigated the leaf and stem hydraulic traits related to drought responses, including leaf-stem embolism resistance (P50leaf; P50stem) estimated using optical and X-ray microtomography methods, leaf pressure-volume and water-releasing curves. Additionally, we investigated the seasonal water potentials, native embolism level (PLC) and xylem water source using stable isotope. We found that C. pergracile exhibited strong resistance to embolism, showing low P50leaf, P50stem, and turgor loss point, despite its rapid leaf water loss. Interestingly, its leaves displayed greater resistance to embolism than its stem, suggesting a lack of effective hydraulic vulnerability segmentation (HVS) to protect the stem from excessive xylem tension. During the dry season, approximately 49% of the water was absorbed from the upper 20-cm-deep soil layer. Consequently, significant diurnal variation in leaf water potentials and an increase in midday PLC from 5.87 ± 2.33% in the wet season to 12.87 ± 4.09% in the dry season were observed. In summary, this study demonstrated that the rapid leaf water loss, high reliance on surface water, and a lack of effective HVS in C. pergracile accelerated water depletion and increased xylem embolism even in the typical dry season, which may explain its high mortality rate during extreme drought events in 2019.
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This study comprehensively compared the effects of laparoscopic and open radical cystectomies on postoperative wound infections and complications in patients with bladder cancer. We conducted a systematic search for relevant studies in PubMed, Embase, Google Scholar, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases, from database inception to October 2023. Two researchers independently screened the literature, extracted data, and assessed the quality based on the inclusion and exclusion criteria. Data analysis was performed using Stata 17.0 software. Overall, 16 studies involving 1427 patients with bladder cancer were included. The analysis revealed that, compared with open radical cystectomy, laparoscopic radical cystectomy significantly reduced the incidence of wound infections (odds ratio [OR] = 0.38, 95% confidence interval [CI]: 0.23-0.64, p < 0.001) and complications (OR = 0.35, 95%CI: 0.26-0.47, p < 0.001) and significantly shortened the hospital stay duration (standardised mean difference [SMD] = -1.85, 95%CI: -2.34 to -1.36, p < 0.001). Thus, this study determined that laparoscopic radical cystectomy for the treatment of bladder cancer effectively reduced the occurrence of wound infections and complications, and significantly shortened the patient's hospital stay, demonstrating notable therapeutic effectiveness worthy of clinical application.
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Cistectomia , Laparoscopia , Infecção da Ferida Cirúrgica , Neoplasias da Bexiga Urinária , Humanos , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/epidemiologia , Neoplasias da Bexiga Urinária/cirurgia , Laparoscopia/métodos , Laparoscopia/efeitos adversos , Cistectomia/efeitos adversos , Cistectomia/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Tempo de Internação/estatística & dados numéricos , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Despite the abundance of research examining the effects of coffee, tea, and alcohol on inflammatory diseases, there is a notable absence of conclusive evidence regarding their direct causal influence on circulating inflammatory cytokines. Previous studies have primarily concentrated on established cytokines, neglecting the potential impact of beverage consumption on lesser-studied but equally important cytokines. METHODS: Information regarding the consumption of coffee, tea, and alcohol was collected from the UK Biobank, with sample sizes of 428,860, 447,485, and 462,346 individuals, respectively. Data on 41 inflammatory cytokines were obtained from summary statistics of 8293 healthy participants from Finnish cohorts. RESULTS: The consumption of coffee was found to be potentially associated with decreased levels of Macrophage colony-stimulating factor (ß = -0.57, 95% CI -1.06 ~ -0.08; p = 0.022) and Stem cell growth factor beta (ß = -0.64, 95% CI -1.16 ~ -0.12; p = 0.016), as well as an increase in TNF-related apoptosis-inducing ligand (ß = 0.43, 95% CI 0.06 ~ 0.8; p = 0.023) levels. Conversely, tea intake was potentially correlated with a reduction in Interleukin-8 (ß = -0.45, 95% CI -0.9 ~ 0; p = 0.045) levels. Moreover, our results indicated an association between alcohol consumption and decreased levels of Regulated on Activation, Normal T Cell Expressed and Secreted (ß = -0.24, 95% CI -0.48 ~ 0; p = 0.047), as well as an increase in Stem cell factor (ß = 0.17, 95% CI 0.02 ~ 0.31; p = 0.023) and Stromal cell-derived factor-1 alpha (ß = 0.20, 95% CI 0.04 ~ 0.36; p = 0.013). CONCLUSION: Revealing the interactions between beverage consumption and various inflammatory cytokines may lead to the discovery of novel therapeutic targets, thereby facilitating dietary interventions to complement clinical disease treatments.
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Consumo de Bebidas Alcoólicas , Café , Citocinas , Análise da Randomização Mendeliana , Chá , Humanos , Citocinas/sangue , Masculino , Feminino , Inflamação/sangue , Adulto , Pessoa de Meia-Idade , Reino UnidoRESUMO
BACKGROUND AND OBJECTIVE: Enhanced external counterpulsation (EECP) is a mechanically assisted circulation technique widely used in the rehabilitation and management of ischemic cardiovascular diseases. It contributes to cardiovascular functions by regulating the afterload of ventricle to improve hemodynamic effects, including increased diastolic blood pressure at aortic root, increased cardiac output and enhanced blood perfusion to multiple organs including coronary circulation. However, the effects of EECP on the coupling of the ventricle and the arterial system, termed ventricular-arterial coupling (VAC), remain elusive. We aimed to investigate the acute effect of EECP on the dynamic interaction between the left ventricle and its afterload of the arterial system from the perspective of ventricular output work. METHODS: A neural network assisted optimization algorithm was proposed to identify the ordinary differential equation (ODE) relation between aortic root blood pressure and flow rate. Based on the optimized order of ODE, a lumped parameter model (LPM) under EECP was developed taking into consideration of the simultaneous action of cardiac and EECP pressure sources. The ventricular output work, in terms of aortic pressure and flow rate cooperated with the LPM, was used to characterize the VAC of ventricle and its afterload. The VAC subjected to the principle of minimal ventricular output work was validated by solving the Euler-Poisson equation of cost function, ultimately determining the waveforms of aortic pressure and flow rate. RESULTS: A third-order ODE can precisely describe the hemodynamic relationship between aortic pressure and flow rate. An optimized dual-source LPM with three energy-storage elements has been constructed, showing the potential in probing VAC under EECP. The LPM simulation results demonstrated that the VAC in terms of aortic pressure and flow rate yielded to the minimal ventricular output work under different EECP pressures. CONCLUSIONS: The ventricular-arterial coupling under EECP is subjected to the minimal ventricular output work, which can serve as a criterion for determining aortic pressure and flow rate. This study provides insight for the understanding of VAC and has the potential in characterizing the performance of the ventricular and arterial system under EECP.
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Algoritmos , Contrapulsação , Ventrículos do Coração , Hemodinâmica , Modelos Cardiovasculares , Humanos , Contrapulsação/métodos , Débito Cardíaco , Artérias/fisiologia , Pressão Sanguínea , Simulação por Computador , Aorta/fisiologia , Redes Neurais de ComputaçãoRESUMO
Gut microbiota-derived microbial compounds may link to the pathogenesis of colorectal cancer (CRC). However, the role of the host-microbiome in the incidence and progression of CRC remains elusive. We performed 16S rRNA sequencing, metabolomics, and proteomic studies on samples from 85 CRC patients who underwent colonoscopy examination and found two distinct changed patterns of microbiome in CRC patients. The relative abundances of Catabacter and Mogibacterium continuously increased from intramucosal carcinoma to advanced stages, whereas Clostridium, Anaerostipes, Vibrio, Flavonifractor, Holdemanella, and Hungatella were significantly altered only in intermediate lesions. Fecal metabolomics analysis exhibited consistent increases in bile acids, indoles, and urobilin as well as a decrease in heme. Serum metabolomics uncovered the highest levels of bilin, glycerides, and nucleosides together with the lowest levels of bile acids and amino acids in the stage of intermediate lesions. Three fecal and one serum dipeptides were elevated in the intermediate lesions. Proteomics analysis of colorectal tissues showed that oxidation and autophagy through the PI3K/Akt-mTOR signaling pathway contribute to the development of CRC. Diagnostic analysis showed multiomics features have good predictive capability, with AUC greater than 0.85. Our overall findings revealed new candidate biomarkers for CRC, with potentially significant diagnostic and prognostic capabilities.
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Neoplasias Colorretais , Fezes , Microbioma Gastrointestinal , Metabolômica , Proteômica , RNA Ribossômico 16S , Humanos , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proteômica/métodos , Fezes/microbiologia , Fezes/química , Metabolômica/métodos , Masculino , RNA Ribossômico 16S/genética , Feminino , Pessoa de Meia-Idade , Idoso , Transdução de Sinais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/sangue , MultiômicaRESUMO
Antarctic krill oil (AKO) is highly sought after by consumers and the food industry due to its richness in a variety of nutrients and physiological activities. However, current extraction methods are not sufficient to better extract AKO and its nutrients, and AKO is susceptible to lipid oxidation during processing and storage, leading to nutrient loss and the formation of off-flavors and toxic compounds. The development of various extraction methods and encapsulation systems for AKO to improve oil yield, nutritional value, antioxidant capacity, and bioavailability has become a research hotspot. This review summarizes the research progress of AKO from extraction to encapsulation system construction. The AKO extraction mechanism, technical parameters, oil yield and composition of solvent extraction, aqueous enzymatic extraction, supercritical/subcritical extraction, and three-liquid-phase salting-out extraction system are described in detail. The principles, choice of emulsifier/wall materials, preparation methods, advantages and disadvantages of four common encapsulation systems for AKO, namely micro/nanoemulsions, microcapsules, liposomes and nanostructured lipid carriers, are summarized. These four encapsulation systems are characterized by high encapsulation efficiency, low production cost, high bioavailability and high antioxidant capacity. Depending on the unique advantages and conditions of different encapsulation methods, as well as consumer demand for health and nutrition, different products can be developed. However, existing AKO encapsulation systems lack relevant studies on digestive absorption and targeted release, and the single product category of commercially available products limits consumer choice. In conjunction with clinical studies of AKO encapsulation systems, the development of encapsulation systems for special populations should be a future research direction.
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Antioxidantes , Euphausiacea , Animais , Estado Nutricional , Valor Nutritivo , LipídeosRESUMO
Camptothecin is a complex monoterpenoid indole alkaloid with remarkable antitumor activity. Given that two C-10 modified camptothecin derivatives, topotecan and irinotecan, have been approved as potent anticancer agents, there is a critical need for methods to access other aromatic ring-functionalized congeners (e.g., C-9, C-10, etc.). However, contemporary methods for chemical oxidation are generally harsh and low-yielding when applied to the camptothecin scaffold, thereby limiting the development of modified derivatives. Reported herein, we have identified four tailoring enzymes responsible for C-9 modifications of camptothecin from Nothapodytes tomentosa, via metabolomic and transcriptomic analysis. These consist of a cytochrome P450 (NtCPT9H) which catalyzes the regioselective oxidation of camptothecin to 9-hydroxycamptothecin, as well as two methyltransferases (NtOMT1/2, converting 9-hydroxycamptothecin to 9-methoxycamptothecin), and a uridine diphosphate-glycosyltransferase (NtUGT5, decorating 9-hydroxycamptothecin to 9-ß-D-glucosyloxycamptothecin). Importantly, the critical residues that contribute to the specific catalytic activity of NtCPT9H have been elucidated through molecular docking and mutagenesis experiments. This work provides a genetic basis for producing camptothecin derivatives through metabolic engineering. This will hasten the discovery of novel C-9 modified camptothecin derivatives, with profound implications for pharmaceutical manufacture.
Assuntos
Camptotecina , Camptotecina/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismoRESUMO
BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), a composite inflammatory biomarker, is associated with the prognosis in patients with colorectal tumors. However, whether the NLR can be used as a predictor of symptomatic postoperative anastomotic leakage (AL) in elderly patients with colon cancer is unclear. AIM: To assess the role of the NLR in predicting the occurrence of symptomatic AL after surgery in elderly patients with colon cancer. METHODS: Data from elderly colon cancer patients who underwent elective radical colectomy with anastomosis at three centers between 2018 and 2022 were retrospectively analyzed. Receiver operating characteristic curve analysis was performed to determine the best predictive cutoff value for the NLR. Twenty-two covariates were matched using a 1:1 propensity score matching method, and univariate and multivariate logistic regression analyses were used to determine risk factors for the development of postoperative AL. RESULTS: Of the 577 patients included, 36 (6.2%) had symptomatic AL. The optimal cutoff value of the NLR for predicting AL was 2.66. After propensity score matching, the incidence of AL was significantly greater in the ≥ 2.66 NLR subgroup than in the < 2.66 NLR subgroup (11.5% vs 2.5%; P = 0.012). Univariate logistic regression analysis revealed statistically significant correlations between blood transfusion intraoperatively and within 2 d postoperatively, preoperative albumin concentration, preoperative prognostic nutritional index, and preoperative NLR and AL occurrence (P < 0.05); multivariate logistic regression analysis revealed that an NLR ≥ 2.66 [odds ratio (OR) = 5.51; 95% confidence interval (CI): 1.50-20.26; P = 0.010] and blood transfusion intraoperatively and within 2 d postoperatively (OR = 2.52; 95%CI: 0.88-7.25; P = 0.049) were risk factors for the occurrence of symptomatic AL. CONCLUSION: A preoperative NLR ≥ 2.66 and blood transfusion intraoperatively and within 2 d postoperatively are associated with a higher incidence of postoperative symptomatic AL in elderly patients with colon cancer. The preoperative NLR has predictive value for postoperative symptomatic AL after elective surgery in elderly patients with colon cancer.
RESUMO
Foodomics has become a popular methodology in food science studies. Mass spectrometry (MS) based metabolomics and proteomics analysis played indispensable roles in foodomics research. So far, several methodologies have been developed to detect the metabolites and proteins in diets and consumers, including sample preparation, MS data acquisition, annotation and interpretation. Moreover, multiomics analysis integrated metabolomics and proteomics have received considerable attentions in the field of food safety and nutrition, because of more comprehensive and deeply. In this context, we intended to review the emerging strategies and their applications in MS-based foodomics, as well as future challenges and trends. The principle and application of multiomics were also discussed, such as the optimization of data acquisition, development of analysis algorithm and exploration of systems biology.
Assuntos
Metabolômica , Proteômica , Proteômica/métodos , Metabolômica/métodos , Tecnologia de Alimentos , Espectrometria de Massas/métodos , Estado NutricionalRESUMO
Cardiovascular diseases are caused by hypercholesterolemia. Astaxanthin (AST) has been reported to exhibit antioxidant and anti-inflammatory properties. However, its bioavailability is poor because of low solubility and instability. In order to improve the bioavailability of AST, we developed an intestinal-responsive composite carrier termed as "liposomes in micropheres" incorporating N-succinyl-chitosan (NSC)-poly(ethylene glycol) (PEG) liposomes that functionalized by neonatal Fc receptors (FcRn) into hydrogels of sodium alginate (SA) and carboxymethyl chitosan (CMCS). In the AST NSC/HSA-PEG liposomes@SA/CMCS microspheres, the AST's encapsulation efficiency (EE) was 96.26% (w/w) and its loading capacity (LC) was 6.47% (w/w). AST NSC/HSA-PEG liposomes had stability in the gastric conditions and achieved long-term release of AST in intestinal conditions. Then, AST NSC/HSA-PEG liposomes@SA/CMCS bind to intestinal epithelial cell targets by the neonatal Fc receptor. In vitro permeation studies show that there was a 4-fold increase of AST NSC/HSA-PEG liposomes@SA/CMCS in AST permeation across the intestinal epithelium. Subsequent in vivo experiments demonstrated that the composite carrier exhibited a remarkable mucoadhesive capacity, allowing for extended intestinal retention of up to 12 h, and it displayed deep penetration through the mucus layer, efficiently entering the intestinal villi epithelial cells, and enhancing the absorption of AST and its bioavailability in vivo. And oral administration of AST NSC/HSA-PEG liposomes@SA/CMCS could effectively prevent hypercholesterolemia caused by a high-fat, high-cholesterol diet (HFHCD). These advancements highlight the potential of NSC/HSA-PEG liposomes@SA/CMCS composite carriers for targeted and oral uptake of hydrophobic bioactives.