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Alcoholrelated liver disease (ALD) is a major health concern worldwide. In recent years, there has been growing interest in natural products and functional foods for preventing and treating ALD due to their potential antioxidant and hepatoprotective properties. Rosa roxburghii Tratt, known for its rich content of bioactive compounds, has demonstrated promising health benefits, including antiinflammatory and antioxidant effects. Fermentation has been utilized as a strategy to enhance the bioavailability and efficacy of natural products. In the present study, using a mixture of Rosa roxburghii Tratt juice, lotus leaf extract and grape seed proanthocyanidins fermented by Lactobacillus plantarum HHLP56, a novel fermented Rosa roxburghii Tratt (FRRT) juice was discovered that can prevent and regulate ethanolinduced liver cell damage. Following fermentation, the pH was significantly decreased, and the content of VC and superoxide dismutase (SOD) were significantly increased, along with a noticeable enhancement in hydroxyl and 2,2diphenyl1picrylhydrazyl free radical scavenging abilities. Alpha Mouse liver 12 cells were exposed to ethanol for 24 h to establish an in vitro liver cell injury model. The present study evaluated the effects of FRRT on cell damage, lipid accumulation and oxidative stress markers. The results revealed that FRRT pretreatment (cells were pretreated with 2.5 and 5 mg/ml FRRT for 2 h) significantly reduced lipid accumulation and oxidative stress in liver cells. Mechanistically, FRRT regulated lipid metabolism by influencing key genes and proteins, such as AMPactivated protein kinase, sterol regulatory element binding transcription factor 1 and StearylCoA desaturase1. Furthermore, FRRT enhanced antioxidant activity by increasing SOD activity, glutathione and catalase levels, while reducing reactive oxygen species and malondialdehyde levels. It also reversed the expression changes of ethanolinduced oxidative stressrelated genes and proteins. In conclusion, a novel functional food ingredient may have been discovered with extensive potential applications. These findings indicated that FRRT has antioxidant properties and potential therapeutic benefits in addressing ethanolinduced liver cell damage through its effects on liver lipid metabolism and oxidative stress.
Subject(s)
AMP-Activated Protein Kinases , Ethanol , Fermentation , Hepatocytes , NF-E2-Related Factor 2 , Plant Extracts , Rosa , Signal Transduction , Animals , Mice , Rosa/chemistry , Signal Transduction/drug effects , Hepatocytes/drug effects , Hepatocytes/metabolism , NF-E2-Related Factor 2/metabolism , Plant Extracts/pharmacology , Plant Extracts/chemistry , AMP-Activated Protein Kinases/metabolism , Oxidative Stress/drug effects , Cell Line , Antioxidants/pharmacology , Fruit and Vegetable Juices , Protective Agents/pharmacologyABSTRACT
The WNT5B ligand regulates the non-canonical wingless-related integration site (WNT)-planar cell polarity (PCP) pathway. However, the detailed mechanism underlying the activity of WNT5B in the WNT-PCP pathway in non-small cell lung cancer (NSCLC) is unclear. In this study, we assessed the clinicopathological significance of WNT5B expression in NSCLC specimens. WNT5B-overexpression and -knockdown NSCLC cell lines were generated in vivo and in vitro, respectively. WNT5B overexpression in NSCLC specimens correlates with advanced tumor node metastasis (TNM) stage, lymph node metastasis, and poor prognosis in patients with NSCLC. Additionally, WNT5B promotes the malignant phenotype of NSCLC cells in vivo and in vitro. Interactions were identified among WNT5B, frizzled3 (FZD3), and disheveled3 (DVL3) in NSCLC cells, leading to the activation of WNT-PCP signaling. The FZD3 receptor initiates DVL3 recruitment to the membrane for phosphorylation in a WNT5B ligand-dependent manner and activates c-Jun N-terminal kinase (JNK) signaling via the small GTPase RAC1. Furthermore, the deletion of the DEP domain of DVL3 abrogated these effects. Overall, we demonstrated a novel signal transduction pathway in which WNT5B recruits DVL3 to the membrane via its DEP domain through interaction with FZD3 to promote RAC1-PCP-JNK signaling, providing a potential target for clinical intervention in NSCLC treatment.
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BACKGROUND: The interplay between genetic and lifestyle factors in the development of bipolar disorder (BD) remains unclear. METHODS: A cohort study was carried out on 365,517 participants from the UK Biobank. Lifestyle scores, based on smoking, physical activity, diet, alcohol consumption, sedentary behavior, sleep duration, and social contact, were grouped as favorable (scores 6-7), intermediate (scores 4-5), or unfavorable (scores 0-3). The BD polygenic risk score (PRS) was also categorized into high, intermediate, and low-risk groups using PRS tertiles. Cox regression models determined hazard ratios (HRs) and 95â¯% confidence intervals (CIs) for BD. RESULTS: During the 12.9-year follow-up, 529 individuals developed BD. Comparing those with favorable lifestyles to those with unfavorable participants, the HR of developing BD was 3.28 (95â¯% CI, 2.76-3.89). Similarly, individuals with a high PRS had a risk of 3.20 (95â¯% CI, 2.83-3.63) compared to those with a low PRS. Notably, individuals with both a high PRS and an unfavorable lifestyle had a significantly higher risk of BD (HRâ¯=â¯6.31, 95â¯% CI, 4.14-9.63) compared to those with a low PRS and a favorable lifestyle. Additionally, the interaction between PRS and lifestyle contributed an additional risk, with a relative excess risk of 1.74 (95â¯% CI, 0.40-3.07) and an attributable proportion due to the interaction of 0.37 (95â¯% CI, 0.16-0.58). CONCLUSIONS: Our findings suggest that genetic liability for BD, measured as PRS, and lifestyle have an additive effect on the risk of developing BD. A favorable lifestyle was associated with a reduced risk of developing BD.
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This study represents the first analysis of the bacterial community in chickens affected by swollen head syndrome, utilizing 16S rRNA gene sequencing. Samples were obtained from clinical laying chickens and were examined for the presence of Avibacterium paragallinarum (APG) and Ornithobacterium rhinotracheale (ORT) using conventional polymerase chain reaction (PCR). From the samples, five APG-positive (APG) and APG-negative (N-APG) samples were chosen, along with five specific pathogen-free chickens, for 16S rRNA gene sequencing. Results showed that APG and ORT were widely detected in the chicken samples with swollen head syndrome (SHS, 9/10), while APG was detected in all five specific pathogen-free (SPF) samples. In contrast, conventional PCR sensitivity was found to be inadequate for diagnosis, with only 35.7% (5/14) and 11.1% (1/9) sensitivity for APG and ORT, respectively, based on 16S rRNA gene sequencing data. Furthermore, 16S rRNA gene sequencing was able to quantify the bacteria in the samples, revealing that the relative abundance of APG in the APG group ranged from 2.7 to 81.3%, while the relative abundance of APG in the N-APG group ranged from 0.1 to 21.0%. Notably, a low level of APG was also detected in all 5 SPF samples. The study also identified a significant number of animal and human common bacterial pathogens, including but not limited to Gallibacterium anatis, Riemerella columbina, Enterococcus cecorum, Mycoplasma synoviae, Helicobacter hepaticus, and Staphylococcus lentus. In conclusion, 16S rRNA gene sequencing is a valuable tool for bacterial pathogen diagnosis and the discovery of novel bacterial pathogens, while conventional PCR is not reliable for diagnosis.
Subject(s)
Chickens , Polymerase Chain Reaction , Poultry Diseases , RNA, Ribosomal, 16S , RNA, Ribosomal, 16S/genetics , Animals , Chickens/microbiology , Polymerase Chain Reaction/methods , Poultry Diseases/microbiology , Poultry Diseases/diagnosis , Bacteria/genetics , Bacteria/classification , Bacteria/isolation & purification , DNA, Bacterial/genetics , Sequence Analysis, DNA , PhylogenyABSTRACT
In addition to considering the main effects, understanding gene-environment (G × E) interactions is imperative for determining the etiology of diseases and the factors that affect their prognosis. In the existing statistical framework for censored survival outcomes, there are several challenges in detecting G × E interactions, such as handling high-dimensional omics data, diverse environmental factors, and algorithmic complications in survival analysis. The effect heredity principle has widely been used in studies involving interaction identification because it incorporates the dependence of the main and interaction effects. However, Bayesian survival models that incorporate the assumption of this principle have not been developed. Therefore, we propose Bayesian heredity-constrained accelerated failure time (BHAFT) models for identifying main and interaction (M-I) effects with novel spike-and-slab or regularized horseshoe priors to incorporate the assumption of effect heredity principle. The R package rstan was used to fit the proposed models. Extensive simulations demonstrated that BHAFT models had outperformed other existing models in terms of signal identification, coefficient estimation, and prognosis prediction. Biologically plausible G × E interactions associated with the prognosis of lung adenocarcinoma were identified using our proposed model. Notably, BHAFT models incorporating the effect heredity principle could identify both main and interaction effects, which are highly useful in exploring G × E interactions in high-dimensional survival analysis. The code and data used in our paper are available at https://github.com/SunNa-bayesian/BHAFT.
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The pod and seed counts are important yield-related traits in soybean. High-precision soybean breeders face the major challenge of accurately phenotyping the number of pods and seeds in a high-throughput manner. Recent advances in artificial intelligence, especially deep learning (DL) models, have provided new avenues for high-throughput phenotyping of crop traits with increased precision. However, the available DL models are less effective for phenotyping pods that are densely packed and overlap in in situ soybean plants; thus, accurate phenotyping of the number of pods and seeds in soybean plant is an important challenge. To address this challenge, the present study proposed a bottom-up model, DEKR-SPrior (disentangled keypoint regression with structural prior), for in situ soybean pod phenotyping, which considers soybean pods and seeds analogous to human people and joints, respectively. In particular, we designed a novel structural prior (SPrior) module that utilizes cosine similarity to improve feature discrimination, which is important for differentiating closely located seeds from highly similar seeds. To further enhance the accuracy of pod location, we cropped full-sized images into smaller and high-resolution subimages for analysis. The results on our image datasets revealed that DEKR-SPrior outperformed multiple bottom-up models, viz., Lightweight-OpenPose, OpenPose, HigherHRNet, and DEKR, reducing the mean absolute error from 25.81 (in the original DEKR) to 21.11 (in the DEKR-SPrior) in pod phenotyping. This paper demonstrated the great potential of DEKR-SPrior for plant phenotyping, and we hope that DEKR-SPrior will help future plant phenotyping.
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BACKGROUND AND OBJECTIVES: The World Health Organization recently released a novel metric for healthy aging: intrinsic capacity (IC). The relationship between IC and the incidence of dementia, and its subtypes, is unknown. We aimed to analyze the relationship between IC and the incidence of dementia and its subtypes. Moreover, we tested whether genetic susceptibility to dementia could be modified by IC. METHODS: This cohort study involved 366,406 participants from the UK Biobank between 2006 and 2010. We analyzed 7 factors that reflected functional status across 4 IC domains to compute a comprehensive IC deficit score. Cox models were used to elucidate the relationship between the IC deficit score and the incidence of dementia. RESULTS: Among the 366,406 participants, 5,207 cases of dementia were documented, encompassing 2,186 and 1,175 cases of Alzheimer disease (AD) and vascular dementia (VD), respectively. Compared with participants with an IC score of 0, individuals with an IC score of 4+ had a markedly elevated risk of dementia (hazard ratio [HR] 2.17, 95% CI 1.92-2.45). In the joint analysis, for participants with a high polygenic risk score (PRS) and an IC score of 4 or more, the HR of all-cause dementia was 8.11 (95% CI 6.28-10.47) compared with individuals with a low PRS and an IC score of 0. Similar results were seen in the AD and VD groups. DISCUSSION: In summary, IC is associated with a higher risk of dementia, particularly in those combined with genetically predisposed to dementia.
Subject(s)
Apolipoproteins E , Biological Specimen Banks , Dementia , Multifactorial Inheritance , Humans , Female , Male , United Kingdom/epidemiology , Aged , Apolipoproteins E/genetics , Multifactorial Inheritance/genetics , Middle Aged , Dementia/genetics , Dementia/epidemiology , Prospective Studies , Genotype , Genetic Predisposition to Disease/genetics , Alzheimer Disease/genetics , Alzheimer Disease/epidemiology , Cohort Studies , Incidence , Risk Factors , Healthy Aging/genetics , Dementia, Vascular/genetics , Dementia, Vascular/epidemiology , Genetic Risk Score , UK BiobankABSTRACT
Benefiting from the complex system composed of various constituents, medicament portions, species, and places of origin, traditional Chinese medicine (TCM) possesses numerous customizable and adaptable efficacies in clinical practice guided by its theories. However, these unique features are also present challenges in areas such as quality control, screening active ingredients, studying cell and organ pharmacology, and characterizing the compatibility between different Chinese medicines. Drawing inspiration from the holistic concept, an integrated strategy and pattern more aligned with TCM research emerges, necessitating the integration of novel technology into TCM modernization. The microfluidic chip serves as a powerful platform for integrating technologies in chemistry, biology, and biophysics. Microfluidics has given rise to innovative patterns like lab-on-a-chip and organoids-on-a-chip, effectively challenging the conventional research paradigms of TCM. This review provides a systematic summary of the nature and advanced utilization of microfluidic chips in TCM, focusing on quality control, active ingredient screening/separation, pharmaceutical analysis, and pharmacological/toxicological assays. Drawing on these remarkable references, the challenges, opportunities, and future trends of microfluidic chips in TCM are also comprehensively discussed, providing valuable insights into the development of TCM.
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Torreya grandis (T. grandis) oil has been reported to alleviate symptoms of slow transit constipation (STC). However, the impact of sciadonic acid (SA), a distinctive fatty acid found in T. grandis oil, on the pathological progression of STC remains unclear. This study aimed to evaluate the effect of SA on STC and uncover the underlying mechanisms. The STC model was established by feeding Balb/c mice with loperamide. After 2 weeks of intervention, SA significantly improved weight loss and intestinal motility decline induced by STC, along with enhancing plasma indices and reducing colon pathological damage. SA effectively reversed the STC-induced decrease in the 5-HT4/cAMP/PKA/AQP4 signaling pathway genes and expression. Furthermore, 16S rRNA analysis demonstrated that SA mitigated the imbalance of the intestinal microbiota induced by STC, by reducing the ratio of Firmicutes to Bacteroidetes (F/B) and increasing the abundance of beneficial bacteria such as Akkermansia. In conclusion, SA intervention alleviated colonic dysfunction in STC mice. The activation of the SA-mediated 5-HT4/cAMP/PKA/AQP4 signaling pathway may serve as a potential target for STC treatment. These findings suggest that SA holds promise as a treatment option for STC and could potentially be extended to other related gut diseases for further investigation.
Subject(s)
Aquaporin 4 , Colon , Constipation , Cyclic AMP-Dependent Protein Kinases , Cyclic AMP , Mice, Inbred BALB C , Receptors, Serotonin, 5-HT4 , Signal Transduction , Animals , Cyclic AMP-Dependent Protein Kinases/metabolism , Cyclic AMP/metabolism , Signal Transduction/drug effects , Constipation/drug therapy , Constipation/metabolism , Colon/metabolism , Colon/drug effects , Receptors, Serotonin, 5-HT4/metabolism , Receptors, Serotonin, 5-HT4/genetics , Male , Mice , Aquaporin 4/metabolism , Aquaporin 4/genetics , Disease Models, Animal , Gastrointestinal Microbiome/drug effects , Gastrointestinal Transit/drug effectsABSTRACT
Cyanidin-3-O-glucoside (C3G) is a type of water-soluble flavonoid compound that is abundantly found in fruits and vegetables. C3G possesses numerous biological activities, however, it is prone to breakdown under environmental conditions. To overcome these issues, we developed nano-nutriosome (NS) carriers created by vortex-mixing and probe-sonication techniques for C3G encapsulation in which the phospholipid and Nutriose® FB06 were chosen as carrier material, and guar gum (GG) as a coating material to formulate a unilamellar and multicompartment structure. This study aimed to develop and evaluate C3G-loaded nano-nutriosomes coated by GG (GG-C3G-NS) for improving physicochemical stability, antioxidant activity, cellular uptake, and controlled release properties. The C3G-NS and GG-C3G-NS are nanosized (143.47 to 154.13 nm), with high encapsulation efficiency (>93.31 %). The NS carriers successfully encapsulated C3G which was confirmed by transmission electron microscopy, differential scanning calorimetry, and Fourier transform infrared spectroscopy. C3G showed more stability in storage, thermal, pH, ionic, and oxidative conditions. Furthermore, the NS exhibited a better-controlled release of C3G in different food stimulant conditions and in vitro release study. Additionally, NS systems enhanced cellular uptake and showed no cytotoxicity. Overall, GG-NS could be a promising nanocarrier for improving the stability, controlled release, and antioxidant activity of bioactive compounds.
Subject(s)
Anthocyanins , Antioxidants , Galactans , Mannans , Plant Gums , Plant Gums/chemistry , Galactans/chemistry , Anthocyanins/chemistry , Anthocyanins/pharmacology , Mannans/chemistry , Antioxidants/chemistry , Antioxidants/pharmacology , Drug Carriers/chemistry , Nanoparticles/chemistry , Drug Liberation , Humans , Hydrogen-Ion ConcentrationABSTRACT
OBJECTIVES: To investigate the incidence rate, clinical characteristics, and prognosis of neonatal stroke in Shenzhen, China. METHODS: Led by Shenzhen Children's Hospital, the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022. The incidence, clinical characteristics, treatment, and prognosis of neonatal stroke in Shenzhen were analyzed. RESULTS: The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137, 1/6 060, and 1/7 704, respectively. Ischemic stroke accounted for 75% (27/36); boys accounted for 64% (23/36). Among the 36 neonates, 31 (86%) had disease onset within 3 days after birth, and 19 (53%) had convulsion as the initial presentation. Cerebral MRI showed that 22 neonates (61%) had left cerebral infarction and 13 (36%) had basal ganglia infarction. Magnetic resonance angiography was performed for 12 neonates, among whom 9 (75%) had involvement of the middle cerebral artery. Electroencephalography was performed for 29 neonates, with sharp waves in 21 neonates (72%) and seizures in 10 neonates (34%). Symptomatic/supportive treatment varied across different hospitals. Neonatal Behavioral Neurological Assessment was performed for 12 neonates (33%, 12/36), with a mean score of (32±4) points. The prognosis of 27 neonates was followed up to around 12 months of age, with 44% (12/27) of the neonates having a good prognosis. CONCLUSIONS: Ischemic stroke is the main type of neonatal stroke, often with convulsions as the initial presentation, involvement of the middle cerebral artery, sharp waves on electroencephalography, and a relatively low neurodevelopment score. Symptomatic/supportive treatment is the main treatment method, and some neonates tend to have a poor prognosis.
Subject(s)
Stroke , Humans , Male , Infant, Newborn , Female , China/epidemiology , Stroke/epidemiology , Prognosis , Electroencephalography , Incidence , Magnetic Resonance ImagingABSTRACT
The Co-free Ni-rich layered cathodes become pivotal to reduce cost and increase benefit toward next-generation Li-ion batteries yet raise a major challenge for their extremely fragile cathode-electrolyte interface (CEI) film. Herein, we report the in situ construction of the Si/B-enriched organic-inorganic hybrid CEI films on LiNi0.9Mn0.1O2 (NM91) with the assistance of tris(trimethylsilyl) borate (TMSB) additive. The hybrid film exhibits superior Young's modulus, mechanical strength, and ductility, which greatly dissipate the microstrain of Co-free Ni-rich cathodes under various states of charge with high structural integrity. Furthermore, the surface oxygen anions have been significantly stabilized by bonding with the Si and B ions of TMSB with high safety. These merits enable a durable Co-free Ni-rich layered cathode with 96.9% and 87.7% capacity retentions (versus 72.7% and 70.2% of NM91) at a high rate of 5C and a high-temperature of 55 °C after 100 cycles. In a pouch-type full cell, 88.8% of initial capacity is still maintained after cycling at 1C for 500 times, greatly expediting the development and application of Co-free Ni-rich layered cathodes.
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BACKGROUND: Contemporary environmental health investigations have identified green space as an emerging factor with promising prospects for bolstering human well-being. The incidence of delirium increases significantly with age and is fatal. To date, there is no research elucidating the enduring implications of green spaces on the occurrence of delirium. Therefore, we explored the relationship between residential greenness and the incidence of delirium in a large community sample from the UK Biobank. METHODS: Enrollment of participants spanned from 2006 to 2010. Assessment of residential greenness involved the land coverage percentage of green space within a buffer range of 300 m and 1000 m. The relationship between residential greenness and delirium was assessed using the Cox proportional hazards model. Further, we investigated the potential mediating effects of physical activity, particulate matter (PM) with diameters ≤2.5 (PM2.5), and nitrogen oxides (NOx). RESULTS: Of 232,678 participants, 3722 participants were diagnosed with delirium during a 13.4-year follow-up period. Compared with participants with green space coverage at a 300 m buffer in the lowest quartile (Q1), those in the highest quartile (Q4) had 15 % (Hazard ratio [HR] = 0.85, 95 % confidence interval [CI]: 0.77, 0.94) lower risk of incident delirium. As for the 1000 m buffer, those in Q4 had a 16 % (HR = 0.84, 95 % CI: 0.76, 0.93) lower risk of incident delirium. The relationship between green space in the 300 m buffer and delirium was mediated partially by physical activity (2.07 %) and PM2.5(49.90 %). Comparable findings were noted for the green space percentage within the 1000 m buffer. CONCLUSIONS: Our results revealed that long-term exposure to residential greenness was related to a lower risk of delirium. Air pollution and physical activity exerted a significant mediating influence in shaping this association.
Subject(s)
Delirium , Particulate Matter , Humans , United Kingdom/epidemiology , Prospective Studies , Delirium/epidemiology , Male , Particulate Matter/analysis , Female , Middle Aged , Aged , Incidence , Biological Specimen Banks , Environmental Exposure/statistics & numerical data , Air Pollution/statistics & numerical data , Residence Characteristics , Exercise , UK BiobankABSTRACT
Ecosystem water use efficiency (WUE) is a crucial indicator of the impact of climate change on terrestrial ecosystems, reflecting the balance between biological processes (photosynthesis and transpiration) and physical processes (evapotranspiration). However, the response mechanisms and driving processes of WUE to drought remain to be further understood. In this study, we analyzed the spatial and temporal dynamics and response mechanisms of WUE in the Yellow River Basin (YRB) using data on Gross Primary Productivity (GPP), Evapotranspiration (ET) and Standardized Precipitation Evapotranspiration Index (SPEI), which revealed the cumulative effect of drought on WUE and assessed the ecosystem's resilience. The study results showed that (1) GPP, ET and WUE in the YRB exhibited a significant increasing trend, with 63.04 % of the area showing a marked increase in WUE. (2) GPP was the dominant factor influencing WUE in 65.36 % of the area, particularly in cropland and grassland, while ET was more influential in forested areas. Vapor pressure deficit (VPD) was identified as the principal driver affecting vegetation GPP in semi-arid and semi-humid regions of the YRB. In contrast, soil moisture (SM) was the limiting factor in arid areas. (3) 71.00 % of the WUE in the basin was affected by drought cumulative effects, with an average cumulative duration of 4.5 months. Arid regions experienced the most extended duration of 7.29 months, compared to 3.05 months in semi-humid regions. (4) 74.85 % of the regional ecosystems exhibited ecological resilience to drought, particularly in the source areas of the western basin of the YRB. Shrublands have the highest drought resilience among vegetation types, while grasslands have the lowest. The resilience of each climatic zone was in the order of semi-humid, semi-arid, and arid order. This study comprehensively analyzed of the spatial and temporal dynamics and response mechanisms of WUE in the YRB, offering a new perspective and scientific basis for understanding and predicting the ecosystem response to climate change.
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This study aimed to evaluate the protective role and potential mechanisms of Xie Zhuo Tiao Zhi decoction (XZTZ) on alcohol-associated liver disease (ALD). XZTZ significantly alleviated alcohol-induced liver dysfunction, based on histological examinations and biochemical parameters after 4-week administration. Mechanically, alcohol-stimulated hepatic oxidative stress was ameliorated by XZTZ, accompanied by the improvement of Nrf2/Keap1 expression and alcohol-activated phosphorylation of pro-inflammatory transcription factors, including JNK, P38, P65, and IκBα, were rescued by XZTZ. In conclusion, XZTZ demonstrates potential in alleviating alcohol-induced liver injury, oxidative stress, and inflammation possibly through modulation of Nrf2/Keap1 and MAPKs/NF-κB signaling pathways, suggesting its potential as a therapeutic option for patients with alcoholic liver disease.
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Growth-retarded yaks are of a high proportion on the Tibetan plateau and reduce the economic income of farmers. Our previous studies discovered a maldevelopment in the ruminal epithelium of growth-retarded yaks, but the molecular mechanisms are still unclear. This study aimed to reveal how the proteomic profile in the ruminal epithelium contributed to the growth retardation of yaks. The proteome of the ruminal epithelium was detected using a high-resolution mass spectrometer. There were 52 proteins significantly differently expressed between the ruminal epithelium of growth-retarded yaks and growth-normal yaks, with 32 downregulated and 20 upregulated in growth-retarded yaks. Functional analysis showed the differently expressed proteins involved in the synthesis and degradation of ketone bodies (p = 0.012), propanoate metabolism (p = 0.018), pyruvate metabolism (p = 0.020), and mineral absorption (p = 0.024). The protein expressions of SLC26A3 and FTH1, enriched in the mineral absorption, were significantly downregulated in growth-retarded yaks. The key enzymes ACAT2 and HMGCS2 enriched in ketone bodies synthesis and key enzyme PCCA enriched in propanoate metabolism had lower protein expressions in the ruminal epithelium of growth-retarded yaks. The ATP concentration and relative mitochondrial DNA copy number in the ruminal epithelium of growth-normal yaks were dramatically higher than those of growth-retarded yaks (p < 0.05). The activities of citrate synthase (CS), the α-ketoglutarate dehydrogenase complex (α-KGDHC), isocitrate dehydrogenase (ICD) in the tricarboxylic acid cycle (TCA), and the mitochondrial respiratory chain complex (MRCC) were significantly decreased in ruminal epithelium of growth-retarded yaks compared to growth-normal yaks (p < 0.05). The mRNA expressions of COQ9, COX4, and LDHA, which are the encoding genes in MRCC I, IV and anaerobic respiration, were also significantly decreased in the ruminal epithelium of growth-retarded yaks (p < 0.05). Correlation analysis revealed that the average daily gain (ADG) was significantly positively correlated to the relative mitochondrial DNA copy number (p < 0.01, r = 0.772) and ATP concentration (p < 0.01, r = 0.728) in the ruminal epithelium, respectively. The ruminal weight was positively correlated to the relative mitochondrial DNA copy number (p < 0.05, r = 0.631) and ATP concentration in ruminal epithelium (p < 0.01, r = 0.957), respectively. The ruminal papillae had a significant positive correlation with ATP concentration in ruminal epithelium (p < 0.01, r = 0.770). These results suggested that growth-retarded yaks had a lower VFA metabolism, ketone bodies synthesis, ion absorption, and ATP synthesis in the ruminal epithelium; it also indicated that the growth retardation of yaks is related to the obstruction of cellular ATP synthesis in rumen epithelial cells.
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This study aimed to investigate the beneficial effects of probiotic yogurt on lipid metabolism and gut microbiota in metabolic-related fatty liver disease (MAFLD) golden hamsters fed on a high-fat diet (HFD). The results demonstrated that probiotic yogurt significantly reversed the adverse effects caused by HFD, such as body and liver weight gain, liver steatosis and damage, sterol deposition, and oxidative stress after 8 weeks of intervention. qRT-PCR analysis showed that golden hamsters fed HFD had upregulated genes related to adipogenesis, increased free fatty acid infiltration, and downregulated genes related to lipolysis and very low-density lipoprotein secretion. Probiotic yogurt supplements significantly inhibited HFD-induced changes in the expression of lipid metabolism-related genes. Furthermore, 16S rRNA gene sequencing of the intestinal content microbiota suggested that probiotic yogurt changed the diversity and composition of the gut microbiota in HFD-fed hamsters. Probiotic yogurt decreased the ratio of the phyla Firmicutes/Bacteroidetes, the relative abundance of the LPS-producing genus Desulfovibrio, and bacteria involved in lipid metabolism, whereas it increased the relative abundance of short-chain fatty acids producing bacteria in HFD-fed hamsters. Predictive functional analysis of the microbial community showed that probiotic yogurt-modified genes involved in LPS biosynthesis and lipid metabolism. In summary, these findings support the possibility that probiotic yogurt significantly improves HFD-induced metabolic disorders through modulating intestinal microflora and lipid metabolism and effectively regulating the occurrence and development of MAFLD. Therefore, probiotic yogurt supplementation may serve as an effective nutrition strategy for the treatment of patients with MAFLD clinically.
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Tumor-derived exosome PD-L1 exhaustsTcells and permits tumor cells to evade immune surveillance; thus, the inhibition of ExoPD-L1 secretion can significantly enhance the clinical efficacy of PD-L1 antibody. In this study, we combined exosome membrane, apoA1 and phospholipid into biomimetic exosome vesicles (apoA1-bExo) which were then incubated with cholesterol modified siRNA to generate apoA1-bExo containing siRNA (apoA1-bExo/siRNA). Thepreparedvesicleswere uniformandsphericalin size and could be loaded effectively with siRNA to protect from nuclease degradation. Compared with bExo/siRNA, apoA1-bExo/siRNA showed stronger tumor targeting, tissue permeability, intracellular accumulation efficiency and antitumor efficiency. A portion of apoA1-bExo/siRNA transport siRNA occurred through the endosome-Golgi-ER pathway similar to bExo/siRNA, but mostly occurred directly through selective uptake pathways mediated by the SR-B1 receptor. apoA1-bExo/siRNA successfully achieved silencing efficiency at the transcription and protein levels (96.78 % and 94.07 %, respectively) and reduced the secretion of ExoPD-L1 from HepG2 cells to 15.92 % of that in the PBS group, thus enhancing the killing activity of co-cultured T cells on HepG2 cells. In addition, relevant pharmacodynamic indices were positively correlated with delivery efficiency and the modification of apoA1 could significantly enhance the intracellular accumulation of siRNA, thus exhibiting stronger activity than bExo/siRNA. Moreover, in addition to curing mice of their implanted tumors, blocking ExoPD-L1 secretion in combination with αPD-1 promoted the infiltration of durable antitumor hCD8+ T cells and hCD45+ T cells into tumor in a immune system-tumor dual humanized mice.
Subject(s)
Exosomes , Neoplasms , Animals , Mice , B7-H1 Antigen , Biomimetics , Cell Line, Tumor , Exosomes/metabolism , Immunity , Neoplasms/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolismABSTRACT
The investigation of exosomes holds substantial importance in the field of disease diagnosis and prognosis, where in the rapid and low-loss isolation of exosomes emerges as a crucial step owing to their exceedingly low concentration in bodily fluids. Herein, bifunctional immunoaffinity magnetic nanoparticles (BI-NPs) were successfully constructed by binding Ti4+ and antibody to magnetic nanoparticles through host-guest interaction. Exosomes in the cell culture supernatant could be effectively captured by the BI-NPs and then gently eluted with α-CD and 10% ammonia solution. Following the elution process, the content of captured exosome protein was determined to be up to 97 µg/mL. A total of 2822 protein groups were identified in the exosomes isolated by BI-NPs, 1060 protein groups were derived from exosomes. At the same time, the mass of exosome protein obtained by BI-NPs was more than 2 times that of UC isolation, and the above results indicated that BI-NPs had high purity enrichment performance. This is attributed to the fact that BI-NPs combine the dual affinity of Ti4+ and antibody to achieve efficient enrichment of exosomes, in addition to the mild elution property of BI-NPs due to the presence of the host-guest system. BI-NPs offer a novel approach for the isolation of exosomes, in order to further promote the application of exosomes in the required fields.
ABSTRACT
Micro-sized single-crystalline Ni-rich cathodes are emerging as prominent candidates owing to their larger compact density and higher safety compared with poly-crystalline counterparts, yet the uneven stress distribution and lattice oxygen loss result in the intragranular crack generation and planar gliding. Herein, taking LiNi0.83Co0.12Mn0.05O2 as an example, an optimal particle size of 3.7 µm is predicted by simulating the stress distributions at various states of charge and their relationship with fracture free-energy, and then, the fitted curves of particle size with calcination temperature and time are further built, which guides the successful synthesis of target-sized particles (m-NCM83) with highly ordered layered structure by a unique high-temperature short-duration pulse lithiation strategy. The m-NCM83 significantly reduces strain energy, Li/O loss, and cationic mixing, thereby inhibiting crack formation, planar gliding, and surface degradation. Accordingly, the m-NCM83 exhibits superior cycling stability with highly structural integrity and dual-doped m-NCM83 further shows excellent 88.1% capacity retention.