Positive Effects of Organic Amendments on Soil Microbes and Their Functionality in Agro-Ecosystems.

Soil microbial characteristics are considered to be an index for soil quality evaluation. It is generally believed that organic amendments replacing chemical fertilizers have positive effects on changing microbial activity and community structure. However, their effects on different agro-ecosystems on a global scale and their differences in different environmental conditions and experimental durations are unclear. This study performed a meta-analysis based on 94 studies with 204 observations to evaluate the overall effects and their differences in different experimental conditions and duration. The results indicated that compared to chemical fertilizer, organic amendments significantly increased total microbial biomass, bacterial biomass, fungal biomass, Gram-positive bacterial biomass and Gram-negative bacterial biomass, and had no effect on the ratio of fungi to bacteria and ratio of Gram-positive bacteria to Gram-negative bacteria. Meanwhile, land use type, mean annual precipitation and soil initial pH are essential factors affecting microbial activity response. Organic-amendment-induced shifts in microbial biomass can be predominantly explained by soil C and nutrient availability changes. Additionally, we observed positive relationships between microbial functionality and microbial biomass, suggesting that organic-amendment-induced changes in microbial activities improved soil microbial functionality.

Meta-Analysis of Organic Fertilization Effects on Soil Bacterial Diversity and Community Composition in Agroecosystems.

Application of organic fertilizers or their combination with chemical fertilizers is a feasible practice for improving soil fertility and reducing soil degradation in agroecosystems, and these regulations are mainly mediated though soil microbial communities. Despite bacteria ranking among the most abundant and diverse groups of soil microorganisms, the effects of long-term organic fertilization (OF) and chemical-organic fertilization (COF) on soil bacterial diversity and community composition remain unclear. In this study, we conducted a meta-analysis and demonstrated that OF had no significant effect on bacterial alpha diversity. Application of chemical fertilizer and crop residue significantly decreased bacterial Richness index. Both OF and COF significantly altered bacterial community structure, with these changes being predominately attributed to shifts in soil pH. For bacterial phyla, both OF and COF significantly increased the relative abundance of Proteobacteria and Bacteroidetes, suggesting that OF and COF may cause the enrichment of copiotrophic taxa. In addition, COF significantly increased the relative abundance of Gammaproteobacteria but decreased the relative abundance of Acidobacteria. Overall, our results suggest that organic and chemical-organic fertilization can effectively maintain bacterial diversity and enhance soil fertility in agroecosystems, and the alteration of soil bacterial community structure is closely intertwined with soil pH.

Simulation and prediction for the spatial heterogeneity of soil selenium bioavailability at different stratigraphic scales.

Stratigraphic lithology strongly influences the spatial heterogeneity of soil available selenium (ASe), however, it is often neglected in regional simulation. Therefore, taking the Jiangjin District, where the soil is richer in selenium (Se), as the research area, the changes of soil ASe at different spatial scales have been simulated by combining Geodetector and three popular models (Multiple linear regression (MLR), Random forest (RF) and BP neural network (BPN)). The results showed that modelling with 'Formation' as the spatial scale could reduce the influence of stratum lithology difference on the spatial heterogeneity of soil ASe and improve the model's prediction accuracy. Compared with the MLR (R2 = 0.52, root mean squares error (RMSE) = 13.217 µg kg-1) and BPN (R2 = 0.55, RMSE = 13.79 µg kg-1), the RF (R2 = 0.67, RMSE = 10.85 µg kg-1) exhibited higher R2 and smaller RMSE, and the simulation effect of soil ASe is the best in the Middle Jurassic Shaximiao Formation (J2s). The outcomes of variable importance analysis revealed that soil total selenium (TSe) and soil organic matter (SOM) were the imperative factors for predicting ASe. The scenario simulation prediction showed that in the next 40 years, due to the combined influence of SOM and pH, the content of ASe in soil developed in the J2s would decrease from 40.8 µg kg-1 to 37.8 µg kg-1, a 7.8 percent drop. The main areas of soil ASe loss were in the western farming areas. The ASe content in dry land and paddy fields decreased by 12.0% and 4.9%, respectively. Therefore, long-term agricultural production activities would lead to soil ASe loss. The present results could provide a new scheme for the simulation and prediction of regional soil ASe, which is helpful for scientific planning, utilization of selenium-rich soil resources, and development of regional agricultural economy.

Differential diagnosis of secondary hypertension based on deep learning.

Secondary hypertension is associated with higher risks of target organ damage and cardiovascular and cerebrovascular disease events. Early aetiology identification can eliminate aetiologies and control blood pressure. However, inexperienced doctors often fail to diagnose secondary hypertension, and comprehensively screening for all causes of high blood pressure increases health care costs. To date, deep learning has rarely been involved in the differential diagnosis of secondary hypertension. Relevant machine learning methods cannot combine textual information such as chief complaints with numerical information such as the laboratory examination results in electronic health records (EHRs), and the use of all features increases health care costs. To reduce redundant examinations and accurately identify secondary hypertension, we propose a two-stage framework that follows clinical procedures. The framework carries out an initial diagnosis process in the first stage, on which basis patients are recommended for disease-related examinations, followed by differential diagnoses of different diseases based on the different characteristics observed in the second stage. We convert the numerical examination results into descriptive sentences, thus blending textual and numerical characteristics. Medical guidelines are introduced through label embedding and attention mechanisms to obtain interactive features. Our model was trained and evaluated using a cross-sectional dataset containing 11,961 patients with hypertension from January 2013 to December 2019. The F1 scores of our model were 0.912, 0.921, 0.869 and 0.894 for primary aldosteronism, thyroid disease, nephritis and nephrotic syndrome and chronic kidney disease, respectively, which are four kinds of secondary hypertension with high incidence rates. The experimental results show that our model can powerfully use the textual and numerical data contained in EHRs to provide effective decision support for the differential diagnosis of secondary hypertension.

Resveratrol intervention attenuates chylomicron secretion via repressing intestinal FXR-induced expression of scavenger receptor SR-B1.

Two common features of dietary polyphenols have hampered our mechanistic understanding of their beneficial effects for decades: targeting multiple organs and extremely low bioavailability. We show here that resveratrol intervention (REV-I) in high-fat diet (HFD)-challenged male mice inhibits chylomicron secretion, associated with reduced expression of jejunal but not hepatic scavenger receptor class B type 1 (SR-B1). Intestinal mucosa-specific SR-B1-/- mice on HFD-challenge exhibit improved lipid homeostasis but show virtually no further response to REV-I. SR-B1 expression in Caco-2 cells cannot be repressed by pure resveratrol compound while fecal-microbiota transplantation from mice on REV-I suppresses jejunal SR-B1 in recipient mice. REV-I reduces fecal levels of bile acids and activity of fecal bile-salt hydrolase. In Caco-2 cells, chenodeoxycholic acid treatment stimulates both FXR and SR-B1. We conclude that gut microbiome is the primary target of REV-I, and REV-I improves lipid homeostasis at least partially via attenuating FXR-stimulated gut SR-B1 elevation.

LASSO Regression-Based Diagnosis of Acute ST-Segment Elevation Myocardial Infarction (STEMI) on Electrocardiogram (ECG).

Electrocardiogram (ECG) is an important tool for the detection of acute ST-segment elevation myocardial infarction (STEMI). However, machine learning (ML) for the diagnosis of STEMI complicated with arrhythmia and infarct-related arteries is still underdeveloped based on real-world data. Therefore, we aimed to develop an ML model using the Least Absolute Shrinkage and Selection Operator (LASSO) to automatically diagnose acute STEMI based on ECG features. A total of 318 patients with STEMI and 502 control subjects were enrolled from Jan 2017 to Jun 2019. Coronary angiography was performed. A total of 180 automatic ECG features of 12-lead ECG were input into the model. The LASSO regression model was trained and validated by the internal training dataset and tested by the internal and external testing datasets. A comparative test was performed between the LASSO regression model and different levels of doctors. To identify the STEMI and non-STEMI, the LASSO model retained 14 variables with AUCs of 0.94 and 0.93 in the internal and external testing datasets, respectively. The performance of LASSO regression was similar to that of experienced cardiologists (AUC: 0.92) but superior (p < 0.05) to internal medicine residents, medical interns, and emergency physicians. Furthermore, in terms of identifying left anterior descending (LAD) or non-LAD, LASSO regression achieved AUCs of 0.92 and 0.98 in the internal and external testing datasets, respectively. This LASSO regression model can achieve high accuracy in diagnosing STEMI and LAD vessel disease, thus providing an assisting diagnostic tool based on ECG, which may improve the early diagnosis of STEMI.

Deep learning assessment of left ventricular hypertrophy based on electrocardiogram.

Background: Current electrocardiogram (ECG) criteria of left ventricular hypertrophy (LVH) have low sensitivity. Deep learning (DL) techniques have been widely used to detect cardiac diseases due to its ability of automatic feature extraction of ECG. However, DL was rarely applied in LVH diagnosis. Our study aimed to construct a DL model for rapid and effective detection of LVH using 12-lead ECG. Methods: We built a DL model based on convolutional neural network-long short-term memory (CNN-LSTM) to detect LVH using 12-lead ECG. The echocardiogram and ECG of 1,863 patients obtained within 1 week after hospital admission were analyzed. Patients were evenly allocated into 3 sets at 3:1:1 ratio: the training set (n = 1,120), the validation set (n = 371) and the test set 1 (n = 372). In addition, we recruited 453 hospitalized patients into the internal test set 2. Different DL model of each subgroup was developed according to gender and relative wall thickness (RWT). Results: The LVH was predicted by the CNN-LSTM model with an area under the curve (AUC) of 0.62 (sensitivity 68%, specificity 57%) in the test set 1, which outperformed Cornell voltage criteria (AUC: 0.57, sensitivity 48%, specificity 72%) and Sokolow-Lyon voltage (AUC: 0.51, sensitivity 14%, specificity 96%). In the internal test set 2, the CNN-LSTM model had a stable performance in predicting LVH with an AUC of 0.59 (sensitivity 65%, specificity 57%). In the subgroup analysis, the CNN-LSTM model predicted LVH by 12-lead ECG with an AUC of 0.66 (sensitivity 72%, specificity 60%) for male patients, which performed better than that for female patients (AUC: 0.59, sensitivity 50%, specificity 71%). Conclusion: Our study established a CNN-LSTM model to diagnose LVH by 12-lead ECG with higher sensitivity than current ECG diagnostic criteria. This CNN-LSTM model may be a simple and effective screening tool of LVH.

Liraglutide stimulates the ß-catenin signaling cascade in mouse epididymal fat tissue.

Although canonical Wnt signaling pathway activation was shown to negatively regulate adipogenesis, recent investigations suggest that Wnt pathway effectors TCF7L2 and ß-catenin (ß-cat) in adipose tissues are also involved in energy homeostasis during adulthood. In assessing the metabolic beneficial effect of GLP-1-based diabetes drugs in high-fat diet (HFD)-challenged mice, we observed that liraglutide treatment affected the expression of a battery of adipose tissue-specific genes, including those that encode adiponectin and leptin, mainly in epididymal white adipose tissue (eWAT). Fourteen-week HFD challenge repressed TCF7L2 and ß-cat S675 phosphorylation in eWAT, while such repression was reversed by liraglutide treatment (150 µg/kg body weight daily) during weeks 10-14. In Glp1r-/-mice, liraglutide failed in stimulating TCF7L2 or ß-cat in eWAT. We detected Glp1r expression in mouse eWAT and its level is enriched in its stromal vascular fraction (SVF). Mouse eWAT-SVF showed reduced expression of Tcf7l2 and its Tcf7l2 level could not be stimulated by liraglutide treatment; while following adipogenic differentiation, rat eWAT-SVF showed elevated Tcf7l2 expression. Direct in vitro liraglutide treatment in eWAT-SVF stimulated CREB S133, ß-cat S675 phosphorylation, and cellular cAMP level. Thus, cAMP/ß-cat signaling cascade can be stimulated by liraglutide in eWAT via GLP-1R expressed in eWAT-SVF.

Comparison of Beneficial Metabolic Effects of Liraglutide and Semaglutide in Male C57BL/6J Mice.

OBJECTIVES: Semaglutide and liraglutide are glucagon-like peptide-1 (GLP-1)-based diabetes drugs. Semaglutide possesses a longer half-life. Utilizing relatively lower doses, we compared the beneficial metabolic effects of these 2 drugs in mice fed a high-fat diet (HFD), aiming to deepen our mechanistic understanding on their energy homeostatic functions. METHODS: Male C57BL/6J mice were fed an HFD for 10 weeks, followed by daily phosphate-buffered saline (PBS, as control); liraglutide (150 µg/kg body weight); or semaglutide (12 µg/kg body weight, low dose [LD]; or 60 µg/kg body weight, high dose [HD]) injection for 4 weeks. Metabolic tolerance and other tests were conducted within the 4-week period. Expression of metabolism-related genes, including Fgf21 in the liver and adipose tissues, was assessed after mice were euthanized. RESULTS: HFD-induced body weight gain, increasing inguinal fat tissue mass, glucose defects and insulin intolerance were effectively and comparably attenuated in the 3 experimental groups. HD semaglutide showed an even better effect on attenuating hyperleptinemia. Liraglutide but not semaglutide treatment enhanced hepatic fibroblast growth factor 21 (FGF21) protein level. All 3 experimental groups showed elevated expression of genes that encode pyruvate dehydrogenase kinase 4 and enoyl-CoA hydratase and 3-hydroxyacyl-coenzyme A dehydrogenase, associated with reduced plasma triglyceride levels. Finally, the plasma "GLP-1" level in HD semaglutide-treated mice was 14-fold higher than in HFD-fed control mice. CONCLUSIONS: Liraglutide, but not semaglutide, increased hepatic FGF21 protein level, whereas semaglutide had a greater effect on attenuating hyperleptinemia. Thus, these 2 GLP-1-based diabetes drugs may target metabolic organs, including liver and adipose tissue, with differing levels of efficacy.

Deep Learning Networks Accurately Detect ST-Segment Elevation Myocardial Infarction and Culprit Vessel.

Early diagnosis of acute ST-segment elevation myocardial infarction (STEMI) and early determination of the culprit vessel are associated with a better clinical outcome. We developed three deep learning (DL) models for detecting STEMIs and culprit vessels based on 12-lead electrocardiography (ECG) and compared them with conclusions of experienced doctors, including cardiologists, emergency physicians, and internists. After screening the coronary angiography (CAG) results, 883 cases (506 control and 377 STEMI) from internal and external datasets were enrolled for testing DL models. Convolutional neural network-long short-term memory (CNN-LSTM) (AUC: 0.99) performed better than CNN, LSTM, and doctors in detecting STEMI. Deep learning models (AUC: 0.96) performed similarly to experienced cardiologists and emergency physicians in discriminating the left anterior descending (LAD) artery. Regarding distinguishing RCA from LCX, DL models were comparable to doctors (AUC: 0.81). In summary, we developed ECG-based DL diagnosis systems to detect STEMI and predict culprit vessel occlusion, thus enhancing the accuracy and effectiveness of STEMI diagnosis.

Gene regulatory network analysis identifies key genes and regulatory mechanisms involved in acute myocardial infarction using bulk and single cell RNA-seq data.

Cardiovascular and cerebrovascular diseases are leading causes of death worldwide, accounting for more than 40% of all deaths in China. Acute myocardial infarction (AMI) is a common cardiovascular disease and traditionally divided into ST-segment (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), which are known with different prognoses and treatment strategies. However, key regulatory genes and pathways involved in AMI that may be used as potential biomarker for prognosis are unknown. In this study, we employed both bulk and single-cell RNA-seq to construct gene regulatory networks and cell-cell communication networks. We first constructed weighted gene co-expression networks for differential expressed genes between STEMI and NSTEMI patients based on whole-blood RNA-seq transcriptomics. Network topological attributes (e.g., node degree, betweenness) were analyzed to identify key genes involved in different functional network modules. Furthermore, we used single-cell RNA-seq data to construct multilayer signaling network to infer regulatory mechanisms of the above key genes. PLAUR (receptor for urokinase plasminogen activator) was found to play a vital role in transducing inter-cellular signals from endothelial cells and fibroblast cells to intra-cellular pathways of myocardial cells, leading to gene expression involved in cellular response to hypoxia. Our study sheds lights on identifying molecular biomarkers for diagnosis and prognosis of AMI, and provides candidate key regulatory genes for further experimental validation.

Ginsenoside Rb1 attenuates age-associated vascular impairment by modulating the Gas6 pathway.

CONTEXT: Ginsenoside Rb1 (Rb1) exerts many beneficial effects and protects against cardiovascular disease. OBJECTIVE: To investigate whether Rb1 could attenuate age-related vascular impairment and identify the mechanism. MATERIALS AND METHODS: Female C57BL/6J mice aged 2 and 18 months, randomly assigned to Young, Young + 20 mg/kg Rb1, Old + vehicle, Old + 10 mg/kg Rb1 and Old + 20 mg/kg Rb1 groups, were daily intraperitoneal injected with vehicle or Rb1 for 3 months. The thoracic aorta segments were used to inspect the endothelium-dependent vasorelaxation. Left thoracic aorta tissues were collected for histological or molecular expression analyses, including ageing-related proteins, markers relevant to calcification and fibrosis, and expression of Gas6/Axl. RESULTS: We found that in Old + vehicle group, the expression of senescence proteins and cellular adhesion molecules were significantly increased, with worse endothelium-dependent thoracic aorta relaxation (58.35% ± 2.50%) than in Young group (88.84% ± 1.20%). However, Rb1 treatment significantly decreased the expression levels of these proteins and preserved endothelium-dependent relaxation in aged mice. Moreover, Rb1 treatment also reduced calcium deposition, collagen deposition, and the protein expression levels of collagen I and collagen III in aged mice. Furthermore, we found that the downregulation of Gas6 protein expression by 41.72% and mRNA expression by 52.73% in aged mice compared with young mice was abrogated by Rb1 treatment. But there was no significant difference on Axl expression among the groups. CONCLUSIONS: Our study confirms that Rb1 could ameliorate vascular injury, suggesting that Rb1 might be a potential anti-ageing related vascular impairment agent.

Estrogen-Wnt signaling cascade regulates expression of hepatic fibroblast growth factor 21.

We have generated the transgenic mouse line LTCFDN in which dominant negative TCF7L2 (TCF7L2DN) is specifically expressed in the liver during adulthood. Male but not female LTCFDN mice showed elevated hepatic and plasma triglyceride (TG) levels, indicating the existence of estrogen-ß-cat/TCF signaling cascade that regulates hepatic lipid homeostasis. We show here that hepatic fibroblast growth factor 21 (FGF21) expression was reduced in male but not in female LTCFDN mice. The reduction was not associated with altered hepatic expression of peroxisome proliferator-activated receptor α (PPARα). In mouse primary hepatocytes (MPH), Wnt-3a treatment increased FGF21 expression in the presence of PPARα inhibitor. Results from our luciferase-reporter assay and chromatin immunoprecipitation suggest that evolutionarily conserved TCF binding motifs (TCFBs) on Fgf21 promoter mediate Wnt-3a-induced Fgf21 transactivation. Female mice showed reduced hepatic FGF21 production and circulating FGF21 level following ovariectomy (OVX), associated with reduced hepatic TCF expression and ß-catenin S675 phosphorylation. Finally, in MPH, estradiol (E2) treatment enhanced FGF21 expression, as well as binding of TCF7L2 and ribonucleic acid (RNA) polymerase II to the Fgf21 promoter; and the enhancement can be attenuated by the G-protein-coupled estrogen receptor 1 (GPER) antagonist G15. Our observations hence indicate that hepatic FGF21 is among the effectors of the newly recognized E2-ß-cat/TCF signaling cascade.NEW & NOTEWORTHY FGF21 is mainly produced in the liver. Therapeutic effect of FGF21 analogues has been demonstrated in clinical trials on reducing hyperlipidemia. We show here that Fgf21 transcription is positively regulated by Wnt pathway effector ß-cat/TCF. Importantly, hepatic ß-cat/TCF activity can be regulated by the female hormone estradiol, involving GPER. The investigation enriched our understanding on hepatic FGF21 hormone production, and expanded our view on metabolic functions of the Wnt pathway in the liver.

Hepatic Fibroblast Growth Factor 21 Is Involved in Mediating Functions of Liraglutide in Mice With Dietary Challenge.

BACKGROUND AND AIMS: Several studies have shown that expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by glucagon-like peptide 1 (GLP-1)-based diabetes drugs. As GLP-1 receptor (GLP-1R) is unlikely to be expressed in hepatocytes, we aimed to compare such stimulation in mice and in mouse hepatocytes, determine the involvement of GLP-1R, and clarify whether FGF21 mediates certain functions of the GLP-1R agonist liraglutide. APPROACH AND RESULTS: Liver FGF21 expression was assessed in mice receiving a daily liraglutide injection for 3 days or in mouse primary hepatocytes (MPHs) undergoing direct liraglutide treatment. The effects of liraglutide on metabolic improvement and FGF21 expression were then assessed in high-fat diet (HFD)-fed mice and compared with the effects of the dipeptidyl-peptidase 4 inhibitor sitagliptin. Animal studies were also performed in Glp1r-/- mice and liver-specific FGF21-knockout (lFgf21-KO) mice. In wild-type mouse liver that underwent RNA sequencing and quantitative reverse-transcription PCR, we observed liraglutide-stimulated hepatic Fgf21 expression and a lack of Glp1r expression. In MPHs, liraglutide did not stimulate Fgf21. In mice with HFD-induced obesity, liraglutide or sitagliptin treatment reduced plasma triglyceride levels, whereas their effect on reducing body-weight gain was different. Importantly, increased hepatic FGF21 expression was observed in liraglutide-treated mice but was not observed in sitagliptin-treated mice. In HFD-fed Glp1r-/- mice, liraglutide showed no beneficial effects and could not stimulate Fgf21 expression. In lFgf21-KO mice undergoing dietary challenge, the body-weight-gain attenuation and lipid homeostatic effects of liraglutide were lost or significantly reduced. CONCLUSIONS: We suggest that liraglutide-stimulated hepatic Fgf21 expression may require GLP-1R to be expressed in extrahepatic organs. Importantly, we revealed that hepatic FGF21 is required for liraglutide to lower body weight and improve hepatic lipid homeostasis. These observations advanced our mechanistic understanding of the function of GLP-1-based drugs in NAFLD.

Ginsenoside Rb1 Protects Human Umbilical Vein Endothelial Cells against High Glucose-Induced Mitochondria-Related Apoptosis through Activating SIRT3 Signalling Pathway.

OBJECTIVE: To investigate whether ginsenoside Rb1 (Rb1) can protect human umbilical vein endothelial cells (HUVECs) against high glucose-induced apoptosis and examine the underlying mechanism. METHODS: HUVECs were divided into 5 groups: control group (5.5 mmol/L glucose), high glucose (HG, 40 mmol/L) treatment group, Rb1 (50 µ mol/L) treatment group, Rb1 plus HG treatment group, and Rb1 and 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP, 16 µ mol/L) plus HG treatment group. Cell viability was evaluated by cell counting kit-8 assay. Mitochondrial and intracellular reactive oxygen species were detected by MitoSox Red mitochondrial superoxide indicator and dichloro-dihydro-fluorescein diacetate assay, respectively. Annexin V/propidium iodide staining and fluorescent dye staining were used to measure the apoptosis and the mitochondrial membrane potential of HUVECs, respectively. The protein expressions of apoptosis-related proteins [Bcl-2, Bax, cleaved caspase-3 and cytochrome c (Cyt-c)], mitochondrial biogenesis-related proteins [proliferator-activated receptor gamma coactivator 1-alpha, nuclear respiratory factor-1 and mitochondrial transcription factor A)], acetylation levels of forkhead box O3a and SOD2, and sirtuin-3 (SIRT3) signalling pathway were measured by immunoblotting and immunoprecipitation. RESULTS: Rb1 ameliorated survival in cells in which apoptosis was induced by high glucose (P<0.05 or P<0.01). Upon the addition of Rb1, mitochondrial and intracellular reactive oxygen species generation and malondialdehyde levels were decreased (P<0.01), while the activities of antioxidant enzymes were increased (P<0.05 or P<0.01). Rb1 preserved the mitochondrial membrane potential and reduced the release of Cyt-c from the mitochondria into the cytosol (P<0.01). In addition, Rb1 upregulated mitochondrial biogenesis-associated proteins (P<0.01). Notably, the cytoprotective effects of Rb1 were correlated with SIRT3 signalling pathway activation (P<0.01). The effect of Rb1 against high glucose-induced mitochondria-related apoptosis was restrained by 3-TYP (P<0.05 or P<0.01). CONCLUSION: Rb1 could protect HUVECs from high glucose-induced apoptosis by promoting mitochondrial function and suppressing oxidative stress through the SIRT3 signalling pathway.

Ginsenoside Rb1 Ameliorates Age-Related Myocardial Dysfunction by Regulating the NF-[Formula: see text]B Signaling Pathway.

Age-related myocardial dysfunction is a very large healthcare burden. Here, we aimed to investigate whether ginsenoside Rb1 (Rb1) improves age-related myocardial dysfunction and to identify the relevant molecular mechanism. Young mice and aged mice were injected with Rb1 or vehicle for 3 months. Then, their cardiac function was inspected by transthoracic echocardiography. Serum and myocardium tissue were collected from all mice for histological or molecular expression analyses, including aging-related proteins, markers relevant to fibrosis and inflammation, and markers indicating the activation of the nuclear factor-kappa B (NF-[Formula: see text]B) pathway. Compared with the control condition, Rb1 treatment significantly increased the ejection fraction percentage and significantly decreased the internal diameter and volume of the left ventricle at the end-systolic and end-diastolic phases in aged mice. Rb1 treatment reduced collagen deposition and collagen I, collagen III, and transforming growth factor-[Formula: see text]1 protein expression levels in aged hearts. Rb1 also decreased the aging-induced myocardial inflammatory response, as measured by serum or myocardial interleukin-6 and tumor necrosis factor-[Formula: see text] levels. Furthermore, Rb1 treatment in aged mice increased cytoplasmic NF-[Formula: see text]B but decreased nuclear NF-[Formula: see text]B, which indicated the suppression of the NF-[Formula: see text]B signaling pathway by regulating the translocation of NF-[Formula: see text]B. Rb1 could alleviate aging-related myocardial dysfunction by suppressing fibrosis and inflammation, which is potentially associated with regulation of the NF-[Formula: see text]B signaling pathway.

Glucagon-like peptide-1 receptor mediates the beneficial effect of liraglutide in an acute lung injury mouse model involving the thioredoxin-interacting protein.

Repurposing clinically used drugs is among the important strategies in drug discovery. Glucagon-like peptide-1 (GLP-1) and its diabetes-based drugs, such as liraglutide, possess a spectrum of extra-pancreatic functions, while GLP-1 receptor (GLP-1R) is most abundantly expressed in the lung. Recent studies have suggested that GLP-1-based drugs exert beneficial effects in chronic, as well as acute, lung injury rodent models. Here, we show that liraglutide pretreatment reduced LPS induced acute lung injury in mice. It significantly reduced lung injury score, wet/dry lung weight ratio, bronchoalveolar lavage fluid immune cell count and protein concentration, and cell apoptosis in the lung, and it was associated with reduced lung inflammatory cytokine and chemokine gene expression. Importantly, these effects were virtually absent in GLP-1R-/- mice. A well-known function of GLP-1 and GLP-based drugs in pancreatic ß-cells is the attenuation of high-glucose stimulated expression of thioredoxin-interacting protein (TxNIP), a key component of inflammasome. LPS-challenged lungs showed elevated TxNIP mRNA and protein expression, which was attenuated by liraglutide treatment in a GLP-1R-dependent manner. Hence, our observations suggest that GLP-1R is essential in mediating beneficial effects of liraglutide in acute lung injury, with the inflammasome component TxNIP as a potential target.

Effects of supplemental nitrogen application on physiological characteristics, dry matter and nitrogen accumulation of winter rapeseed (Brassica napus L.) under waterlogging stress.

Waterlogging stress is a common limiting factor for winter rapeseed, which greatly affects the growth and potential production. The present study was conducted to investigate the effects of waterlogging with different durations (0day (D0), 6days (D6) and 9days (D9)) and supplemental nitrogen fertilization (N1, 0 kg ha-1; N2, 30 kg ha-1; N3, 60 kg ha-1 and N4, 90 kg ha-1) on the physiological characteristics, dry matter and nitrogen accumulation in winter rapeseed (Chuanyou36). The results showed that the supplementary application of nitrogen fertilizer could effectively improve the physiological indexes of winter rapeseed in both pot and field experiments. The supplemental nitrogen increased the chlorophyll content in leaves, enhanced the activities of SOD, CAT, and POD, and decreased the MDA content in leaves and roots of rapeseed. The chlorophyll contents, the antioxidant enzyme activity of leaves and roots significantly increased under D6N3 and D9N4 conditions in both (pot and field) experiments. However, MDA contents significantly decreased compared with waterlogging without nitrogen application. Moreover, the application of nitrogen fertilizer after waterlogging increased the accumulation of dry matter and nitrogen in rapeseed at different growth stages. Therefore, waterlogging stress significantly inhibited the growth and development of rapeseed, but the application of nitrogen fertilizer could effectively reduce the damage of waterlogging. The N-induced increase in waterlogging tolerance of rapeseed might be attributed to the strong antioxidant defense system, maintenance of photosynthetic pigments and the nutrient balance.

Ginsenoside Rb1 reduces H2O2­induced HUVEC dysfunction by stimulating the sirtuin­1/AMP­activated protein kinase pathway.

Endothelial dysfunction and senescence are closely associated with cardiovascular diseases including atherosclerosis and hypertension. Ginsenoside Rb1 (Rb1), the major active constituent of ginseng, has been investigated intensively because of its anti­obesity and anti­inflammatory effects. In a previous study, hydrogen peroxide (H2O2) was applied to induce human umbilical vein endothelial cell (HUVEC) aging. It was demonstrated that Sirtuin­1 (SIRT1) was activated by Rb1 to protect HUVECs from H2O2­induced senescence. However, the mechanisms are not fully understood. The present study examined the role of AMP­activated protein kinase (AMPK), an energy sensor of cellular metabolism, in the signaling pathway of SIRT1 during H2O2­stimulated HUVEC aging. It was identified that Rb1 restored the H2O2­induced reduction of SIRT1 expression, which was consistent with our previous study, together with the activation of AMPK phosphorylation. Using compound C, an AMPK inhibitor, the role of AMPK in the protective effect of Rb1 against H2O2­induced HUVEC senescence was examined. It was identified that the induction of phosphorylated AMPK by Rb1 markedly increased endothelial nitric oxide synthase expression and nitric oxide production, and suppressed PAI­1 expression, which were abrogated in HUVECs pretreated with compound C. Further experiments demonstrated that nicotinamide, a SIRT1 inhibitor, downregulated the phosphorylation of AMPK and reduced the protective effects of Rb1 against H2O2­induced endothelial aging. Taken together, these results provide new insights into the possible molecular mechanisms by which Rb1 protects against H2O2­induced HUVEC senescence via the SIRT1/AMPK pathway.

Ginsenoside Rb1 Alleviates Oxidative Low-Density Lipoprotein-Induced Vascular Endothelium Senescence via the SIRT1/Beclin-1/Autophagy Axis.

Oxidative low-density lipoprotein (ox-LDL) induces endothelium senescence and promotes atherosclerosis. Ginsenoside Rb1 (gRb1) has been proved to protect human umbilical vein cells (HUVECs), but its effect on ox-LDL-induced endothelium senescence and the underlying mechanism remains unknown. This study is to explore the involvement of the SIRT1/Beclin-1/autophagy axis in the effect of gRb1 on protecting endothelium against ox-LDL-induced senescence. Hyperlipidemia of Sprague Dawley rats was induced by high-fat diet, and gRb1 was intraperitoneal injected. A senescence model of HUVECs induced by ox-LDL was also established. The results showed that gRb1 alleviated hyperlipidemia-induced endothelium senescence and ox-LDL-induced HUVECs senescence. GRb1 also restored the reductions in SIRT1 and autophagy, which were involved in the anti-senescence effects. Beclin-1 acetylation was reduced, and the correlation between SIRT1 and Beclin-1 was increased by gRb1. Results of our study demonstrated the anti-senescence function of gRb1 against hyperlipidemia in the endothelium, and the underlying mechanism involves the SIRT1/Beclin-1/autophagy axis.