Comprehensive pharmacological and experimental study of Ginsenoside Re as a potential therapeutic agent for non-alcoholic fatty liver disease.

OBJECTIVE: Ginsenoside Re, a unique tetracyclic triterpenoid compound found in ginseng, has been suggested in previous reports to improve non-alcoholic fatty liver disease (NAFLD) by modulating lipid imbalance. This study aims to elucidate the potential mechanisms of Ginsenoside Re in treating NAFLD through a combination of bioinformatics analysis and biological experiments. METHODS: Network pharmacology methods were employed to systematically depict the effective components and mechanisms of Ginsenoside Re in improving NAFLD. Molecular docking was utilized to evaluate the binding affinity of Ginsenoside Re with NAFLD-related targets and identify potential targets. NAFLD-related target genes were obtained from the GEO database for gene enrichment analysis, revealing signaling pathways, biological processes, and gene differential expression. Finally, animal experiments were conducted to verify the mechanism of action of Ginsenoside Re in NAFLD. RESULTS: Network pharmacology analysis revealed that Ginsenoside Re improves NAFLD by modulating targets such as AKT1 and TLR4, findings corroborated by molecular docking, GEO database analysis, and experimental validation. Further investigation found that Ginsenoside Re ameliorates lipid metabolism disorders and inflammatory responses induced by NAFLD by modulating the PI3K/AKT and TLR4/NF-κB signaling pathways. CONCLUSION: Our study demonstrates the pharmacological effects of Ginsenoside Re in treating NAFLD, implicating multiple components, targets, and pathways. This provides a solid foundation for considering Ginsenoside Re as an alternative therapy for NAFLD, with promising clinical applications.

Collaborative Enhancement of Consistency and Accuracy in US Diagnosis of Thyroid Nodules Using Large Language Models.

Background Large language models (LLMs) hold substantial promise for medical imaging interpretation. However, there is a lack of studies on their feasibility in handling reasoning questions associated with medical diagnosis. Purpose To investigate the viability of leveraging three publicly available LLMs to enhance consistency and diagnostic accuracy in medical imaging based on standardized reporting, with pathology as the reference standard. Materials and Methods US images of thyroid nodules with pathologic results were retrospectively collected from a tertiary referral hospital between July 2022 and December 2022 and used to evaluate malignancy diagnoses generated by three LLMs-OpenAI's ChatGPT 3.5, ChatGPT 4.0, and Google's Bard. Inter- and intra-LLM agreement of diagnosis were evaluated. Then, diagnostic performance, including accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC), was evaluated and compared for the LLMs and three interactive approaches: human reader combined with LLMs, image-to-text model combined with LLMs, and an end-to-end convolutional neural network model. Results A total of 1161 US images of thyroid nodules (498 benign, 663 malignant) from 725 patients (mean age, 42.2 years ± 14.1 [SD]; 516 women) were evaluated. ChatGPT 4.0 and Bard displayed substantial to almost perfect intra-LLM agreement (κ range, 0.65-0.86 [95% CI: 0.64, 0.86]), while ChatGPT 3.5 showed fair to substantial agreement (κ range, 0.36-0.68 [95% CI: 0.36, 0.68]). ChatGPT 4.0 had an accuracy of 78%-86% (95% CI: 76%, 88%) and sensitivity of 86%-95% (95% CI: 83%, 96%), compared with 74%-86% (95% CI: 71%, 88%) and 74%-91% (95% CI: 71%, 93%), respectively, for Bard. Moreover, with ChatGPT 4.0, the image-to-text-LLM strategy exhibited an AUC (0.83 [95% CI: 0.80, 0.85]) and accuracy (84% [95% CI: 82%, 86%]) comparable to those of the human-LLM interaction strategy with two senior readers and one junior reader and exceeding those of the human-LLM interaction strategy with one junior reader. Conclusion LLMs, particularly integrated with image-to-text approaches, show potential in enhancing diagnostic medical imaging. ChatGPT 4.0 was optimal for consistency and diagnostic accuracy when compared with Bard and ChatGPT 3.5. © RSNA, 2024 Supplemental material is available for this article.

Simulating the effects of optimizing sowing date and variety shift on maize production at finer scale in northeast China under future climate.

BACKGROUND: Global warming and the rising occurrences of climate extremes have become formidable challenges for maize production in northeast China. The optimization of sowing date and variety choice stand out as two economic approaches for maize to enhance its resilience to climate change. Nevertheless, assessment of the potential of optimizing sowing date and variety shift on maize yield at finer scale remains underexamined. This study investigated the implications of optimizing sowing date and implementing variety shift on maize yield from a regional perspective. RESULTS: Compared to the reference period (1986-2005), climate change would decrease by 11.5-34.6% (the range describes the differences among climate scenarios and agro-ecological regions) maize yield in the 2050s (2040-2059) if no adaption measure were to be implemented. The combined adaption (optimizing sowing date and variety shift) can improve maize yield by 38.8 ± 11.3%, 42.7 ± 9.7% and 33.9 ± 7.6% under the SSP1-2.6, SSP2-4.5 and SSP5-8.5 scenarios, respectively. The current sowing window typically falls within the projected optimal sowing window, defined as the period capable of achieving 90% of the maximum yield within the potential sowing window under future climate conditions. Consequently, the potential of the effect of optimizing sowing window on maize yield is limited. In contrast, variety shift results in higher yield improvement, as temperature rise creates favorable conditions for transplanting varieties with an extended growth period, particularly in high latitudes and mountainous regions. Under future climate, cumulative precipitation and compound drought and hot days during maize growing seasons are two key factors influencing maize production. CONCLUSIONS: The optimization of sowing date and variety choice can improve maize yield in northeast China. In addition, maize production should consider varieties with longer growth period and drought and heat tolerance to adapt to climate change. © 2023 Society of Chemical Industry.

Complementary Role of CEUS and CT/MR LI-RADS for Diagnosis of Recurrent HCC.

PURPOSE: We retrospectively compared the diagnostic performance of contrast-enhanced ultrasonography (CEUS) and contrast-enhanced computer tomography-magnetic resonance imaging (CT/MRI) for recurrent hepatocellular carcinoma (HCC) after curative treatment. MATERIALS AND METHODS: After curative treatment with 421 ultrasound (US) detected lesions, 303 HCC patients underwent both CEUS and CT/MRI. Each lesion was assigned a Liver Imaging Reporting and Data System (LI-RADS) category according to CEUS and CT/MRI LI-RADS. Receiver-operating characteristic (ROC) curves were computed to determine the optimal diagnosis algorithms for CEUS, CT and MRI. The diagnostic accuracy, sensitivity, specificity, and area under the curve (AUC) were compared between CEUS and CT/MRI. RESULTS: Among the 421 lesions, 218 were diagnosed as recurrent HCC, whereas 203 lesions were diagnosed as benign. In recurrent HCC, CEUS detected more arterial hyperenhancement (APHE) and washout than CT and more APHE than MRI. CEUS yielded better diagnostic performance than CT (AUC: 0.981 vs. 0.958) (p = 0.024) comparable diagnostic performance to MRI (AUC: 0.952 vs. 0.933) (p > 0.05) when using their optimal diagnostic criteria. CEUS missed 12 recurrent HCCs, CT missed one, and MRI missed none. The detection rate of recurrent HCC on CEUS (94.8%, 218/230) was lower than that on CT/MRI (99.6%, 259/260) (p = 0.001). Lesions located on the US blind spots and visualization score C would hinder the ability of CEUS to detect recurrent HCC. CONCLUSION: CEUS demonstrated excellent diagnostic performance but an inferior detection rate for recurrent HCC. CEUS and CT/MRI played a complementary role in the detection and characterization of recurrent HCC.

Quantitative flood disaster loss-resilience with the multilevel hybrid evaluation model.

The severity of global flood disasters is growing, causing loss of human life and property. Building a high-resilience social system, an important means of sustainable flood control, can address these flood-related issues. Numerous studies have carried out disaster resilience evaluations and explored the correlation between flood disaster loss and intensity, but neglected to analyze the role of resilience construction in disaster loss reduction. This study proposed a research route for linking flood loss and disaster loss to quantify the relationship between the two. Take Guangdong Province, China as a study case, the mixed-effects (ME) model and multilevel hybrid evaluation model (MHEM) were established to assess disaster loss and resilience of cities, respectively. Subsequently, disaster resilience curves were built to quantitatively evaluate disaster resilience and corresponding disaster loss. The results show that (1) the ME model can concurrently build the disaster intensity-loss curves of multiple cities with high fitting accuracy. The MHEM combines multiple methods to determine the evaluation result with the highest consistency, showing high reliability. (2) The central and southern regions of Guangdong Province have low disaster loss and high resilience, while the northern regions have high disaster loss and low resilience. (3) With the improvement of disaster resistance, the reduction in disaster loss gradually decreases. Disaster loss in low-resilience cities exhibits greater randomness than that in high-resilience cities, and increasing their resilience can more significantly reduce their level of loss. This study provides a quantitative basis and available methods for comprehensive responses to natural disasters and adaptation to global climate change.

US LI-RADS in surveillance for recurrent hepatocellular carcinoma after curative treatment.

OBJECTIVES: To investigate the performance of US LI-RADS in surveillance for recurrent hepatocellular carcinoma (RHCC) after curative treatment. MATERIALS AND METHODS: This study enrolled 644 patients between January 2018 and August 2018 as a derivation cohort, and 397 patients from September 2018 to December 2018 as a validation cohort. The US surveillance after HCC curative treatment was performed. The US LI-RADS observation categories and visualization scores were analyzed. Four criteria using US LI-RADS or Alpha-fetoprotein (AFP) as the surveillance algorithm were evaluated. The sensitivity, specificity, and negative predictive value (NPV) were calculated. RESULTS: A total of 212 (32.9%) patients in derivation cohort and 158 (39.8%) patients in validation cohort were detected to have RHCCs. The criterion of US-2/3 or AFP ≥ 20 µg/L had higher sensitivity (derivation, 96.7% vs 92.9% vs 81.1% vs 90.6%; validation, 96.2% vs 90.5% vs 80.4% vs 89.9%) and NPV (derivation, 95.7% vs 93.3% vs 88.0% vs 91.8%; validation, 94.6% vs 89.4% vs 83.6% vs 89.0%), but lower specificity (derivation, 35.9% vs 48.2% vs 67.6% vs 51.9%; validation, 43.5% vs 52.7% vs 66.1% vs 54.0%) than criterion of US-2/3, US-3, and US-3 or AFP ≥ 20 µg/L. Analysis of the visualization score subgroups confirmed that the sensitivity (89.2-97.6% vs 81.0-83.3%) and NPV(88.4-98.0% vs 80.0-83.3%) of score A and score B groups were higher than score C group in criterion of US-2/3 in both two cohorts. CONCLUSIONS: In the surveillance for RHCC, US LI-RADS with AFP had a high sensitivity and NPV when US-2/3 or AFP ≥ 20 µg/L was considered a criterion. CLINICAL RELEVANCE STATEMENT: The criterion of US-2/3 or AFP ≥ 20 µg/L improves sensitivity and NPV for RHCC surveillance, which provides a valuable reference for patients in RHCC surveillance after curative treatment. KEY POINTS: • US LI-RADS with AFP had high sensitivity and NPV in surveillance for RHCC when considering US-2/3 or AFP ≥ 20 µg/L as a criterion. • After US with AFP surveillance, patients with US-2/3 or AFP ≥ 20 µg/L should perform enhanced imaging for confirmative diagnosis. Patients with US-1 or AFP < 20 µg/L continue to repeat US with AFP surveillance. • Patients with risk factors for poor visualization scores limited the sensitivity of US surveillance in RHCC.

Integration of Artificial Intelligence Decision Aids to Reduce Workload and Enhance Efficiency in Thyroid Nodule Management.

Importance: To optimize the integration of artificial intelligence (AI) decision aids and reduce workload in thyroid nodule management, it is critical to incorporate personalized AI into the decision-making processes of radiologists with varying levels of expertise. Objective: To develop an optimized integration of AI decision aids for reducing radiologists' workload while maintaining diagnostic performance compared with traditional AI-assisted strategy. Design, Setting, and Participants: In this diagnostic study, a retrospective set of 1754 ultrasonographic images of 1048 patients with 1754 thyroid nodules from July 1, 2018, to July 31, 2019, was used to build an optimized strategy based on how 16 junior and senior radiologists incorporated AI-assisted diagnosis results with different image features. In the prospective set of this diagnostic study, 300 ultrasonographic images of 268 patients with 300 thyroid nodules from May 1 to December 31, 2021, were used to compare the optimized strategy with the traditional all-AI strategy in terms of diagnostic performance and workload reduction. Data analyses were completed in September 2022. Main Outcomes and Measures: The retrospective set of images was used to develop an optimized integration of AI decision aids for junior and senior radiologists based on the selection of AI-assisted significant or nonsignificant features. In the prospective set of images, the diagnostic performance, time-based cost, and assisted diagnosis were compared between the optimized strategy and the traditional all-AI strategy. Results: The retrospective set included 1754 ultrasonographic images from 1048 patients (mean [SD] age, 42.1 [13.2] years; 749 women [71.5%]) with 1754 thyroid nodules (mean [SD] size, 16.4 [10.6] mm); 748 nodules (42.6%) were benign, and 1006 (57.4%) were malignant. The prospective set included 300 ultrasonographic images from 268 patients (mean [SD] age, 41.7 [14.1] years; 194 women [72.4%]) with 300 thyroid nodules (mean [SD] size, 17.2 [6.8] mm); 125 nodules (41.7%) were benign, and 175 (58.3%) were malignant. For junior radiologists, the ultrasonographic features that were not improved by AI assistance included cystic or almost completely cystic nodules, anechoic nodules, spongiform nodules, and nodules smaller than 5 mm, whereas for senior radiologists the features that were not improved by AI assistance were cystic or almost completely cystic nodules, anechoic nodules, spongiform nodules, very hypoechoic nodules, nodules taller than wide, lobulated or irregular nodules, and extrathyroidal extension. Compared with the traditional all-AI strategy, the optimized strategy was associated with increased mean task completion times for junior radiologists (reader 11, from 15.2 seconds [95% CI, 13.2-17.2 seconds] to 19.4 seconds [95% CI, 15.6-23.3 seconds]; reader 12, from 12.7 seconds [95% CI, 11.4-13.9 seconds] to 15.6 seconds [95% CI, 13.6-17.7 seconds]), but shorter times for senior radiologists (reader 14, from 19.4 seconds [95% CI, 18.1-20.7 seconds] to 16.8 seconds [95% CI, 15.3-18.3 seconds]; reader 16, from 12.5 seconds [95% CI, 12.1-12.9 seconds] to 10.0 seconds [95% CI, 9.5-10.5 seconds]). There was no significant difference in sensitivity (range, 91%-100%) or specificity (range, 94%-98%) between the 2 strategies for readers 11 to 16. Conclusions and Relevance: This diagnostic study suggests that an optimized AI strategy in thyroid nodule management may reduce diagnostic time-based costs without sacrificing diagnostic accuracy for senior radiologists, while the traditional all-AI strategy may still be more beneficial for junior radiologists.

A comprehensive meta-analysis of the impacts of intensified drought and elevated CO2 on forage growth.

Forage crops are used worldwide as key feed sources for dairy systems. However, their productivity and quality are limited due to intensified drought events, elevated carbon dioxide (CO2), and their interaction with climate change, with consequences for the security of animal husbandry and the agricultural economy. Although studies have quantified the impacts of such stresses on forage growth, these impacts have been less systematically investigated in a global context due to differences among various forage groups, regional microclimates, and environmental factors. Herein we employed nine forage growth-related variables involving three perspectives, i.e., photosynthetic parameters, production, and quality, from research articles published between 1990 and 2021 via a meta-analysis. A linear mixed-effect model was then used to explore the quantitative relationship between these factors in a restricted dataset. Decreasing trends in all four photosynthetic parameters were detected across different eco-geographical regions with increasing drought stress. The maximum decrease in DMY occurred in the Mediterranean, with 52.8% under drought conditions. Globally, eCO2 significantly increased photosynthetic rate (Pn) and instantaneous water use efficiency (WUEi) by 40.8% and 62.1%, respectively, which also had positive effects on forage dry matter yield (DMY) (+25.1%), especially for forage in Northern Europe. However, this stress would significantly decrease forage quality by decreasing crude protein (CP) (-19.7%) and nitrogen content (N content) (-13.5%). These negative impacts would be aggravated under the co-occurrence of drought and eCO2, including a significant increase in WUEi (+111.1%) and a decrease in DMY (-12.3%). Gramineae showed a more sensitive response to drought stress in photosynthetic parameters and DMY than Leguminosae, but the latter exhibited a better response in photosynthetic parameters and production under eCO2. Our analysis provides a consensus concerning how the growth parameters of forage have changed under environmental stresses.

Refined revealing the chain path of multiple ecosystem services under diverse environmental factor gradients.

A fragile karst ecosystem presents ecosystem services affected by the environment and interactions between ecosystem services. However, the ecosystem in the karst area is characterized by low environmental capacity and low resistance to force disturbance. Current research mainly focuses on the trade-off/synergy of ecosystem services in the karst area yet it lacks inductive analysis of the multiple chain path among ecosystem services. This paper quantitatively identified dominant factors influencing spatial differentiation of surface runoff, soil moisture, sediment yield, and net primary productivity (NPP) and determined the chain path. The chain paths of surface runoff-soil moisture-NPP and NPP-surface runoff-sediment yield were analyzed. The results showed that land use and soil type were the dominant factors, and chain effects of ecosystem services were diverse under the various dominant factor gradients. The mediation effects of paddy soil (97.21 %) and mountain meadow soil (55.56 %) were high, and surface runoff had a greater impact on NPP by affecting soil moisture. Among the diverse land use types, the mediation effect of surface runoff on NPP affecting sediment yield varied greatly (from 5 to 100 %). In addition, its variation trend was consistent with that of the soil moisture as the mediation variable. The mediation effect of surface runoff on construction land was the highest (99.43 %). This study provides the scientific basis for selecting more effective water and soil conservation measures by analyzing the chain relationships of multiple ecosystem services under different environmental factor gradients.

Clinical Value of Neutrophil CD64 Index, PCT, and CRP in Acute Pancreatitis Complicated with Abdominal Infection.

Objective: To study the clinical diagnostic value of neutrophil CD64 index, PCT, and CRP in patients with acute pancreatitis with abdominal infection. Methods: A number of patients with acute pancreatitis (n = 234) participated in the study. According to the infection and health conditions, they were further divided into the non-infection group (n = 122), infection group (n = 78), and sepsis group (n = 34), and 40 healthy subjects were selected in the control group (n = 40). Expression levels of infection indexes, such as CD64 index, PCT, and CRP, were detected and compared. ROC curves were drawn to compare the efficacy of each index in the diagnosis of acute pancreatitis with abdominal infection and sepsis. The study was retrospectively registered under the China Clinical Trial Registry as a trial number ChiCTR2100054308. Results: All indexes were significantly higher in three clinical groups than the healthy control group (p < 0.05). The CD64 index, CD64 positive rate, and PCT in the infected group were significantly higher than those in the uninfected group (ALL p < 0.05). The PCT of patients infected with Gram-negative bacteria was significantly higher than that of Gram-positive bacteria-infected patients (p < 0.05). CD64 index had the best diagnostic efficiency for acute pancreatitis infection, with 82.14% sensitivity, 88.51% specificity, and 0.707 Youden indexes. The CD64 Youden index (0.780) for sepsis diagnosis was the highest, while the AUC of PCT was the highest (0.897). Conclusion: CD64 index combined with PCT has good sensitivity and specificity in diagnosing acute pancreatitis infection and sepsis.

RCAN1 deficiency aggravates sepsis-induced cardiac remodeling and dysfunction by accelerating mitochondrial pathological fission.

OBJECTIVE: Cardiac dysfunction and remodeling are serious complications of sepsis and are the main causes of death in sepsis. RCAN1 is a feedback regulator of cardiac hypertrophy. Here, we aim to investigate the role of RCAN1 in septic cardiomyopathy. METHODS: Mice were randomly divided into control-WT, control-RCAN1-/-, LPS-induced WT and LPS-induced RCAN1-/- groups, some with Midiv-1 or KN93 treatment. The protein levels of RCAN1, p-ERK1/2, NFAT3, Drp1, p-Drp1, p-CaMKII in mouse hearts or cultured cardiomyocytes were determined by Western blotting. Myocardial function was assessed by echocardiography. Cardiac hypertrophy and fibrosis were detected by H&E and Masson's trichrome staining. Mitochondrial morphology was examined by transmission electron microscope. Serum level of LDH was detected by ELISA. RESULTS: Our data show that RCAN1 was downregulated in septic mouse heart and LPS-induced cardiomyocytes. RCAN1-/- mice showed a severe impairment of cardiac function, and increased myocardial hypertrophy and fibrosis. The protein levels of NFAT3 and p-ERK1/2 were significantly increased in the heart tissues of RCAN1-/- mice. Further, RCAN1 deficiency aggravated sepsis-induced cardiac mitochondrial injury as indicated by increased ROS production, pathological fission and the loss of mitochondrial membrane potential. Inhibition of fission with Mdivi-1 reversed LPS-induced cardiac hypertrophy, fibrosis and dysfunction in RCAN1-/- mice. Moreover, RCAN1 depletion promoted mitochondrial translocation of CaMKII, which enhanced fission and septic hypertrophy, while inhibition of CaMKII with KN93 reduced excessive fission, improved LPS-mediated cardiac remodeling and dysfunction in RCAN1-/- mice. CONCLUSIONS: Our finding demonstrated that RCAN1 deficiency aggravated mitochondrial injury and septic cardiomyopathy through activating CaMKII. RCAN1 serves as a novel therapeutic target for treatment of sepsis-related cardiac remodeling and dysfunction.

Spatial Distribution of Soil Heavy Metals and Associated Environmental Risks near Major Roads in Southern Tibet, China.

Soil heavy metal pollution is becoming an increasingly serious environmental problem. This study was performed to investigate the contents of surface soil heavy metals (Cu, Zn, Pb, Cd) near six roads in the southern part of the Tibetan Plateau. Multivariate statistics, geoaccumulation index, potential ecological risk, and a human health assessment model were used to study the spatial pollution pattern and identify the main pollutants and regions of concern. The mean Igeo was ranked in the order Cd > Cu > Zn > Pb, with the average concentrations of Cd, Zn, and Cu exceeding their corresponding background levels 4.36-, 1.00-, and 1.8-fold, respectively. Soil Cd level was classified as posing a considerable potential risk near national highways and a high potential risk near non-national highways, whereas soil Cu, Zn, and Pb were associated with a low potential ecological risk for each class of roads. Furthermore, the non-carcinogenic risk due to soil heavy metals for each class of roads was within the acceptable risk level for three exposure pathways for both adults and children, but the carcinogenic risk attributable to soil Pb exceeded the threshold for children near highways G318, G562, and G219 and for adults near highway G318. Our work not only underscores the importance of assessing potential threats to ecological and human health due to soil heavy metal pollution on road surfaces but also provides quantitative guidance for remediation actions.

[Comparison of apical root resorption of maxillary incisors between adolescents and adults after orthodontic treatment].

PURPOSE: To compare apical root resorption of maxillary incisors between adolescents and adults after orthodontic treatment. METHODS: Patients receiving orthodontic treatment in Affiliated Hospital of Chifeng University from May 2014 to August 2016 were enrolled, and divided into two age groups: adolescent group (32) and adult group (36). The included subjects received orthodontic fixed appliance treatment with straight-wire technique combined with Hawley type retainer for one year. After treatment, all patients were followed up for one year. Then the apical root resorption of maxillary incisors was evaluated by cone-beam CT (CBCT) at 4 time points, including pre-treatment (T1), end of treatment (T2), 6 months after treatment (T3), and 12 months after treatment (T4). Data were processed by SPSS 20.0 software package. RESULTS: The external root volume of maxillary central incisor, lateral incisors, mandibular central incisors and mandibular lateral incisors of both sides at T2-T4 was significantly lower than that at T1(P<0.05). There was partial increase in root volume of both groups at T3 and T4, while no significant difference from that at T2 (P>0.05). △root volume T3-T2 and △root volume T4-T3 had no significant difference between the two groups (P>0.05). △root volume T3-T2 in the adolescent group was significantly smaller than that in the adult group (P<0.05). Correlation analysis showed that the △root volumeT1-T2 was significantly positively correlated with age (P<0.05), meanwhile △root volume T3-T2 and △root volume T4-T3 were negatively correlated with age (P<0.05). CONCLUSIONS: Age is an important factor affecting the volume of root after orthodontic treatment. Adolescent patients with Class II division 1 malocclusion have a strong ability of self-healing after orthodontic treatment.

Aliskiren Improved the Endothelial Repair Capacity of Endothelial Progenitor Cells from Patients with Hypertension via the Tie2/PI3k/Akt/eNOS Signalling Pathway.

BACKGROUND: Studies show that aliskiren exerts favourable effects not only on endothelial progenitor cells (EPCs) but also on endothelial function. However, the mechanism of the favourable effect of aliskiren on EPCs from patients with hypertension is unclear and remains to be further studied. METHODS: The object of this study was to investigate and assess the in vitro function of EPCs pretreated with aliskiren. After treated with aliskiren, the human EPCs were transplanted into a nude mouse model of carotid artery injury, and the in vivo reendothelialization of injured artery was estimated by staining denuded areas with Evans blue dye via tail vein injection. RESULTS: We found that aliskiren increased the in vitro migration, proliferation, and adhesion of EPCs from patients with hypertension in a dose-dependent manner and improved the reendothelialization capability of these EPCs. Furthermore, aliskiren increased the phosphorylation of Tie2, Akt, and eNOS. After the blockade of the Tie2 signalling pathway, the favourable effects of aliskiren on the in vitro function and in vivo reendothelialization capability of EPCs were suppressed. CONCLUSIONS: This study demonstrates that aliskiren can improve the in vitro function and in vivo reendothelialization capability of EPCs from patients with hypertension via the activation of the Tie2/PI3k/Akt/eNOS signalling pathway. These findings further indicate that aliskiren is an effective pharmacological treatment for cell-based repair in hypertension-related vascular injury.

Impact of spring phenology variation on GPP and its lag feedback for winter wheat over the North China Plain.

Spring green-up date (GUD) is a sensitive indicator of climate change, and of great significance to winter wheat production. However, our knowledge of the chain relationships among them is relatively weak. In this study, based on 8-day Enhanced Vegetation Index (EVI) data from Moderate Resolution Imaging Spectroradiometer (MODIS) from 2001 to 2015, we first assessed the performance of four algorithms for extracting winter wheat GUD in the North China Plain (NCP). A multiple linear regression model was then established to quantitatively determine the contributions of the time lag effects of hydrothermal variation on GUD. We further investigated the interactions between GUD and gross primary production (GPP) comprehensively. Our results showed that the rate of change in curvature algorithm (RCCmax) had better performance in capturing the spatiotemporal variation of winter wheat GUD relative to the other three methods (Kmax, CRmax, and cumCRmax). Regarding the non-identical lag time effects of hydrothermal factors, hydrothermal variations could explain winter wheat GUD variations for 82.05% of all pixels, 36.78% higher than that without considering the time lag effects. Variation in GUD negatively correlated with winter wheat GPP after green up in most parts of the NCP, significantly in 35.75% of all pixels with a mean rate of 1.89 g C m-2 yr-1 day-1. Meanwhile, winter wheat GPP exerted a strongly positive feedback on GUD in >82.42% of all pixels (significant in 28.01% of all pixels), characterized by a humped-shape pattern along the long-term average plant productivity. This finding highlights the complex interaction between spring phenology and plant productivity, and also suggests the importance of preseason climate factors on spring phenology.

Role of the microRNA­214/Bax axis in the progression of acute liver failure.

Acute liver failure (ALF) is a fatal liver disease characterized by severe hepatocyte destruction. MicroRNAs (miRNAs/miRs) have been reported to serve a key role in a number of liver diseases. Therefore, the aim of the present study was to investigate the role and underlying mechanism of miR­214 in ALF. ALF murine and hepatocyte models were established using D­galactosamine (D­GalN) and lipopolysaccharide (LPS) or D­GalN + tumor necrosis factor (TNF)­α, respectively. The expression levels of miR­214 and Bax were detected by reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and/or western blotting. Furthermore, an automatic biochemical analyzer was used to measure the levels of aspartate aminotransferase (AST) or alanine aminotransferase (ALT). The levels of TNF­α and interleukin (IL)­6 were detected by ELISA and RT­qPCR. In addition, TUNEL staining and flow cytometry were used to analyze cell apoptosis, and the protein expression of caspase­3 was determined by western blotting. It was identified that the levels of AST and ALT were increased and that hepatocyte apoptosis was enhanced in the D­GalN/LPS­stimulated group compared with the control. Furthermore, higher expression of caspase­3 was observed in the D­GalN/LPS­stimulated group. In addition, it was demonstrated that miR­214 was downregulated, while Bax was upregulated in D­GalN/LPS­stimulated mice and D­GalN/TNF­α­stimulated BNLCL2 cells. Moreover, in D­GalN/TNF­α­stimulated BNLCL2 cells, miR­214 overexpression suppressed apoptosis and decreased TNF­α and IL­6 levels, and these effects were reversed by the Bax plasmid. It was also identified that overexpression of miR­214 significantly decreased Bax mRNA and protein expression levels in vitro. Collectively, the present results suggested that miR­214 inhibited hepatocyte apoptosis during ALF development via targeting Bax, thus indicating that miR­214 may be a potential target for ALF treatment.

Shear Stress Triggers Angiogenesis of Late Endothelial Progenitor Cells via the PTEN/Akt/GTPCH/BH4 Pathway.

BACKGROUND: Shear stress is an effective modulator of endothelial progenitor cells (EPCs) and has been suggested to play an important role in angiogenesis. The phosphatase and tensin homolog (PTEN)/Akt and guanosine triphosphate cyclohydrolase (GTPCH)/tetrahydrobiopterin (BH4) pathways regulate the function of early EPCs. However, the role of these pathways in the shear stress-induced angiogenesis of late EPCs remains poorly understood. Therefore, we aim to investigate whether shear stress could upregulate the angiogenesis capacity of late EPCs and to further explore the possible underlying mechanisms. METHODS: Late EPCs were subjected to laminar shear stress (LSS), and their in vitro migration, proliferation, and tube formation capacity were determined. In addition, the in vivo angiogenesis capacity was explored, along with the expression of molecules involved in the PTEN/Akt and GTPCH/BH4 pathways. RESULTS: LSS elevated the in vitro activities of late EPCs, which were accompanied by downregulated PTEN expression, accelerated Akt phosphorylation, and GTPCH/BH4 pathway activation (all P < 0.05). Following Akt inhibition, LSS-induced upregulated GTPCH expression, BH4, and NO level of EPCs were suppressed. LSS significantly improved the migration, proliferation, and tube formation ability (15 dyn/cm2 LSS vs. stationary: 72.2 ± 5.5 vs. 47.3 ± 7.3, 0.517 ± 0.05 vs. 0.367 ± 0.038, and 1.664 ± 0.315 vs. 1 ± 0, respectively; all P < 0.05) along with the in vivo angiogenesis capacity of late EPCs, contributing to the recovery of limb ischemia. These effects were also blocked by Akt inhibition or GTPCH knockdown (P < 0.05, respectively). CONCLUSIONS: This study provides the first evidence that shear stress triggers angiogenesis in late EPCs via the PTEN/Akt/GTPCH/BH4 pathway, providing a potential nonpharmacologic therapeutic strategy for promoting angiogenesis in ischemia-related diseases.

Elevated GTP Cyclohydrolase I Pathway in Endothelial Progenitor Cells of Overweight Premenopausal Women.

Background/Aims. Sexual differences exist in endothelial progenitor cells (EPCs), and various cardiovascular risk factors are associated with the preservation of endothelial function in premenopausal women. However, it is unclear whether differences in endothelial function and circulating EPCs exist between overweight premenopausal women and age-matched men. Methods. We compared EPC counting and functions in normal-weight and overweight premenopausal women and men, evaluated endothelial function in each group, and detected the expression of the guanosine triphosphate cyclohydrolase I (GTPCH I) pathway. Results. The number of EPCs was lower in the male group than in the female group, regardless of normal-weight or overweight status, and there was no significant difference between the different weight groups among females or males. Endothelial function and EPC migration and proliferation were preserved in overweight premenopausal women compared with overweight men as were nitric oxide (NO) levels in plasma and secreted by EPCs. Endothelial function, the circulating EPC population, and NO levels were not different between normal-weight and overweight premenopausal women. Flow-mediated dilatation was significantly correlated with EPC function, plasma NO levels, and EPC-secreted NO. Conclusions. This investigation provides the first evidence for sex-based differences in EPC activity and endothelial function in overweight middle-aged individuals; these differences are associated with alterations in NO production and may partly occur through downregulation of the GTPCH I pathway. The present results provide new insights into the mechanism underlying the preserved endothelial function in overweight premenopausal women and may uncover a potential therapeutic target for endothelial repair in overweight population.

Reduced Circulating Endothelial Progenitor Cells and Downregulated GTCPH I Pathway Related to Endothelial Dysfunction in Premenopausal Women with Isolated Impaired Glucose Tolerance.

BACKGROUND: Individuals at a prediabetic stage have had an augmented cardiovascular disease (CVD) risk and CVD-related mortality compared to normal glucose tolerance (NGT) individuals, which may be attributed to the impaired vascular endothelial repair capacity. In this study, circulating endothelial progenitor cells' (EPCs) number and activity were evaluated, and the underlying mechanisms in premenopausal women with impaired glucose regulation were explored. METHODS: Circulating EPCs' number and activity and flow-mediated dilation (FMD) were compared in premenopausal women with NGT, isolated impaired fasting glucose (i-IFG), or isolated impaired glucose tolerance (i-IGT). Plasma nitric oxide (NO), EPCs-secreted NO, and intracellular BH4 levels were also measured. The key proteins (Tie2, Akt, eNOS, and GTPCH I) in the guanosine triphosphate cyclohydrolase/tetrahydrobiopterin (GTPCH/BH4) pathway and Tie2/Akt/eNOS signaling pathway were evaluated in these women. RESULTS: It was observed that the i-IGT premenopausal women not i-IFG premenopausal women had a significant reduction in circulating EPCs' number and activity as well as reduced FMD when compared to NGT subjects. Plasma NO levels or EPCs-secreted NO also decreased only in i-IGT women. The expression of GTCPH I as well as intracellular BH4 levels declined in i-IGT women; however, the alternations of key proteins' expression in the Tie2/Akt/eNOS signaling pathway were not observed in either i-IGT or i-IFG women. CONCLUSIONS: The endothelial repair capacity was impaired in i-IGT premenopausal women but was preserved in i-IFG counterparts. The underlying mechanism may be associated with the downregulated GTCPH I pathway and reduced NO productions.