Mediator subunit MED1 deficiency prevents carbon tetrachloride-induced hepatic fibrosis in mice.

Mediator subunit mediator 1 (MED1) mediates ligand-dependent binding of the mediator coactivator complex to various nuclear receptors and plays a critical role in embryonic development, lipid and glucose metabolism, liver regeneration, and tumorigenesis. However, the precise role of MED1 in the development of liver fibrosis has been unclear. Here, we showed that MED1 expression was increased in livers from nonalcoholic steatohepatitis (NASH) patients and mice and positively correlated with transforming growth factor ß (TGF-ß) signaling and profibrotic factors. Upon treatment with carbon tetrachloride (CCl4), hepatic fibrosis was much less in liver-specific MED1 deletion (MED1ΔLiv) mice than in MED1fl/fl littermates. TGF-ß/Smad2/3 signaling pathway was inhibited, and gene expression of fibrotic markers, including α-smooth muscle actin (α-SMA), collagen type 1 α 1 (Col1a1), matrix metalloproteinase-2 (Mmp2), and metallopeptidase inhibitor 1 (Timp1) were decreased in livers of MED1ΔLiv mice with CCl4 injection. Transcriptomic analysis revealed that the differentially expressed genes in livers of CCl4-administered MED1ΔLiv mice were enriched in the pathway of oxidoreductase activity, followed by robustly reduced oxidoreductase activity-related genes, such as Gm4756, Txnrd3, and Etfbkmt. More importantly, we found that the reduction of reactive oxygen species (ROS) in MED1 knockdown hepatocytes blocked the activation of TGF-ß/Smad2/3 pathway and the expression of fibrotic genes in LX2 cells. These results indicate that MED1 is a positive regulator for hepatic fibrogenesis, and MED1 may be considered as a potential therapeutic target for the regression of liver fibrosis.NEW & NOTEWORTHY In this study, we present the first evidence that liver mediator 1 (MED1) deficiency attenuated carbon tetrachloride-induced hepatic fibrosis in mouse. The underlying mechanism is that MED1 deficiency reduces reactive oxygen species (ROS) production in hepatocytes, thus restricts the activation of TGF-ß/Smad2/3 signaling pathway and fibrogenic genes expression in hepatic stellate cells (HSCs). These data suggest that MED1 is an essential regulator for hepatic fibrogenesis, and MED1 may be considered as a potential therapeutic target for liver fibrosis.

MED1 Deficiency in Macrophages Aggravates Isoproterenol-Induced Cardiac Fibrosis in Mice.

Mediator 1 (MED1), a key subunit of the mediator complex, interacts with various nuclear receptors and functions in lipid metabolism and energy homeostasis. Dilated cardiomyopathy-related ventricular dilatation and heart failure have been reported in mice with cardiomyocyte-specific Med1 deficiency. However, the contribution of macrophage-specific MED1 in cardiac remodeling remains unclear. In this study, macrophage-specific Med1 knockout (Med1ΔMac) mice were generated and exposed to isoproterenol (ISO) to induce cardiac fibrosis; these mice showed aggravated cardiac fibrosis compared with Med1fl/fl mice. The levels of expression of marker genes for myofibroblast transdifferentiation [α-smooth muscle actin (SMA)] and of profibrotic genes, including Col1a1, Col3a1, Postn, Mmp2, Timp1, and Fn1, were significantly increased in the cardiac tissues of Med1ΔMac mice with ISO-induced myocardial fibrosis. In particular, the transforming growth factor (TGF)-ß-Smad2/3 signaling pathway was activated. In bone marrow-derived and peritoneal macrophages, Med1 deficiency was also associated with elevated levels of expression of proinflammatory genes, including Il6, Tnfa, and Il1b. These findings indicate that macrophage-specific MED1 deficiency may aggravate ISO-induced cardiac fibrosis via the regulation of the TGF-ß-SMAD2/3 pathway, and the underlying mechanism may involve MED1 deficiency triggering the activation of inflammatory cytokines in macrophages, which in turn may stimulate phenotypic switch of cardiac fibroblasts and accelerate cardiac fibrosis. Thus, MED1 is a potential therapeutic target for cardiac fibrosis.

Grazing practices affect soil microbial networks but not diversity and composition in alpine meadows of northeastern Qinghai-Tibetan plateau.

Livestock grazing is the primary practice in alpine meadows and can alter soil microbiomes, which is critical for ecosystem functions and services. Seasonal grazing (SG) and continuous grazing (CG) are two kinds of different grazing practices that dominate alpine meadows on the Qinghai-Tibetan Plateau (QTP), and how they affect soil microbial communities remains in-depth exploration. The present study was conducted to investigate the effects of different grazing practices (i.e., SG and CG) on the diversity, composition, and co-occurrence networks of soil bacteria and fungi in QTP alpine meadows. Soil microbial α- and ß-diversity showed no obvious difference between SG and CG grasslands. Grazing practices had little impact on soil microbial composition, except that the relative abundance of Proteobacteria and Ascomycota showed significant difference between SG and CG grasslands. Soil microbial networks were more complex and less stable in SG grasslands than that in CG grasslands, and the bacterial networks were more complex than fungal networks. Soil fungal diversity was more strongly correlated with environmental factors than bacteria, whereas both fungal and bacterial structures were mainly influenced by soil pH, total nitrogen, and ammonium nitrogen. These findings indicate that microbial associations are more sensitive to grazing practices than microbial diversity and composition, and that SG may be a better grazing practice for ecological benefits in alpine meadows.

Divergent response to abiotic factor determines the decoupling of water and carbon fluxes over an artificial C4 shrub in desert.

Knowledge on relationship and determinants of water and carbon dioxide (CO2) exchange is crucial to land managers and policy makers especially for the desertified land restoration. However, there remains highly uncertain in terms of water use and carbon sequestration for artificial plantation in desert. Here, continuous water and carbon fluxes were measured using eddy covariance (EC) in conjunction with hydrometeorological measurements over an artificial C4 shrub, Haloxylon ammodendron (C. A. Mey.) Bunge, from July 2020 to 2021 in Tengger Desert, China. Throughout 2021, evapotranspiration (ET) was 189.5 mm, of which 85% (150 mm) occurred during growing season, that was comparable with the summation of precipitation (132.2 mm), dew (33.5 mm) and potential other sources (e.g. deep subsoil water). This ecosystem was a strong carbon sink with net ecosystem production (NEP) up to 446.4 g C m-2 yr-1, much higher than surrounding sites. Gross primary production (GPP, 598.7 g C m-2 yr-1) in this shrubland was comparable with that of other shrublands, whereas ecosystem respiration (Re, 152.3 g C m-2 yr-1) was lower. Random Forest showed that environmental factors can explain 71.56% and 80.07% variation of GPP and ET, respectively. Interestingly, environmental factors have divergent effect on water and carbon exchange, i.e., soil hydrothermic factors (soil moisture content and soil temperature) determine the magnitude and seasonal pattern of ET and Re, while aerodynamics factors (net radiation, atmospheric temperature and wind speed) determine GPP and NEP. As such, divergent response of abiotic factors resulted in the decoupling of water and carbon exchange. Our results suggest that H. ammodendron is a suitable species for large-scale afforestation in dryland given its low water use but high carbon sequestration. Therefore, we infer that artificial planting H. ammodendron in dryland could provide an opportunity for climate change mitigation, and the long-term time series data is needed to confirm its sustainable role of carbon sequestration in the future.

Urotensin II activates the ferroptosis pathway through circ0004372/miR-124/SERTAD4 to promote the activation of vascular adventitial fibroblasts.

Both vascular adventitial fibroblasts (VAFs) and urotensin II (UII) play important roles in vascular remodeling diseases, but the mechanism of UII in VAFs is still unclear. UII inhibited miR-124 expression through up-regulating circ0004372 expression, thereby promoting SERTAD4 expression. UII significantly promoted the generation of ROS, MDA and 4-HNE, reduced the activities of SOD, GST and GR, increased Fe2+ concentration and inhibited GPX4 expression through circ0004372/miR-124/SERTAD4. Both UII and ferroptosis inducer Erastin significantly promoted the expression of α-SMA, Collagen I and TGF-ß1 in VAFs, but circ0004372 siRNA, miR-124 mimics, SERTAD4 siRNA or Ferrostatin-1 significantly inhibited the effect of UII and Erastin on cell activation. When co-transfected with circ0004372 siRNA and miR-124 inhibitors or miR-124 mimics and SERTAD4 overexpression vector, UII still significantly increased the expression of α-SMA, Collagen I and TGF-ß1. After transfection with circ0004372 overexpression vector, miR-124 inhibitors or SERTAD4 overexpression vector and then treating with UII and Ferrostatin-1, the expression of α-SMA, Collagen I and TGF-ß1 was still significant; when the circ0004372 overexpression vector and miR-124 mimics or miR-124 inhibitors and SERTAD4 siRNA were co-transfected and then UII and Ferrostatin-1 were added, the expression of α-SMA, Collagen I and TGF-ß1 was not significantly increased. Therefore, these results indicate that UII promotes the activation of VAFs through the circ0004372/miR-124/SERTAD4/ferroptosis pathway.

Sensitivity analysis and estimation using a hierarchical Bayesian method for the parameters of the FvCB biochemical photosynthetic model.

Photosynthesis is a major process included in land surface models. Accurately estimating the parameters of the photosynthetic sub-models can greatly improve the ability of these models to accurately simulate the carbon cycle of terrestrial ecosystems. Here, we used a hierarchical Bayesian approach to fit the Farquhar-von Caemmerer-Berry model, which is based on the biochemistry of photosynthesis using 236 curves for the relationship between net CO2 assimilation and changes in the intercellular CO2 concentration. An advantage of the hierarchical Bayesian algorithm is that parameters can be estimated at multiple levels (plant, species, plant functional type, and population level) simultaneously. The parameters of the hierarchical strategy were based on the results of a sensitivity analysis. The Michaelis-Menten constant (Kc25), enthalpies of activation (EJ and EV), and two optical parameters (θ and α) demonstrated considerable variation at different levels, which suggests that this variation cannot be ignored. The maximum electron transport rate (Jmax25), maximum rate of Rubisco activity (Vcmax25), and dark respiration in the light (Rd25) were higher for broad-leaved plants than for needle-leaved plants. Comparison of the model's simulated outputs with observed data showed strong and significant positive correlations, particularly when the model was parameterized at the plant level. In summary, our study is the first effort to combine sensitivity analysis and hierarchical Bayesian parameter estimation. The resulting realistic parameter distributions for the four levels provide a reference for current and future land surface models. Furthermore, the observed variation in the parameters will require attention when using photosynthetic parameters in future models.

Diagnostic Utility of Triglyceride-Glucose Index in Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study on Lean Population.

Background: Approximately 10-20% of individuals with non-alcoholic fatty liver disease (NAFLD) are lean, and the underlying pathophysiology is not yet understood. This study aims to explore the characteristics and the diagnostic value of triglyceride-glucose index (TyG) in early diagnosis of lean NAFLD. Methods: 99 patients with lean NAFLD and 1891 healthy controls were included in the health examination. The characteristics were compared between groups. Restricted cubic spline was utilized to analyze the relationship between TyG index and the risk of lean NAFLD. Logistic regression and receiver operating curve (ROC) were applied to explore the diagnostic value of TyG index for lean NAFLD. Results: Overall, 99 (4.97%) patients had lean NAFLD. Patients with lean NAFLD have significant abnormal glycolipid metabolism and higher TyG index. Restriction cube spline analysis showed a significant dose-response relationship between the TyG index and risk of lean NAFLD. After adjusting for confounders, the relationship remained and the risk of developing lean NAFLD increased 2.99 times for per unit increase of TyG index (95% CI: 1.94, 4.67, P<0.001). The areas under the ROC of the TyG index for lean NAFLD detection were 0.851 (0.815 to 0.886). Conclusion: The TyG index is positively associated with the risk of developing lean NAFLD and could be a useful marker for early diagnosis of lean NAFLD.

Diagnostic performance of the quantitative flow ratio and CT-FFR for coronary lesion-specific ischemia.

Fractional flow reserve (FFR) has become the gold standard for evaluating coronary lesion-specific ischemia. However, FFR is an invasive method that may cause possible complications in the coronary artery and requires expensive equipment, which limits its use. Promising noninvasive diagnostic methods, such as computed tomography angiography-derived FFR (CT-FFR) and the quantitative flow ratio (QFR), have been proposed. In this study, we evaluated the diagnostic performance of the QFR and CT-FFR in predicting coronary lesion-specific ischemia, with the FFR serving as the reference standard. Patients with suspected or known coronary artery disease who underwent coronary CT angiography revealing 30-90% diameter stenosis in the main coronary artery (≥ 2.0 mm reference diameter) were enrolled. The FFR was measured during invasive coronary angiography (within 15 days after coronary CT angiography). An FFR ≤ 0.8 was the reference standard for coronary lesion-specific ischemia. A total of 103 vessels from 92 consecutive patients (aged 59.8 ± 9.2 years; 60.9% were men) were evaluated. The diagnostic performance of a QFR ≤ 0.80 for predicting coronary lesion-specific ischemia demonstrated good diagnostic accuracy, sensitivity, and specificity (92.2%, 87.2%, and 96.4%, respectively), with an area under the receiver operating characteristic curve (AUC) of 0.987 (P < 0.0001). The diagnostic performance of a CT-FFR ≤ 0.80 for predicting coronary lesion-specific ischemia also demonstrated good diagnostic accuracy, sensitivity, and specificity (96.1%, 95.7%, and 96.4%, respectively), with an AUC of 0.967 (P < 0.0001). However, there was no significant difference in the AUC between a QFR ≤ 0.80 and a CT-FFR ≤ 0.80 for predicting coronary lesion-specific ischemia (P = 0.319). There was an excellent correlation between the QFR and FFR (r = 0.856, P < 0.0001). The CT-FFR and FFR also showed a good direct correlation (r = 0.816, P < 0.0001). The QFR and CT-FFR are strongly correlated with the FFR and can provide excellent clinical diagnostic performance for coronary lesion-specific ischemia detection.

Association of the awareness of the epidemic, mental health status with mobile phone screen use time in Chinese college students during COVID-19 isolation and control.

OBJECTIVE: This study aimed to investigate the awareness of the epidemic among college students and their mental health as well as to explore the association between their awareness of the epidemic mental health and the daily mobile phone screen use time, in order to provide guidance for the publicity of school epidemic prevention and control knowledge and the psychological counseling of students. METHODS: A cross-sectional design was employed among 780 college students, The Pandemic Fatigue Questionnaire, epidemic prevention and control knowledge and the mental health Scale were used to collect data through an online survey. RESULTS: 1. Awareness rate of the transmission routes and protective measures of COVID-19 among college students is higher when the daily mobile screen use time is 3-7 hours. 2. 21.79% of the 780 college students felt stressed; 24.87% felt anxious; 19.23% showed depression. 3. The scores of each subscale in the daily mobile phone screen use time of 3-7 hours and more than 7 hours were higher, and the scores of each subscale in the group of more than 7 hours were the highest. Further correlation analysis found that the time spent on mobile phone screens was positively correlated with stress, anxiety, and depression scores (r = 0.155, 0.180, 0.182, P<0.01). CONCLUSION: During the COVID-19 isolation and control period, college students with different mobile screen usage time have different understandings of the epidemic. Long-term mobile screen use is related to the occurrence of psychological problems such as stress, anxiety, and depression. Therefore, education departments and schools should pay attention to college students' mobile phone use time to reduce the occurrence of bad psychological state of students.

Associations between chronic stress and hair cortisol in children: A systematic review and meta-analysis.

OBJECTIVES: This review systematically examined the associations between chronic stress and hair cortisol concentration (HCC) in children, and the potential modification effects of type, measurement period and scales of chronic stress, child age and sex, hair length and HCC measurement method, characteristics of study site, and congruence between time periods measured for chronic stress and HCC. METHODS: Pubmed, Wed of Science, and APA PsycINFO were systematically searched for articles examining the association between chronic stress and HCC. RESULTS: Thirteen studies from five countries with 1,455 participants were included in the systematic review and nine studies were included in the meta-analysis. Meta-analysis revealed that chronic stress was associated with HCC (pooled-r = 0.09, 95 % CI: 0.03, 0.16). Stratified analyses revealed that type, measurement time and scales of chronic stress, hair length and measurement method of HCC, and the congruence between time periods measured for chronic stress and HCC modified such correlations. The positive correlations between chronic stress and HCC were significant for studies measuring chronic stress as stressful life events, assessing chronic stress within the past six months, extracting HCC from 1 cm, 3 cm, or 6 cm of hair, measuring HCC by LC-MS/MS, or having congruence between time periods measured for chronic stress and HCC. The potential modifying effects of sex and country developmental status could not be concluded due to the limited number of studies included. CONCLUSIONS: Chronic stress was positively correlated with HCC, varying by characteristics and measurements of chronic stress and HCC. HCC could be a biomarker for chronic stress among children.

Development and validation of a model to predict the risk of hypertension using anthropometric indicators in the Chinese population: a retrospective cohort study.

BACKGROUND: The prevalence of hypertension and obesity in China has sharply increased in recent decades. We aimed to develop and validate a novel model for predicting the risk of hypertension based on anthropometric indicators relating to obesity in the general population of China. METHODS: In this retrospective study, 6196 participants from the China Health and Nutrition Survey (CHNS) during the 2009-2015 waves were included. Risk factors for hypertension were assessed by LASSO regression combined with multivariate logistic regression analysis. A nomogram was developed as a predictive model based on the screening prediction factors. The discrimination and calibration of the model were evaluated by receiver operating curve (ROC) and calibration plots, respectively. Decision curve analysis (DCA) was used to evaluate the clinical application value of the model. RESULTS: A total of 6196 participants were divided into two sets at a ratio of 7:3, using computer-generated random numbers: 4337 individuals were assigned to the training set and 1859 to the validation set. The training set was divided into a hypertension group (n = 1016) and a non-hypertension group (n = 3321) based on the follow-up outcomes for hypertension. Predictive factors of hypertension included age, drinking, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and arm-to-height ratio (AHtR) at baseline as predictors. The area under the ROC curve (AUC) for the training and validation sets was 0.906 (95% CI: 0.897-0.915) and 0.905 (95% CI: 0.887-0.922), respectively. In bootstrap validation, the C-index was 0.905 (95% CI: 0.888-0.921). The model also had good predictive accuracy according to the calibration plot. DCA demonstrated that people would benefit more when the threshold probability was between 5% and 80%. CONCLUSION: A nomogram model was successfully established to effectively predict the risk of hypertension based on anthropometric indicators. The model could be a feasible tool for hypertension screening in the general population of China.

Prevalence, correlates, and network analysis of depression and its association with quality of life in survivors with myocardial infarction during the COVID-19 pandemic.

BACKGROUND: Depression is common among myocardial infarction (MI) survivors and is strongly associated with poor quality of life (QOL). The aim of this study was to examine the prevalence, correlates and the network structure of depression, and its association with QOL in MI survivors during the COVID-19 pandemic. METHODS: This cross-sectional study evaluated depression and QOL in MI survivors with the Chinese version of the nine-item Patient Health Questionnaire (PHQ-9) and the World Health Organization Quality of Life-BREF (WHOQOL-BREF), respectively. Univariable analyses, multivariable analyses, and network analyses were performed. RESULTS: The prevalence of depression (PHQ-9 total score ≥ 5) among 565 MI survivors during the COVID-19 pandemic was 38.1 % (95 % CI: 34.1-42.1 %), which was significantly associated with poor QOL. Patients with depression were less likely to consult a doctor regularly after discharge, and more likely to experience more severe anxiety symptoms and fatigue. Item PHQ4 "Fatigue" was the most central symptom in the network, followed by PHQ6 "Guilt" and PHQ2 "Sad mood". The flow network showed that PHQ4 "Fatigue" had the highest negative association with QOL. CONCLUSION: Depression was prevalent among MI survivors during the COVID-19 pandemic and was significantly associated with poor QOL. Those who failed to consult a doctor regularly after discharge or reported severe anxiety symptoms and fatigue should be screened for depression. Effective interventions for MI survivors targeting central symptoms, especially fatigue, are needed to reduce the negative impact of depression and improve QOL.

Association of triglyceride glucose-body mass index with non-small cell lung cancer risk: A case-control study on Chinese adults.

Background and objectives: Insulin resistance (IR) is closely related to non-small-cell lung cancer (NSCLC) risk. Recently, triglyceride glucose-body mass index (TyG-BMI) has been recognized as one of the simple indexes of insulin resistance (IR). However, there are limited data on the relationship between TyG-BMI and NSCLC. Here, we investigated the association of TyG-BMI with NSCLC risk in Chinese adults. Methods: This study consisted of 477 NSCLC cases and 954 healthy subjects. All participants were enrolled from 3201 Hospital affiliated to the Medical Department of Xi'an Jiaotong University. TyG-BMI was calculated based on the values of fasting blood glucose, triglyceride, and BMI. The association of TyG-BMI with NSCLC risk was estimated by logistic regression analysis. Results: The mean value of TyG-BMI was statistically increased in patients with NSCLC compared to the control group (201.11 ± 28.18 vs. 174 ± 23.78, P < 0.01). There was a significant positive association between TyG-BMI and NSCLC (OR = 1.014; 95% CI 1.007-1.021; P < 0.001) after controlling for confounding factors. Moreover, the prevalence of NSCLC was significantly elevated in participants in the high TyG-BMI tertiles than those in the intermediate and low TyG-BMI tertiles (60.46% vs. 12.61% vs. 26.83%, P < 0.01). Importantly, TyG-BMI achieved a significant diagnostic accuracy for NSCLC, with an AUC (area under the curve) of 0.769 and a cutoff value of 184.87. Conclusion: The findings suggest that TyG-BMI is a useful tool for assessing NSCLC risk. Thus, it is essential to follow up on high TyG-BMI, and lifestyle modification is needed to prevent NSCLC in people with high TyG-BMI.

Correction: A fluorescent biosensor for cardiac biomarker myoglobin detection based on carbon dots and deoxyribonuclease I-aided target recycling signal amplification.

[This corrects the article DOI: 10.1039/C8RA09459D.].

Circulating Tumor-Derived Endothelial Cells: An Effective Biomarker for Breast Cancer Screening and Prognosis Prediction.

Background: Circulating tumor-derived endothelial cell (CTEC) is a new potential tumor biomarker to be associated with cancer development and treatment efficacy. However, few evidences are available for breast cancer. Methods: Eighty-nine breast cancer patients were recruited, and preoperative and postoperative blood samples were collected. Besides, 20 noncancer persons were enrolled as controls. An improved subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) method was adopted to codetect CD31+ aneuploid CTEC and CD31- aneuploid circulating tumor cell (CTC). Then, the clinical significance of CTCs and CTECs on breast cancer screening and prognosis prediction was evaluated and compared. Results: The positive rate of CTCs and CTECs in newly diagnosed breast cancer patients was 68.75% and 71.88%. Among detected aneuploid circulating rare cells, CTEC accounts for a greater proportion than CTC in breast cancer patients. CTEC-positive rate and level were significantly higher in breast cancer patients with lymph node metastasis (LNM) than those without LNM (P=0.043), while there was no significant difference in CTC. CTEC (area under the curve, AUC = 0.859) had better performance than CTC (AUC = 0.795) to distinguish breast cancer patients from controls by receiver operator characteristic curve analysis. Preoperative CTEC count ≥ 2 was a significant risk factor for reducing PFS of breast cancer patients. Conclusions: CTECs may function as a reliable supplementary biomarker in breast cancer screening and prognosis prediction.

Sodium glucose cotransporter 2 inhibitor dapagliflozin depressed adiposity and ameliorated hepatic steatosis in high-fat diet induced obese mice.

With the increasing obesity prevalence, the rates of obesity-related diseases, including type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases, have increased dramatically. Dapagliflozin, one of the sodium glucose cotransporter inhibitors, not only exerts hypoglycaemic effects through increasing urinary glucose excretion but alsoreprograms the metabolic system, leading to benefits in metabolic and cardiovascular diseases. In this study, pre-established obese mice on a high-fat diet were given dapagliflozin by gavage for fourweeks. It showed that dapagliflozin can enhance fat utilization and browning of adipose tissue and improve local oxidative stress, thus inhibiting fat accumulation and hepatic steatosis without disturbance in body weight or plasma glycolipid level. Overall, our study highlights the potential clinical application of SGLT2 inhibition in the prevention of obesity and related metabolic diseases, such as insulin resistance, NAFLD, and diabetes.

Ultrasound combined with microbubbles enhances the renoprotective effects of methylprednisolone in rats with adriamycin-induced nephropathy.

The purpose of this study was to investigate the effect of ultrasound combined with microbbules (SonoVueTM) on the potency of methylprednisolone in attenuating the renal injury induced by adriamycin in rats. Animal model was established by two intravenous injections of 4 mg/kg adriamycin with a 2-week interval in rats. One week later, the adriamycin injected rats were randomly divided into 7 groups, receiving various treatments daily for 2 weeks. Two doses of methylprednisolone (20 or 40 mg/kg) were administrated alone or 20 mg/kg methylprednisolone and 100 µL SonoVueTM microbbules (1-5 × 108 bubbles/mL; mean diameter of bubbles: 2.5 µm) was co-administrated by intravenous injections from the tail vein. The ultrasound was applied at a frequency of 0.8 MHz and a spatial average temporal average intensity of 2.79 W/cm2 for 5 min at a 50% duty cycle (1 s on 1 s off) on the back skin of the anatomic position of the kidney in rats of two groups combined with ultrasound. Renal injury were analyzed using immunohistochemical staining, real-time PCR, light and transmission electron microcopies. The kidney function related biochemical indexes were measured by automatic biochemistry analyzer. The results showed that adriamycin induced a typical renal injury and 40 mg/kg methylprednisolone injection significantly ameliorated the abnormality of key parameters such as proteinuria, renal mRNA and protein expression levels of nephrin, collagens III and IV as well as podocyte impairment, glomerulosclerosis and tubulointerstitial injury indexes. However, a sub-dose of methylprednisolone at 20 mg/kg was ineffective when administered intravenously, but its potency at this dosage was enhanced by co-administration with 100 µL SonoVueTM microbubbles plus ultrasound irradiation. In conclusion, ultrasound combined with microbubbles can significantly increase local renal drug delivery leading to enhanced therapeutic effect of low dose methylprednisolone in ameliorating adriamycin-induced nephropathy in rats.

Quercetin improves vascular endothelial function through promotion of autophagy in hypertensive rats.

AIMS: Endothelial dysfunction is a hallmark of hypertension. Herein, we assessed the effect of quercetin, a common dietary antioxidant, on endothelial function of spontaneously hypertensive rats (SHRs), and investigated the underlying molecular mechanisms. MAIN METHODS: The Wistar-Kyoto (WKY) and SHR rats were administered vehicle (1% w/v methyl cellulose) or quercetin (10 mg/kg body weight) by oral gavage once a day for 6 weeks. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured with a tail-cuff system. Functional of rat mesenteric arterioles was assessed by the temperature-controlled myograph. A dose-response curve was generated by the cumulative addition of acetylcholine (ACh) or sodium nitroprusside (SNP). NO production in the culture medium was assessed by measuring the concentration of nitrite, a stable metabolite of NO, using a modified Griess reagent. KEY FINDINGS: Quercetin improved endothelial function and decreased blood pressure in SHRs. Endothelial autophagy, an important cellular homeostatic process, was increased in the early phase of treatment, and decreased in the late phase of treatment. Quercetin promoted autophagy in cultured endothelial cells under both normal and oxidative stress conditions. Pharmacological inhibition of autophagy aggravated endothelial dysfunction in quercetin-treated endothelial cells under oxidative stress, and attenuated the antihypertensive and endothelial protective effects of quercetin in SHRs. SIGNIFICANCE: Quercetin protects endothelial function in hypertensive rats through promotion of autophagy. Thus, autophagy could serve as a potential therapeutic target for hypertension.

A fluorescent biosensor for cardiac biomarker myoglobin detection based on carbon dots and deoxyribonuclease I-aided target recycling signal amplification.

A sensitive biosensor using carbon dots and deoxyribonuclease I-aided target recycling signal amplification has been developed to detect myoglobin (MB), which is an important cardiac biomarker and plays a major role in the diagnosis of acute myocardial infarction (AMI). Here, in the absence of MB, the MB aptamer (Ap) is absorbed on the surface of carbon dots (CDs) through π-π stacking interactions, resulting in quenching of the fluorescent label by forming CD-aptamer complexes. Upon adding MB, the Ap sequences could be specifically recognized by MB, leading to the recovery of quenched fluorescence. Thus, quantitative evaluation of MB concentration has been achieved in a broad range from 50 pg mL-1 to 100 ng mL-1, and the detection limit is as low as 20 pg mL-1. This strategy is capable of specific and sensitive detection of MB in human serum, urine, and saliva and can be used for the diagnosis of AMI in the future.

Genetic analysis and major quantitative trait locus mapping of leaf widths at different positions in multiple populations.

BACKGROUND: Leaf width is an important agricultural trait in maize. Leaf development is dependent on cell proliferation and expansion, and these processes exhibit polarity with respect to the longitudinal and transverse axes of the leaf. However, the molecular mechanism of the genetic control of seed vigor remains unknown in maize, and a better understanding of this mechanism is required. METHODOLOGY/PRINCIPAL FINDINGS: To reveal the genetic architecture of leaf width, a comprehensive evaluation using four RIL populations was performed, followed by a meta-analysis. Forty-six QTLs associated with the widths of leaves at different positions above the uppermost ear were detected in the four RIL populations in three environments. The individual effects of the QTLs ranged from 4.33% to 18.01% of the observed phenotypic variation, with 14 QTLs showing effects of over 10%. We identified three common QTLs associated with leaf width at all of the examined positions, in addition to one common QTL associated with leaf width at three of the positions and six common QTLs associated with leaf width at two of the positions. The results indicate that leaf width at different leaf positions may be affected by one QTL or several of the same QTLs. Such traits may also be regulated by many different QTLs. Thirty-one of the forty-six initial QTLs were integrated into eight mQTLs through a meta-analysis, and 10 of the 14 initial QTLs presenting an R2>10% were integrated into six mQTLs. CONCLUSIONS/SIGNIFICANCE: mQTL1-2, mQTL3-1, mQTL7, and mQTL8 were composed of the initial QTLs showing an R2>10% and included four to six of the initial QTLs that were associated with two to four positions in a single population. Therefore, these four chromosome regions may be hot spots for important QTLs for these traits. Thus, they warrant further studies and may be useful for marker-assisted breeding.