Clinical value of prenatal ultrasound in diagnosis and classification of common arterial trunk.

OBJECTIVES: To investigate the clinical value of prenatal ultrasound in the diagnosis of the common arterial trunk (CAT) classification and associated malformations. MATERIALS AND METHODS: The 2D ultrasound images, spatiotemporal image correlations (STICs) and clinical data of 88 fetuses diagnosed with CAT malformations by prenatal ultrasound were retrospectively analyzed and classified. The correlation between different types, fetal malformation and pregnancy outcomes were analyzed. RESULTS: Among the 88 fetuses, there were 39 cases (44.32%) of type A1, 40 cases (45.45%) of type A2, 8 cases (9.09%) of type A3, and 1 case of type A4 (1.14%). There were 16 cases (18.18%) with isolated CAT, 48 cases (54.55%) with complex intra-cardiac structural abnormalities, and 24 cases (27.27%) with intra-cardiac and extra-cardiac structural abnormalities. In extra-cardiac structural malformations, 14 cases were associated with 1 other system abnormality, 4 cases with 2 other system abnormalities, 3 cases with 3 other system abnormalities, while 3 cases were combined with 4 other system abnormalities, among which the facial and physical abnormalities had the highest incidence (39.13%). The STIC images were completely displayed in all 88 cases. There was a statistical difference between isolated CAT and CAT combined with other abnormalities in fetal pregnancy outcomes. CONCLUSIONS: Prenatal ultrasound had a high clinical application value in CAT classification. Pregnancy outcomes were highly correlated with the classification and associated intra-cardiac and extra-cardiac structural malformations. The early evaluation of fetal prognosis before birth has important value for clinical intervention.

[Tracking Riverine Nitrate Sources and Transformations in the Yiluo River Basin by Nitrogen and Oxygen Isotopes].

The impacts of natural processes and anthropogenic input on riverine nitrate (NO-3) could be identified by NO-3 concentrations and nitrogen and oxygen isotope ratios (δ15N-NO-3 and δ18O-NO-3); however, the effects of variable land use on riverine NO-3 sources and transformations remain unclear. In particular, the human impacts on riverine NO-3 in mountain areas are still unknown. The Yihe River and Luohe River were used to elucidate this question due to their spatially heterogeneous land use. Hydrochemical compositions, water isotope ratios (δD-H2O and δ18O-H2O), and δ15N-NO-3 and δ18O-NO-3 values were utilized to constrain the NO-3 sources and transformations affected by different land use types. The results indicated that ① the mean nitrate concentrations in the Yihe River and Luohe River waters were 6.57 and 9.29 mg·L-1, the mean values of δ15N-NO-3 were 9.6‰ and 10.4‰, and the average δ18O-NO-3 values were -2.2‰ and -2.7‰, respectively. Based on the analysis of δ15N-NO-3 and δ18O-NO-3 values, the NO-3 in the Yihe and Luohe Rivers were derived from multiple sources, and nitrogen removal existed in the Luohe River, but the biological removal in the Yihe River was weak. ② The contributions of different nitrate sources were calculated using a Bayesian isotope mixing model (BIMM) based on δ15N-NO-3 and δ18O-NO-3 values of river water in the mainstream and tributaries with spatial locations. The results revealed that sewage and manure had major impacts on riverine nitrate in the upper reaches of both the Luohe River and Yihe River, where forest vegetation was widely distributed. However, the contributions from soil organic nitrogen and chemical fertilizer were higher in the upper reaches than in downstream ones. The contributions of sewage and manure still increased in the downstream reaches. Our results confirmed the primary impacts of point sources, e.g., sewage and manure, on riverine nitrate in the studied area, and the contributions of nonpoint sources, e.g., chemical fertilizer, had not increased as the agricultural activities elevated the downstream. Therefore, more attention should be paid to point source pollution treatment, and the high-quality development of ecological civilization in the Yellow River Basin should be maintained.

Role of galectin-3 in cardiac dysfunction induced by subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a severe acute cerebrovascular event that not only impairs the central nervous system but also negatively affects various other organs, including the heart. The underlying mechanisms, however, remain unclear. In this study, we discovered that mice with SAH exhibited significant cardiac injuries, such as extended QT and QTc intervals, cardiac fibrosis, and reduced cardiac ejection fractions. This phenomenon was accompanied by increased galectin-3 expression in the cardiac ventricle and can be reversed by galectin-3 inhibitor TD139. Interestingly, we also observed increased co-expression of galectin-3 in macrophage within the heart tissue of SAH mice. Additionally, when macrophage activation was suppressed using the beta-blocker propranolol, cardiac function improved, and galectin-3 expression in the cardiac tissue decreased. Collectively, our findings offer new insights into the role of galectin-3 in SAH-related cardiac dysfunction and suggest a macrophage-galectin-3 axis as a potential therapeutic strategy.

PCSK9 involves in the high-fat diet-induced abnormal testicular function of male mice.

In brief: Impaired spermatogenesis resulting from disturbed cholesterol metabolism due to intake of high-fat diet (HFD) has been widely recognized, however, the role of preprotein invertase subtilin 9 (PCSK9), which is a negative regulator of cholesterol metabolism, has never been reported. This study aims to reveal the role of PCSK9 on spermatogenesis induced by HFD in mice. Abstract: Long-term consumption of a high-fat diet (HFD) is an important factor that leads to impaired spermatogenesis exhibiting poor sperm quantity and quality. However, the mechanism of this is yet to be elucidated. Disrupted cholesterol homeostasis is one of many crucial pathological factors which could contribute to impaired spermatogenesis. As a negative regulator of cholesterol metabolism, preprotein invertase subtilin 9 (PCSK9) mediates low density lipoprotein receptor (LDLR) degradation to the lysosome, thereby reducing the expression of LDLR on the cell membrane and increasing serum low-density lipoprotein cholesterol level, resulting in lipid metabolism disorders. Here, we aim to study whether PCSK9 is a pathological factor for impaired spermatogenesis induced by HFD and the underlying mechanism. To meet the purpose of our study, we utilized wild-type C57BL/6 male mice and PCSK9 knockout mice with same background as experimental subjects and alirocumab, a PCSK9 inhibitor, was used for treatment. Results indicated that HFD induced higher PCSK9 expression in serum, liver, and testes, and serum PCSK9 is negatively correlated with spermatogenesis, while both PCSK9 inhibitor treatment and PCSK9 knockout methodologies ameliorated impaired lipid metabolism and spermatogenesis in mice fed a HFD. This could be due to the overexpression of PCSK9 induced by HFD leading to dyslipidemia, resulting in testicular lipotoxicity, thus activating the Bcl-2-Bax-Caspase3 apoptosis signaling pathway in testes, particularly in Leydig cells. Our study demonstrates that PCSK9 is an important pathological factor in the dysfunction of spermatogenesis in mice induced by HFD. This finding could provide innovative ideas for the diagnosis and treatment of male infertility.

Hyperandrogen-induced polyol pathway flux increase affects ovarian function in polycystic ovary syndrome via excessive oxidative stress.

AIMS: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in the women of childbearing age. It is characterized by hyperandrogenism and abnormal follicular growth and ovulation. The polyol pathway is a glucose metabolism bypass pathway initiated by aldose reductase (ADR). Androgen induces the expression of ADR in the male reproductive tract, which has a general physiological significance for male reproductive function. Here we investigate whether hyperandrogenemia in PCOS leads to increased flux of the polyol pathway in ovarian tissue, which in turn affects follicular maturation and ovulation through oxidative stress. MAIN METHODS: We used clinical epidemiological methods to collect serum and granulosa cells from clinical subjects for a clinical case-control study. At the same time, cell biology and molecular biology techniques were used to conduct animal and cell experiments to further explore the mechanism of hyperandrogen-induced ovarian polyol pathway hyperactivity and damage to ovarian function. KEY FINDINGS: Here, we find that hyperandrogenism of PCOS can induce the expression of ovarian aldose reductase, which leads to the increase of the polyol pathway flux, and affects ovarian function through excessive oxidative stress. SIGNIFICANCE: Our research has enriched the pathological mechanism of PCOS and may provide a new clue for the clinical treatment of PCOS.

Progress in Research on Antitumor Drugs and Dynamic Changes in Skeletal Muscles.

Objective: To review the research progress of reltionship between antitumor drugs and the dynamic changes of the skeletal muscles during treatment phase. Background: Sarcopenia is a common disease in patients with tumors, and it has been agreed that patients with tumors and sarcopenia experience more serious adverse reactions and have a shorter long-term survival after antitumor therapy than patients without sarcopenia. Antitumor drugs whilst beneficial for tumor regression, interferes and synergizes with cancer-induced muscle wasting/sarcopenia, induced myodemia or intramuscular fat and the two conditions often overlap making it difficult to drive conclusions. In recent years, increasing attention has been paid to the dynamic changes in skeletal muscles during antitumor drug therapy. Dynamic changes refer not only measurement skeletal muscle quantity at baseline level, but give more emphasis on the increasing or decreasing level during or end of the whole treatment course. Methods: We retrievaled published English-language original research articles via pubmed, those studies mainly focused on repeated measurements of skeletal muscle index using computed tomography (CT) in cancer patients who received antitumor drug treatment but not received interventions that produced muscle mass change (such as exercise and nutritional interventions). Conclusion: This article will summarize the research progress to date. Most of antineoplastic drug cause skeletal muscle loss during the treatment course, loss of L3 skeletal muscle index is always associated with poor clinical outcomes.

Isoflurane Attenuates Cerebral Ischaemia-Reperfusion Injury via the TLR4-NLRP3 Signalling Pathway in Diabetic Mice.

Ischaemic stroke is a severe disease worldwide. Restoration of blood flow after ischaemic stroke leads to cerebral ischaemia-reperfusion injury (CIRI). Various operations, such as cardiac surgery with deep hypothermic circulatory arrest, predictably cause cerebral ischaemia. Diabetes is related to the occurrence of perioperative stroke and exacerbates neurological impairment after stroke. Therefore, the choice of anaesthetic drugs has certain clinical significance for patients with diabetes. Isoflurane (ISO) exerts neuroprotective and anti-neuroinflammatory effects in patients without diabetes. However, the role of ISO in cerebral ischaemia in the context of diabetes is still unknown. Toll-like receptor 4 (TLR4) and NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation play important roles in microglia-mediated neuroinflammatory injury. In this study, we treated a diabetic middle cerebral artery occlusion mouse model with ISO. We found that diabetes exacerbated cerebral ischaemia damage and that ISO exerted neuroprotective effects in diabetic mice. Then, we found that ISO decreased TLR4-NLRP3 inflammasome activation in microglia and the excessive autophagy induced by CIRI in diabetic mice. The TLR4-specific agonist CRX-527 reversed the neuroprotective effects of ISO. In summary, our study indicated that ISO exerts neuroprotective effects against the neuroinflammation and autophagy observed during diabetic stroke via the TLR4-NLRP3 signalling pathway.

Contribution of high-fat diet-induced PCSK9 upregulation to a mouse model of PCOS is mediated partly by SREBP2.

The incidence of polycystic ovary syndrome (PCOS) due to high-fat diet (HFD) consumption has been increasing significantly. However, the mechanism by which a HFD contributes to the pathogenesis of PCOS has not been elucidated. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein that regulates cholesterol metabolism. Our previous study revealed abnormally high PCSK9 levels in serum from patients with PCOS and in serum and hepatic and ovarian tissues from PCOS model mice, suggesting that PCSK9 is involved in the pathogenesis of PCOS. However, the factor that induces high PCSK9 expression in PCOS remains unclear. In this study, Pcsk9 knockout mice were used to further explore the role of PCSK9 in PCOS. We also studied the effects of a HFD on the expression of PCSK9 and sterol regulatory element-binding protein 2 (SREBP2), a regulator of cholesterol homeostasis and a key transcription factor that regulates the expression of PCSK9, and the roles of these proteins in PCOS pathology. Our results indicated HFD may play an important role by inducing abnormally high PCSK9 expression via SREBP2 upregulation. We further investigated the effects of an effective SREBP inhibitor, fatostain, and found that it could reduce HFD-induced PCSK9 expression, ameliorate hyperlipidemia and improve follicular development in PCOS model mice. Our study thus further elucidates the important role of an HFD in the pathogenesis of PCOS and provides a new clue in the prevention and treatment of this disorder.

Chemical-activity-based quality marker screening strategy for Viscum articulatum.

Viscum articulatum Burm. f. is a parasitic plant rich in flavonoids, triterpenoids, and catechins and has a high nutritional value. It has been reported that consuming V. articulatum can prevent cardiac diseases. In this study, six bioactive compounds, including catechins, triterpenoids, and phenylpropanoid glycosides, were determined in alcohol extracts of the plant using HPLC. The anti-inflammatory and antioxidant activities of three catechins, two triterpenoids, and three combination drugs were measured in cardiomyocytes, and the results showed that the anti-inflammatory activity was significantly enhanced while retaining strong antioxidant activity when epicatechin and ursolic acid were used in combination. The main quality markers epicatechin and ursolic acid were screened based on the specificity of the genuine herb and a potent synergistic effect, and the lowest limitation contents of V. articulatum which could discriminate it from some other taxonomically similar materials were accordingly determined. This self-built lowest limitation content of the two screened quality markers could quickly and accurately reflect the efficacy in terms of chemical composition and reverse the disorderly market use of nongenuine herbs or confusing species for adulteration. This study is of some significance for market regulation, drug development, and clinical medication.

NLRP3 Inflammasome: A Potential Target in Isoflurane Pretreatment Alleviates Stroke-Induced Retinal Injury in Diabetes.

Ischemic stroke remains a devastating disease which is the leading cause of death worldwide. Visual impairment after stroke is a common complication which may lead to vision loss, greatly impacting life quality of patients. While ischemic stroke is traditionally characterized by a blockage of blood flow to the brain, this may coincide with reduced blood flow to the eye, resulting in retinal ischemia and leading to visual impairment. Diabetes increases the risk of ischemic stroke and induces diabetic retinopathy; the latter may be more sensitive to the ischemic retinal injury. In diabetic status, the underlying mechanism in stroke-induced retinal injury has not been fully clarified. The NLR pyrin domain containing 3 (NLRP3) inflammasome is an important activator of inflammation, which may play a critical role in catalyzing and forming certain pro-inflammatory cytokines in both cerebral and retinal ischemia. Isoflurane has been demonstrated to inhibit the activation of the NLRP3 inflammasome and show neuroprotective effects. In this study, we established a diabetic mouse model and performed the middle cerebral artery occlusion procedure to induce ischemic stroke. Our results revealed that cerebral ischemia-induced retinal injury in the diabetic model. Isoflurane pretreatment alleviated the cerebral and retinal injury after ischemic stroke. Of note, isoflurane pretreatment inhibited the NLRP3 inflammasome activation in the retina, indicating that isoflurane pretreatment may provide substantial retinal protection in stroke-induced retinal injury in diabetes.

[Contamination Characteristics of Surface Runoff in Densely Populated Areas in Downstream Yangtze River, China].

Urban surface runoff is an important non-point pollution source, and research on contamination characteristics of runoff is urgent for improving urban aquatic environment quality. Typical cities along the downstream Yangtze River, Wuxi and Nanjing, were selected in this study, and runoff samples from various underlying surfaces were collected to investigate contamination characteristics of heavy metals and dissolved organic matter (DOM). The results indicated that the concentration of heavy metals have exceed water quality standards in underlying surfaces partly, the decreasing order of metal contaminations was Zn > Cu > Pb > Sb > Cd. Contamination characteristics of surface runoff were found to exhibit significant differences, and arterial traffic exhibited the severe contamination of both heavy metals and DOM. Spectral characteristics indicated that the structure of DOM exhibited significant differences in various underlying surfaces, and DOM humification levels in Wuxi showed the following decreasing order:roof covering > sidewalk > parking area > grassy area > arterial traffic, aromaticity indexes exhibited order as:arterial traffic > grassy area > sidewalk > roof covering > parking area. Differential absorption spectroscopy (DAS) and FT-IR analyses indicated that DOM exhibited strong combination effects with cationic metal pollutants (Cu), which mainly occur with C＝C structure and carboxylic and phenolic groups; DOM presented weak combination with anion metal pollutant (Sb), indicating that Sb likely exists as a free anion in runoff. The annual total loadings of metal contaminations in the study area were as follows:Zn > Cu > Pb > Sb > Cd. The loadings of Zn were 4.83 kg·a-1 and 3.21 kg·a-1 in Wuxi and Nanjing, respectively. Annual loadings of DOM reached 0.93 g·(m2·a)-1 and 8.72 g·(m2·a)-1. The results indicated that corresponding pollution reduction measures should be implemented for different underlying surfaces to reduce contaminant concentrations; our findings may provide essential information for improving the aquatic environment quality in downstream Yangtze River.

Quality Assessment and Antioxidant Activities of the Blossoms of Inula Nervosa Wall.

BACKGROUND: Currently, although Inula nervosa Wall is substantially investigated, little is understood about blossoms of Inula nervosa Wall (BINW). OBJECTIVE: In this work, we systematically investigated the antioxidant activity of the extract from BINW by various standard assays including 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical ability, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) di-ammonium salt radical cation (ABTS), and ferric reducing antioxidant potential (FRAP). METHODS: Chemical compounds were tentatively identified through an UHPLC-QTOF-MS system. Furthermore, the contents of nine compounds were detected with UHPLC method coupled with photodiode array (PDA) detector. By carefully analyzing the quantitative data via clusters analysis and principal component analysis (PCA). RESULTS: Forty-six compounds were tentatively identified, and our results showed that nine compound samples in 21 batches of BINW collected from different areas could be differentiated and analyzed by a heatmap visualization. In addition, the contents of nine compounds (flavonoids, phenolic acids) exhibited a total of higher amounts and better antioxidant activities from Yunnan than those from the other three origins. CONCLUSIONS: Our study not only developed a powerful platform to explain the difference between traditional Chinese medicines species that are closely related through the chemometric and chemical profiling, but also presented a useful method to establish quality criteria of BINW with multiple origins. HIGHLIGHTS: To characterize the BINW in detail, we not only performed DPPH, FRAP, and ABTS assays to investigate its antioxidant activity, but also established UHPLC-QTOF-MS/MS- and UHPLC-PDA-based methods to comprehensively identify and qualitatively analyze its components.

Ultrasensitive Electrochemiluminescence Biosensor Based on Closed Bipolar Electrode for Alkaline Phosphatase Detection in Single Liver Cancer Cell.

An ultrasensitive electrochemiluminescence (ECL) biosensor was proposed based on a closed bipolar electrode (BPE) for the detection of alkaline phosphatase (ALP). For most of the BPE-ECL biosensors, an effective signal amplification strategy was the key to enhance the sensitivity of the system. Herein, the signal amplification strategy of the enzyme catalysis was utilized in the BPE-ECL system. Au nanoparticles (NPs) were electrodeposited on the cathode surface of the ITO electrode to improve the stability and sensitivity of the signal. Compared with the previous BPE-ECL biosensors, the sensitivity was increased by at least 3 orders of magnitude. The biosensor showed high sensitivity and specificity of ALP detection with a detection limit of as low as 3.7 aM. Besides, it was further applied to the detection of ALP in different types of cells and successfully realized ALP detection in single Hep G2 cell, which had a huge application prospect in single biomolecule detection or single cell analysis.

The Effects of Altered Endometrial Glucose Homeostasis on Embryo Implantation in Type 2 Diabetic Mice.

Type 2 diabetes mellitus (T2DM) is a disease characterized by hyperglycemia resulting from insulin resistance. In recent years, the incidence of T2DM has been increasing. Women with T2DM often suffer from infertility and early miscarriage; however, the underlying mechanisms remain unclear. Insulin is the most important regulatory hormone of glycogen metabolism. In addition, 5' adenosine monophosphate-activated protein kinase (AMPK) is an important regulator of glycogen metabolism. Patients with T2DM have inhibited AMPK expression in the liver, which leads to impaired glucose metabolism. However, the role of AMPK in endometrial glycogen metabolism has not been reported. In this study, a mouse model of T2DM was established to investigate whether altered endometrial glucose metabolism affects early embryo implantation. Metformin and insulin were used for therapy; the resulting changes to glycogen metabolism and embryo implantation were examined. The results indicate that the concentrations of glycogen decreased significantly in T2DM mice, resulting in insufficient energy supplies for proper endometrial function, and thereby impeding embryonic implantation. Interestingly, endometrial AMPK was not found to be overactivated. Insulin treatment was found to partially resolve the embryo implantation defects in T2DM mice. Metformin improved blood glucose but did not have a significant effect on local endometrial glucose metabolism. This study explored the changes in endometrial glucose metabolism in T2DM mouse, and the effects of these changes on embryo implantation. We found that insulin, but not metformin, significantly resolved embryo implantation problems. These findings will help to increase our understanding of the pathomechanisms of infertility and early miscarriage in women with T2DM.

TILRR (FREM1 isoform 2) is a prognostic biomarker correlated with immune infiltration in breast cancer.

In atherosclerosis, upregulated TILRR (FREM1 isoform 2) expression increases immune cell infiltration. We hypothesized that TILRR expression is also correlated with cancer progression. By analyzing data from Oncomine and the Tumor Immune Estimation Resource, we found that TILRR mRNA expression was significantly lower in breast cancer tissue than adjacent normal tissue. Kaplan-Meier survival analysis and immunohistochemical staining revealed shortened overall survival and disease-free survival in patients with low TILRR expression. TILRR transcript expression was positively correlated with immune score, immune cell biomarkers and the expression of CXCL10 and CXCL11. TILRR expression was also positively correlated with CD8+ and CD4+ T-cell infiltration. These correlations were verified using the ESTIMATE algorithm, gene set enrichment analysis and Q-PCR. We concluded that impaired TILRR expression is correlated with breast cancer prognosis and immune cell infiltration.

Effects of Dexmedetomidine on the Pharmacokinetics of Parecoxib and Its Metabolite Valdecoxib in Beagles by UPLC-MS/MS.

A sensitive and reliable ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous determination of parecoxib and its metabolite valdecoxib in beagles. The effects of dexmedetomidine on the pharmacokinetics of parecoxib and valdecoxib in beagles were studied. The plasma was precipitated by acetonitrile, and the two analytes were separated on an Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm); the mobile phase was acetonitrile and 0.1% formic acid with gradient mode, and the flow rate was 0.4 mL/min. In the negative ion mode, the two analytes and internal standard (IS) were monitored by multiple reaction monitoring (MRM), and the mass transition pairs were as follows: m/z 369.1 → 119.1 for parecoxib, m/z 313.0 → 118.0 for valdecoxib, and m/z 380.0 → 316.0 for celecoxib (IS). Six beagles were designed as a double cycle self-control experiment. In the first cycle, after intramuscular injection of parecoxib 1.33 mg/kg, 1.0 mL blood samples were collected at different times (group A). In the second cycle, the same six beagles were intravenously injected with 2 µg/kg dexmedetomidine for 7 days after one week of washing period. On day 7, after intravenous injection of 2 µg/kg dexmedetomidine for 0.5 hours, 6 beagle dogs were intramuscularly injected with 1.33 mg/kg parecoxib, and blood samples were collected at different time points (group A). The concentration of parecoxib and valdecoxib was detected by UPLC-MS/MS, and the main pharmacokinetic parameters were calculated by DAS 2.0 software. Under the experimental conditions, the method has a good linear relationship for both analytes. The interday and intraday precision was less than 8.07%; the accuracy values were from -1.20% to 2.76%. C max of parecoxib in group A and group B was 2148.59 ± 406.13 ng/mL and 2100.49 ± 356.94 ng/mL, t 1/2 was 0.85 ± 0.36 h and 0.85 ± 0.36 h, and AUC(0-t) was 2429.96 ± 323.22 ng·h/mL and 2506.38 ± 544.83 ng·h/mL, respectively. C max of valdecoxib in group A and group B was 2059.15 ± 281.86 ng/mL and 2837.39 ± 276.78 ng/mL, t 1/2 was 2.44 ± 1.55 h and 2.91 ± 1.27 h, and AUC(0-t) was 4971.61 ± 696.56 ng·h/mL and 6770.65 ± 453.25 ng·h/mL, respectively. There was no significant change in the pharmacokinetics of parecoxib in groups A and B. C max and AUC(0 - ∞) of valdecoxib in group A were 37.79% and 36.19% higher than those in group B, respectively, and t 1/2 was increased from 2.44 h to 2.91 h. V z /F and CL z /F were correspondingly reduced, respectively. The developed UPLC-MS/MS method for simultaneous determination of parecoxib and valdecoxib in beagle plasma was specific, accurate, rapid, and suitable for the pharmacokinetics and drug-drug interactions of parecoxib and valdecoxib. Dexmedetomidine can inhibit the metabolism of valdecoxib in beagles and increase the exposure of valdecoxib, but it does not affect the pharmacokinetics of parecoxib.

Macrophage-NLRP3 Inflammasome Activation Exacerbates Cardiac Dysfunction after Ischemic Stroke in a Mouse Model of Diabetes.

Ischemic stroke is one of the leading causes of death worldwide. In the post-stroke stage, cardiac dysfunction is common and is known as the brain-heart interaction. Diabetes mellitus worsens the post-stroke outcome. Stroke-induced systemic inflammation is the major causative factor for the sequential complications, but the mechanism underlying the brain-heart interaction in diabetes has not been clarified. The NLRP3 (NLR pyrin domain-containing 3) inflammasome, an important component of the inflammation after stroke, is mainly activated in M1-polarized macrophages. In this study, we found that the cardiac dysfunction induced by ischemic stroke is more severe in a mouse model of type 2 diabetes. Meanwhile, M1-polarized macrophage infiltration and NLRP3 inflammasome activation increased in the cardiac ventricle after diabetic stroke. Importantly, the NLRP3 inflammasome inhibitor CY-09 restored cardiac function, indicating that the M1-polarized macrophage-NLRP3 inflammasome activation is a pathway underlying the brain-heart interaction after diabetic stroke.

Impact of Disturbed Glucose Homeostasis Regulated by AMPK in Endometrium on Embryo Implantation in Diabetes Mice.

The incidence of diabetes in women of childbearing age has been increasing recently and implantation failure and early abortion are important reasons for infertility in diabetic women. Glycogen synthesis and decomposition are the cores of glucose homeostasis in endometrium and AMPK is activated when cellular energy consumption increases. Embryo implantation is a complex process required huge energy. Yet the changes of glucose metabolism in endometrium and its impact on embryo implantation in diabetic women are still unclear. In this research, we established diabetic pregnancy mice model by intraperitoneal injecting streptozotocin on pregnant day 1. We first tested the changes of endometrial glucose homeostasis and embryo implantation. Next, we demonstrated abnormal activation of AMPK in the endometrium of diabetic mice and its affecting endometrial glucose homeostasis. Finally, we compared the endometrial glucose homeostasis and embryo implantation outcome in diabetic pregnant mice treated with insulin or insulin combined with metformin. The results indicated that there was disturbed glucose homeostasis associated with excessive activation of AMPK in endometrium of diabetic pregnant mice. AMPK inhibitor improved the over-activation of AMPK pathway in the endometrium, meanwhile, partially corrected the abnormal glycogen metabolism and improved the implantation. Insulin improved the disorder of endometrial glucose homeostasis and implantation of diabetic mice. Our research explores the causes of high abortion and infertility rate in diabetic women which is to provide a therapeutic reference for patients with diabetes complicated with infertility and early abortion.

A colorimetric and electrochemical dual-mode biosensor for thrombin using a magnetic separation technique.

In general, protein detection relies primarily on enzyme-linked immunosorbent assays. Here, we constructed a colorimetric and electrochemical dual-mode biosensor for thrombin detection based on the mechanism of aptamer recognition. Magnetic nanobeads (MBs) were used as carriers for separation and enrichment to quickly capture thrombin (TB) in the complex matrix. Also, the combination of MBs and the magnetic electrode array (MEA) effectively avoided the poisoning of the electrode by biological samples. Furthermore, hybridization chain reaction (HCR) was indirectly used to achieve amplification of TB. A large number of horseradish peroxidases (HRPs) were coupled with the amplified long nucleic acid fragments. Based on the color and current response of the substrate TMB catalyzed by HRP, a dual-mode detection system for thrombin was established to ensure the accuracy of the test results. The method had a minimum resolution of 10 nM to the naked eye and an electrochemical detection limit as low as 0.35 nM. In addition, the sensor provided good anti-interference ability in a complex matrix and showed great potential to detect TB in complex samples.

Ultrasensitive electrochemical detection of microRNA-21 with wide linear dynamic range based on dual signal amplification.

Abnormal expression of microRNAs is closely related to human diseases. Ultrasensitive detection of microRNAs with wide linear dynamic range is necessary as the concentrations of microRNAs distributed in biological samples usually range from fM to nM. Here, we constructed an ultrasensitive electrochemical sensor for microRNA-21 based on the integration of a dual signal amplification strategy of hybridization chain reaction (HCR) and enzyme-induced metallization (EIM) with anodic stripping voltammetry (ASV). MicroRNA-21 was captured by capture probe H1 (CP H1) modified magnetic nanobeads (MBs) and amplified by HCR. Multiple alkaline phosphatases (ALP) were coupled based on the specific reaction of biotin and streptavidin. A dual amplification strategy of HCR and EIM enhanced electrochemical signal by approximately 120-fold from the perspectives of target amplification and detection signal amplification, which decreased the detection limit of microRNA-21 to 0.12 fM. Compared to the reports previously reported, a wider linear dynamic range of 2.5 fM to 25 nM spanning 7 orders of magnitude was obtained. The method provides high sensitivity, specificity and a wider linear dynamic range, which shows a great potential in the early diagnosis of diseases.