Endometriosis-targeted MRI imaging using bevacizumab-modified nanoparticles aimed at vascular endothelial growth factor.

Endometriosis is a tumor-like disease with high recurrence. In this case, the accurate imaging-based diagnosis of endometriosis can help clinicians eradicate it by improving their surgical plan. However, although contrast agents can improve the visibility of the tissue of interest in vivo via magnetic resonance imaging (MRI), the lack of biomarkers in endometriosis hinders the development of agents for its targeted imaging and diagnosis. Herein, aiming at the enriched vascular endothelial growth factor (VEGF) in endometriosis, we developed a targeting MRI contrast agent modified with bevacizumab, i.e., NaGdF4@PEG@bevacizumab-Cy5.5 nanoparticles (NPBCNs), to detect endometriosis. NPBCNs showed negligible cytotoxicity and high affinity towards VEGF in endometrial cells in vitro. Furthermore, NPBCNs generated a strong signal enhancement in vivo in endometriosis lesions in rats in T1-weighted images via MRI at 3 days post-injection, as confirmed by the histopathological staining results and fluorescence imaging on the same day. Our approach can enable NPBCNs to target endometriosis effectively, thus avoiding missed diagnoses.

Magnetic Resonance Imaging-guided Focused Ultrasound Surgery in a Swine Adenomyosis Model.

RATIONALE AND OBJECTIVES: The purpose of this study was to explore the feasibility of magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS) for the treatment of an adenomyosis model of Bama pigs and the changes in the level of oxytocin receptor (OTR), vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) in the myometrium tissues of Bama pigs after MRgFUS. MATERIALS AND METHODS: Three Bama pig models of adenomyosis were established by autologous endometrial implantation and evaluated by magnetic resonance imaging, computed tomography, and hematoxylin-eosin (H&E) staining. After the successful construction of the model, the pigs underwent MRgFUS. Before the modeling surgery, three months after the modeling, and two months after ablation, the myometrium tissues were clipped, then embedded and H&E stained for immunohistochemical examination. The average optical density of OTR, VEGF, and COX-2 were semi-quantitatively analyzed. RESULTS: The adenomyosis models were established in all Bama pigs and confirmed by magnetic resonance imaging, computed tomography and H&E staining. Magnetic resonance imaging and computed tomography examination showed that the uterine wall at the modeling site was significantly thickened with uneven enhancement after contrast injection. All Bama pigs with adenomyosis lesions underwent MRgFUS without complications. The expression level of OTR and COX-2 in the myometrium increased three months after modeling surgery and decreased two months after MRgFUS. The expression level of VEGF decreased two months after MRgFUS. CONCLUSION: Autologous endometrial implantation is effective in establishing the adenomyosis model of Bama pigs. It is feasible to treat adenomyosis in the Bama pig model with MRgFUS. The levels of OTR, COX-2 and VEGF in the local myometrium decreased after MRgFUS, which may be associated with symptom relief after treatment.

Cyclic changes in T2* relaxometry of human uterus during the menstrual cycle using BOLD MR imaging.

PURPOSE: To evaluate dynamic changes of T2* values within the endometrium, junctional zone and myometrium during the menstrual cycle using blood oxygen level-dependent (BOLD) magnetic resonance imaging. METHOD: Volunteers underwent MRI scans on menstrual phase, ovulatory phase and luteal phase, including T2-weighted imaging and BOLD MR imaging. Multi-gradient-recalled echo (MGRE) sequence was used to obtain BOLD MR images. T2* values of different uterine layers, including endometrium, junctional zone and myometrium, on sagittal images were analyzed quantitatively. RESULTS: Twenty-four subjects calculated T2* values successfully. The T2* values of each zonal structure during menstruation were significantly lower than those during ovulatory phase (P < 0.05) and luteal phase (P < 0.001). The T2* value of junctional zone was significantly lower than that of the myometrium over all three menstrual phases (P = 0.000, menstrual; P = 0.000, ovulatory; P = 0.001, luteal). The mean T2* value in endometrium during the ovulatory phase was the highest of the uterine zones over menstrual cycle. During menstrual phase, there was no statistical difference between endometrium and junctional zone (P > 0.05). Conversely, the comparison of the T2* values between endometrium and myometrium, junctional zone and myometrium both showed significant difference (P = 0.000). The mean T2* values within endometrium during ovulatory phase and luteal phase were significantly higher than those within junctional zone and myometrium (P < 0.05). CONCLUSIONS: Cyclic changes of T2* values in each zonal structure of the uterus were revealed during the menstrual cycle by means of BOLD technique, which may be potentially beneficial in investigating dysmenorrhea, guiding assisted reproductive technologies and monitoring hypoxia in gynecological tumors.

The effect of listening to preferred music after a stressful task on performance and psychophysiological responses in collegiate golfers.

Background: This study explores whether listening to preferred music after a stressful situation affects putting and swinging performance, heart rate (HR), HR variability (HRV), and anxiety among amateur golfers. Methods: Twenty healthy amateur collegiate golfers voluntarily participated in this study (age 20.1 ± 1.17 yrs., height = 173.8 ± 7.74 cm, body weight = 72.35 ± 12.67 kg). Pre- and post-intervention HR and HRV measurements were taken, along with a self-report of the State-Trait Anxiety Inventory (STAI-S) and Triple Factor Anxiety Inventory (TFAI). Participants were exposed to a stressful situation through the Stroop Colour and Word Test (SCWT) and then instructed to perform three golf-practice sessions in a golf simulator, separated by 48-72 hours of recovery, under different conditions: control, pre-task music, and synchronised music. Results: No significant difference was identified between the experimental conditions for swinging (in terms of total distance (p = 0.116), carry distance (p = 0.608), speed of the ball (p = 0.819), and launch angle (p = 0.550) and putting performance (the number of successful putts on target (p > 0.05) and distance error between the target and ball (p = 0.122). No main effect for condition and time of intervention, as well as no interaction between these two factors was found for HR, HRV, and STAI-S (p = 0.116). However, the pre and post-intervention percentages of physiological items of the TFAI indicated a large, significant difference in synchronised music trial (p = 0.012, pre-task trial = -1.92% < control trial = 0% < synchronised trial = 4.58%). Conclusions: The results imply that following a stressful situation, listening to preferred music before and/or during golf has no immediate effect on golf performance, anxiety, and psychophysiological responses in collegiate golfers.

A Modified Bowel Displacement Technique for Magnetic Resonance Imaging-Guided Focused Ultrasound Surgery in the Treatment of Uterine Fibroids and Adenomyosis.

OBJECTIVE: The clinical application of magnetic resonance imaging-guided focused ultrasound (MRgFUS) surgery for treatment of symptomatic uterine fibroids is often limited because of the bowel between the abdominal wall and uterus. If bowels are in the pathway of sonication path, firstly filling the bladder, then filling the rectum, and emptying the bladder subsequently can be used to avoid them in recent research. The purpose of this study was to evaluate whether the modified bowel displacement technique (rectal filling first and then bladder filling, with or without subsequent bladder emptying) was feasible to create secure acoustic window. METHODS: A total of 78 patients who had undergone MRgFUS treatment for uterine fibroids and adenomyosis from January 2020 to November 2020 were included in this retrospective study. Of the 78 patients, 19 patients were treated using a modified bowel displacement technique, whereas the rest of the patients did not require intestinal displacement. High-intensity focused ultrasound was performed using GE Sightec HDXT 1.5 Tesla MR and ExAblate high-intensity focused ultrasound system. RESULTS: Of the 19 patients requiring bowel displacement techniques, 17 patients successfully completed MRgFUS surgery. Magnetic resonance imaging-guided focused ultrasound surgery was feasible in 4 patients after rectal filling, bladder filling, and subsequent bladder emptying. The others received ablation through the extended bladder because of bowel descending after emptying the bladder. The surgery caused no intestinal or uterine complications and no serious discomfort to the patient. CONCLUSIONS: The modified bowel displacement technique was effective in displacing interposed bowels during MRgFUS treatment to create safe acoustic pathway for ablating uterine fibroids and adenomyosis.

Normalized wall index, intraplaque hemorrhage and ulceration of carotid plaques correlate with the severity of ischemic stroke.

BACKGROUND AND AIMS: Carotid atherosclerosis is considered an important cause of ischemic stroke. Tthis study aimed to explore the relationship between plaque features and the severity of stroke, and to identify plaque risk factors for the assessment of the severity of ischemic stroke. METHODS: Symptomatic patients with carotid atherosclerotic plaques were prospectively recruited and underwent high-resolution vessel wall magnetic resonance imaging (VW-MRI). Two trained MRI readers independently identified intraplaque hemorrhage (IPH), calcification (CA), surface CA, deep CA, and ulceration. They measured and calculated the maximum vessel diameter (Max VD), maximum wall thickness (Max WT), total vessel area, lumen area, normalized wall index (NWI), plaque volume, IPH volume, IPH proportion, CA volume, and CA proportion. Patients were divided into two groups according to their National Institutes of Health Stroke Scale (NIHSS) scores (NIHSS ≤1 vs. NIHSS >1). Clinical characteristics and carotid plaque features were compared using the Mann-Whitney U test or Chi-square test as appropriate. Odds ratio (OR) and corresponding 95% confidence interval (CI) of plaque features to distinguish patients with NIHSS >1 were calculated. Spearman's rank correlations or Pearson correlations were determined for plaque features and NIHSS scores. RESULTS: Of the 97 included patients, 34 (35.05%) with NIHSS >1 had significantly greater NWI (p < 0.05), larger IPH volume (p < 0.01), and greater IPH proportion (p < 0.01), and higher prevalence of IPH (OR, 5.654; 95%CI, 2.272-14.070; p < 0.01) and ulceration (OR, 2.891; 95%CI, 1.090-7.667; p = 0.033) than patients with NIHSS ≤1. Max WT (r = 0.24, p = 0.018), NWI (r = 0.22, p = 0.032), IPH (r = 0.27, p = 0.007), IPH volume (r = 0.35, p < 0.01), IPH proportion (r = 0.28, p = 0.005), and ulceration (r = 0.35, p < 0.01) had positive correlations with NIHSS scores. CONCLUSIONS: NWI, IPH, and ulceration of carotid atherosclerotic plaque based on high-resolution VW-MRI may be useful indicators for assessing the severity of ischemic stroke in patients with atherosclerosis. NIHSS score is related to max WT, NWI, IPH, IPH volume, IPH proportion, and ulceration.

Chemerin isoform analysis in human biofluids using an LC/MRM-MS-based targeted proteomics approach with stable isotope-labeled standard.

Targeted proteomics has advantages over earlier conventional technologies for protein detection. We developed and validated an LC/MRM-MS-based targeted proteomic method combined with immunoaffinity precipitation for the enrichment and detection of low abundance chemerin isoforms in human biofluids. After tryptic digestion, each chemerin isoform was characterized by isoform-specific peptides, and the absolute quantification was achieved by using stable isotope-labeled peptides as internal standards. In serum, follicular fluid and synovial fluid, a total of 6 chemerin isoforms were identified and quantified, among which a novel natural isoform 153Q was discovered for the first time. The relative content of the six chemerin isoforms in human serum was 157S ≫ 156F ≫ 158K > 154F ≥ 155A > 153Q in the ratio of 25:17:5:2.5:2.2:1, respectively. The absolute contents were in the range of 88-3.5 ng/mL. This distribution remained consistent among the 3 biofluids analyzed. Total chemerin were found to be increased in both polycystic ovary syndrome (serum and follicular fluid) and rheumatoid arthritis (serum) patients. However, chemerin isoform analysis revealed that only 156F & 157S were increased in the former, while 155A, 156F & 157S were increased in the latter. This demonstrates the potential of this method in detailed characterization of changes in chemerin isoforms that may be of clinical relevance.

Alterations of Sphingolipid Metabolism in Different Types of Polycystic Ovary Syndrome.

The roles of sphingolipids in polycystic ovary syndrome (PCOS) are still unknown. This study aimed to investigate the sphingolipid characteristics for different types of PCOS using liquid chromatography-mass spectrometry (LC-MS). A total of 107 women with PCOS and 37 healthy women as normal controls were studied. PCOS patients were further classified into non-obesity with insulin resistance (IR) (NOIR), obesity with IR (OIR), and non-obesity and non-IR (NIR) subgroups. A total of 87 serum sphingolipids, including 9 sphingosines, 3 sphinganines, 1 sphingosine-1-phosphate (S1P), 19 ceramides (Cers), 1 ceramide-1-phosphate, 44 sphingomyelins (SMs), 4 hexosylceramides, and 6 lactosylceramides (LacCers) were analyzed using an improved sphingolipidomic approach based on LC-MS. Notable elevations in the levels of S1P, Cer, and SM were observed in PCOS patients when compared with healthy women, and SM species with long saturated acyl chains showed potential as novel biomarkers of PCOS. In addition, the level of LacCer was only elevated in NIR, and there was almost no change in NOIR and OIR. This study is the first to report the comprehensive sphingolipidomic profiling of different subgroups of PCOS with or without IR or obesity and suggests that serum sphingolipids might be useful as diagnostic biomarkers for different types of PCOS.

Serum-plasma matched metabolomics for comprehensive characterization of benign thyroid nodule and papillary thyroid carcinoma.

Metabolomics offers a noninvasive methodology to identify metabolic markers for pathogenesis and diagnosis of diseases. This work aimed to characterize circulating metabolic signatures of benign thyroid nodule (BTN) and papillary thyroid carcinoma (PTC) via serum-plasma matched metabolomics. A cohort of 1,540 serum-plasma matched samples and 114 tissues were obtained from healthy volunteers, BTN and PTC patients enrolled from 6 independent centers. Untargeted metabolomics was determined by liquid chromatography-quadrupole time-of-flight mass spectrometric and multivariate statistical analyses. The use of serum-plasma matched samples afforded a broad-scope detection of 1,570 metabolic features. Metabolic phenotypes revealed significant pattern differences for healthy versus BTN and healthy versus PTC. Perturbed metabolic pathways related mainly to amino acid and lipid metabolism. It is worth noting that, BTN and PTC showed no significant differences but rather overlap in circulating metabolic signatures, and this observation was replicated in all study centers. For differential diagnosis of healthy versus thyroid nodules (BTN + PTC), a panel of 6 metabolic markers, namely myo-inositol, α-N-phenylacetyl-L-glutamine, proline betaine, L-glutamic acid, LysoPC(18:0) and LysoPC(18:1) provided area under the curve of 97.68% in the discovery phase and predictive accuracies of 84.78-98.18% in the 4 validation centers. Taken together, serum-plasma matched metabolomics showed significant differences in circulating metabolites for healthy versus nodules but not for BTN versus PTC. Our results highlight the true metabolic nature of thyroid nodules, and potentially decrease overtreatment that exposes patients to unnecessary risks.

Comprehensive Metabolomic Characterization of Coronary Artery Diseases.

BACKGROUND: Pathogenesis and diagnostic biomarkers for diseases can be discovered by metabolomic profiling of human fluids. If the various types of coronary artery disease (CAD) can be accurately characterized by metabolomics, effective treatment may be targeted without using unnecessary therapies and resources. OBJECTIVES: The authors studied disturbed metabolic pathways to assess the diagnostic value of metabolomics-based biomarkers in different types of CAD. METHODS: A cohort of 2,324 patients from 4 independent centers was studied. Patients underwent coronary angiography for suspected CAD. Groups were divided as follows: normal coronary artery (NCA), nonobstructive coronary atherosclerosis (NOCA), stable angina (SA), unstable angina (UA), and acute myocardial infarction (AMI). Plasma metabolomic profiles were determined by liquid chromatography-quadrupole time-of-flight mass spectrometry and were analyzed by multivariate statistics. RESULTS: We made 12 cross-comparisons to and within CAD to characterize metabolic disturbances. We focused on comparisons of NOCA versus NCA, SA versus NOCA, UA versus SA, and AMI versus UA. Other comparisons were made, including SA versus NCA, UA versus NCA, AMI versus NCA, UA versus NOCA, AMI versus NOCA, AMI versus SA, significant CAD (SA/UA/AMI) versus nonsignificant CAD (NCA/NOCA), and acute coronary syndrome (UA/AMI) versus SA. A total of 89 differential metabolites were identified. The altered metabolic pathways included reduced phospholipid catabolism, increased amino acid metabolism, increased short-chain acylcarnitines, decrease in tricarboxylic acid cycle, and less biosynthesis of primary bile acid. For differential diagnosis, 12 panels of specific metabolomics-based biomarkers provided areas under the curve of 0.938 to 0.996 in the discovery phase (n = 1,086), predictive values of 89.2% to 96.0% in the test phase (n = 933), and 85.3% to 96.4% in the 3-center external sets (n = 305). CONCLUSIONS: Plasma metabolomics are powerful for characterizing metabolic disturbances. Differences in small-molecule metabolites may reflect underlying CAD and serve as biomarkers for CAD progression.

Multiple Functions of Ten-eleven Translocation 1 during Tumorigenesis.

OBJECTIVE: Aberrant expression of ten-eleven translocation 1 (TET1) plays a critical role in tumor development and progression. We systematically summarized the latest research progress on the role and mechanisms of TET1 in cancer biology. DATA SOURCES: Relevant articles published in English from 1980 to April 2016 were selected from the PubMed database. The terms "ten-eleven translocation 1," "5mC," "5hmC," "microRNA," "hypoxia," and "embryonic stem cell" were used for the search. STUDY SELECTION: Articles focusing on the role and mechanism of TET1 in tumor were reviewed, including clinical and basic research articles. RESULTS: TET proteins, the key enzymes converting 5-methylcytosine to 5-hydroxymethylcytosine, play vital roles in DNA demethylation regulation. Recent studies have shown that loss of TET1 is associated with tumorigenesis and can be used as a potential biomarker for cancer therapy, which indicates that TET1 serves as tumor suppressor gene. Moreover, besides its dioxygenase activity, TET1 could induce epithelial-mesenchymal transition and act as a coactivator to regulate gene transcription, such as developmental regulator in embryonic stem cells (ESCs) and hypoxia-responsive gene in cancer. The regulation of TET1 is also correlated with microRNA in a posttranscriptional modification process. Hence, it is complex but critical to comprehend the mechanisms of TET1 in the biology of ESCs and cancer. CONCLUSIONS: TET1 not only serves as a demethylation enzyme but also plays multiple roles during tumorigenesis and progression. More studies should be carried out to elucidate the exact mechanisms of TET1 and its associations with cancer before considering it as a therapeutic tool.

Significant pharmacokinetic differences of berberine are attributable to variations in gut microbiota between Africans and Chinese.

We investigated the influence of gut microbiotal metabolism on the pharmacokinetics of berberine in healthy male Africans and Chinese. The Cmax and AUC in the Africans were 2.67-fold and 2.0-fold higher than the Chinese, respectively. Microbiotal compositions by 16S rRNA pyrosequencing showed higher abundance of the genera Prevotella, Bacteroides, and Megamonas (34.22, 13.88, and 10.68%, respectively) in the Chinese than the Africans (30.08, 9.43, and 0.48%, respectively). Scatter plot showed a strong negative correlation between the microbiotal abundance and the berberine AUC, especially for the genus Prevotella (r = -0.813) and its species. A more extensive metabolism was observed in Chinese with 1.83-fold higher metabolites, possibly contributing to the lower AUC than the Africans. In conclusion, significant PK differences of berberine were observed between Africans and Chinese, which is partly attributable to variations in gut microbiota and its corresponding metabolic capacity.

Human plasma metabolomics for identifying differential metabolites and predicting molecular subtypes of breast cancer.

PURPOSE: This work aims to identify differential metabolites and predicting molecular subtypes of breast cancer (BC). METHODS: Plasma samples were collected from 96 BC patients and 79 normal participants. Metabolic profiles were determined by liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry based on multivariate statistical data analysis. RESULTS: We observed 64 differential metabolites between BC and normal group. Compared to human epidermal growth factor receptor 2 (HER2)-negative patients, HER2-positive group showed elevated aerobic glycolysis, gluconeogenesis, and increased fatty acid biosynthesis with reduced Krebs cycle. Compared with estrogen receptor (ER)-negative group, ER-positive patients showed elevated alanine, aspartate and glutamate metabolism, decreased glycerolipid catabolism, and enhanced purine metabolism. A panel of 8 differential metabolites, including carnitine, lysophosphatidylcholine (20:4), proline, alanine, lysophosphatidylcholine (16:1), glycochenodeoxycholic acid, valine, and 2-octenedioic acid, was identified for the classification of BC subtypes. These markers showed potential diagnostic value with average area under the curve at 0.925 (95% CI 0.867-0.983) for the training set (n=51) and 0.893 (95% CI 0.847-0.939) for the test set (n=45). CONCLUSION: Human plasma metabolomics is useful in identifying differential metabolites and predicting breast cancer subtypes.

[Electroacupuncture Combined with Clomiphene Promotes Pregnancy and Blastocyst Implantation Possibly by Up-regulating Expression of Insulin Receptor and Insulin Receptor Substrate 1 Proteins in Endometrium in Rats with PCOS].

OBJECTIVE: To observe the effect of electroacupuncture (EA) intervention combined with clomiphene critate (CC) on the blastocyst implantation and pregnancy rate and expression of insulin receptor (INSR) and insulin receptor substrate 1 (IRS 1) proteins in the endometrium in rats with polycystic ovary syndrome (PCOS), so as to reveal its mechanisms underlying improvement of PCOS. METHODS: One hundred and twenty-five female SD rats were randomly divided into normal control, PCOS model, medication (CC), EA and EA+CC groups (n=25 in each group, 15 for checking blastocyst implantation, and 10 for Western blot). The PCOS model was established by subcutaneous injection of Dehydroepiandrosterone (DHEA) and fed with high-fat diet. Rats of the normal control group were treated by subcutaneous injection of sesame oil and fed with the normal forage. EA stimulation was applied to "Zhongwan" (CV 12), "Guanyuan" (CV 4) and bilateral "Tianshu" (ST 25) for 30 min, 3 times a week, 5 weeks altogether. Rats of the CC and EA+CC groups were fed with CC (100 mg·kg-1·d-1) for 2 days after regular restriction (30 min, 3 times a week, 5 weeks altogether). The pregnancy was determined by vaginal smear tests and the number of blastocyst implantation determined by examination of the uterus after execution. The expression of INSR and IRS 1 proteins in the endometrium was detected by Western blot. RESULTS: The pregnancy rate and the number of blastocyst implantation were significantly lower in the model group than in the normal control group (P<0.05), and remarkably increased after EA and EA+CC interventions (P<0.05). The effects of EA+CC were obviously superior to those of simple EA and simple medication in raising the pregnancy rate and the number of blastocyst implantation (P<0.05). No significant differences were found between the EA and CC groups in the pregnancy rate and the number of blastocyst implantation (P>0.05). The relative expression levels of both INSR and IRS 1 proteins were markedly lower in the model group than in the normal control group (P<0.05), and significantly higher in both EA and EA+CC groups than in the model group (P<0.05). No significant differences were found between the model and the CC groups and between the EA and EA+CC groups in the expression levels of INSR and IRS 1 proteins (P>0.05). CONCLUSIONS: EA intervention can improve pregnancy rate and the number of blastocyst implantation in PCOS rats, which may be related to its effects in up-regulating the expression of INSR and IRS 1 proteins in the endometrium.

[Effects of Electroacupuncture on mRNA Expressions of Insulin-receptor Substrates 1 and 2 in the Endometrium of PCOS Rats and Insulin Sensitivity].

Objective To observe the effects of electroacupuncture (EA) on gene expressions of insulin receptor substrate 1 (IRS1) and insulin receptor substrate 2 (IRS2) in the endometrium and insulin sensitivity (IS) of polycystic ovary syndrome (PCOS) rats, thereby providing basic evidence of clinical ap- plication of EA for improving the pregnancy rate of PCOS patients and reducing the abortion rate. Methods Dehydroepiandrosterone (DHEA) was subcutaneously injected to 24-day-old female SD rats to induce P- COS model. Besides, rats were fed with high-fat diet. Rats in the normal group were subcutaneously injected with sesame oil and fed with common forage. PCOS model rats were randomly divided into the model group and the EA group. All rats were intervened from 80 days old. Of them, EA was started to rats in the EA group, three times per week for 5 successive weeks. Rats in the normal group and the model group were only bound every day, but with no acupuncture, three times per week for 5 successive weeks. Blood was collected from caudal vein before and after treatment. Fasting blood glucose (FPG) was detected by oxidase method. Fasting insulin (FINS) level was determined by Roche electrochemical luminescence method. Homeostasis model assessment of insulin resistance ( HOMA-IR) index was also calculated. All rats were killed by decapitation by the end of intervention, and their endometria were collected. mRNA expressions of IRS1 and IRS2 in the endometrial tissue were detected by Real-time fluorescence quantitative PCR method. Results Pre-post-treatment changes of FPG level were not significantly different among the three groups (P >0. 05). Before treatment FINS level and HOMA-IR index were significantly higher in the model group than in the normal group (P <0. 05). After treatment, they were significantly lower in the EA group than in the model group (P <0. 05). Compared with the normal group, mRNA expressions of IRS1 and IRS2 in the endometrial tissue were decreased in the model group (P <0. 05). Compared with the model group, mRNA expressions of IRS1 and IRS2 in the endometrial tissue were increased in the EA group (P < 0. 05). Conclusion EA could improve IS and elevate mRNA expressions of IRS1 and IRS2 in the endome- trial tissue of PCOS rats, which might be one of mechanisms for improving endometrial IS.

[Effective Ingredients of Yangjing Zhongyu Decoction Regulated Androgen Biosyntheses by Mitogen-Activated Protein Kinase Pathway in Porcine Granulose Cells].

OBJECTIVE: To study the molecular mechanism of Yangjing Zhongyu Decoction (YZD) n-butanol extracts (ZDC) and ethyl acetate extracts (YSYZ) in reducing androgen in porcine granulose cells by mitogen-activated protein kinase (MAPK) pathway. METHODS: Porcine granulose cells were isolated and cultured. They were inoculated by MAPK inhibitor PD98059 at different concentrations, and then they were divided into the blank control group (0), 1, 3, 10, and 25 micromol/L groups. After 24-h culture the cytochrome P450c17a (CYP17) mRNA expression level was detected using Real-time fluorescent quantitative PCR. Contents of androgen (testosterone) in the supernate were detected using RIA and optimal PD98059 concentration screened. After intervened by 10 micromol/L PD98059 for 24 h, the culture solution was intervened by effective ingredients of with or without YZD or YSYZ at various concentrations (0, 1 , 5, 25, 50 mg/mL) at various time points (3, 6, 18, 24 h). Expression levels of p-ERK1/2, c-Fos and CYP17 were detected by Western blot. Testosterone content in the supernate was determined by radioimmunoassay (RIA). RESULTS: Ten pLmol/L PD98059 could obviously decrease p-ERK1/2 protein expression and increase CYP17 mRMA expression, and elevate testosterone content in the supernate (P < 0.05). ZDC and YSYZ at 25 ng/mL could increase p-ERK1/2 protein expression and c-Fos levels, and reduce CYP17 protein expression, and lower testosterone content in the supernate after 6-h intervention (P < 0.01). CONCLUSION: Effective ingredients of YZD could reduce androgen production in porcine granulose cells through increasing activities of MAPK.

[Effect of low-frequency electroacupuncture intervention on oxidative stress and glucose metabolism in rats with polycystic ovary syndrome].

OBJECTIVE: To observe the effect of low-frequency electroacupuncture (EA) treatment on oxidative stress and metabolism disorder in polycystic ovary syndrome (PCOS) rats, so as to study its underlying mechanisms in improving PCOS. METHODS: Thirty female SD rats were randomized into control group, model group and EA group (n = 10 in each group). The PCOS model was established by subcutaneous injection of testosterone propionate (1 mg/100 g, 10 mg/mL) for 8 weeks. EA (2 Hz) was applied to "Zhongwan" (CV 12) , "Guanyuan" (CV 4) and bilateral "Sanyinjiao" (SP 6) or "Housanli" (ST 36) for 30 min, once daily (except weekends) for 5 weeks. Serum testosterone (T) , sex hormone-binding globulin (SHBG) and fasting serum insulin (FINS) contents were detected by ELISA, serum malondialdehyde (MDA) and superoxide dismutase (SOD) levels were assayed by thiobarbituric acid (TBA) and xanthine oxidation (XTO) methods, respectively, and fasting blood glucose (FBG) was determined by roche glucose meter. In addition, homeostasis model assessment for insulin resistance (HOMA-IR) and modified B cell function index (MBCI) were calculated. RESULTS: Compared with the control group, serum T, FBG, FINS, HOMA-IR, and serum MDA levels were significantly increased in the model group (P < 0.01), while serum SHBG, MBCI and SOD levels were considerably decreased in the model group (P < 0.01). Following EA treatment, all the increased serum T, FBG, FINS, HOMA-IR, and serum MDA levels, and the decreased serum SHBG, MBCI and SOD levels were reversed obviously (P < 0.05, P < 0.01). CONCLUSION: EA treatment may normalize insulin sensitivity, ameliorate insulin resistance and hyperinsulinemia in PCOS rats, probably by regulating the function of pancreatic islets ß cell and by reducing oxidative stress and free androgen.

MIF, secreted by human hepatic sinusoidal endothelial cells, promotes chemotaxis and outgrowth of colorectal cancer in liver prometastasis.

Growth and invasion of metastatic colorectal cancer (CRC) cells in the liver depend on microenvironment. Here, we showed that human hepatic sinusoidal endothelial cells (HHSECs) induce chemotaxis and outgrowth of CRC cells. Macrophage migration inhibitory factor (MIF), released by HHSECs, stimulated chemotaxis of CRC cells. MIF secreted by HHSECs, but not by CRC cells themselves, promoted migration and epithelial-mesenchymal transition (EMT) and facilitated proliferation and apoptotic resistance of CRC cells. In orthotopic implantation models in nude mice, exogenous MIF stimulated growth of CRC cells and metastasis. Furthermore, MIF accelerated mobility of CRC cells by suppressing F-actin depolymerization and phosphorylating cofilin. Noteworthy, MIF levels were correlated with the size of hepatic metastases. We suggest that HHSECs and paracrine MIF promote initial migration and proliferation of CRC cells in the hepatic sinusoids to generate liver metastases.

Erbin interacts with c-Cbl and promotes tumourigenesis and tumour growth in colorectal cancer by preventing c-Cbl-mediated ubiquitination and down-regulation of EGFR.

The epidermal growth factor receptor (EGFR) is implicated in many types of cancer, including colorectal cancer (CRC), and has become one of the most common candidates for targeted therapy. Here, we found that Erbin, a member of the leucine-rich repeat and PDZ domain (LAP) family, plays a key role in EGFR signalling. Erbin inhibited EGFR ubiquitination and stabilized the EGFR protein by interacting with c-Cbl. Moreover, the PDZ domain of Erbin was critical for the interaction between Erbin and c-Cbl and EGFR ubiquitination. Interestingly, Erbin expression was elevated in tumour samples from CRC patients, increased in advanced clinical stage disease and correlated with EGFR expression. In vivo studies using mouse xenograft models of CRC showed that Erbin promotes tumour growth, and that the effects of Erbin on tumour growth are mainly related to the regulatory effects of Erbin on EGFR. The azoxymethane (AOM)-induced colon carcinogenesis model in Erbin(ΔC) (/) (ΔC) mice, with the PDZ domain of Erbin deleted, demonstrated that the PDZ domain of Erbin and its regulation of EGFR signalling are necessary for the tumourigenesis and tumour growth of CRC. We found that Erbin promotes tumourigenesis and tumour growth in CRC by stabilizing EGFR. Our study sheds light on developing Erbin, especially its PDZ domain, as a potential target for CRC treatment.

Waist-to-Height Ratio: a simple, effective and practical screening tool for childhood obesity and metabolic syndrome.

OBJECTIVE: This study aimed to evaluate the diagnostic value of Waist-to-Height Ratio in early detection of obesity and metabolic syndrome in Chinese children and adolescents. METHOD: A cross-sectional study was conducted in six cities in China in 2010 with 16,914 children and adolescents aged 7-17 years. Participants were randomly divided into the training and testing sets. Diagnostic values were estimated using sensitivity, specificity and areas under receiver operating characteristic curves. RESULTS: The coefficients of variation of Waist-to-Height Ratio among age groups were lower than that of body mass index and waist circumstance. The area under receiver operating characteristic curve of Waist-to-Height Ratio was 0.968 in boys and 0.949 in girls for general obesity evaluation, and 0.983 in boys and 0.984 in girls for central obesity. The optimal cut-offs of Waist-to-Height Ratio were 0.47 in boys and 0.45 in girls in the training set and validated in the testing set. For metabolic syndrome evaluation, the sensitivity and specificity were 0.858 and 0.825 in boys, 0.864 and 0.812 in girls under the suggested cut-offs. CONCLUSION: Waist-to-Height Ratio was a simple, effective and practical tool for mass screening childhood obesity and metabolic syndrome in China. It will have potential values in public health practice.