The impact of lipoprotein(a) level on cardiac pathologies in diabetes: a cardiac CT study.

OBJECTIVES: We aimed to explore the imaging profile of coronary atherosclerosis, perivascular inflammation, myocardial perfusion, and interstitial fibrosis in diabetes stratified by lipoprotein(a) [Lp(a)] levels. METHODS: In this prospective study, we enrolled diabetic patients who had undergone computed tomography (CT) angiography, stress CT-myocardial perfusion imaging, and late iodine enhancement in 20 months. Then, we categorized them into elevated and normal groups based on an Lp(a) cutoff level of 30 mg/dL. All imaging data, including coronary atherosclerosis parameters, pericoronary adipose tissue (PCAT) density, stress myocardial blood flow (MBF), and extracellular volume (ECV), were collected for further analysis. RESULTS: In total, 207 participants (mean age: 59.1 ± 12.0 years, 111 males) were included in this study. Patients with elevated Lp(a) level had more pronounced percent atheroma volume (2.55% (1.01-9.01%) versus 1.30% (0-4.95%), p = 0.010), and demonstrated a higher incidence of positive remodeling, spotty calcification, and high-risk plaque (HRP) than those with normal Lp(a) levels (75.6% versus 54.8%, p = 0.015; 26.8% versus 9.6%, p = 0.003; 51.2% versus 30.1%, p = 0.011, respectively). Results of the multivariate analysis revealed that after adjusting for all clinical characteristics, elevated Lp(a) levels were an independent parameter associated with HRP (odds ratio = 2.608; 95% confidence interval: 1.254-5.423, p = 0.010). However, no significant difference was found between the two groups in terms of PCAT density, stress MBF, and ECV. CONCLUSIONS: Elevated Lp(a) levels are associated with extensive coronary atherosclerosis and HRP development. However, they are not related to perivascular inflammation, decreased myocardial perfusion, and interstitial fibrosis in diabetes. CLINICAL RELEVANCE STATEMENT: Elevated lipoprotein(a) levels are associated with extensive coronary atherosclerosis and a high incidence of HRPs. However, they are not related to perivascular inflammation, decreased myocardial perfusion, and interstitial fibrosis in diabetes. KEY POINTS: Diabetes is a known risk factor that accelerates cardiovascular disease progression. Diabetics with elevated lipoprotein(a) (Lp(a)) levels had a higher percent atheroma volume and positive remodeling, spotty calcification, and HRPs. Patients with diabetes should be screened for elevated Lp(a) using CCTA for comprehensive evaluation of atherosclerotic characteristics.

Glucagon-like peptide-1 receptor agonists decrease hyperinsulinemia and hyperandrogenemia in dehydroepiandrosterone-induced polycystic ovary syndrome mice and are associated with mitigating inflammation and inducing browning of white adipose tissue†.

Polycystic ovary syndrome is a complicated hormonal and metabolic disorder. The exact pathogenesis of polycystic ovary syndrome is not clear thus far. Inflammation is involved in the progression of polycystic ovary syndrome. In addition, brown adipose tissue activity is impaired in polycystic ovary syndrome. Interestingly, glucagon-like peptide-1 receptor agonists have been reported to alleviate inflammation and promote browning of white adipose tissue. In this study, the effects of glucagon-like peptide-1 receptor agonists on polycystic ovary syndrome mice were explored. Mice were randomly assigned into four groups: control, dehydroepiandrosterone, dehydroepiandrosterone + liraglutide, and dehydroepiandrosterone + semaglutide. Relative indexes were measured after glucagon-like peptide-1 receptor agonist intervention. Glucose metabolism in polycystic ovary syndrome mice was ameliorated by glucagon-like peptide-1 receptor agonists, while the reproductive endocrine disorder of polycystic ovary syndrome mice was partially reversed. The messenger ribonucleic acid levels of steroidogenic enzymes and the expression of inflammatory mediators in serum and ovaries of polycystic ovary syndrome mice were improved. Furthermore, toll-like receptor 4 and phosphorylation of nuclear factor-kappa B protein levels were decreased by glucagon-like peptide-1 receptor agonists in ovary. Notably, after glucagon-like peptide-1 receptor agonist intervention, the expression of brown adipose tissue marker levels was considerably raised in the white adipose tissue of polycystic ovary syndrome mice. In conclusion, the hyperinsulinemia and hyperandrogenemia of polycystic ovary syndrome mice were alleviated by glucagon-like peptide-1 receptor agonist intervention, which was associated with mitigating inflammation and stimulating adipose tissue browning.

CT-derived fractional flow reserve for prediction of major adverse cardiovascular events in diabetic patients.

OBJECTIVES: To investigate the prognostic value of computed tomography fractional flow reserve (CT-FFR) in patients with diabetes and to establish a risk stratification model for major adverse cardiac event (MACE). METHODS: Diabetic patients with intermediate pre-test probability of coronary artery disease were prospectively enrolled. All patients were referred for coronary computed tomography angiography and followed up for at least 2 years. In the training cohort comprising of 957 patients, two models were developed: model1 with the inclusion of clinical and conventional imaging parameters, model2 incorporating the above parameters + CT-FFR. An internal validation cohort comprising 411 patients and an independent external test cohort of 429 patients were used to validate the proposed models. RESULTS: 1797 patients (mean age: 61.0 ± 7.0 years, 1031 males) were finally included in the present study. MACE occurred in 7.18% (129/1797) of the current cohort during follow- up. Multivariate Cox regression analysis revealed that CT-FFR ≤ 0.80 (hazard ratio [HR] = 4.534, p < 0.001), HbA1c (HR = 1.142, p = 0.015) and low attenuation plaque (LAP) (HR = 3.973, p = 0.041) were the independent predictors for MACE. In the training cohort, the Log-likelihood test showed statistical significance between model1 and model2 (p < 0.001). The C-index of model2 was significantly larger than that of model1 (C-index = 0.82 [0.77-0.87] vs. 0.80 [0.75-0.85], p = 0.021). Similar findings were found in internal validation and external test cohorts. CONCLUSION: CT-FFR was a strong independent predictor for MACE in diabetic cohort. The model incorporating CT-FFR, LAP and HbA1c yielded excellent performance in predicting MACE.

Diet-mediated metaorganismal relay biotransformation: health effects and pathways.

In recent years, the concept of metaorganism expands our insight into how diet-microbe-host interactions contribute to human health and diseases. We realized that many biological metabolic processes in the host can be summarized into metaorganismal relay pathways, in which metabolites such as trimethylamine-N­oxide, short-chain fatty acids and bile acids act as double-edged swords (beneficial or harmful effects) in the initiation and progression of diseases. Pleiotropic effects of metabolites are derived from several influencing factors including dose level, targeted organ of effect, action duration and species of these metabolites. Based on the pleiotropic effects of metabolites, personalized therapeutic approaches including microecological agents, enzymatic regulators and changes in dietary habits to govern related metabolite production may provide a new insight in promoting human health. In this review, we summarize our current knowledge of metaorganismal relay pathways and elaborate on the pleiotropic effects of metabolites in these pathways, with special emphasis on related therapeutic nutritional interventions.

Prediction of microvascular complications in diabetic patients without obstructive coronary stenosis based on peri-coronary adipose tissue attenuation model.

OBJECTIVES: To investigate the predictive value of peri-coronary adipose tissue (PCAT) attenuation for microvascular complications in diabetic patients without significant stenosis and to develop a prediction model for early risk stratification. METHODS: This study retrospectively included patients clinically identified for coronary computed tomography angiography (CCTA) and type 2 diabetes between January 2017 and December 2020. All patients were followed up for at least 1 year. The clinical data and CCTA-based imaging characteristics (including PCAT of major epicardial vessels, high-risk plaque features) were recorded. In the training cohort comprising of 579 patients, two models were developed: model 1 with the inclusion of clinical factors and model 2 incorporating clinical factors + RCAPCAT using multivariable logistic regression analysis. An internal validation cohort comprising 249 patients and an independent external validation cohort of 269 patients were used to validate the proposed models. RESULTS: Microvascular complications occurred in 69.1% (758/1097) of the current cohort during follow-up. In the training cohort, model 2 exhibited improved predictive power over model 1 based on clinical factors (AUC = 0.820 versus 0.781, p = 0.003) with lower prediction error (Brier score = 0.146 versus 0.164) compared to model 1. Model 2 accurately categorized 78.58% of patients with diabetic microvascular complications. Similar performance of model 2 in the internal validation cohort and the external validation cohort was further confirmed. CONCLUSIONS: The model incorporating clinical factors and RCAPCAT predicts the development of microvascular complications in diabetic patients without significant coronary stenosis. KEY POINTS: • Hypertension, HbA1c, duration of diabetes, and RCAPCAT were independent risk factors for microvascular complications. • The prediction model integrating RCAPCAT exhibited improved predictive power over the model only based on clinical factors (AUC = 0.820 versus 0.781, p = 0.003) and showed lower prediction error (Brier score=0.146 versus 0.164).

Human Wharton's jelly-derived mesenchymal stem cells prevent pregnancy loss in a rat by JAK/STAT-mediated immunomodulation.

AIM: Spontaneous abortion (SA) is a multiple-original syndrome with immune imbalance as one of its major risk factors. As Wharton's jelly-mesenchymal stem cells (WJ-MSCs) are considered to be able to prevent abortion, this study aims to explore the currently poorly understood underlining molecular signaling pathways and regulatory mechanisms of WJ-MSCs in pregnancy maintenance. METHODS: Abortion mode is established by subcutaneous injection of bromocriptine in rat on day 9 and abortion prevention is achieved by WJ-MSCs injection via tail vein. WJ-MSCs were cultured with/without the inhibitors of JAK/STAT or NF-κB. The uterus was collected on the 14th day of gestation and the rate of embryo absorption was calculated. The expression of Th1/Th2/Th3 cytokines in decidual, placental tissue, and peripheral blood was analyzed. RESULTS: WJ-MSCs treatment significantly reduced the abortion rate in bromocriptine-treated pregnancy such that it was not significantly different from a normal pregnancy. JAK/STAT inhibition abolished pregnancy preserving effects of WJ-MSCs but NF-κB inhibition did not. The levels of Th1-related cytokines and mRNA levels in the bromocriptine abortion model were significantly higher than the normal pregnancy group and ethanol control group, while levels of the Th2-related cytokines and mRNA levels significantly decreased. WJ-MSCs transfusion into the abortion model restored cytokine profiles such that they were not significantly different from the normal pregnancy group and ethanol control group. JAK/STAT inhibition of WJ-MSCs prevented their effect on cytokine and mRNA levels, but NF-κB inhibition did not. CONCLUSIONS: WJ-MSCs significantly lower the rate of embryo resorption of spontaneous abortion by reducing Th1-related cytokines while increasing Th2 and Th3-related cytokines in JAK/STAT-dependent manner.

Molecular Networking, Network Pharmacology, and Molecular Docking Approaches Employed to Investigate the Changes in Ephedrae Herba before and after Honey-Processing.

Raw Ephedrae herba (REH) and honey-processed Ephedrae herba (HEH) were the different decoction pieces of Ephedrae herba (EH). Honey-processing that changes REH into HEH has been shown to relieve cough and asthma to a synergistic extent. However, the chemical markers and the synergistic mechanism of HEH need to be further studied. In this study, the ultra-high performance liquid chromatography coupled with hybrid quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS) and molecular networking (MN) were used to investigate the chemical composition of REH and HEH, which led to the identification of 92 compounds. A total of 38 differential chemical markers for REH and HEH were identified using principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Network pharmacology suggests that the synergistic effect of HEH in relieving cough and asthma may be due to 31 differential chemical markers acting through 111 biological targets. Among them, four compounds and two targets probably played an important role based on the results of molecular docking. This study enriched our knowledge about the chemical composition of REH and HEH, as well as the synergistic mechanism of HEH.

Exosome-shuttled miR-7162-3p from human umbilical cord derived mesenchymal stem cells repair endometrial stromal cell injury by restricting APOL6.

BACKGROUND: Recent studies have shown that exosomes (Exos) derived from stem cells can be used as paracrine factors to regenerate cells and tissues via shuttling miRNAs. Exos derived from human umbilical cord derived mesenchymal stem cells (UCMSCs) have been found to alleviate mifepristone-induced endometrial stromal cell (ESC) injury in vitro. Information on the functions and mechanisms of Exos from UCMSC-induced endometrial repair is limited and requires more study. METHODS: UCMSC-Exos were isolated and identified by Transmission Electron Microscopy, Nanoparticle Tracking Analysis software, and western blot assays. The damaged-ESC model and the UCMSC co-culture system were established, while GW4869, a noncompetitive neutral sphingomyelinase (N-SMase) inhibitor, was used to investigate the effects of UCMSC-Exos on mifepristone-induced ESC injury. Cell apoptosis of damaged ESCs treated with UCMSCs was detected using the TUNEL assay and flow cytometry analysis. Then, miRNA microarrays were performed to detect differentially expressed miRNA profiles in both UCMSCs and ESCs after co-culturing. A subset of upregulated miRNAs was validated by qRT-PCR, and miRNA mimics/inhibitor were used to investigate the functions of miR-7162-3p. The miRNA-mRNA interactions were predicted by Targetscan software, while the miRNA binding sites were predicted by miRcode software. Moreover, dual-luciferase reporter, western blot assays and qPCR were conducted to identify the regulatory mechanisms between miR-7162-3p and APOL6. RESULTS: UCMSCs attenuated mifepristone-induced endometrial stromal cell apoptosis by Exos, while three miRNAs (miR-6831-5p, miR-4669, and miR-7162-3p) were both upregulated in UCMSCs and ESCs after co-culture, and were candidate effectors of UCMSC-Exos-mediated endometrial repair. We showed that miR-7162-3p was shuttled by Exos from UCMSCs and regulated the expression of APOL6 by targeting its 3'-UTR in ESCs. CONCLUSIONS: These results showed UCMSC-Exos protected ESCs from mifepristone-induced apoptosis and played an active role in repairing the damaged ESCs by in vitro shuttling of miR-7162-3p. The miR-7162-3p-overexpressed UCMSC-Exos may therefore be used in cell-free therapy of endometrial injury.

Association of ST6GAL1 and CYP19A1 polymorphisms in the 3'-UTR with astrocytoma risk and prognosis in a Chinese Han population.

BACKGROUND: Astrocytoma is a common type of central nervous system tumor. In this study, we investigated the correlation between ST6GAL1 and CYP19A1 polymorphisms and the risk and prognosis of astrocytoma. METHODS: A total of 365 astrocytoma patients and 379 healthy controls were genotyped using the Agena MassARRAY system. The correlation between ST6GAL1 and CYP19A1 variants and astrocytoma risk was calculated using logistic regression. The survival rate of patients with astrocytoma was analyzed to evaluate prognosis. RESULTS: We found that the ST6GAL1-rs2239611 significantly decreased the risk of astrocytoma in the codominant model (p = 0.044) and dominant model (p = 0.049). In stratified analyses, CYP19A1-rs2255192 might be associated with a higher risk of astrocytoma among the low-grade subgroup under recessive (p = 0.034) and additive (p = 0.030) models. However, CYP19A1-rs4646 had a risk-decreasing effect on the high-grade subgroup in the codominant model (p = 0.044). The results of Cox regression analysis showed that the CYP19A1-rs2239611 and -rs1042757 polymorphisms were significantly correlated with the prognosis of astrocytoma. CONCLUSION: Our results suggest that ST6GAL1 and CYP19A1 genes may be a potential biomarker of genetic susceptibility and prognosis to astrocytoma in the Chinese Han population.

Reduced Expression of Hydrogen Sulfide-Generating Enzymes Down-Regulates 15-Hydroxyprostaglandin Dehydrogenase in Chorion during Term and Preterm Labor.

Chorionic NAD-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) plays a pivotal role in controlling the amount of prostaglandins in the uterus and has been implicated in the process of labor. Prior studies identified hydrogen sulfide-generating enzymes cystathionine-ß-synthetase (CBS) and cystathionine-γ-lyase (CSE) in fetal membranes. We investigated whether hydrogen sulfide is involved in the regulation of PGDH expression in the chorion during labor. The chorionic tissues were obtained from pregnant women at preterm in labor and at term in labor or not in labor at term. Levels of CSE and CBS and hydrogen sulfide production rate were down-regulated in term in labor and preterm in labor groups compared with not in labor at term group. The CBS level correlated to PGDH expression in the chorion. Hydrogen sulfide donor NaHS and precursor l-cysteine dose-dependently stimulated PGDH expression and activity in cultured chorionic trophoblasts. The effect of l-cysteine was blocked by CBS inhibitor and CBS siRNA but not by CSE inhibitor and CSE siRNA. Hydrogen sulfide treatment suppressed miR-26b and miR-199a expression in chorionic trophoblasts. miR-26b and miR-199a mimics blocked hydrogen sulfide upregulation of PGDH expression. Our results indicate that hydrogen sulfide plays pivotal roles in maintenance of PGDH expression in the chorion during human pregnancy. Reduced expression of hydrogen sulfide-generating enzymes contributes to an increased amount of prostaglandins in the uterus during labor.

EZH2 upregulation by ERα induces proliferation and migration of papillary thyroid carcinoma.

BACKGROUND: The incidence of papillary thyroid carcinoma (PTC) has been increasing worldwide in recent years. Therefore, novel potential therapeutic targets for PTC are urgently needed. Enhancer of zeste homolog 2 (EZH2), a methyltransferase belonging to PRC2, plays important roles in epigenetic silencing and cell cycle regulation. EZH2 overexpression has been found in several malignant tumor tissues, while its expression and function in PTC are largely unknown. METHODS: Sixty-five cases of PTC tissue confirmed by pathology and 30 cases of normal thyroid tissue adjacent to PTC tissue were collected from patients undergoing surgical treatment, between February 2003 and February 2006. We investigated the clinic pathologic significance of EZH2 expression using Realtime-PCR and IHC in 65 human PTC tissues and 30 normal thyroid tissue samples. The EZH2 expression in human PTC cell lines (K1 and W3) and the normal thyroid follicular epithelial cell line Nthy-ori 3-1 was analyzed by Western blotting and Realtime PCR. The expressions of ERα and ERß in cell lines were analyzed by Realtime PCR.The tumor cell biological behavior was evaluated by CCK8 assay, colony formation assay, transwell migration assay and xenograft tumors model. RESULTS: Higher rate of EZH2 expression was found in PTC tissues than in normal thyroid tissues, EZH2 expression is associated with lymph node metastasis and recurrent. Inhibition of EZH2 in PTC cell lines downregulates cellular proliferation and migration. PTC is a disease with high incidence of female and E2-ERα upregulates EZH2 expression. CONCLUSIONS: These results suggest a potential role of EZH2 for the PTC growth and metastasis. As a novel therapy, a pharmacological therapy targeting EZH2 has full potential in treatment of PTC.

TNIP1 alleviates hepatic ischemia/reperfusion injury via the TLR2-Myd88 pathway.

Hepatic ischemia/reperfusion (I/R) injury induces oxidative stress, hepatocyte apoptosis, and release of inflammatory cytokines, which together causes liver damage and even organ dysfunction. TNF-α-induced protein 3-interacting protein 1 (TNIP1) reportedly decreases expression of genes associated with stress response and inflammation. Thus, we investigated the effects of TNIP1 on hepatic cells injury caused by hypoxia/reoxygenation (H/R). Reduced expression of TNIP1 was determined in I/R mice compared to normal mice. Then, TNIP1 transgene mice were used to determine the effects of TNIP1 on mice after treatment for I/R. In the normal transgene (NTG) group, serum liver damage markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and gamma glutamyl transferase (GGT) in I/R mice significantly increased compared to the sham-operated mice. However, in the TNIP1 transgene (TNIP1-TG) group, those levels in I/R mice were reduced than that in NTG mice. Additionally, cell viability and apoptosis in the hepatic cell line L02 were detected after H/R treatment, MTT assay showed that cell viability was inhibited after H/R treatment, but reversed after ad-TNIP1 transfection. Cell apoptosis also was inhibited after ad-TNIP1 transfection, as shown by the caspase-3 and caspase-9 levels and Bcl-2 and Bax values. Furthermore, TNIP1 overexpression also attenuated the inflammatory response of L02 cells after H/R treatment. Finally, treatment with TNIP1 reduced the elevated expression of TLR2, TLR4, and Myd88 after H/R injury, but overexpression of TLR4 reversed the effects of TNIP1. In conclusion, TNIP1 may protect H/R-induced hepatic cell injury by inhibiting the TLR4/Myd88 pathway.

Treatment of Ischemia-Reperfusion Injury of the Skin Flap Using Human Umbilical Cord Mesenchymal Stem Cells (hUC-MSCs) Transfected with "F-5" Gene.

BACKGROUND Recent studies have shown that skin flap transplantation technique plays an important role in surgical procedures. However, there are many problems in the process of skin flap transplantation surgeries, especially ischemia-reperfusion injury, which directly affects the survival rate of the skin flap and patient prognosis after surgeries. MATERIAL AND METHODS In this study, we used a new method of the "stem cells-gene" combination therapy. The "F-5" gene fragment of heat shock protein 90-α (Hsp90-α) was transfected into human umbilical cord mesenchymal stem cells (hUC-MSCs) by genetic engineering technique. RESULTS The synergistic effects of "F-5" gene and hUC-MSCs in the treatment of ischemia-reperfusion injury of the skin flap were confirmed by histochemical and immunohistochemical methods. CONCLUSIONS This study showed that the hUC-MSCs transfected with "F-5" gene can effectively improve the repair of ischemia-reperfusion injury.

Association of betatrophin with metabolic characteristics in overweight/obese and lean women with PCOS.

As a new hormone, betatrophin has gained attention as a potential new target to combat insulin resistance (IR) and diabetes. Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder among women of the reproductive age with long term sequelae which include IR and metabolic syndrome. The aim of this study is to evaluate the circulating plasma betatrophin levels in overweight/obese or lean women with or without PCOS and also to elucidate possible correlations with anthropometric and metabolic parameters. Thirty-two patients with PCOS as well as fifty-three control subjects were enrolled after obtaining informed written consent. Clinical and biochemical parameters of all subjects were determined. Plasma adiponectin, GLP-1 and betatrophin levels were measured by ELISA. Plasma betatrophin levels were significantly increased in lean patients with PCOS compared with lean and obese controls. Moreover, in PCOS group, betatrophin levels were significantly negatively correlated with waist hip ratio (WHR), fasting insulin level (FINS) and HOMA-IR, whereas, significantly positively correlated with adiponectin level. Multiple regression analysis showed that HOMA-IR was an independent factor influencing serum betatrophin levels. Further follow-up studies are needed to highlight whether and how increased betatrophin secretion play an important role in IR and carbohydrates metabolism in patients with PCOS.

Gender Disparity in the Relationship between Prevalence of Thyroid Nodules and Metabolic Syndrome Components: The SHDC-CDPC Community-Based Study.

The study is aimed to investigate the pathogenesis underlying the increased prevalence of thyroid nodule (TN) in different levels of metabolic syndrome (MetS) components and analyze the relationships between TN and MetS components. A total of 6,798 subjects, including 2201 patients with TN, were enrolled in this study. Anthropometric, biochemical, thyroid ultrasonographic, and other metabolic parameters were all measured. There was obviously sexual difference in the prevalence of TN (males 26.0%, females 38.5%, resp.). The prevalence of TN in hyperuricemia (45.7% versus 37.4%, P = 0.001), NAFLD (41.2% versus 36.4%, P < 0.05), and MetS (41.4% versus 35.4%, P < 0.001) groups was significantly increased only in females. Insulin resistance [OR = 1.31 (1.15, 1.49)], MetS [OR = 1.18 (1.03, 1.35)], and diabetes [OR = 1.25 (1.06, 1.48)] were all independent risk factors for TN in total subjects, whereas, after stratified analysis of gender, MetS [OR = 1.29, (1.09, 1.53)] and diabetes [OR = 1.47, (1.17, 1.84)] are still strongly and independently associated with the higher risks of TN in female subjects, but not in males. Our results suggest that the components of MetS might associate with the higher risks of TN in women than in men, but further cohort study of this gender disparity in the association between TN and MetS is required.

Expression of 15-Hydroxyprostaglandin Dehydrogenase in Human Chorion Is Associated with Peroxisome Proliferator-Activated Receptor Isoform Expression in Term Labor.

Chorionic NAD-dependent 15-hydroxy prostaglandin dehydrogenase (PGDH) plays a pivotal role in controlling the amount of prostaglandins in the uterus. Peroxisome proliferator-activated receptors (PPARs) are implicated to be involved in parturition. In this study, we investigated whether PPARs are involved in control of PGDH expression in chorion. The chorionic tissues were collected from the following groups of the women with singleton pregnancy: term no labor (TNL), term labor (TL) and preterm labor (PTL). Chorionic trophoblasts were isolated and cultured in vitro. Immunocytochemistry analysis showed that PPARα, PPARß, and PPARγ were localized to trophoblasts in chorion. The protein levels of PGDH, PPARß, and PPARγ were localized to trophoblasts in chorion. The protein levels of PPARα, PPARß, and PPARγ were reduced in TL tissues compared to that of TNL group. PPARα, PPARß, and PPARγ expression correlated to PGDH in TNL tissues, whereas only PPARγ expression correlated to PGDH in TL chorion tissues. PGDH expression was decreased in PTL tissues compared with TL group, whereas the expression of PPARs was not significantly different between TL and PTL groups. The agonists of three PPARs dose-dependently stimulated PGDH activity, mRNA, and protein expression in cultured chorionic cells. PPARs did not affect the stability of PGDH mRNA but stimulated the transcriptional activity of HPGD gene. Our results suggest that PPARs play pivotal roles in maintenance of PGDH expression in chorion during human pregnancy.

Tea polyphenols may attenuate the neurocognitive impairment caused by global cerebral ischemia/reperfusion injury via anti-apoptosis.

BACKGROUND/AIMS: Global cerebral ischemia/reperfusion (GCIR) may incur neurocognitive impairment. Tea polyphenols (TP) have strong anti-oxidant capacity. This study planned to investigate the protective effect of TP against the neurocognitive impairment caused by GCIR and its mechanism. METHODS: One-stage anterior approach for cerebral four-vessel occlusion (4VO) was used to construct the GCIR model. Sprague Dawley rats were randomly classified into Sham group, GCIR group, and TP group (n = 50 per group). Besides receiving the same 4VO, the rats in TP group were treated with TP (6.4%) injection from the tail vein 30 minutes before cerebral ischemia. Morris water-maze test was used to evaluate the changes in space recognition and memory and open field activity test to assess the activity and motor function of rats. The cell apoptotic study in hippocampal CA1 region at specified time points (12, 24, 48, and 72 hours after surgery) was carried out by the flow cytometry, histology (hematoxylin and eosin staining), and immunohistochemical (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining) examinations. One-way analysis of variance and least significant difference t-test were used and statistical significance considered at P < 0.05. RESULTS: Compared with the GCIR group, the TP group was significantly attenuated in the impairment of space recognition and memory caused by GCIR and so was the neuronal apoptosis in the hippocampal CA1 region (P < 0.05). CONCLUSION: TP may attenuate the impairment of space recognition and memory caused by GCIR via anti-apoptosis.

Exendin-4 Promotes Beta Cell Proliferation via PI3k/Akt Signalling Pathway.

BACKGROUND/AIMS: Prevention of diabetes requires maintenance of a functional beta-cell mass, the postnatal growth of which depends on beta cell proliferation. Past studies have shown evidence of an effect of an incretin analogue, Exendin-4, in promoting beta cell proliferation, whereas the underlying molecular mechanisms are not completely understood. METHODS: Here we studied the effects of Exendin-4 on beta cell proliferation in vitro and in vivo through analysing BrdU-incorporated beta cells. We also analysed the effects of Exendin-4 on beta cell mass in vivo, and on beta cell number in vitro. Then, we applied specific inhibitors of different signalling pathways and analysed their effects on Exendin-4-induced beta cell proliferation. RESULTS: Exendin-4 increased beta cell proliferation in vitro and in vivo, resulting in significant increases in beta cell mass and beta cell number, respectively. Inhibition of PI3K/Akt signalling, but not inhibition of either ERK/MAPK pathway, or JNK pathway, significantly abolished the effects of Exendin-4 in promoting beta cell proliferation. CONCLUSION: Exendin-4 promotes beta cell proliferation via PI3k/Akt signaling pathway.

Prostaglandin F2α regulates the expression of uterine activation proteins via multiple signalling pathways.

Prostaglandin F2α (PGF2A) has multiple roles in the birth process in addition to its vital contractile role. Our previous study has demonstrated that PGF2A can modulate uterine activation proteins (UAPs) in cultured pregnant human myometrial smooth muscle cells (HMSMCs). The objective of this study was to define the signalling pathways responsible for PGF2A modulation of UAPs in myometrium. It was found that PGF2A stimulated the expression of (GJA1) connexin 43 (CX43), prostaglandin endoperoxide synthase 2 (PTGS2) and oxytocin receptor (OTR) in cultured HMSMCs. The inhibitors of phospholipase C (PLC) and protein kinase C (PKC) blocked PGF2A-stimulated expression of CX43. The inhibitors of ERK, P38 and NFκB also blocked the effect of PGF2A on CX43 expression, whereas PI3K and calcineurin/nuclear factor of activated T-cells (NFAT) pathway inhibitors did not reverse the effect of PGF2A on CX43. For PTGS2 and OTR, PLC, PI3K, P38 and calcineurin/NFAT signalling pathways were involved in PGF2A action, whereas PKC and NFκB signalling were not involved. In addition, PGF2A activated NFAT, PI3K, NFκB, ERK and P38 signalling pathways. Our data suggest that PGF2A stimulates CX43, PTGS2 and OTR through divergent signalling pathways.

Effect of Desflurane versus Sevoflurane in Pediatric Anesthesia: A Meta-Analysis.

PURPOSE: To compare the effect of desflurane versus sevoflurane in pediatric anesthesia by conducting meta-analysis. METHODS: Studies were searched from PubMed, Medline, Springer, Elsevier Science Direct, Cochrane Library and Google Scholar up to July 2014. Weighted mean difference (WMD) or risk ratio (RR) and 95% confidence intervals (CIs) were considered as effect sizes. Heterogeneity across studies was assessed by Cochran Q test and I2 statistic. The random effects model was performed in the meta-analysis when heterogeneity was observed, or the fixed effect model was used. Review Manager 5.1 software was applied for the meta-analysis. RESULTS: A total of 11 studies (13 comparisons) involving 1,273 objects were included in this meta-analysis. No heterogeneity was observed between studies for any comparison but for postoperative extubation time. The results showed significant differences between desflurane and sevoflurane groups for postoperative extubation time (WMD = -3.87, 95%CI = -6.14 to -1.60, P < 0.01), eye opening time (WMD = -1.11, 95%CI = -1.49 to -0.72, P < 0.01), awakening time (WMD = -4.27, 95%CI = -5.28 to -3.26, P < 0.01) and agitation (RR = 1.44, 95%CI = 1.05 to 1.96, P = 0.02). No significant differences (P > 0.05) were detected for discharge from the recovery room, oculocardiac reflex, nausea and vomiting and severe pain. CONCLUSIONS: Desflurane may have less adverse effects than sevoflurane when used in pediatric anesthesia with significantly shorter postoperative extubation time, eye opening time and awakening time as well as slighter agitation.