Direct rosiglitazone action on steroidogenesis and proinflammatory factor production in human granulosa-lutein cells

<p>Abstract</p> <p>Background</p> <p>Ovarian granulosa cells are the predominant source of estradiol and progesterone biosynthesis in vivo. Rosiglitazone, a synthetic agonist of the peroxisome proliferator-activated receptor gamma (PPAR gamma), is applied as the treatment of insulin resistance including women with PCOS. The aim of the study was to investigate the direct effects of rosiglitazone on steroidogenesis and proinflammatory factor production in human granulosa-lutein cells (GLCs).</p> <p>Methods</p> <p>Primary human GLCs were separated during in vitro fertilization and cultured in the presence of rosiglitazone, GW9662 (an antagonist of PPAR gamma) and hCG. The mRNA expression of key steroidogenic factors including 3beta- hydroxysteriod dehydrogenase (3beta-HSD), cytochrome P-450 scc (CYP11A1), cytochrome P-450 aromatase (CYP19A1), and steroidogenic acute regulatory protein (StAR) were detected by quantitative real-time PCR. Estradiol and progesterone levels in GLCs cultures were measured by chemiluminescence immunoassay, and the proinflammtory factors (TNFalpha and IL-6) in conditioned culture media were measured by ELISA.</p> <p>Results</p> <p>PPAR gamma mRNA levels increased up to 3.24 fold by rosiglitazone at the concentration of 30 microM compared to control (P < 0.05). hCG alone or hCG with rosiglitazone had no significant effects on PPAR gamma mRNA levels. The CYP19A1 mRNA level at exposure to rosiglitazone alone showed a drop, but was not significantly reduced comparing to control. The expression levels of enzymes 3beta-HSD and CYP11A1 in all treatments did not alter significantly. The StAR mRNA expression at exposure to rosiglitazone was significantly increased comparing to control (P < 0.05). The media concentrations of E2 and progesterone by rosiglitazone treatment showed a declining trend comparing to control or cotreatment with hCG, which did not reach significance. Most importantly, treatment with rosiglitazone decreased TNFalpha secretion in a statistically significant manner compared with control (P < 0.05). The concentration of IL-6 following rosiglitazone exposure did not significantly decrease comparing to control.</p> <p>Conclusion</p> <p>In cultured GLCs, rosiglitazone stimulated StAR expression, but did not significantly affect steroidogenic enzymes, as well as E2 and progesterone production. Moreover, rosiglitazone significantly decreased the production of TNFalpha in human GLCs, suggesting that PPAR gamma may play a role in the regulation of GLCs functions through inhibiting proinflammatory factors.</p

Composite Hydrogels with the Simultaneous Release of VEGF and MCP-1 for Enhancing Angiogenesis for Bone Tissue Engineering Applications

Rapid new microvascular network induction was critical for bone regeneration, which required the spatiotemporal delivery of growth factors and transplantation of endothelial cells. In this study, the linear poly(d,l-lactic-co-glycolic acid)-b-methoxy poly(ethylene glycol) (PLGA-mPEG) block copolymer microspheres were prepared for simultaneously delivering vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1). Then, vascular endothelial cells (VECs) with growth factor loaded microspheres were composited into a star-shaped PLGA-mPEG block copolymer solution. After this, composite hydrogel (microspheres ratio: 5 wt%) was formed by increasing the temperature to 37 °C. The release profiles of VEGF and MCP-1 from composite hydrogels in 30 days were investigated to confirm the different simultaneous delivery systems. The VECs exhibited a good proliferation in the composite hydrogels, which proved that the composite hydrogels had a good cytocompatibility. Furthermore, in vivo animal experiments showed that the vessel density and the mean vessel diameters increased over weeks after the composite hydrogels were implanted into the necrosis site of the rabbit femoral head. The above results suggested that the VECs-laden hydrogel composited with the dual-growth factor simultaneous release system has the potential to enhance angiogenesis in bone tissue engineering

Anisotropic in-plane heat transport of Kitaev magnet Na2_2Co2_2TeO6_6

We report a study on low-temperature heat transport of Kitaev magnet Na$_2$Co$_2$TeO$_6$, with the heat current and magnetic fields along the honeycomb spin layer (the $ab$ plane). The zero-field thermal conductivity of $\kappa^a_{xx}$ and $\kappa^{a*}_{xx}$ display similar temperature dependence and small difference in their magnitudes; whereas, their magnetic field (parallel to the heat current) dependence are quite different and are related to the field-induced magnetic transitions. The $\kappa^a_{xx}(B)$ data for $B \parallel a$ at very low temperatures have an anomaly at 10.25--10.5 T, which reveals an unexplored magnetic transition. The planar thermal Hall conductivity $\kappa^a_{xy}$ and $\kappa^{a*}_{xy}$ show very weak signals at low fields and rather large values with sign change at high fields. This may point to a possible magnetic structure transition or the change of the magnon band topology that induces a radical change of magnon Berry curvature distribution before entering the spin polarized state. These results put clear constraints on the high-field phase and the theoretical models for Na$_2$Co$_2$TeO$_6$.Comment: 7 pages, 4 figure

Addition of Risk-enhancing Factors Improves Risk Assessment of Atherosclerotic Cardiovascular Disease in Middle-aged and Older Chinese Adults: Findings from the Chinese Multi-provincial Cohort Study

Objective: This study aimed to examine whether integrating risk-enhancing factors into the Chinese Society of Cardiology-recommended clinical risk assessment tool (i.e., the CSC model) for atherosclerotic cardiovascular disease (ASCVD) might improve 10-year ASCVD risk stratification in Chinese adults. Methods: A total of 4910 Chinese participants who were 50–79 years of age and free of cardiovascular disease in the 2007–2008 Survey from the Chinese Multi-provincial Cohort Study were included. We assessed the updated model’s clinical utility (i.e., Harrell’s C-index and net reclassification improvement [NRI]) by adding risk-enhancing factors individually or the number of risk-enhancing factors to the CSC model, for all individuals or those at intermediate risk. Risk-enhancing factors, including a family history of CVD, triglycerides ≥2.3 mmol/L, high-sensitivity C-reactive protein ≥2 mg/L, Lipoprotein (a) ≥50 mg/dL, non-high-density lipoprotein cholesterol ≥4.9 mmol/L, overweight/obesity, and central obesity, were evaluated. ASCVD events were defined as a composite endpoint comprising ischemic stroke and acute coronary heart disease events (including nonfatal acute myocardial infarction and all coronary deaths). Results: During a median 10-year follow-up, 449 (9.1%) ASCVD events were recorded. Addition of ≥2 risk-enhancing factors to the CSC model yielded a significant improvement in the C-index (1.0%, 95% confidence interval [CI]: 0.2–1.7%) and a modest improvement in the NRI (2.0%, 95% CI: −1.2–5.4%) in the total population. For intermediate-risk individuals, particularly individuals at high risk of developing ASCVD, significant improvements in NRI were observed after adding ≥2 risk-enhancing factors (17.4%, 95% CI: 5.6–28.5%) to the CSC model. Conclusions: Addition of ≥2 risk-enhancing factors refined 10-year ASCVD risk stratification, particularly for intermediate-risk individuals, supporting their potential in helping tailor targeted interventions in clinical practice

Changes of Adult Population Health Status in China from 2003 to 2008

Objectives: The purpose of this study was to examine the change in health status of China’s adult population between the years of 2003 and 2008 due to rapid economic growth and medical system improvement. Methods: Data from the third and fourth Chinese national health services surveys covering 141,927 residents in 2003 and 136,371 residents in 2008 who were aged.18 years were analyzed. Results: Chinese respondents in 2008 were more likely to report disease than in 2003. Smoking slightly decreased among men and women, and regular exercise showed much improvement. Stratified analyses revealed significant subpopulation disparities in rate ratios for 2008/2003 in the presence of chronic disease, with greater increases among women, elderly, the Han nationality, unmarried and widow, illiterate, rural, and regions east of China than other groups. Conclusions: Chinese adults in 2008 had worse health status than in 2003 in terms of presence of chronic disease. China’s reform of health care will face more complex challenges in coming years from the deteriorating health status in Chinese adults

Subtype-Based Analysis of Cell-in-Cell Structures in Esophageal Squamous Cell Carcinoma

Cell-in-cell (CIC) structures are defined as the special structures with one or more cells enclosed inside another one. Increasing data indicated that CIC structures were functional surrogates of complicated cell behaviors and prognosis predictor in heterogeneous cancers. However, the CIC structure profiling and its prognostic value have not been reported in human esophageal squamous cell Carcinoma (ESCC). We conducted the analysis of subtyped CIC-based profiling in ESCC using “epithelium-macrophage-leukocyte” (EML) multiplex staining and examined the prognostic value of CIC structure profiling through Kaplan-Meier plotting and Cox regression model. Totally, five CIC structure subtypes were identified in ESCC tissue and the majority of them was homotypic CIC (hoCIC) with tumor cells inside tumor cells (TiT). By univariate and multivariate analyses, TiT was shown to be an independent prognostic factor for resectable ESCC, and patients with higher density of TiT tended to have longer post-operational survival time. Furthermore, in subpopulation analysis stratified by TNM stage, high TiT density was associated with longer overall survival (OS) in patients of TNM stages III and IV as compared with patients with low TiT density (mean OS: 51 vs 15 months, P = 0.04) and T3 stage (mean OS: 57 vs 17 months, P=0.024). Together, we reported the first CIC structure profiling in ESCC and explored the prognostic value of subtyped CIC structures, which supported the notion that functional pathology with CIC structure profiling is an emerging prognostic factor for human cancers, such as ESCC

Verification of specific G-quadruplex structure by using a novel cyanine dye supramolecular assembly: II. The binding characterization with specific intramolecular G-quadruplex and the recognizing mechanism

The supramolecular assembly of a novel cyanine dye, 3,3′-di(3-sulfopropyl)-4,5,4′,5′-dibenzo-9-ethyl-thiacarbocyanine triethylammonium salt (ETC) was designed to verify specific intramolecular G-quadruplexes from duplex and single-strand DNAs. Spectral results have shown that ETC presented two major distinct signatures with specific intramolecular G-quadruplexes in vitro: (i) dramatic changes in the absorption spectra (including disappearance of absorption peak around 660 nm and appearance of independent new peak around 584 nm); (ii) ∼70 times enhancement of fluorescence signal at 600 nm. Furthermore, based on 1H-nuclear magnetic resonance and circular dichroism results, the preferring binding of ETC to specific intramolecular G-quadruplexes probably result from end-stacking, and the loop structure nearby also plays an important role

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK