GnRH-mediated suppression of S100A4 expression inhibits endometrial epithelial cell proliferation in sheep via GNAI2/MAPK signaling.

Background: Gonadotrophin-releasing hormone (GnRH) administration significantly decreases the pregnancy rate of recipient ewes after embryo transfer, possibly because GnRH affects endometrial epithelial cell function. Therefore, this study investigated the effect of GnRH on endometrial epithelial cells. Methods: Transcriptome sequencing was used to determine the regulatory effect of GnRH on the ewe endometrium, and the S100A4 gene, which showed altered transcription, was screened as a candidate regulator of this effect. Endometrial epithelial cells were further isolated, the S100A4 protein was immunoprecipitated, and host proteins that interacted with S100A4 were identified by mass spectrometry. We further verified the effects of S100A4 and GNAI2 on the proliferation of endometrial epithelial cells via overexpression/knockdown experiments and subsequent CCK-8 and EdU assays. The effect of S100A4 deletion in endometrial cells on reproduction was verified in mice with S100A4 knockout. Results: Our results showed that S100A4 gene transcription in endometrial cells was significantly inhibited after GnRH administration. GNAI2 was identified as a downstream interacting protein of S100A4, and S100A4 was confirmed to activate the MAPK signaling pathway to promote cell proliferation by targeting GNAI2. Conclusion: GnRH can suppress the expression of S100A4 in the endometrium, consequently inhibiting the proliferation of endometrial cells through the S100A4/GNAI2/MAPK signaling pathway. These findings suggest a potential explanation for the limited efficacy of GnRH in promoting embryo implantation.

Prognostic value of coronary CT angiography and CT myocardial perfusion imaging among patients with and without Diabetes.

OBJECTIVES: Whether stress CT myocardial perfusion imaging (CT-MPI) improves risk assessment in patients with diabetes mellitus (DM) remains unexplored. We aimed to evaluate the prognostic value of coronary CT angiography (CCTA) and stress CT-MPI in suspected coronary artery disease (CAD) patients with and without DM. METHODS: A total of 334 patients with suspected CAD who underwent CCTA and stress CT-MPI from May 2020 to July 2021 were retrospectively analyzed. The endpoint was major adverse cardiovascular events (MACEs). Multivariable Cox regression analysis was used to evaluate the risk factors for MACEs, including clinical risk factors, CCTA characteristics and CT-MPI characteristics. RESULTS: After a median follow-up of 21 months,15 patients of the DM group and 16 patients of the non-DM group experienced MACEs. Multivariate Cox stepwise regression analysis showed that abnormal perfusion myocardial segments ratio was associated with MACEs after adjusting for clinical risk factors and CCTA characteristics in all patients (HR:1.023, p < 0.001), DM group (HR:1.024, p = 0.008) and non-DM group (HR:1.028, p = 0.003). By adding CT-MPI characteristics to CCTA characteristics and clinical risk factors, the global chi-square for predicting MACEs increased from 62.24 to 78.84 in all patients (p < 0.001), from 19.18 to 27.30 in DM group (p = 0.004) and from 39.51 to 48.65 in non-DM group (p = 0.003); the increment of C-index in all patients, DM group and non-DM group were 0.018, 0.054 and 0.019, respectively. CONCLUSION: In all patients and those with and without DM, CT-MPI has incremental prognostic value over clinical risk factors alone or combined with CCTA characteristics in predicting MACEs.

Lack of Incremental Prognostic Value of Pericoronary Adipose Tissue Computed Tomography Attenuation Beyond Coronary Artery Disease Reporting and Data System for Major Adverse Cardiovascular Events in Patients With Acute Chest Pain.

BACKGROUND: Pericoronary adipose tissue (PCAT) and Coronary Artery Disease Reporting and Data System (CAD-RADS) category had prognostic values for major adverse cardiovascular events (MACEs). However, little is known about the difference between CAD-RADS and PCAT computed tomography (CT) attenuation for predicting MACEs. This study was to compare the prognostic value of PCAT and CAD-RADS for MACEs in patients with acute chest pain. METHODS: Between January 2010 and December 2021, all consecutive emergency patients with acute chest pain referred for coronary computed tomography angiography were enrolled in this retrospective study. MACEs included unstable angina requiring hospitalization, coronary revascularization, nonfatal myocardial infarction, and all-cause death. Patients' clinical characteristics, CAD-RADS, and PCAT CT attenuation were used to evaluate risk factors of MACEs using multivariable Cox regression analysis. RESULTS: A total of 1313 patients were evaluated (mean age, 57.13±12.57 years; 782 men). During a median follow-up of 38 months, 142 of the 1313 patients (10.81%) experienced MACEs. Multivariable Cox regression analysis showed that CAD-RADS categories 2, 3, 4, 5 (hazard ratio range, 2.286-8.325; all P<0.005) and right coronary artery PCAT CT attenuation (hazard ratio, 1.033; P=0.006) were independent predictors of MACEs after adjusting for clinical risk factors. The C statistics revealed that CAD-RADS improved risk stratification compared with PCAT CT alone (C-index, 0.760 versus 0.712; P=0.036). However, the benefit of right coronary artery PCAT CT attenuation combined with CAD-RADS was not significant compared with CAD-RADS alone (0.777 versus 0.760; P=0.129). CONCLUSIONS: Right coronary artery PCAT CT attenuation and CAD-RADS were independent predictors of MACEs. However, no incremental prognostic value of right coronary artery PCAT CT attenuation beyond CAD-RADS was detected for MACEs in patients with acute chest pain.

The V protein in oncolytic Newcastle disease virus promotes HepG2 hepatoma cell proliferation at the single-cell level.

BACKGROUND: Newcastle disease virus (NDV) is an oncolytic virus that can inhibit cancer cell proliferation and kill cancer cells. The NDV nonstructural V protein can regulate viral replication; however, whether the V protein contributes to NDV oncolysis is unclear. RESULTS: This study revealed that NDV inhibited tumor cell proliferation and that V protein expression promoted the proliferation of HepG2 cells, as determined at the single-cell level. In addition, to identify the regulatory mechanism of the V protein in HepG2 cells, transcriptome sequencing was performed and indicated that the expression/activation of multiple cell proliferation-related genes/signaling pathways were changed in cells overexpressing the V protein. Hence, the MAPK and WNT signaling pathways were selected for verification, and after blocking these two signaling pathways with inhibitors, the V protein promotion of cell proliferation was found to be attenuated. CONCLUSIONS: The results showed that the V protein regulated the proliferation of cancer cells through multiple signaling pathways, providing valuable references for future studies on the mechanism by which the V protein regulates cancer cell proliferation.

Nonalcoholic fatty liver disease is associated with myocardial ischemia by CT myocardial perfusion imaging, independent of clinical and coronary CT angiography characteristics.

OBJECTIVE: The aim of this study was to evaluate whether patients with nonalcoholic fatty liver disease (NAFLD) have more myocardial malperfusion on CT myocardial perfusion imaging (CT-MPI), as well as to further assess if NAFLD is a predictor of myocardial ischemia independently. METHODS: A total of 310 consecutive patients were included for analysis. All patients were divided into two groups according to the presence or absence of NAFLD, which was diagnosed by noncontrast cardiac CT partially covered liver and spleen. Clinical characteristics as well as imaging features including coronary artery calcium score, CCTA, and CT-MPI findings were analyzed. Univariable and multivariable logistic regression analyses were used to find out the relationship between NAFLD and myocardial ischemia. RESULTS: NAFLD (unadjusted hazard ratio [HR]: 2.4, 95% confidence interval [CI]: 1.2 to 4.4, p = 0.008), male (HR: 2.6, 95% CI: 1.5 to 4.5, p = 0.001), obstructive CAD (HR: 2.3, 95% CI: 1.3 to 4.2, p = 0.004), and FAI ≥ -70.1 HU (HR: 3.1, 95% CI: 1.8 to 5.5, p < 0.001) were associated with myocardial ischemia in univariable analysis. After adjusting for traditional CAD risk factors and CT characteristics in the multivariable regression analysis, NAFLD (HR: 2.3, 95% CI: 1.2 to 4.4, p = 0.016) was an independent predictor of myocardial ischemia. CONCLUSION: Our data suggest that myocardial ischemia was more prevalent in patients with NAFLD, and NAFLD is a predictor of myocardial ischemia independent of traditional cardiovascular risk factors and CCTA characteristics. KEY POINTS: • NAFLD patients had higher calcium score, incidence of obstructive coronary artery disease, grade of CAD-RADS, quantitative plaque characteristics, and incidence of fat attenuation index ≥ -70.1 HU. • NAFLD patients had a higher incidence of myocardial ischemia, myocardial hypoperfusion, and hypoperfusion myocardial segments ratio. • NAFLD was a predictor of myocardial ischemia, independent of traditional cardiovascular risk factors, and CCTA characteristics.

Conformational Change and Activity Enhancement of Rabbit Muscle Lactate Dehydrogenase Induced by Polyethyleneimine.

For a better understanding on the interaction between polyethyleneimine (PEI) and proteins, spectroscopic studies including UV-vis absorption, resonance Rayleigh scattering, fluorescence, and circular dichroism were conducted to reveal the conformational change of rabbit muscle lactate dehydrogenase (rmLDH) and related to the bioactivity of the enzyme. Regardless of the electrostatic repulsion, PEI could bind on the surface of rmLDH, a basic protein, via hydrogen binding of the dense amine groups and hydrophobic interaction of methyl groups. The competitive binding by PEI led to a reduction of the binding efficiency of rmLDH toward ß-nicotinamide adenine dinucleotide, the coenzyme, and sodium pyruvate, the substrate. However, the complex formation with PEI induced a less ordered conformation and an enhanced surface hydrophobicity of rmLDH, facilitating the turnover of the enzyme and generally resulting in an increased activity. PEI of higher molecular weight was more efficient to induce alteration in the conformation and catalytic activity of the enzyme.