Reticulocalbin 2 promotes the prolifer ation and migration of oral squamous cell carcinoma by regulating the EGFR ERK pathway

Purpose: To investigate the expression of reticulocalbin-2 (RCN2) in human oral squamous cell carcinoma (OSCC) tissues and cell lines and its effects on the proliferation and migration of OSCC cells.Methods: Immunohistochemical (IHC) assays were performed to evaluate the expression of RCN2 in 30 histologically-confirmed OSCC patient tissues and adjacent tissues. Immunoblot assays were performed to examine the expression of RCN2 in an oral mucosal keratinocyte cell line and OSCC cell lines, while the effects of RCN2 on OSCC cell proliferation were assessed by CCK-8 and colony formation assays. The effects of RCN2 on OSCC cell motility were determined using wound closure and Transwell assays. Furthermore, the effect of RCN2 on EGFR/ERK pathway in OSCC cells was evaluated by immunoblot assay.Results: Overexpression of RCN2 occurred in OSCC tissues and cells (p < 0.01). RCN2 also increased the proliferation of OSCC cells and stimulated the motility of OSCC cells in vitro (p < 0.01). These effects occurred as a result of the regulation of EGFR/ERK signaling pathway by RCN2.Conclusion: RCN2 is a potential therapeutic target for OSCC treatment. However, further in vivo studies are required to validate these findings

Antibacterial sensitizers from natural plants: A powerful weapon against methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) is a drug-resistant bacterium that can cause a range of infections with high morbidity and mortality, including pneumonia, etc. Therefore, development of new drugs or therapeutic strategies against MRSA is urgently needed. Increasing evidence has shown that combining antibiotics with “antibacterial sensitizers” which itself has no effect on MRSA, is highly effective against MRSA. Many studies showed the development of antibacterial sensitizers from natural plants may be a promising strategy against MRSA because of their low side effects, low toxicity and multi-acting target. In our paper, we first reviewed the resistance mechanisms of MRSA including “Resistance to Beta-Lactams”, “Resistance to Glycopeptide antibiotics”, “Resistance to Macrolides, Aminoglycosides, and Oxazolidinones” etc. Moreover, we summarized the possible targets for antibacterial sensitizers against MRSA. Furthermore, we reviewed the synergy effects of active monomeric compounds from natural plants combined with antibiotics against MRSA and their corresponding mechanisms over the last two decades. This review provides a novel approach to overcome antibiotic resistance in MRSA

Five-Minute Cognitive Test as A New Quick Screening of Cognitive Impairment in The Elderly

This study aims to develop a new evaluation method for quickly and conveniently screening cognitive impairment in the elderly. The five-minute cognitive test (FCT) was designed to capture deficits in five domains of cognitive abilities, including episodic memory, language fluency, time orientation, visuospatial function, and executive function. Subsequently, FCT efficiencies in differentiating normally cognitive ability from cognitive impairment were explored and compared with that of the Mini-Mental Status Evaluation (MMSE). Equipercentile equating method was utilized to create a crosswalk between scores of the FCT and MMSE. Further, the association of scores of the FCT and MMSE with hippocampal volumes was investigated. There were 241 subjects aged 60 years or above enrolled in this study, including 107 adults with cognitive abilities in normal range, 107 patients with mild cognitive impairment (MCI), and 27 patients with mild Alzheimer disease (AD). The AUC of FCT for detection of cognitive impairment (MCI and mild AD) was 0.885 (95% CI 0.838 to 0.922). The sensitivity and specificity of FCT for the diagnosis of cognitive impairment were 80.6% and 84.11 %, respectively. FCT’s diagnostic performance was superior to that of MMSE in the same cohort. Mean completion time of FCT was 339.9 ± 67.7 seconds (5-6 min). In addition, a conversion table between scores on the FCT and MMSE was created. Further, the FCT scores were positively correlated with hippocampal volumes. The FCT is a novel, reliable, and valid cognitive screening test for the detection of dementia at early stages

25(OH)VitD and human endocrine and functional fertility parameters in women undergoing IVF/ICSI

Background: Vitamin D plays an important role in reproduction. Evidence shown that free 25-hydroxyvitamin D (25(OH)VitD) was more accurate than total 25(OH)VitD in reflecting the status of 25(OH)VitD during pregnancy. However, the relationship between free 25(OH)VitD and female fertility parameters has not been reported yet. Therefore, this study aims to compare the correlation of free and total 25(OH)VitD with fertility parameters in infertility females undergoing in vitro fertilization and embryo transfer (IVF-ET) or intracytoplasmic sperm injection (ICSI). Methods: According to the inclusion and exclusion criteria, 2569 infertility patients who received IVF-ET or ICSI treatment for the first time participated in this study. Five milliliter peripheral blood samples of the patients were collected on the day before embryo transfer (ET). Enzyme linked immunosorbent assay (ELISA) kits was used to detect free 25(OH)VitD and total 25(OH)VitD, and clinical information was collected. Spearman’s rho was used to evaluate the association between the variables. Results: The median (IQR) of free 25(OH)VitD was 4.71 (4.11-5.31) pg/mL and total 25(OH)VitD was 19.54 (16.52-22.83) ng/m. The correlation between them, however, was week (rho=0.311). Compared to total 25(OH)VitD, free 25(OH)VitD was slightly better correlated with basal follicle-stimulating hormone (FSH) (rho=0.041, P=0.036), basal estradiol (E2) (rho=0.089, P<0.001), anti-Müllerian hormone (AMH) (rho=-0.057, P=0.004), antral follicle count (AFC) (rho=-0.053, P=0.007), E2 (rho=-0.080, P<0.001), number of oocytes retrieval (rho=-0.079, P<0.001) and progesterone (P)/E2 on hCG trigger day (rho=0.081, P<0.001). Conclusions: Overall, there was only a rather weak correlation of free as well as total 25(OH)VitD with human endocrine and functional fertility parameters in women undergoing IVF/ICSI. Neither free nor total 25(OH)VitD seems to play a major role in human embryo implantation

miR-132-3p Priming Enhances the Effects of Mesenchymal Stromal Cell-Derived Exosomes on Ameliorating Brain Ischemic Injury

Backgrounds/aims: Mesenchymal stromal cell-derived exosomes (MSC-EXs) could exert protective effects on recipient cells by transferring the contained microRNAs (miRs), and miR-132-3p is one of angiogenic miRs. However, whether the combination of MSC-EXs and miR-132-3p has better effects in ischemic cerebrovascular disease remains unknown. Methods: Mouse MSCs transfected with scrambler control or miR-132-3p mimics were used to generate MSC-EXs and miR-132-3p-overexpressed MSC-EXs (MSC-EXsmiR-132-3p). The effects of EXs on hypoxia/reoxygenation (H/R)-injured ECs in ROS generation, apoptosis, and barrier function were analyzed. The levels of RASA1, Ras, phosphorylations of PI3K, Akt and endothelial nitric oxide synthesis (eNOS), and tight junction proteins (Claudin-5 and ZO-1) were measured. Ras and PI3K inhibitors were used for pathway analysis. In transient middle cerebral artery occlusion (tMCAO) mouse model, the effects of MSC-EXs on the cerebral vascular ROS production and apoptosis, cerebral vascular density (cMVD), Evans blue extravasation, brain water content, neurological deficit score (NDS), and infarct volume were determined. Results: MSC-EXs could deliver their carried miR-132-3p into target ECs, which functionally downregulated the target protein RASA1, while upregulated the expression of Ras and the downstream PI3K phosphorylation. Compared to MSC-EXs, MSC-EXsmiR-132-3p were more effective in decreasing ROS production, apoptosis, and tight junction disruption in H/R-injured ECs. These effects were associated with increased levels of phosphorylated Akt and eNOS, which could be abolished by PI3K inhibitor (LY294002) or Ras inhibitor (NSC 23766). In the tMCAO mouse model, the infusion of MSC-EXsmiR-132-3p was more effective than MSC-EXs in reducing cerebral vascular ROS production, BBB dysfunction, and brain injury. Conclusion: Our results suggest that miR-132-3p promotes the beneficial effects of MSC-EXs on brain ischemic injury through protecting cerebral EC functions

Even high normal blood pressure affects live birth rate in women undergoing fresh embryo transfer

STUDY QUESTION Do differences in blood pressure within the normal range have any impacts on the live birth rate (primary outcome) or biochemical pregnancy rate (beta-hCG positivity), clinical pregnancy rate (heart beating in ultrasound), abortion rate and ectopic pregnancy rate (secondary outcomes) of fresh embryo transfer in women undergoing their IVF/ICSI treatment? SUMMARY ANSWER Even rather small differences in baseline blood pressure in women with normal blood pressure according to current guidelines undergoing fresh embryo transfer after IVF/ICSI affects substantially the live birth rate. WHAT IS KNOWN ALREADY Pre-pregnancy hypertension is a well-known risk factor for adverse pregnancy events such as preeclampsia, fetal growth restriction, placental abruption and adverse neonatal events. It is likewise well known that hypertension during pregnancy in women undergoing ART is associated with adverse pregnancy outcomes. However, whether blood pressure at the high end of the normal range has an impact on ART is unknown. STUDY DESIGN, SIZE, DURATION It is a prospective observational cohort study based on a single IVF center between January 2017 and December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS Two thousand four hundred and eighteen women with normal blood pressure undergoing fresh embryo transfer after IVF/ICSI at the Reproductive and Genetic Hospital of CITIC-Xiangya were enrolled in this study. MAIN RESULTS AND THE ROLE OF CHANCE Blood pressure was measured at the first visit when women consulted the IVF center due to infertility. In women with a successful pregnancy outcome (1487 live births out of 2418 women undergoing fresh embryo transfer after IVF/ICSI), systolic blood pressure (SBP) (114.1 ± 9.48 mmHg versus 115.4 ± 9.8 mmHg, P = 0.001) and diastolic blood pressure (DBP) (74.5 ± 7.5 mmHg versus 75.3 ± 7.34 mmHg, P = 0.006) were lower than in those who did not achieve live births. Multivariate logistic regression analysis revealed that SBP (OR: 0.987, 95% CI: 0.979–0.996, P = 0.004) and DBP (OR: 0.986, 95% CI: 0.975–0.998, P = 0.016) were negatively associated with live birth. Similarly, SBP was significantly negatively related to clinical pregnancy rate (OR: 0.990, 95% CI: 0.981–0.999, P = 0.033), while for DBP the association was not statistically significant (OR: 0.994, 95% CI: 0.982–1.006, P = 0.343). However, both SBP and DBP were positively associated with miscarriage OR: 1.021 (95% CI: 1.004–1.037, P = 0.013) and OR: 1.027 (95% CI: 1.005–1.049, P = 0.014), respectively. Both SBP and DBP were unrelated to biochemical pregnancy (hCG positivity), implantation and ectopic pregnancy rate. LIMITATIONS, REASONS FOR CAUTION Whether lowering blood pressure before initiating ART treatment in women with SBP or DBP higher than the thresholds defined in our study will confer a benefit is unknown. Also, we cannot exclude bias due to different ethnicities. Moreover, participants in our study only received fresh embryo transfer, whether the results could apply to frozen embryo transfer is unclear. WIDER IMPLICATIONS OF THE FINDINGS Our study challenges the current blood pressure goals in women undergoing fresh embryo transfer after IVF/ICSI. Further studies are needed to figure out the mechanism and effective approach to increase IVF/ICSI pregnancy outcomes. STUDY FUNDING/COMPETING INTEREST(S) Hunan Provincial Grant for Innovative Province Construction (2019SK4012). The authors declare that there were no conflicts of interest in this study. TRIAL REGISTRATION NUMBER N/A

All-Trans-Retinoic Acid Suppresses Neointimal Hyperplasia and Inhibits Vascular Smooth Muscle Cell Proliferation and Migration via Activation of AMPK Signaling Pathway

The proliferation and migration of vascular smooth muscle cells (VSMC) is extensively involved in pathogenesis of neointimal hyperplasia. All-trans-retinoic acid (ATRA) is a natural metabolite of vitamin A. Here, we investigated the involvement of AMP-activated protein kinase (AMPK) in the anti-neointimal hyperplasia effects of ATRA. We found that treatment with ATRA significantly reduced neointimal hyperplasia in the left common carotid artery ligation mouse model. ATRA reduced the proliferation and migration of VSMC, A7r5 and HASMC cell lines. Our results also demonstrated that ATRA altered the expression of proliferation-related proteins, including CyclinD1, CyclinD3, CyclinA2, CDK2, CDK4, and CDK6 in VSMC. ATRA dose-dependently enhanced the phosphorylation level of AMPKα (Thr172) in the left common carotid artery of experimental mice. Also, the phosphorylation level of AMPKα in A7r5 and HASMC was significantly increased. In addition, ATRA dose-dependently reduced the phosphorylation levels of mTOR and mTOR target proteins p70 S6 kinase (p70S6K) and 4E-binding protein 1 (4EBP1) in A7r5 and HASMC. Notably, the inhibition of AMPKα by AMPK inhibitor (compound C) negated the protective effect of ATRA on VSMC proliferation in A7r5. Also, knockdown of AMPKα by siRNA partly abolished the anti-proliferative and anti-migratory effects of ATRA in HASMC. Molecular docking analysis showed that ATRA could dock to the agonist binding site of AMPK, and the binding energy between AMPK and ATRA was -7.91 kcal/mol. Molecular dynamics simulations showed that the binding of AMPK-ATRA was stable. These data demonstrated that ATRA might inhibit neointimal hyperplasia and suppress VSMC proliferation and migration by direct activation of AMPK and inhibition of mTOR signaling