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Context The effect of kaempferol, a regulator of oestrogen receptors, on atherosclerosis (AS) and the underlying mechanism is elusive. Objective To explore the effect and mechanism of kaempferol on AS. Methods and materials In vivo , C57BL/6 and apolipoprotein E (APOE) –/– mice were randomly categorized into six groups (C57BL/6: control, ovariectomy (OVX), high-fat diet (HFD); APOE –/– : OVX-HFD, OVX-HFD + kaempferol (50 mg/kg) and OVX-HFD + kaempferol (100 mg/kg) and administered with kaempferol for 16 weeks, intragastrically. Oil-Red and haematoxylin–eosin (HE) staining were employed to examine the effect of kaempferol. In vitro , human aortic endothelial cells (HAECs) were pre-treated with or without kaempferol (5, 10 or 20 μM), followed by administration with kaempferol and oxidized low-density lipoprotein (ox-LDL) (200 μg/mL). The effect of kaempferol was evaluated using flow cytometry, and TdT-mediated dUTP Nick-End Labelling (TUNEL). Results In vivo , kaempferol (50 and 100 mg/kg) normalized the morphology of blood vessels and lipid levels and suppressed inflammation and apoptosis. It also activated the G protein-coupled oestrogen receptor (GPER) and PI3K/AKT/nuclear factor-erythroid 2-related factor 2 (Nrf2) pathways. In vitro , ox-LDL (200 μg/mL) reduced the cell viability to 50% (IC 50 ). Kaempferol (5, 10 or 20 μM) induced-GPER activation increased cell viability to nearly 10%, 19.8%, 30%, and the decreased cellular reactive oxygen species (ROS) generation (16.7%, 25.6%, 31.1%), respectively, consequently attenuating postmenopausal AS. However, the protective effects of kaempferol were blocked through co-treatment with si-GPER. Conclusions The beneficial effects of kaempferol against postmenopausal AS are associated with the PI3K/AKT/Nrf2 pathways, mediated by the activation of GPER.

Overcoming resistance to radiation is a great challenge in cancer therapy. Here, we highlight that targeting valosin‐containing protein (VCP) improves radiation sensitivity in esophageal squamous cell carcinoma (ESCC) cell lines and show the potential of using VCP as a prognosis marker in locally advanced ESCC treated with radiation therapy. Esophageal squamous cell carcinoma cell lines with high VCP expression were treated with VCP inhibitor combined with radiotherapy. Cell proliferation, colony formation, cell death, and endoplasmic reticulum (ER) stress signaling were evaluated. Moreover, patients with newly diagnosed locally advanced ESCC who were treated with radiotherapy were analyzed. Immunohistochemistry was used to detect the expression of VCP. The correlation between overall survival and VCP was investigated. Esophageal squamous cell carcinoma cells treated with VCP inhibitor and radiotherapy showed attenuated cell proliferation and colony formation and enhanced apoptosis. Further investigation showed this combined strategy activated the ER stress signaling involved in unfolded protein response, and inhibited the ER‐associated degradation (ERAD) pathway. Clinical analysis revealed a significant survival benefit in the low VCP expression group. Targeting VCP resulted in antitumor activity and enhanced the efficacy of radiation therapy in ESCC cells in vitro. Valosin‐containing protein is a promising and novel target. In patients with locally advanced ESCC who received radiotherapy, VCP can be considered as a useful prognostic indicator of overall survival. Valosin‐containing protein inhibitors could be developed for use as effective cancer therapies, in combination with radiation therapy.

Many studies have evaluated the association between serum levels of mannose-binding lectin (MBL) and sepsis; however, the findings are inconclusive and conflicting. For a better understanding of MBL in sepsis, we conducted a comprehensive meta-analysis. Potential relevant studies were identified covering Science Citation Index, the Cochrane Library, PubMed, Embase, CINAHL, and Current Contents Index databases. Two reviewers extracted data and assessed studies independently. Statistical analyses were conducted with the version 12.0 STATA statistical software. Ten papers were collected for meta-analysis. Results identified that sepsis patients had considerably lower MBL level than those in the controls (standardized mean difference (SMD) = 1.59, 95 % confidence interval (95%CI) = 0.86∼2.31, P < 0.001). Ethnicity-subgroup analysis showed that sepsis patients were associated with decreased serum MBL level in contrast to the healthy controls in Asians (SMD = 3.07, 95%CI = 1.27∼4.88, P = 0.001) and Caucasians (SMD = 1.00, 95%CI = 0.35∼1.65, P = 0.003). In the group-stratified subgroup analysis, subjects with lower serum MBL level did underpin susceptibility to sepsis in the infants subgroup (SMD = 2.57, 95%CI = 1.59∼3.55, P < 0.001); however, this was not the case in the adults subgroup (SMD = 0.13, 95%CI = -1.30∼1.55, P = 0.862). Our study suggests an important involvement of serum MBL level in sepsis patients considering their lower level compared to controls, especially among infants.

Background: Premenstrual syndrome (PMS) is a menstrual cycle-related disorder which causes physical and mood changes prior to menstruation and is associated with the functional dysregulation of the brain. Acupuncture is an effective alternative therapy for treating PMS, and sanyinjiao (SP6) is one of the most common acupoints used for improving the symptoms of PMS. However, the mechanism behind acupuncture’s efficacy for relieving PMS symptoms remains unclear. The aim of this study was to identify the brain response patterns induced by acupuncture at acupoint SP6 in patients with PMS.Materials and Methods: Twenty-three females with PMS were enrolled in this study. All patients underwent resting-state fMRI data collection before and after 6 min of electroacupuncture stimulation (EAS) at SP6. A regional homogeneity (ReHo) approach was used to compare patients’ brain responses before and after EAS at SP6 using REST software. The present study was registered at http://www.chictr.org.cn, and the Clinical Trial Registration Number is ChiCTR-OPC-15005918.Results: EAS at SP6 elicited decreased ReHo value at the bilateral precuneus, right inferior frontal cortex (IFC) and left middle frontal cortex (MFC). In contrast, increased ReHo value was found at the bilateral thalamus, bilateral insula, left putamen and right primary somatosensory cortex (S1).Conclusions: Our study provides an underlying neuroimaging evidence that the aberrant neural activity of PMS patients could be regulated by acupuncture at SP6.

Indoleamine 2,3-dioxygenase (IDO1) plays an important role in tumor immune evasion. In this study, we investigated the changes of tumor IDO1 expression and CD8+ tumor-infiltrating lymphocytes (TILs) status in tumor microenvironment (TME) after neoadjuvant chemoradiotherapy (NCRT) or neoadjuvant chemotherapy (NCT) in esophageal squamous cell carcinoma (ESCC), respectively. Moreover, the potential predictive value of the changes of tumor IDO1 expression and CD8+TILs status on pathologic response and clinical outcome was further evaluated. By matching propensity scores in 295 patients, a total of 85 ESCC patients with neoadjuvant therapy followed by surgery were recruited, including 17 patients with NCRT and 68 patients with NCT. Tumor IDO1 expression and CD8+TILs within TME in paired specimens were evaluated by immunohistochemistry, and the changes of tumor IDO1 expression and CD8+TILs between the paired specimens were estimated. Tumor IDO1 expression significantly increased from baseline to postoperative tumor tissue after NCT ( p = 0.002), whereas no significant difference was detected after NCRT ( p = 0.44). The density of CD8+TILs in the tumor-invasive margin increased significantly after neoadjuvant therapy, and there was no significant difference in density changes of CD8+TILs between the NCRT and NCT groups ( p = 0.118). Upregulation of tumor IDO1 expression after neoadjuvant therapy was associated with poor pathologic response ( p = 0.002). Lastly, multivariate Cox analysis showed that IDO1-rise patients after neoadjuvant therapy were related to poor prognosis ( p = 0.047). These results indicated that chemotherapy could promote tumor IDO1 expression, and the increased tumor IDO1 expression after neoadjuvant therapy predicted poor pathologic response and prognosis in ESCC.

BACKGROUND: Vimentin (VIM) is considered a prognostic marker in colorectal cancer (CRC). Our aim is to identify genes that fulfil a "X-low implies VIM-high" Boolean relationship and to evaluate their prognostic value and potential mechanism. METHODS: Potential biomarkers related to VIM expression were searched using a bioinformatics approach across gene-expression arrays. Based on subgroup analysis of 2 CRC cohorts, the selected gene was tested for its association with patient's survival outcomes. The regulatory link between the selected gene and VIM was further examined with in vitro models. RESULTS: PPM1H was identified as the top candidate in our search. Patients with PPM1H-low tumours have a lower 5-year diseasefree survival rate than patients with PPM1H-high tumours in 2 independent cohorts. In multivariate Cox analysis, patients with PPM1H-low tumours were independently associated with relapse in both the discovery cohort (hazard ratio [HR], 1.362; 95% confidence interval [CI], 1.015-1.826; P = 0.039) and the validation cohort (HR for DFS, 4.052; 95% CI, 2.634-6.234; P < 0.001). PPM1H knockdown in CRC cells and growth in the corresponding conditional medium increased VIM expression and colon fibroblast proliferation, indicating a transformation of cancer-association fibroblasts (CAFs). Conversely, educated CAFs also facilitated the growth of CRC cells with low PPM1H expression. CONCLUSIONS: Lack of tumour PPM1H expression identifies a patient subgroup with a high relapse risk, and CRC cells with low expression of PPM1H activate CAFs and inversely get promoted by CAFs.

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