Multivariate analyses on male factors and construction of a nomogram for predicting low in vitro fertilization rate.

Low fertilization rate (LFR) and total fertilization failure (TFF) are often encountered in routine in vitro fertilization (IVF) procedure. To solve this problem, multivariate analyses on the relationship between male factors and in vitro fertilization rate were performed, and a nomogram for prediction of LFR was constructed. This retrospective study contained 2011 couples who received IVF treatment from January 2017 to December 2021. Man factors and in vitro fertilization rate were collected. Among these couples, 1347 cases had in vitro fertilization rates ≥30 % (control group), and 664 cases had in vitro fertilization rates <30 % (LFR group). Univariate analyses of male factors found that between the two groups there were significant differences (p < 0.05) in sperm progressive motility (SPR), sperm concentration (SC), total sperm number, normal sperm morphology rate (NSMR), DNA fragmentation index (DFI), sperm acrosin activity (SAA) and the clinical diagnosis of primary or secondary infertility. Multivariate logistic regression analyses showed that SPR, SAA, and SC were independent risk factors for LFR. An algorithm and a correspondent nomogram for predicting high LFR risk were constructed using data from the training cohort. The LFR nomogram exhibited an excellent discrimination power and a high fitting degree in both the training cohort (AUC = 0.90, 95 % CI: 0.88-0.92), (H-L: x2 = 5.43, p = 0.71) and validation cohort (AUC = 0.89, 95 % CI:0.87-0.92), (H-L: x2 = 7.85, p = 0.45), respectively. The decision curve analysis (DCA) demonstrated a high efficiency of the LFR nomogram for clinical utility. SPR, SAA, and SC are independent risk factors for LFR. The LFR nomogram established based on these factors could be a useful tool to predict high risk of LFR, and patients with high risk of LFR can be guided to direct ICSI procedure. Clinical application of the LFR nomogram may increase the in vitro fertilization rate by facilitating the decision making in IVF service.

Neutralization of EG.5, EG.5.1, BA.2.86, and JN.1 by antisera from dimeric receptor-binding domain subunit vaccines and 41 human monoclonal antibodies.

BACKGROUND: The recently circulating Omicron variants BA.2.86 and JN.1 were identified with more than 30 amino acid changes on the spike protein compared to BA.2 or XBB.1.5. This study aimed to comprehensively assess the immune escape potential of BA.2.86, JN.1, EG.5, and EG.5.1. METHODS: We collected human and murine sera to evaluate serological neutralization activities. The participants received three doses of coronavirus disease 2019 (COVID-19) vaccines or a booster dose of the ZF2022-A vaccine (Delta-BA.5 receptor-binding domain [RBD]-heterodimer immunogen) or experienced a breakthrough infection (BTI). The ZF2202-A vaccine is under clinical trial study (ClinicalTrials.gov: NCT05850507). BALB/c mice were vaccinated with a panel of severe acute respiratory syndrome coronavirus 2 RBD-dimer proteins. The antibody evasion properties of these variants were analyzed with 41 representative human monoclonal antibodies targeting the eight RBD epitopes. FINDINGS: We found that BA.2.86 had less neutralization evasion than EG.5 and EG.5.1 in humans. The ZF2202-A booster induced significantly higher neutralizing titers than BTI. Furthermore, BA.2.86 and JN.1 exhibited stronger antibody evasion than EG.5 and EG.5.1 on RBD-4 and RBD-5 epitopes. Compared to BA.2.86, JN.1 further lost the ability to bind to several RBD-1 monoclonal antibodies and displayed further immune escape. CONCLUSIONS: Our data showed that the currently dominating sub-variant, JN.1, showed increased immune evasion compared to BA.2.86 and EG.5.1, which is highly concerning. This study provides a timely risk assessment of the interested sub-variants and the basis for updating COVID-19 vaccines. FUNDING: This work was funded by the National Key R&D Program of China, the National Natural Science Foundation of China, the Beijing Life Science Academy, the Bill & Melinda Gates Foundation, and the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation (CPSF).

Key mechanistic features of the trade-off between antibody escape and host cell binding in the SARS-CoV-2 Omicron variant spike proteins.

Since SARS-CoV-2 Omicron variant emerged, it is constantly evolving into multiple sub-variants, including BF.7, BQ.1, BQ.1.1, XBB, XBB.1.5 and the recently emerged BA.2.86 and JN.1. Receptor binding and immune evasion are recognized as two major drivers for evolution of the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein. However, the underlying mechanism of interplay between two factors remains incompletely understood. Herein, we determined the structures of human ACE2 complexed with BF.7, BQ.1, BQ.1.1, XBB and XBB.1.5 RBDs. Based on the ACE2/RBD structures of these sub-variants and a comparison with the known complex structures, we found that R346T substitution in the RBD enhanced ACE2 binding upon an interaction with the residue R493, but not Q493, via a mechanism involving long-range conformation changes. Furthermore, we found that R493Q and F486V exert a balanced impact, through which immune evasion capability was somewhat compromised to achieve an optimal receptor binding. We propose a "two-steps-forward and one-step-backward" model to describe such a compromise between receptor binding affinity and immune evasion during RBD evolution of Omicron sub-variants.

Co-catalpol alleviates fluoxetine-induced main toxicity: Involvement of ATF3/FSP1 signaling-mediated inhibition of ferroptosis.

BACKGROUND: Fluoxetine is often used as a well-known first-line antidepressant. However, it is accompanied with hepatogenic injury as its main organ toxicity, thereby limiting its application despite its superior efficacy. Fluoxetine is commonly traditionally used combined with some Chinese antidepressant prescriptions containing Rehmannia glutinosa (Dihuang) for depression therapy and hepatoprotection. Our previous experiments showed that co-Dihuang can alleviate fluoxetine-induced liver injury while efficiencies, and catalpol may be the key ingredient to characterize the toxicity-reducing and synergistic effects. However, whether co-catalpol can alleviate fluoxetine-induced liver injury and its toxicity-reducing mechanism remain unclear. PURPOSE: On the basis of the first recognition of the dose and duration at which pre-fluoxetine caused hepatic injury, co-catalpol's alleviation of fluoxetine-induced hepatic injury and its pathway was comprehensively elucidated. METHOD AND RESULTS: The hepatoprotection of co-catalpol was evaluated by serum biochemical indexes sensitive to hepatic injury and multiple staining techniques for hepatic pathologic analysis. Subsequently, the pathway by which catalpol alleviated fluoxetine-induced hepatic injury was predicted by network pharmacology to be predominantly the inhibition of ferroptosis. These were validated and confirmed in subsequent experiments with key technologies and diagnostic reagents related to ferroptosis. Further molecular docking showed that activating transcription factor 3 (ATF3) and ferroptosis suppressor protein 1 (FSP1) were the the most prospective molecules for catalpol and fluoxetine among many ferroptosis-related molecules. The critical role of ATF3/FSP1 signaling was further observed by surface plasmon resonance, diagnostic reagents, transmission electron microscopy, Western blot, real-time PCR, immunofluorescence, and immunohistochemistry. Results showed that fluoxetine directly bound to ATF3 and FSP1; agonisting ATF3 or blocking FSP1 abolished the alleviation of catalpol on fluoxetine-induced liver injury, and both exacerbated ferroptosis. Moreover, co-catalpol significantly enhanced the antidepressant efficacy of fluoxetine against depressive behaviours in mice. CONCLUSION: The hepatic impairment properties of fluoxetine were largely dependent on ATF3/FSP1 target-mediated ferroptosis. Co-catalpol alleviated fluoxetine-induced hepatic injury while enhancing its antidepressant efficacy, and that ATF3/FSP1 signaling-mediated inhibition of ferroptosis was involved in its co-administration detoxification mechanism. This study was the first to reveal the hepatotoxicity characteristics, targets, and mechanisms of fluoxetine; provide a detoxification and efficiency regimen by co-catalpol; and elucidate the detoxification mechanism.

Analysis of factors affecting ultrasound examination time: A quantitative study.

BACKGROUND: Numerous studies have focused on reducing patient absences and effectively scheduling exams. However, very few studies have analyzed the factors influencing examination time and predicted examination time. OBJECTIVES: To investigate the factors affecting ultrasound examination visit length and provide a reference for interventions to optimize ultrasound appointments. METHODS: This cross-sectional study was conducted at a fertility clinic in China. Ultrasound examination time and clinical characteristics were obtained from the electronic records. Univariate and multivariate analyses used 33,432 patients who attended our clinic center between August 1 and October 30, 2018. A quantile regression model was constructed to examine associations between ultrasound examination time and statistically significant variables in the univariate analysis. RESULTS: Of the 33,432 patients included in this study, 29,085 (87%) were female and 4,347 (13%) were male. Their mean examination time was 6 ± 3 minutes. The doctor's title and gender, equipment, and patient's age, examination site, gender, and origin were all statistically significant. Physical examination and outpatient clinic patients had shorter examination times than inpatients. Female physicians had longer examination times than male physicians. Examination time was positively correlated with thyroid, breast, liver, gallbladder, spleen, pancreas, kidney, heart, vascular, adrenal, gynecological, early pregnancy, nuchal translucency, prostate, scrotum, and mid-to-late pregnancy fetal sites. Moreover, NT and mid-to-late pregnancy fetal sites showed a clear and continuous positive trend with increasing examination time. CONCLUSION: The length of the ultrasound examination was correlated with the examination site, physician title, physician gender, patient age, patient gender, patient origin, and instrumentation. The reliability of inspection time predicted by variables such as the physicians' title, sex, sites examined, and the number of sites examined was higher when they were longer.

Investigation of the principle of concoction by using the processing excipient Glycyrrhiza uralensis Fisch. juice to reduce the main toxicity of Dioscorea bulbifera L. and enhance its main efficacy as expectorant and cough suppressant.

ETHNOPHARMACOLOGICAL RELEVANCE: Dioscorea bulbifera L. (Rhizoma Dioscoreae Bulbiferae; RDB) is commonly used as an expectorant and cough suppressant herb but is accompanied by severe hepatotoxicity. Using the juice of auxiliary herbs (such as Glycyrrhiza uralensis Fisch. (Glycyrrhizae Radix et Rhizoma; GRR) juice) in concocting poisonous Chinese medicine is a conventional method to reduce toxicity or increase effects. Our previous study found that concoction with GRR juice provided a detoxifying effect against the major toxic hepatotoxicity induced by RDB, but the principle for the detoxification of the concoction is unknown to date. AIM OF THE STUDY: The principle of concoction was investigated by using the processing excipient GRR juice to reduce the major toxic hepatotoxicity of RDB, and the efficacy of RDB as an expectorant and cough suppressant was enhanced. MATERIALS AND METHODS: In this study, common factors (RDB:GRR ratio, concocted temperature, and concocted time) in the concoction process were used for the preparation of each RDB concocted with GRR juice by using an orthogonal experimental design. We measured the content of the main toxic compound diosbulbin B (DB) and serum biochemical indicators and performed pathological analysis in liver tissues of mice to determine the best detoxification process of RDB concocted with GRR juice. On this basis, the biological mechanisms of target organs were detected by Western blot and enzyme-linked immunosorbent assay at the inflammation and apoptosis levels. Further, the effects of RDB on expectorant and cough suppressant with GRR juice were evaluated by the conventional tests of phenol red expectorant and concentrated ammonia-induced cough. Lastly, the major compounds in the GRR juice introduced to RDB concoction were determined. RESULTS: RDB concocted with GRR juice significantly alleviated DB content, serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase levels, and improved liver pathological damages. The best detoxification process was achieved by using an RDB:GRR ratio of 100:20 at 120 °C for 20 min. Further, RDB concocted with GRR juice down-regulated the protein levels of nuclear factor kappa B (NF-κB), cyclooxygenase 2 (COX-2), and Bcl-2 related X protein (Bax) in the liver and enhanced the expectorant and cough suppressant effects of RDB. Finally, liquiritin (LQ) and glycyrrhizic acid (GA) in the GRR juice were introduced to the RDB concoction. CONCLUSION: Concoction with GRR juice not only effectively reduced the major toxic hepatotoxicity of RDB but also enhanced its main efficacy as an expectorant and cough suppressant, and that the rationale for the detoxification and/or potentiation of RDB was related to the reduction in the content of the main hepatotoxic compound, DB, the introduction of the hepatoprotective active compounds, LQ and GA, in the auxiliary GRR juice, as well as the inhibition of NF-κB/COX-2/Bax signaling-mediated inflammation and apoptosis.

[Gender differences in antidepressant effect of raw Rehmanniae Radix].

For the first time, this study evaluated the gender differences and mechanisms of the antidepressant effects of raw Rehmanniae Radix(RRR) based on the classic depression model with traditional Chinese medicine syndrome of Yin deficiency and internal heat. The depression model with Yin deficiency and internal heat was established by the widely recognized and applied method of thyroxine induction of the classic depression model with Yin deficiency and internal heat(chronic unpredictable mild stress). Male and female mice were simultaneously treated with RRR. The study analyzed indicators of nourishing Yin and clearing heat, conventional antidepressant efficacy test indicators, and important biomolecules reflecting the pathogenesis and prevention and treatment mechanisms of depression, and conducted a correlation analysis of antidepressant efficacy, Yin-nourishing and heat-clearing efficacy, and biological mechanism in different genders, thereby comprehensively assessing the antidepressant effects of RRR on depression of Yin deficiency and internal heat, as well as its gender differences and mechanisms. RRR exhibited antidepressant effects in both male and female mouse models, and its antidepressant efficacy showed gender differences, with a superior effect observed in females. Moreover, the effects of RRR on enhancing or improving hippocampal neuronal pathology, nucleus-positive areas, postsynaptic dense area protein 95, and synaptophysin protein expression were more significant in females than in males. In addition, RRR significantly reversed the abnormal upregulation of nuclear factor(NF)-κB/cyclooxygenase 2(COX2)/NOD-like receptor thermal protein domain associated protein 3(NLRP3) pathway proteins in the hippocampus of both male and female mouse models. The antidepressant effects of RRR were more pronounced in depression female mice with Yin deficiency and internal heat syndrome, possibly due to the improvement of neuronal damage and enhancement of neuroplasticity. The antidepressant mechanisms of RRR for depression with Yin deficiency and internal heat syndrome may be associated with the downregulation of the NF-κB/COX2/NLRP3 pathway to reduce neuronal damage and enhance neuroplasticity.

Low acrosin activity is associated with decreased Spam1/acrosin expression and GSH deficiency-caused premature acrosome release of human sperm cells.

Low acrosin activity (LAA) is associated with sperm function anomaly and poor outcomes of in vitro fertilization. In this study, we confirm that 993 semen samples with LAA had a reduced sperm motility and low in vitro fertilization rate in comparison with 1332 normal controls (NC). Proteomic comparison between 11 LAA and 11 NC sperm samples identified 35 upregulated and 99 downregulated proteins in the LAA group. Indeed, proteomic data showed that acrosome enzymes Spam1 and Acrosin were among the downregulated proteins in the LAA group, which was validated by quantitative PCR and immunefluorescent staining of sperm cells. The KEEG pathway analysis revealed a deficiency of GSH and Gln biosynthesis in LAA sperm cells. Immunofluorescent staining of sperms and quantitative PCR verified downregulation of GLUL and GCLC, the key enzymes for GSH and Gln biosynthesis. Moreover, the results of ELISA assay confirmed low levels of GSH and Gln in LAA sperm cells. Mechanistic studies showed that addition of 10 mM H2O2 to semen samples led to a significant reduction of acrosin activity and sperm motility, most possibly by triggering premature acrosome release. In contrast, the presence of 20 mM GSH blocked the oxidative effects of H2O2. Since GSH counteracts the oxidative stress and Gln participates in TCA cycling, their deficiency may affect the redox balance as well as energy production of sperm cells. These findings shed new light on the pathological mechanisms of infertility associated with LAA. Male infertility patients could benefit from GSH supplement by improvement of acrosin activity and other sperm functions.

Predictive value of first-trimester GPR120 levels in gestational diabetes mellitus.

Background: Early diagnosis of gestational diabetes mellitus (GDM) reduces the risk of unfavorable perinatal and maternal consequences. Currently, there are no recognized biomarkers or clinical prediction models for use in clinical practice to diagnosing GDM during early pregnancy. The purpose of this research is to detect the serum G-protein coupled receptor 120 (GPR120) levels during early pregnancy and construct a model for predicting GDM. Methods: This prospective cohort study was implemented at the Women's Hospital of Jiangnan University between November 2019 and November 2022. All clinical indicators were assessed at the Hospital Laboratory. GPR120 expression was measured in white blood cells through quantitative PCR. Thereafter, the least absolute shrinkage and selection operator (LASSO) regression analysis technique was employed for optimizing the selection of the variables, while the multivariate logistic regression technique was implemented for constructing the nomogram model to anticipate the risk of GDM. The calibration curve analysis, area under the receiver operating characteristic curve (AUC) analysis, and the decision curve analysis (DCA) were conducted for assessing the performance of the constructed nomogram. Results: Herein, we included a total of 250 pregnant women (125 with GDM). The results showed that the GDM group showed significantly higher GPR120 expression levels in their first trimester compared to the normal pregnancy group (p < 0.05). LASSO and multivariate regression analyses were carried out to construct a GDM nomogram during the first trimester. The indicators used in the nomogram included fasting plasma glucose, total cholesterol, lipoproteins, and GPR120 levels. The nomogram exhibited good performance in the training (AUC 0.996, 95% confidence interval [CI] = 0.989-0.999) and validation sets (AUC=0.992) for predicting GDM. The Akaike Information Criterion of the nomogram was 37.961. The nomogram showed a cutoff value of 0.714 (sensitivity = 0.989; specificity = 0.977). The nomogram displayed good calibration and discrimination, while the DCA was conducted for validating the clinical applicability of the nomogram. Conclusions: The patients in the GDM group showed a high GPR120 expression level during the first trimester. Therefore, GPR120 expression could be used as an effective biomarker for predicting the onset of GDM. The nomogram incorporating GPR120 levels in early pregnancy showed good predictive ability for the onset of GDM.

TMEM33 as a Prognostic Biomarker of Cervical Cancer and Its Correlation with Immune Infiltration.

In women all over the world, cervical cancer (CC) ranks as the fourth most common form of cancer to be diagnosed. It was previously reported that transmembrane protein 33(TMEM33) could report a poor prognosis in several cancers. The current study is aimed at investigating the potential prognostic value of TMEM33 and its relevance to the tumor microenvironment in CC in a comprehensive manner. In this study, CC specimens presented noticeably higher TMEM33 expression level in comparison to nontumor specimens. In pan-cancer assays, it was found that TMEM33 was present at a high level in many different kinds of tumors. We found that patients with CC patients who had a high TMEM33 expression presented worse overall survival (OS) and disease-free survival (DFS) relative to patients who had a low TMEM33 expression. According to the results of a multivariate analysis, a high level of TMEM33 expression can significantly and independently predict the prognosis of CC. The levels of TMEM33 were found to have a negative correlation with resting dendritic cells, resting mast cells, plasma cells, T cells CD8, T cells regulatory, and regulatory T cells. Finally, we confirmed that TMEM33 was overexpressed in CC cells, and its knockdown distinctly suppressed the proliferation and invasion of CC cells. Overall, we provided evidences that TMEM33 could be used as a potential biomarker to assess the prognosis and the level of immune infiltration in CC.

An updated atlas of antibody evasion by SARS-CoV-2 Omicron sub-variants including BQ.1.1 and XBB.

Emerging Omicron sub-variants are causing global concerns, and their immune evasion should be monitored continuously. We previously evaluated the escape of Omicron BA.1, BA.1.1, BA.2, and BA.3 from an atlas of 50 monoclonal antibodies (mAbs), covering seven epitope classes of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD). Here, we update the atlas of totally 77 mAbs against emerging sub-variants including BQ.1.1 and XBB and find that BA.4/5, BQ.1.1, and XBB display further evasion. Besides, investigation into the correlation of binding and neutralization of mAbs reveals the important role of antigenic conformation in mAb functioning. Moreover, the complex structures of BA.2 RBD/BD-604/S304 and BA.4/5 RBD/BD-604/S304/S309 further elucidate the molecular mechanism of antibody evasion by these sub-variants. By focusing on the identified broadly potent mAbs, we find a general hotspot epitope on the RBD, which could guide the design of vaccines and calls for new broad-spectrum countermeasures against COVID-19.

Preparation and Application of Double Network Interpenetrating Colon Targeting Hydrogel Based on Konjac Glucomannan and N-Isopropylacrylamide.

Konjac glucomannan (KGM) can be degraded by colon-specific enzymes in the colonic environment, making it one of the materials for treating colonic diseases, which has attracted more and more attention. However, during drug administration, especially in the gastric environment and due to its easy swelling, the structure of KGM is usually destroyed and the drug is released, thereby reducing the bioavailability of the drug. To solve this problem, the easy swelling and drug release properties of KGM hydrogels are avoided by creating interpenetrating polymer network hydrogels. In this study, N-isopropylacrylamide (NIPAM) is first formed into a hydrogel framework under the action of a cross-linking agent to stabilize the gel shape before the gel is heated under alkaline conditions to make KGM molecules wrap around the NIPAM framework. The structure of the IPN(KGM/NIPAM) gel was confirmed using Fourier transform infrared spectroscopy (FT-IR) and x-ray diffractometer (XRD). In the stomach and small intestine, it was found that the release rate and swelling rate of the gel were 30% and 100%, which were lower than 60% and 180% of KGM gel. The experimental results showed that this double network hydrogel has a good colon-directed release profile and fine drug carrier ability. This provides a new idea for the development of konjac glucomannan colon-targeting hydrogel.

Lower grip strength and insufficient physical activity can increase depressive symptoms among middle-aged and older European adults: a longitudinal study.

OBJECTIVES: The present study aimed to identify the gender-specific trajectories of grip strength using group-based trajectories, explore the interaction between grip strength and physical activity on depression, and investigate the association of physical activity with the change in depression by different grip strength groups among middle-aged and older European adults. METHODS: A total of 14,098 participants aged 50 years or older from the Survey of Health, Ageing and Retirement in Europe 2007-2019 were included in this study. Group-based trajectory modeling was used to identify the low, middle and high group of grip strength by gender. Generalized estimated equations were fitted to analyze the interaction effect. The data of wave 2-wave 5 and wave 2-wave 7 were chosen to conduct sensitivity analyses. RESULTS: Significant interactions between grip strength group and physical inactivity were found (x2 interaction = 11.16, P = 0.004). Significant interactions between physical inactivity and time on depression were identified in low (x2 interaction = 27.83, P < 0.001) and moderate (x2 interaction = 23.67, P < 0.001) grip strength, but a similar result was not found in high grip strength (x2 interaction = 4.39, P = 0.495). Participants in the physical inactivity group had higher depression scores in the low and moderate grip strength groups. Sensitivity analyses yield almost similar results. CONCLUSIONS: Grip strength and physical inactivity interact with depression. Lower grip strength and insufficient physical activity can increase depressive symptoms. People with lower grip strength and physical inactivity should pay special attention to the prevention of depression.

Atlas of currently available human neutralizing antibodies against SARS-CoV-2 and escape by Omicron sub-variants BA.1/BA.1.1/BA.2/BA.3.

SARS-CoV-2 Omicron variant has presented significant challenges to current antibodies and vaccines. Herein, we systematically compared the efficacy of 50 human monoclonal antibodies (mAbs), covering the seven identified epitope classes of the SARS-CoV-2 RBD, against Omicron sub-variants BA.1, BA.1.1, BA.2, and BA.3. Binding and pseudovirus-based neutralizing assays revealed that 37 of the 50 mAbs lost neutralizing activities, whereas the others displayed variably decreased activities against the four Omicron sub-variants. BA.2 was found to be more sensitive to RBD-5 antibodies than the other sub-variants. Furthermore, a quaternary complex structure of BA.1 RBD with three mAbs showing different neutralizing potencies against Omicron provided a basis for understanding the immune evasion of Omicron sub-variants and revealed the lack of G446S mutation accounting for the sensitivity of BA.2 to RBD-5 mAbs. Our results may guide the application of the available mAbs and facilitate the development of universal therapeutic antibodies and vaccines against COVID-19.

Nrf2 improves hippocampal synaptic plasticity, learning and memory through the circ-Vps41/miR-26a-5p/CaMKIV regulatory network.

Antioxidant response transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2/Nfe2l2) is a neuroprotective agent in learning and memory impairment. This study provides a new perspective to explore the regulatory mechanisms of Nrf2. Here, we found that Nrf2 regulated circular RNA circ-Vps41 to increase hippocampal synaptic plasticity; Nrf2 bound the Vps41 promoter to activate transcription of the Vps41 gene and promote expression of circ-Vps41; circ-Vps41 positively correlated with Nrf2, synaptic plasticity, and learning and memory but negatively correlated with reactive oxygen species; and Nrf2 promoted CaMKIV expression by increasing levels of circ-Vps41, which can absorb miR-26a-5p that targets CaMKIV. Our findings revealed a new circRNA-based regulatory network regulated by Nrf2 and provided novel insights into the potential mechanism involved in the improvement of learning and memory impairment.

Cholesterol and saturated fatty acids synergistically promote the malignant progression of prostate cancer.

The excessive accumulation of saturated fatty acids and cholesterol have been linked to prostate cancer (Pca). Here, we found that lipoproteins, apolipoproteins, triglycerides and free fatty acids are significantly higher in the peripheral blood of prostate cancer patients than in non-cancer patients. Furthermore, the expression of ACC1, FASN and HMGCR is significantly higher in prostate cancer tissues than that in non-cancer tissues, and positively correlated with the gleason score. Using genetically engineered mouse models, we found that in a mouse model of high grade prostatic intraneoplasia (HGPIN), a combination of fatty acid synthase (FASN) overexpression and cholesterol efflux pump (Abca1) knockout resulted in the progression of prostatic intraneoplasia (PIN) to invasive PCa with 100% penetrance, as well as an increase in prostate cancer stem cell (PCSC)population, accompanied by activation of PGE2 and TGF-ß signaling pathway. Our study suggests that the steady rise in prostate cancer incidence and mortality among Chinese population during the last several decades may be attribute to a combinational effect of fatty acid and cholesterol, and reduction in dietary fat and cholesterol intake could slow down the progression from occult lesions to prostate cancer.

TAZ is overexpressed in prostate cancers and regulates the proliferation, migration and apoptosis of prostate cancer PC3 cells.

TAZ (transcriptional coactivator with PDZ­binding motif), which is also known as WW domain­containing transcription regulator 1 (WWTR1), a downstream effector of the Hippo pathway, has been reported to regulate cancer cell proliferation, migration and apoptosis by acting as a transcriptional coactivator. However, the function of TAZ in prostate cancer cells has not been investigated. In the present study, TAZ expression in prostate cancer (PCa) and benign prostatic hyperplasia tissues, PCa cell lines, and normal prostate epithelial cells was determined with the use of immunohistochemistry. TAZ was knocked down by shRNA in the PC3 cells, a prostate cancer cell line, and cell viability and migration assays were performed to determine the biological functions of TAZ. A mouse subcutaneous xenograft model was used to determine the in vivo effects of TAZ knockdown on tumor growth. We demonstrated that TAZ is overexpressed in PCa tissues, and the expression levels were found to be positively correlated with the Gleason scores of cancer grade. Moreover, TAZ knockdown inhibited PC3 cell proliferation, reduced cell migration, and induced apoptosis. Further experiments demonstrated that TAZ knockdown may lead to PC3 cell apoptosis through the exogenous apoptotic pathway by inducing the expression and cleavage of caspase­4 and ­7. In the tumor xenograft model, TAZ knockdown led to a decreased tumor growth rate. Taken together, the experimental results indicate that TAZ plays a significant role in the proliferation, migration and apoptosis of prostate cancer cells. TAZ could be a useful biomarker for PCa diagnosis/prognosis, and it could be a potential target for the treatment of prostate cancers.

Metabolic Alterations Induced by Kudingcha Lead to Cancer Cell Apoptosis and Metastasis Inhibition.

Kudingcha is implicated in alleviating metabolic disorders in traditional Chinese medicine. However, the role of Kudingcha, one of the Ligustrum robustum species, in metabolic regulations and its antitumor activity in triple-negative breast cancer (TNBC) remains to be determined. Two breast cancer cell lines and immunocompetent and immunodeficient mice were used to evaluate the therapeutic effects of Kudingcha treatment. The production of reactive oxygen species (ROS) and glucose uptake were examined by flow cytometry. Metabolic shift was examined by metabonomics and western blot analysis. In this study, we found that aqueous extract of Kudingcha dose dependently inhibited cell growth and induced apoptosis in vitro and in vivo. Moreover, Kudingcha supplementation significantly reduced cancer metastasis. Kudingcha significantly inhibited glycolysis and glutamine metabolism. In addition, we demonstrated that the antitumor effects of Kudingcha were dependent on ROS production, which was increased by ß-oxidation and oxidative phosphorylation. These findings provide a novel potential benefit of Kudingcha from targeting the cancer metabolism.

Increased GPR120 level is associated with gestational diabetes mellitus.

G-protein coupled receptor 120 (GPR120 or FFAR4) functions as a receptor for free fatty acids and plays a critical role in lipid metabolism. Studies have shown a close relationship between GDM and lipid metabolism disorders, whether GPR120 participates in the metabolic regulation of GDM remains unclear. In this study, 29 women with GDM and 33 normal pregnant women were enrolled. Lipid profiles were determined by lipidomics, expression of GPR120 and FGF21 was measured in the white blood cells, and regulation of FGF21 by GPR120 was investigated in THP-1 cells as well as human peripheral blood monocytes. Lipidomics reveal altered lipid metabolism in patients with GDM. The expression of both GPR120 and FGF21 is significantly higher in the GDM than in the control at the 32nd and 37th weeks of pregnancy, but the differences disappear by the 2nd day post-delivery. Generally positive correlations are found between the total amount of lipids and expression levels of GPR120 and FGF21 in GDM patients. FGF21 expression is induced by GPR120 activation in THP-1 cells and WBCs. GPR120 may act as a metabolic regulator, through the induction of FGF21, to control lipid metabolism, and GDM patients may manifest a GPR120 insensitivity.

Draft Genome Sequences of Three Escherichia coli Sequence Type 131 Strains.

Escherichia coli sequence type 131 (ST131) is an important global health issue nowadays and is responsible for many clinical infections. Here, we present the complete genome sequences of two ST131 clinical isolates and one ST131 fecal isolate.