LncRNA SNHG26 promotes gastric cancer progression and metastasis by inducing c-Myc protein translation and an energy metabolism positive feedback loop.

Metastasis is a bottleneck in cancer treatment. Studies have shown the pivotal roles of long noncoding RNAs (lncRNAs) in regulating cancer metastasis; however, our understanding of lncRNAs in gastric cancer (GC) remains limited. RNA-seq was performed on metastasis-inclined GC tissues to uncover metastasis-associated lncRNAs, revealing upregulated small nucleolar RNA host gene 26 (SNHG26) expression, which predicted poor GC patient prognosis. Functional experiments revealed that SNHG26 promoted cellular epithelial-mesenchymal transition and proliferation in vitro and in vivo. Mechanistically, SNHG26 was found to interact with nucleolin (NCL), thereby modulating c-Myc expression by increasing its translation, and in turn promoting energy metabolism via hexokinase 2 (HK2), which facilitates GC malignancy. The increase in energy metabolism supplies sufficient energy to promote c-Myc translation and expression, forming a positive feedback loop. In addition, metabolic and translation inhibitors can block this loop, thus inhibiting cell proliferation and mobility, indicating potential therapeutic prospects in GC.

[Screening and expression analysis of transcription factors involved in genuineness of Codonopsis pilosula in Shanxi].

This study aims to mine the transcription factors that affect the genuineness of Codonopsis pilosula in Shanxi based on the transcriptome data of C. pilosula samples collected from Shanxi and Gansu, and then analyze the gene expression patterns, which will provide a theoretical basis for the molecular assisted breeding of C. pilosula. Gene ontology(GO) functional annotation, conserved motif prediction, and gene expression pattern analysis were performed for the differential transcription factors predicted based on the transcriptome data of C. pilosula from different habitats. A total of 61 differentially expressed genes(DEGs) were screened out from the transcriptome data. Most of the DEGs belonged to AP2/ERF-ERF family, with the conserved motif of [2X]-[LG]-[3X]-T-[3X]-[AARAYDRAA]-[3X]-[RG]-[2X]-A-[2X]-[NFP]. Forty-three of the DEGs showed significantly higher gene expression in C. pilosula samples from Shanxi than in the samples from Gansu, including 11 genes in the AP2/ERF-ERF family, 5 genes in the NAC fa-mily, 1 gene in the bHLH family, and 2 genes in the RWP-RK family, while 18 transcription factors showed higher expression levels in the samples from Gansu. GO annotation predicted that most of the DEGs were enriched in GO terms related to transcriptional binding activity(103), metabolic process(26), and stress response(23). The expression of transcription factor genes, CpNAC92, CpNAC100, CpbHLH128, and CpRAP2-7 was higher in the samples from Shanxi and in the roots of C. pilosula. CpNAC92, CpbHLH128, and CpRAP2-7 responded to the low temperature, temperature difference, and iron stresses, while CpNAC100 only responded to low temperature and iron stresses. The screening and expression analysis of the specific transcription factors CpNAC92, CpNAC100, CpbHLH128, and CpRAP2-7 in C. pilosula in Shanxi laid a theoretical foundation for further research on the mechanism of genuineness formation of C. pilosula.

Network analysis of internet addiction and sleep disturbance symptoms.

BACKGROUND: Internet addiction (IA) is a behavioral addiction to problematic internet use. IA is associated with poorer sleep quality. Few studies to date, however, have explored the interactions between symptoms of IA and symptoms of sleep disturbance. This study uses network analysis to identify bridge symptoms by analyzing these interactions in a large sample of students. METHOD: We recruited 1977 university students to participate in our study. Each student completed the Internet Addiction Test (IAT) and the Pittsburgh Sleep Quality Index (PSQI). We used these collected data for network analysis to identify the bridge symptoms in the IAT-PSQI network by calculating the bridge centrality. Furthermore, the closest symptom connected with the bridge symptom was found to identify the comorbidity mechanisms. RESULTS: The core symptom of IA and the sleep disturbance network was "I08" (Study efficiency suffers due to internet use). The bridge symptoms between IA and sleep disturbance were "I14" (Surfing the internet late instead of sleeping), "P_DD" (Daytime dysfunction), and "I02" (Spending much time online instead of socializing in real life). Among the symptoms, "I14" had the highest bridge centrality. The edge connecting nodes "I14" and "P_SDu" (Sleep duration) had the strongest weight (0.102) around all the symptoms of sleep disturbance. Nodes "I14" and "I15" (Thinking about online shopping, games, social networking, and other network activities when unable to access the internet) had the strongest weight (0.181), connecting all the symptoms of IA. CONCLUSIONS: IA leads to poorer sleep quality, most likely by shortening sleep duration. Preoccupation with and craving the internet while being offline may lead to this situation. Healthy sleep habits should be learned, and craving may be a good point at which to treat the symptoms of IA and sleep disturbance.

Gut microbiota mediates the pharmacokinetics of Zhi-zi-chi decoction for the personalized treatment of depression.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhi-zi-chi decoction (ZZCD), from "Treatise on Febrile Diseases", is a typical traditional Chinese medicine herb pair, which consists of Gardeniae Fructus (GF) and Semen Sojae Praeparatu (SSP). In clinical research, ZZCD was widely used to fight depression, remove annoyance. Many studies have reported that gut microbiota is critical target for the influence of depress through gut-brain axis, and our previously studies have found that ZZCD exhibiting antidepressant effect was through the gut-brain axis. However, the specific mechanism by which gut microbiota mediates the pharmacokinetics parameters of active compounds from ZZCD during the process of depression treatment has not yet been studied. AIM OF THE STUDY: To explore the differences in pharmacokinetics characters of bioactive iridoids from ZZCD and study the changes of gut microbiota at different stages of depression with the personalized medicine of ZZCD. MATERIALS AND METHODS: A new strategy exploring the relationship among disease phenotypes (D), intestinal microbiota (I), enzymes (E) and traits of metabolism (T) named as "DIET" was established. Firstly, a fast, selective and sensitive ultra-performance liquid chromatography coupled with tandem mass spectrometer (UPLC-MS/MS) was established and validated to quality the main bioactive compounds from ZZCD and compare the pharmacokinetics and bioavailability of different iridoids prototypes and metabolites from ZZCD between normal and chronic unpredictable mild stress rats. Subsequently, the activity of corresponding metabolic enzymes of anti-depressive compounds, ß-glucosidases and sulfotransferases, were analyzed by ρ-nitrophenyl-ß -D-glucopyranoside and sulfotransferases ELISA kits, respectively. Finally, 16S rRNA gene sequencing was adopt to analyze intestinal bacteria composition for the treatment of depression by ZZCD. RESULTS: The antidepressant effect of ZZCD was promoted due to the increased exposures and reduced eliminations of anti-depressive compounds, especially geniposide and genipin 1-gentiobioside, under the depression state. With the ZZCD treatment, the depression was improved, but the exposures of anti-depressive compounds from ZZCD gradually decreased. Meanwhile, there were the corresponding decreased trends on the activity of ß-glucosidases and sulfotransferases. With the consumption of ZZDC and the improvement of depression, the exposures of anti-depressive iridoid glycosides decreased and the activity of metabolism enzymes restored. Meanwhile, the dysbiosis of pathogenic bacteria (Bacteroidota) induced by depression was ameliorated and the probiotics (Firmicutes) at the phylum and genus level raised, the two phyla are closely related to the production of ß-glucosidase and sulfotransferases. CONCLUSIONS: It is the first proposed that ZZCD could personalized to treat depression at different stages targeting gut microbiota and gut microbiome could emerged as a potential diagnostic and therapeutic biomarker in depression.

Defensins: defenders of human reproductive health.

BACKGROUND: Reproductive tract infection is an important factor leading to male and female infertility. Among female infertility factors, microbial and viral infections are the main factors affecting female reproductive health and causing tubal infertility, ectopic tubal pregnancy and premature delivery. Among male infertility factors, 13-15% of male infertility is related to infection. Defensins are cationic antibacterial and antiviral peptides, classified into α-defensins, ß-defensins and θ-defensins. Humans only have α-defensins and ß-defensins. Apart from their direct antimicrobial functions, defensins have an immunomodulatory function and are involved in many physiological processes. Studies have shown that defensins are widely distributed in the female reproductive tract (FRT) and male reproductive tract (MRT), playing a dual role of host defence and fertility protection. However, to our knowledge, the distribution, regulation and function of defensins in the reproductive tract and their relation to reproduction have not been reviewed. OBJECTIVE AND RATIONALE: This review summarizes the expression, distribution and regulation of defensins in the reproductive tracts to reveal the updated research on the dual role of defensins in host defence and the protection of fertility. SEARCH METHODS: A systematic search was conducted in PubMed using the related keywords through April 2022. Related data from original researches and reviews were integrated to comprehensively review the current findings and understanding of defensins in the human reproductive system. Meanwhile, female and male transcriptome data in the GEO database were screened to analyze defensins in the human reproductive tracts. OUTCOMES: Two transcriptome databases from the GEO database (GSE7307 and GSE150852) combined with existing researches reveal the expression levels and role of the defensins in the reproductive tracts. In the FRT, a high expression level of α-defensin is found, and the expression levels of defensins in the vulva and vagina are higher than those in other organs. The expression of defensins in the endometrium varies with menstrual cycle stages and with microbial invasion. Defensins also participate in the local immune response to regulate the risk of spontaneous preterm birth. In the MRT, a high expression level of ß-defensins is also found. It is mainly highly expressed in the epididymal caput and corpus, indicating that defensins play an important role in sperm maturation. The expression of defensins in the MRT varies with androgen levels, age and the status of microbial invasion. They protect the male reproductive system from bacterial infections by neutralizing lipopolysaccharide and downregulating pro-inflammatory cytokines. In addition, animal and clinical studies have shown that defensins play an important role in sperm maturation, motility and fertilization. WIDER IMPLICATIONS: As a broad-spectrum antimicrobial peptide without drug resistance, defensin has great potential for developing new natural antimicrobial treatments for reproductive tract infections. However, increasing evidence has shown that defensins can not only inhibit microbial invasion but can also promote the invasion and adhesion of some microorganisms in certain biological environments, such as human immunodeficiency virus. Therefore, the safety of defensins as reproductive tract anti-infective drugs needs more in-depth research. In addition, the modulatory role of defensins in fertility requires more in-depth research since the current conclusions are based on small-size samples. At present, scientists have made many attempts at the clinical transformation of defensins. However, defensins have problems such as poor stability, low bioavailability and difficulties in their synthesis. Therefore, the production of safe, effective and low-cost drugs remains a challenge.

Efficacy and safety of methylene blue in patients with vasodilatory shock: A systematic review and meta-analysis.

Background: The role of methylene blue (MB) in patients with vasodilatory shock is unclear. The purpose of this systematic review and meta-analysis was to evaluate the efficacy and safety of MB in patients with vasodilatory shock. Methods: We searched MEDLINE at PubMed, Embase, Web of Science, Cochrane, CNKI, CBM and Wanfang Medical databases for all observational and intervention studies comparing the effect of MB vs. control in vasodilatory shock patients. This study was performed in accordance with the PRISMA statement. There were no language restrictions for inclusion. Results: A total of 15 studies with 832 patients were included. Pooled data demonstrated that administration of MB along with vasopressors significantly reduced mortality [odds ratio (OR) 0.54, 95% confidence interval (CI) 0.34 to 0.85, P = 0.008; I 2 = 7%]. This benefit in mortality rate was also seen in a subgroup analysis including randomized controlled trials and quasi-randomized controlled trials. In addition, the vasopressor requirement was reduced in the MB group [mean difference (MD) -0.77, 95%CI -1.26 to -0.28, P = 0.002; I 2 = 80%]. Regarding hemodynamics, MB increased the mean arterial pressure, heart rate and peripheral vascular resistance. In respect to organ function, MB was associated with a lower incidence of renal failure, while in regards to oxygen metabolism, it was linked to reduced lactate levels. MB had no effect on the other outcomes and no serious side effects. Conclusions: Concomitant administration of MB and vasopressors improved hemodynamics, decreased vasopressor requirements, reduced lactate levels, and improved survival in patients with vasodilatory shock. However, further studies are required to confirm these findings. Systematic review registration: Identifier: CRD42021281847.

Pore-Space Partition through an Embedding Metal-Carboxylate Chain-Induced Topology Upgrade Strategy for the Separation of Acetylene/Ethylene.

Ethylene (C2H4) is one of the most significant substances in the petrochemical industry; however, the capture of acetylene (C2H2) in about 1% from C2H2/C2H4 mixtures is a difficult task because of the similarity of their physical properties. With the aggravation of the energy crisis, using metal-organic framework (MOF) materials to purify C2H4 through adsorptive separation is a promising way to save energy and reduce emission. Pore-space partition (PSP) with the aim of enhancing the density of the binding sites and the strength of the host-guest interactions is an effective means to promote a solution for the challenging gas separation problems. Herein, we report a new embedding metal-carboxylate chain-induced topology upgrade strategy within a MOF to realize PSP and separation of C2H2/C2H4 mixtures. As a proof of concept, we construct a microporous MOF (NUM-12) utilizing the in situ insertion of cobalt terephthalic chains into a pretargeted ant-type framework during synthesis. Because of the attainment of an elaborately tuned aperture size and a specific pore environment through this strategy, NUM-12a (activated NUM-12) not only has a remarkable gas sorption capacity and strong interactions for C2H2 but also possesses an excellent purification performance for C2H2/C2H4 mixtures. Both experiments and simulation calculations clearly reveal that NUM-12 is a promising candidate for the separation of C2H2/C2H4, proving the feasibility of this new strategy for developing newly fashioned MOFs with adjustable structure and performance.

Improving Protein Subcellular Location Classification by Incorporating Three-Dimensional Structure Information.

The subcellular locations of proteins are closely related to their functions. In the past few decades, the application of machine learning algorithms to predict protein subcellular locations has been an important topic in proteomics. However, most studies in this field used only amino acid sequences as the data source. Only a few works focused on other protein data types. For example, three-dimensional structures, which contain far more functional protein information than sequences, remain to be explored. In this work, we extracted various handcrafted features to describe the protein structures from physical, chemical, and topological aspects, as well as the learned features obtained by deep neural networks. We then used these features to classify the protein subcellular locations. Our experimental results demonstrated that some of these structural features have a certain effect on the protein location classification, and can help improve the performance of sequence-based location predictors. Our method provides a new view for the analysis of protein spatial distribution, and is anticipated to be used in revealing the relationships between protein structures and functions.

COVID-19 and the digestive system: A comprehensive review.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is spreading at an alarming rate, and it has created an unprecedented health emergency threatening tens of millions of people worldwide. Previous studies have indicated that SARS-CoV-2 ribonucleic acid could be detected in the feces of patients even after smear-negative respiratory samples. However, demonstration of confirmed fecal-oral transmission has been difficult. Clinical studies have shown an incidence rate of gastrointestinal (GI) symptoms ranging from 2% to 79.1% in patients with COVID-19. They may precede or accompany respiratory symptoms. The most common GI symptoms included nausea, diarrhea, and abdominal pain. In addition, some patients also had liver injury, pancreatic damage, and even acute mesenteric ischemia/thrombosis. Although the incidence rates reported in different centers were quite different, the digestive system was the clinical component of the COVID-19 section. Studies have shown that angiotensin-converting enzyme 2, the receptor of SARS-CoV-2, was not only expressed in the lungs, but also in the upper esophagus, small intestine, liver, and colon. The possible mechanism of GI symptoms in COVID-19 patients may include direct viral invasion into target cells, dysregulation of angiotensin-converting enzyme 2, immune-mediated tissue injury, and gut dysbiosis caused by microbiota. Additionally, numerous experiences, guidelines, recommendations, and position statements were published or released by different organizations and societies worldwide to optimize the management practice of outpatients, inpatients, and endoscopy in the era of COVID-19. In this review, based on our previous work and relevant literature, we mainly discuss potential fecal-oral transmission, GI manifestations, abdominal imaging findings, relevant pathophysiological mechanisms, and infection control and prevention measures in the time of COVID-19.

Theacrine, a Potent Antidepressant Purine Alkaloid from a Special Chinese Tea, Promotes Adult Hippocampal Neurogenesis in Stressed Mice.

Daily intake of tea has been known to relate to a low risk of depression. In this study, we report that a special variety of tea in China, Camellia assamica var. kucha (kucha), possesses antidepressant effects but with less adverse effects as compared to traditional tea Camellia sinensis. This action of kucha is related to its high amount of theacrine, a purine alkaloid structurally similar to caffeine. We investigated the antidepressant-like effects and mechanisms of theacrine in chronic water immersion restraint stress and chronic unpredictable mild stress mice models. PC12 cells and primary hippocampal neural stem cells were treated with stress hormone corticosterone (CORT) to reveal the potential antidepression mechanism of theacrine from the perspective of adult hippocampus neurogenesis. Results of behavioral and neurotransmitter analysis showed that intragastric administration of theacrine significantly counteracted chronic stress-induced depression-like disorders and abnormal 5-hydroxytryptamine (5-HT) metabolism with less central excitability. Further investigation from both in vivo and in vitro experiments indicated that the antidepressant mechanism of theacrine was associated with promoting adult hippocampal neurogenesis, via the modulation of the phosphodiesterase-4 (PDE4)/cyclic adenosine monophosphate (cAMP)/cAMP response-element binding (CREB)/brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathway. Collectively, our findings could promote the prevalence of kucha as a common beverage with uses for health care and contribute to the development of theacrine as a potential novel antidepressant medicine.

Phospholipase iPLA2ß averts ferroptosis by eliminating a redox lipid death signal.

Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2ß (iPLA2ß, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2ß averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson's disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant SncaA53T mice, with decreased iPLA2ß expression and a PD-relevant phenotype. Thus, iPLA2ß is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.

Hypermethylation of secreted frizzled related protein 2 gene promoter serves as a noninvasive biomarker for HBV-associated hepatocellular carcinoma.

For patients with hepatocellular carcinoma (HCC), early detection is critical to improve survival. Secreted frizzled-related protein 2 (SFRP2) is a candidate tumor suppressor as Wnt antagonist and SFRP2 promoter has been found hypermethylated in various malignancies. This study aimed to investigate the methylation status of SFRP2 promoter in hepatitis B virus (HBV) associated HCC and estimate its diagnostic value as a non-invasive biomarker. A total of 293 patients, including 132 patients with HBV-associated HCC, 121 with chronic hepatitis B (CHB) and 40 healthy controls (HCs) were enrolled. SFRP2 methylation level in peripheral mononuclear cells (PBMCs) was quantitatively detected by MethyLight. SFRP2 methylation level was significantly higher in patients with HBV-associated HCC than in those with CHB (p < 0.001) and HCs (p < 0.001) while mRNA level of SFRP2 was significantly lower in HCC group than the other two groups (p < 0.05). In HCC subgroup, SFRP2 methylation level markedly increased in patients >50 years old, female, with negative HBeAg, negative HBV-DNA and poor differentiation compared with the remaining groups (P < 0.05). Furthermore, SFRP2 methylation level showed a significantly better diagnostic value than alpha-fetoprotein (AFP) and the combination of AFP and methylation levels of SFRP2 markedly improved the area under the receiver operating characteristic curve (p < 0.05). In conclusion, hypermethylation of SFRP2 promoter exists in HBV-associated HCC. The combination of SFRP2 methylation level in PBMCs and AFP could significantly improve the diagnostic ability of AFP in discriminating HBV-associated HCC from CHB and SFRP2 methylation level had the potential to serve as a non-invasive biomarker for HCC diagnosis.

Epidemiological features of infectious disease related public health emergencies in Zhejiang Province, 2010-2018 / 预防医学

Objective@#To learn the epidemiological characteristics of infectious disease related public health emergencies in Zhejiang Province from 2010 to 2018 for the prevention and control. @*Methods@#The surveillance data was extracted from National Public Health Emergency Management Information System. Descriptive epidemiology method was used to analyze main diseases as well as distribution characteristics of time and places. @*Results@#A total of 445 events were reported, which caused 14362 cases and 34 deaths, with a attack rate of 0.69% and mortality rate of 0.24%. There were 298 events with less than 30 cases, accounting for 66.97%. The event classification was dominated by general events ( 242 events, 54.38% ) and ungraded events ( 201 events, 45.17% ). The main diseases were chickenpox ( 134 events, 30.11% ), hand foot mouth disease ( 59 events, 13.26% ) and other infectious diarrhea ( 51 events, 11.46% ). The incidence peaked from April to June ( 129 events, 28.99% ) and from November to December ( 131 events, 29.44% ). Ningbo ranked the top in the number of reported events ( 141 events, 31.69% ). Most events ( 322 events, 72.36% ) occurred in schools.@*Conclusions@#The infectious disease related public health emergencies in Zhejiang Province from 2010 to 2018 were mainly caused by chickenpox, hand-foot-mouth disease and other infectious diarrhea. The two peaks of the emergencies occurred from April to June and from November to December. Ningbo was the main area reporting infectious diseases, and schools were the main places.

Diagnostic Value of the Hypomethylation of the WISP1 Promoter in Patients with Hepatocellular Carcinoma Associated with Hepatitis B Virus.

Wnt1-inducible signaling pathway protein 1 (WISP1) regulates cell proliferation, differentiation, adhesion, migration and survival. Abnormal WISP1 expression is associated with the carcinogenesis of hepatocellular carcinoma (HCC). Aberrant DNA methylation is one of the major epigenetic alterations in HCC. However, the methylation status of the WISP1 promoter is still unclear. We therefore aimed to determine the methylation status of the WISP1 promoter and evaluate its clinical value in HCC. The study enrolled 251 participants, including 123 participants with HCC, 90 participants with chronic hepatitis B (CHB) and 38 healthy controls (HCs). WISP1 methylation status, mRNA levels and plasma soluble WISP1 were detected by methylation-specific polymerase chain reaction (MSP), quantitative real-time PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. We found that the methylation frequency of WISP1 in patients with HCC was significantly lower than that in patients with CHB and HCs, while the relative expression levels of WISP1 mRNA were markedly higher in patients with HCC than in patients with CHB and HCs. Furthermore, the plasma soluble WISP1 in patients with HCC was obviously lower than in that in patients with CHB and HCs. Alpha-fetoprotein (AFP) is a widely recognized biomarker to diagnose HCC which lacks enough sensitivity and specificity. WISP1 promoter methylation status combined with AFP significantly improved the diagnostic ability in discriminating HCC from CHB compared with AFP or WISP1 methylation status alone. In conclusion, hypomethylation of the WISP1 gene promoter may serve as a noninvasive biomarker for detecting HBV-associated HCC.

A U-shaped Association of Breastfeeding Duration with Cognitive Impairment in Chinese Postmenopausal Women.

Breastfeeding is related to maternal health. However, the association of women's breastfeeding duration with cognitive function in their later life is limited and inconsistent. The aim of this study was to accurately evaluate the association in Chinese postmenopausal women. We analyzed the data from Zhejiang Ageing and Health Cohort Study including 5487 postmenopausal women. Cognitive impairment was assessed via the Mini-Mental State Examination. Data on breastfeeding duration was collected in the reproductive history section within the questionnaire. Generalized additive models (GAMs) and logistic regression models, controlled for an extensive range of potential confounders, were generated to examine the associations. A U-shaped association was identified between breastfeeding duration and cognitive impairment based on GAM. The nadir with lowest odds of cognitive impairment was ascertained by quadratic model as 12 months. The logistic models showed that compared with women breastfeeding 12 months per child, the fully adjusted odds ratios (ORs) were 1.50 (95% Confidence Interval (CI): 1.20-1.88), 1.58 (95% CI: 1.29-1.93), 1.33 (95% CI: 1.06-1.68), 2.08 (95% CI: 1.64-2.65) for those averagely breastfeeding <6, 6-<12,>12-18,>18 months, respectively. Furthermore, we did not observe significant effect modification of the association. Future longitudinal studies are needed to confirm the association.

TNFRSF12A and a new prognostic model identified from methylation combined with expression profiles to predict overall survival in hepatocellular carcinoma.

BACKGROUND: It has been proved that DNA methylation, as an epigenetic regulatory mode, plays a crucial role in the initiation, progression and invasion of hepatocellular carcinoma (HCC). However, there still are some pathways and factors that regulates the carcinogenesis of HCC remains unclear. METHODS: The original datasets comparing DNA methylation, clinical information and transcriptome profiling between HCC and normal controls were downloaded from The Cancer Genome Atlas (TCGA) database. R software was used to screen for methylation-differential genes (MDGs) and methylation-driven genes. Gene-functional enrichment analysis, ConsensusPathDB pathway analysis, protein-protein interaction (PPI) network construction and survival analysis were performed; methylation-specific polymerase chain reaction (MSP) and real-time quantitative polymerase chain reaction (RT-qPCR) were used for validation. RESULTS: One hundred and sixty-seven MDGs and 285 methylation-driven genes were identified. Function and pathway enrichment analysis revealed that they are associated with sequence-specific DNA binding, nuclear nucleosome, regulation of insulin-like growth factor transport, etc. An eight-gene (HIST1H1D, RP11-476B1.1, OR2AK2, TNFRSF12A, CTD-2313N18.8, AC133644.2, RP11-467L13.4 and LINC00989) prognostic model was identified from the MDGs; its methylation degree can strongly predict the overall survival of HCC. Among them, TNFRSF12A being the only one belongs to both MDGs and methylation-driver genes, shows a significant independent correlation with the prognosis of HCC. That was validated in further details. CONCLUSIONS: Our research has identified a registry of novel genes and pathways that's important for regulating the carcinogenesis of HCC. In addition, we identified a strong molecular model for prognostic prediction. These findings will not only provide guidance for clinical individualized treatment, but also to set us targets for further research on the molecular mechanism of HCC.

DietaryAdvancedGlycationEnd Products-InducedCognitive Impairment in Aged ICR Mice: Protective Role of Quercetin.

SCOPE: Dietary advanced glycation products (dAGEs) have been reported to induce cognitive impairment while quercetin possesses potential neuroprotective effects. The aim is to explore whether dAGEs would induce similar cognitive impairment from both young and aged ICR mice, and the protective effects of quercetin. METHODS AND RESULTS: A total of 32 aged ICR mice (15-month-old) and 16 young ICR mice (3-month-old) are randomly assigned into the following six groups: Young mice control group, young mice fed with AGEs diet group, old mice control group, old mice fed with AGEs diet group, old mice with quercetin supplemented diet group, old mice fed with AGE diet supplemented with quercetin group. Dietary AGEs induced cognitive impairment only in aged, but not in young, ICR mice, while quercetin intervention is capable of reversing dAGEs-induced cognitive dysfunction. This may be since quercetin 1) increased miR-219, miR-15a, and miR-132 expression, inhibited p-ERK1/2, and tau phosphorylation; and 2) improved gut microbiota richness and diversity, inhibited phylum Tenericutes and Proteobacteria, and elevated butyric acid from cecum. CONCLUSION: Prolonged application of quercetin may be beneficial in the elderly, especially for those with high consumption of dAGEs.

Lovastatin attenuates hypertension induced by renal tubule-specific knockout of ATP-binding cassette transporter A1, by inhibiting epithelial sodium channels.

BACKGROUND AND PURPOSE: We have shown that cholesterol is synthesized in the principal cells of renal cortical collecting ducts (CCD) and stimulates the epithelial sodium channels (ENaC). Here we have determined whether lovastatin, a cholesterol synthesis inhibitor, can antagonize the hypertension induced by activated ENaC, following deletion of the cholesterol transporter (ATP-binding cassette transporter A1; ABCA1). EXPERIMENTAL APPROACH: We selectively deleted ABCA1 in the principal cells of mouse CCD and used the cell-attached patch-clamp technique to record ENaC activity. Western blot and immunofluorescence staining were used to evaluate protein expression levels. Systolic BP was measured with the tail-cuff method. KEY RESULTS: Specific deletion of ABCA1 elevated BP and ENaC single-channel activity in the principal cells of CCD in mice. These effects were antagonized by lovastatin. ABCA1 deletion elevated intracellular cholesterol levels, which was accompanied by elevated ROS, increased expression of serum/glucocorticoid regulated kinase 1 (Sgk1), phosphorylated neural precursor cell-expressed developmentally down-regulated protein 4-2 (Nedd4-2) and furin, along with shorten the primary cilium, and reduced ATP levels in urine. CONCLUSIONS AND IMPLICATIONS: These data suggest that specific deletion of ABCA1 in principal cells increases BP by stimulating ENaC channels via a cholesterol-dependent pathway which induces several secondary responses associated with oxidative stress, activated Sgk1/Nedd4-2, increased furin expression, and reduced cilium-mediated release of ATP. As ABCA1 can be blocked by cyclosporine A, these results suggest further investigation of the possible use of statins to treat CsA-induced hypertension.

Intracellular cholesterol stimulates ENaC by interacting with phosphatidylinositol­4,5­bisphosphate and mediates cyclosporine A-induced hypertension.

We have previously shown that blockade of ATP-binding cassette transporter A1 (ABCA1) with cyclosporine A (CsA) stimulates the epithelial sodium channel (ENaC) in cultured distal nephron cells. Here we show that CsA elevated systolic blood pressure in both wild-type and apolipoprotein E (ApoE) knockout (KO) mice to a similar level. The elevated systolic blood pressure was completely reversed by inhibition of cholesterol (Cho) synthesis with lovastatin. Inside-out patch-clamp data show that intracellular Cho stimulated ENaC in cultured distal nephron cells by interacting with phosphatidylinositol­4,5­bisphosphate (PIP2), an ENaC activator. Confocal microscopy data show that both α­ENaC and PIP2 were localized in microvilli via a Cho-dependent mechanism. Deletion of membrane Cho reduced the levels of γ­ENaC in the apical membrane. Reduced ABCA1 expression and elevated intracellular Cho were observed in old mice, compared to young mice. In parallel, cell-attached patch-clamp data from the split-open cortical collecting ducts (CCD) show that ENaC activity was significantly increased in old mice. These data suggest that elevation of intracellular Cho due to blockade of ABCA1 stimulates ENaC, which may contribute to CsA-induced hypertension. This study also implies that reduced ABCA1 expression may mediate age-related hypertension by increasing ENaC activity via elevation of intracellular Cho.