Extracellular vesicles from helicobacter pylori-infected cells and helicobacter pylori outer membrane vesicles in atherosclerosis.

BACKGROUND: The role of H. pylori infection has been reported in various extragastric diseases, particularly, the correlation between H. pylori and atherosclerosis (AS) have received lots of attention. Some scholars demonstrated that the presence of H. pylori-specific DNA in the sclerotic plaques of atheromatous patients provides biological evidences, with indicating that H. pylori infection is a potential factor of AS. However, the underlying mechanism of H. pylori or their products cross the epithelial barriers to enter the blood circulation remains unclear. Recent studies have shown that the extracellular vesicles (EVs) derived from H. pylori-infected gastric epithelial cells encapsulated H. pylori virulence factor cytotoxin-associated gene A (CagA) and existed in the blood samples of patients or mice, which indicating that they can carry CagA into the blood circulation. Based on these findings, some researchers proposed a hypothesis that H. pylori is involved in the pathogenesis of AS via EVs-based mechanisms. In addition, outer membrane vesicles (OMVs) serve as transport vehicles to deliver H. pylori virulence factors to epithelial cells. It is necessary to discuss the role of H. pylori OMVs in the development of AS. OBJECTIVES: This review will focus on the correlation between H. pylori infection and AS and tried to unveil the possible role of EVs from H. pylori-infected cells and H. pylori OMVs in the pathogenesis of AS, with a view to providing help in refining our knowledge in this aspect. METHODS: All of information included in this review was retrieved from published studies on H. pylori infection in AS. RESULTS: H. pylori infection may be an atherosclerotic risk factor and drives researchers to reevaluate the role of H. pylori in the pathogenesis of AS. Some findings proposed a new hypothesis that H. pylori may be involved in the pathogenesis of AS through EVs-based mechanisms. Besides EVs from H. pylori-infected cells, whether H. pylori OMVs may play some role in the pathogenesis of AS is still remain unclear. CONCLUSION: Existing epidemiological and clinical evidence had shown that there is a possible association between H. pylori and AS. However, except for the larger randomized controlled trials, more basic research about EVs from H. pylori-infected cells and H. pylori OMVs is the need of the hour to unveil the possible role of H. pylori infection in the pathogenesis of AS.

Study of mitophagy and ATP-related metabolomics based on ß-amyloid levels in Alzheimer's disease.

The aggregation of ß-amyloid (Aß) peptide in Alzheimer's disease (AD) is characterized by mitochondrial dysfunction and mitophagy impairment. Mitophagy is a homeostatic mechanism by which autophagy selectively eliminates damaged mitochondria. Valinomycin is a respiratory chain inhibitor that activates mitophagy via the PINK1/Parkin signaling pathway. However, the mechanism underlying the association between mitophagy and valinomycin in Aß formation has not been explored. Here, we demonstrate that genetically modified (N2a/APP695swe) cells overexpressing a mutant amyloid precursor protein (APP) serve as an in vitro model of AD for studying mitophagy and ATP-related metabolomics. Our results prove that valinomycin induced a time-dependent increase in the mitophagy activation of N2a/APP695swe cells as indicated by increased levels of PINK1, Parkin, and LC3II as well as increased the colocalization of Parkin-Tom20 and fewer mitochondria (indicated by decreased Tom20 levels). Valinomycin significantly decreased Aß1-42 and Aß1-40 levels after 3 h of treatment. ATP levels and ATP-related metabolites were significantly increased at this time. Our findings suggest that the elimination of impaired mitochondria via valinomycin-induced mitophagy ameliorates AD by decreasing Aß and improving ATP levels.

Curcumin ameliorates lipid metabolic disorder and cognitive dysfunction via the ABCA1 transmembrane transport system in APP/PS1 double transgenic mice.

The disorder of lipid metabolism, especially cholesterol metabolism, can promote Alzheimer's Disease. Curcumin can ameliorate lipid metabolic disorder in the brain of Alzheimer's Disease patients, while the mechanism is not clear. APP/PS1 (APPswe/PSEN1dE9) double transgenic mice were divided into dementia, low-dose, and high-dose groups and then fed for six months with different dietary concentrations of curcumin. Morris water maze was used to evaluate the transgenic mice's special cognitive and memory ability in each group. In contrast, the cholesterol oxidase-colorimetric method was used to measure total serum cholesterol and high-density lipoprotein levels. Immunohistochemistry was used to evaluate the expression of liver X receptor-ß, ATP binding cassette A1 and apolipoprotein A1 of the hippocampus and Aß42 in the brains of transgenic mice. The mRNA and protein expression levels of liver X receptor-ß, retinoid X receptor-α and ATP binding cassette A1 were evaluated using qRT-PCR and Western blotting, respectively. Curcumin improved the special cognitive and memory ability of transgenic Alzheimer's Disease Mice. The total serum cholesterol decreased in Alzheimer's Disease mice fed the curcumin diet, while the high-density lipoprotein increased. The curcumin diet was associated with reduced expression of Aß and increased expression of liver X receptor-ß, ATP binding cassette A1, and apolipoprotein A1 in the CA1 region of the hippocampus. The mRNA and protein levels of retinoid X receptor-α, liver X receptor-ß, and ATP binding cassette A1 were higher in the brains of Alzheimer's Disease mice fed the curcumin diet. Our results point to the mechanism by which curcumin improves lipid metabolic disorders in Alzheimer's Disease via the ATP binding cassette A1 transmembrane transport system.

Maladaptive metacognitive beliefs mediated the effect of intolerance of uncertainty on depression.

Both elevated intolerance of uncertainty (IU) and maladaptive metacognitive beliefs (MBs) were associated with depression. However, the relationship between MBs and IU in clinical depression is unclear. The current study aimed to investigate the putative impairment of MBs and IU in major depressive disorder (MDD) and explore the relationship between these two factors with depressive symptoms. Metacognition Questionnaire-30 Items (MCQ-30), Intolerance of Uncertainty Scale-Short Form (IUS-12) and clinical rating scales were administered to 53 patients with MDD and 56 healthy controls (HCs). Stepwise regressions were performed to explore independent contributions of MBs and IU on depression. Mediation analysis was used to examine associations among variables. Patients with MDD reported higher IUS-12 and MCQ-30 scores than HCs. Stepwise regressions revealed a unique contribution of negative MBs concerning the consequences of not controlling thoughts (MCQ-NC) on depression symptoms while controlling the effects of age, gender, anxiety symptoms and IU. MCQ-NC and negative MBs concerning the uncontrollability and danger of negative thinking (MCQ-NEG) completely mediated the effects of IU on depression and anxiety symptoms. Our results provided clear evidence that maladaptive negative MBs are directly associated with depression symptoms, and mediated the effect of IU on depression and anxiety symptoms, suggesting that IU and MBs influence clinical symptoms in a hierarchical manner.

Integrating proteomic or transcriptomic data into metabolic models using linear bound flux balance analysis.

Motivation: Transcriptomics and proteomics data have been integrated into constraint-based models to influence flux predictions. However, it has been reported recently for Escherichia coli and Saccharomyces cerevisiae, that model predictions from parsimonious flux balance analysis (pFBA), which does not use expression data, are as good or better than predictions from various algorithms that integrate transcriptomics or proteomics data into constraint-based models. Results: In this paper, we describe a novel constraint-based method called Linear Bound Flux Balance Analysis (LBFBA), which uses expression data (either transcriptomic or proteomic) to predict metabolic fluxes. The method uses expression data to place soft constraints on individual fluxes, which can be violated. Parameters in the soft constraints are first estimated from a training expression and flux dataset before being used to predict fluxes from expression data in other conditions. We applied LBFBA to E.coli and S.cerevisiae datasets and found that LBFBA predictions were more accurate than pFBA predictions, with average normalized errors roughly half of those from pFBA. For the first time, we demonstrate a computational method that integrates expression data into constraint-based models and improves quantitative flux predictions over pFBA. Availability and implementation: Code is available in the Supplementary data available at Bioinformatics online. Supplementary information: Supplementary data are available at Bioinformatics online.

Correction: Directed Evolution Reveals Unexpected Epistatic Interactions That Alter Metabolic Regulation and Enable Anaerobic Xylose Use by Saccharomyces cerevisiae.

[This corrects the article DOI: 10.1371/journal.pgen.1006372.].

Directed Evolution Reveals Unexpected Epistatic Interactions That Alter Metabolic Regulation and Enable Anaerobic Xylose Use by Saccharomyces cerevisiae.

The inability of native Saccharomyces cerevisiae to convert xylose from plant biomass into biofuels remains a major challenge for the production of renewable bioenergy. Despite extensive knowledge of the regulatory networks controlling carbon metabolism in yeast, little is known about how to reprogram S. cerevisiae to ferment xylose at rates comparable to glucose. Here we combined genome sequencing, proteomic profiling, and metabolomic analyses to identify and characterize the responsible mutations in a series of evolved strains capable of metabolizing xylose aerobically or anaerobically. We report that rapid xylose conversion by engineered and evolved S. cerevisiae strains depends upon epistatic interactions among genes encoding a xylose reductase (GRE3), a component of MAP Kinase (MAPK) signaling (HOG1), a regulator of Protein Kinase A (PKA) signaling (IRA2), and a scaffolding protein for mitochondrial iron-sulfur (Fe-S) cluster biogenesis (ISU1). Interestingly, the mutation in IRA2 only impacted anaerobic xylose consumption and required the loss of ISU1 function, indicating a previously unknown connection between PKA signaling, Fe-S cluster biogenesis, and anaerobiosis. Proteomic and metabolomic comparisons revealed that the xylose-metabolizing mutant strains exhibit altered metabolic pathways relative to the parental strain when grown in xylose. Further analyses revealed that interacting mutations in HOG1 and ISU1 unexpectedly elevated mitochondrial respiratory proteins and enabled rapid aerobic respiration of xylose and other non-fermentable carbon substrates. Our findings suggest a surprising connection between Fe-S cluster biogenesis and signaling that facilitates aerobic respiration and anaerobic fermentation of xylose, underscoring how much remains unknown about the eukaryotic signaling systems that regulate carbon metabolism.

Combined serum CTRP7 and CTRP15 levels as a novel biomarker for insulin resistance and type 2 diabetes mellitus.

Aims: This study aimed to examine the alterations in the serum CTRP7 and CTRP15 concentrations in patients newly diagnosed with type 2 diabetes mellitus (T2DM) and to assess the diagnostic potential of the log10 (CTRP7+CTRP15) for insulin resistance (IR) and T2DM. Methods: Serum CTRP7, CTRP15, and adiponectin levels were measured using an enzyme-linked immunosorbent assay (ELISA). Bioinformatics analysis was conducted to investigate CTRP7 and CTRP15-related genes and metabolic signaling pathways. Results: Log10 (CTRP7+CTRP15) levels were notably elevated in the impaired glucose tolerance (IGT) and T2DM cohorts compared with those in the normal control (NGT) cohort. Log10(CTRP7+CTRP15) exhibited positive correlations with HOMA-IR, area under the glucose curve (AUCg), HbA1c%, triglyceride (TG), visceral adiposity index (VAI), body mass index (BMI), and free fatty acid (FFA), levels but negative correlations with adiponectin. Multivariate stepwise regression analysis revealed that HOMA-IR, BMI, HbA1c and FFA levels were independent factors affecting the log10 (CTRP7+CTRP15). Logistic regression analysis revealed that log10 (CTRP7+CTRP15) was independently associated with T2DM and significantly associated with increased risk. Receiver operating characteristic (ROC) curve analysis indicated that the predictive value of log10 (CTRP7+CTRP15) for T2DM and IR was superior to that of CTRP7 or CTRP15 alone. Intervention studies demonstrated that insulin, FFAs and acute exercise contribute to the elevation of serum CTRP7 levels, while hyperglycemia inhibited CTRP7 secretion. Short-term changes in blood glucose, insulin, FFA and acute exercise had minimal effects on serum CTRP15 levels. Bioinformatics analysis revealed that CTRP7 and CTRP15 interact with multiple metabolism-related genes and are enriched in glucose and lipid metabolism-related pathways. Conclusion: Log10 (CTRP7+CTRP15) may serve as a valuable diagnostic marker for the management of metabolic-related diseases, particularly T2DM and IR.

Central NUCB2/nesfatin-1 signaling ameliorates liver steatosis through suppression of endoplasmic reticulum stress in the hypothalamus.

BACKGROUND & AIMS: Nucleobindin-2 (NUCB2)/nesfatin-1, a signal with recognized anorexigenic and insulin-sensitizing properties in peripheral tissues, is expressed within the hypothalamus. However, the potential involvement of central nesfatin-1 signaling in the pathophysiology of hepatic steatosis remains unknown. This study aimed to determine whether and how central NUCB2/nesfatin-1 plays a role in liver steatosis. METHODS: We generated Nucb2 knockout (Nucb2-/-) rats and administered continuous intracerebroventricular (ICV) nesfatin-1 infusion, while observing its effect on liver steatosis. The molecular mechanism of action of nesfatin-1 was elucidated via proteomics, phosphoproteomics and molecular biology methods. RESULTS: Herein, we present compelling evidence indicating diminished NUCB2 expression in the hypothalamus of obese rodents. We demonstrated that chronic ICV infusion of nesfatin-1 mitigated both diet-induced obesity and liver steatosis in high-fat diet (HFD)-fed Nucb2-/- rats by regulating hypothalamic endoplasmic reticulum (ER) stress and Akt phosphorylation. Furthermore, we revealed that the increase in hypothalamic insulin resistance (IR) and ER stress induced by tunicamycin infusion or Ero1α overexpression exacerbated hepatic steatosis and offset the favorable influence of central nesfatin-1 on hepatic steatosis. The metabolic action of central nesfatin-1 is contingent upon vagal nerve transmission to the liver. Mechanistically, nesfatin-1 impedes ER stress and interacts with Ero1α to repress its Ser106 phosphorylation. This leads to the enhancement of Akt activity in the hypothalamus, culminating in the inhibition of hepatic lipogenesis. CONCLUSIONS: These findings underscore the importance of hypothalamic NUCB2/nesfatin-1 as a key mediator in the top-down neural mechanism that combats diet-induced liver steatosis.

Brain structural alterations in internet gaming disorder: Focus on the mesocorticolimbic dopaminergic system.

AIMS: This study aimed to identify gray/white matter volume (GMV/WMV) alterations in Internet Gaming Disorder (IGD), with a special focus on the subregions of the mesocorticolimbic dopaminergic system and their clinical association. RESULTS: Compared with healthy controls, IGDs showed bigger GMV in the bilateral caudate and the left nucleus accumbens (NAc), and bigger WMV in the inferior parietal lobule. The comparison of regions of interest (ROI) confirmed increased GMV in the bilateral caudate (including the dorsal anterior, body, and tail) and the left core of NAc in IGD, but no significant WMV alterations in the mesocorticolimbic dopaminergic system. GMVs in the left lateral orbital gyrus of orbitofrontal cortex (OFC) were associated with craving for games, while GMVs in the left anterior insula, right NAc, right caudate, and right OFC were associated with self-control in IGD. CONCLUSIONS: IGD was accompanied by changed GMV, but not WMV, in the mesocorticolimbic dopaminergic system. GMV in the mesocorticolimbic dopaminergic system may contribute to impaired self-control and craving in IGD.

Enhanced Pavlovian-to-instrumental transfer in internet gaming disorder.

Background and aims: The Pavlovian-to-instrumental transfer (PIT) effect is a phenomenon that Pavlovian conditioned cues that could influence one's instrumental behavior. In several substance and behavioral addictions, such as tobacco use disorder and gambling disorder, addiction-related cues could promote independently trained instrumental drug-seeking/drug-taking behaviors, indicating a specific PIT effect. However, it is unclear whether Internet gaming disorder (IGD) would show a similar change in PIT effects as other addictions. The study aimed to explore the specific PIT effects in IGD. Methods: We administrated a PIT task to individuals with IGD (n = 40) and matched health controls (HCs, n = 50), and compared the magnitude of specific PIT effects between the two groups. The severity of the IGD symptoms was assessed by the Chinese version 9-item Internet Gaming Disorder Scale (IGDS) and the Internet Addiction Test (IAT). Results: We found that: (1) related to the HCs group, the IGD group showed enhanced specific PITgame effects, where gaming-related cues lead to an increased choice rate of gaming-related responses; (2) in the IGD group, the magnitude of specific PITgame effects were positively correlated with IAT scores (rho = 0.39, p = 0.014). Discussion and Conclusions: Individuals with IGD showed enhanced specific PIT effects related to HCs, which were associated with the severity of addictive symptoms. Our results highlighted the incentive salience of gaming-related cues in IGD.

Fulminant Type 1 Diabetes Mellitus Associated With Drug Hypersensitivity and Epstein-Barr Virus Infection: A Case Report.

Background: Fulminant type 1 diabetes mellitus (FT1DM) is a new subtype of type 1 diabetes, first proposed by Japanese scholars in 2000. Herein, the functions of the islets are rapidly destroyed. Its pathogenesis is related to viral infection. Most people have been infected with Epstein-Barr virus (EBV), and many people have also suffered from drug hypersensitivity, however, few cases of FT1DM which were caused by both of the two conditions have been reported. Thus, below, we describe one such valuable case. Case Summary: The plasma glucose levels of a 73-year-old man diagnosed with drug-induced dermatitis showed a sudden increase (42 mmol/L) during methylprednisolone therapy. The urine ketone test was positive. The glycated hemoglobin level was 7%, endogenous insulin secretion decreased significantly, and the islet-related autoantibodies were negative. The patient was diagnosed with FT1DM. The lymphocyte EBV-DNA showed high copies numbers. The general condition of the patient improved after symptomatic treatment with insulin. However, the systemic allergic reaction aggravated after the use of iodinated contrast agents, prednisone, and thymic pentapeptide. The re-test for EBV-DNA showed significantly high relative levels, thus indicating the presence of EBV infection. We think that drug hypersensitivity and EBV infection together led to FT1DM in this case. After an indication for multiple daily insulin therapy, the patient's blood glucose was quickly controlled and he was discharged on the 38th-day post-admission. Conclusion: FT1DM is a rare case, however, drug hypersensitivity and EBV infection are not rare in the population. This is a rare case of FT1DM caused by drug hypersensitivity reaction and EBV infection. Through this case report, we emphasize the importance of the relationship between drug hypersensitivity, EBV infection and FT1DM and vigilance for the occurrence of FT1DM among hypersensitive individuals in clinical practice.

The Relationships among Plasma Fetuin-B, Thyroid Autoimmunity, and Fertilization Rate In Vitro Fertilization and Embryo Transfer.

Objective: The objective of the study is to investigate the relationships between fetuin-B, thyroid autoimmunity (TAI), and pregnancy outcomes in women undergoing in vitro fertilization and embryo transfer (IVF-ET). Design, Patients, and Measurements. In this prospective study, 180 women who were preparing for pregnancy with IVF-ET were included. There were 120 women with TAI positive and 60 negative controls matched with age and BMI. Results: The 180 women had mean ± SD age of 31.4 ± 4.0 years, with a mean ± SD BMI of 21.0 ± 1.6 kg/m2. There was a significant difference in the level of fetuin-B in women with TAI positive compared with TAI negative group (65.2 ± 18.5 vs. 76.4 ± 25.1, P=0.001). Fetuin-B had a negative relationship with thyroid antibodies even after adjusting for other variables (OR (95%CI) = 0.98 (0.96-0.99), P=0.002). Compared with women with TAI negative, those with TAI positive had a significantly higher risk of low fertilization (20.0% vs. 6.7%; P=0.035). And we found no difference in terms of pregnancy, abortion, implantation, and live birth rate between the two groups. Logistic regression analysis showed that both fetuin-B and TAI were the independent factors to lead the low fertilization of IVF-ET (OR (95%CI) = 0.96 (0.94-0.99) and 4.084 (1.39-15.30), P=0.004 and 0.019, respectively). Conclusion: Fetuin-B was significantly associated with TAI and low fertilization rate in women undergoing IVF-ET. Decreased fetuin-B in women with TAI may be the underlying reason for the lower IVF-ET success rate.

Character strengths as protective factors against behavior problems in early adolescent.

Character strengths could effectively prevent negative psychological outcomes in adults. However, there was little research conducted among early adolescents. The present study aimed to explore character strengths that were independently related to fewer behavior problems in early adolescents. In total, 521 early adolescents (mean age 10.92 ± 0.04, range 10-12 years) were recruited from primary schools in Sichuan, China. Character strengths were measured using the Values in Action Inventory of Strengths for Youth (VIA-Youth). Behavior problems were measured using the Conners Parent Symptom Questionnaire (PSQ). The results showed that behavior problems were negatively correlated with character strengths (r = -0.14 to -0.3, p < 0.05 Bonferroni corrected). Character strengths explained a significant proportion of additional variance (14-22%) in five types of behavior problems after controlling the effect of demographic factors (residence, left-behind experiences, maternal education level). Moreover, several specific character strengths showed an independent contribution (ß = -0.34 to -0.14 for self-regulation, perseverance, zest, humility, and leadership; ß = 0.21 to 0.34, for hope; all p < 0.05) to behavior problems. Our study revealed that character strengths were protective factors against behavior problems in early adolescents.

Initial validation of the Chinese version VIA Youth-96 and age-related changes in character strengths among adolescents.

This study aimed to preliminary examine the psychometric properties of the Chinese version 96-item VIA Inventory for Youth (VIA Youth-96) by analyzing the internal consistency, factorial validity, and criterion validity, and to examine the age-related changes in character strengths (CSs) among adolescents. The sample consisted of 959 adolescents aged 10-17 (49.5% boys). Participants completed the Chinese version VIA Youth-96, along with the Perceived Parental Autonomy Support Scale, and questionnaires assessing life satisfaction and self-efficacy online. The Chinese version VIA Youth-96 showed a good fit for the original four-factor structure, and CS scores were significantly correlated with life satisfaction and self-efficacy indicating a good criterion validity of the scale. The internal consistency was 0.54-0.86 for subscales. Moreover, this study revealed significant age-related changes in CSs among adolescents, eight CSs significantly linearly declined by age. These results suggested that the Chinese version VIA Youth-96 is a valid tool for assessing CSs in adolescents and that CSs are declined linearly by age during adolescence.

CTRP7 Is a Biomarker Related to Insulin Resistance and Oxidative Stress: Cross-Sectional and Intervention Studies In Vivo and In Vitro.

Objective: CTRP7 is a cytokine that is known to be associated with obesity. However, its relationship with insulin resistance (IR) and metabolic diseases remains unknown. The aim of this study is to investigate the relationship between CTRP7 and IR under in vivo and in vitro conditions. Methods: CTRP7 expression in mice and hepatocytes was determined using RT-qPCR and western blotting. Circulating CTRP7 concentrations were measured with an ELISA kit. EHC, OGTT, lipid-infusion, physical activity, and cold-stimulation experiments were performed in humans and mice. SOD, GSH, and MDA were measured by commercial kits. ROS levels were detected using dichlorofluorescein diacetate. Results: The expression levels of CTRP7 protein in the liver and fat of ob/ob and db/db mice were higher than that of WT mice. Individuals with IGT, T2DM, and obesity had higher circulating CTRP7 levels. CTRP7 levels were associated with HOMA-IR, obesity, and other metabolic parameters. During OGTT, serum CTRP7 levels gradually decreased, while CTRP7 levels significantly increased during EHC in response to hyperinsulinemia in healthy individuals without IR. In addition, lipid infusion-induced IR further increased serum CTRP7 levels in healthy adults. Physical activity increased serum CTRP7 levels in healthy individuals and CTRP7 protein expression in iWAT and skeletal muscle in mice. Under in vitro conditions, the expression of the CTRP7 protein was inhibited in a glucose concentration-dependent manner but was promoted by FFAs and insulin stimulation in hepatocytes. Furthermore, CTRP7 overexpression facilitated oxidative stress and suppressed the phosphorylation of insulin signaling molecules in hepatocytes. Conclusions: Our evidence shows that CTRP7 could be a useful biomarker and potential treatment target in IR and metabolic disorders.

Protein Expression Profile in IVF Follicular Fluid and Pregnancy Outcome Analysis in Euthyroid Women with Thyroid Autoimmunity.

The objective of this study is to investigate the influence of the thyroid autoantibodies on the protein expression in follicular fluid and the clinical outcome of assisted reproductive technology. A total of 602 patients treated for infertility were screened; 49 euthyroid women who were positive for thyroid autoantibodies and 63 negative controls were recruited. Follicular fluid samples were analyzed using proteomics. Validation of target proteins in follicular fluid was performed by using parallel reaction monitoring. Differentially expressed proteins in follicular fluid, clinical pregnancy rate, abortion rate, and live-birth rate were analyzed. Clinical pregnancy rates and take-home baby rates in the thyroid autoimmunity (TAI) group were less than in the control group, but abortion rates in the TAI group were higher than in the control group (all P < 0.005). A total of 49 proteins were differentially expressed in the TAI-positive group. In Gene Ontology secondary annotations of all the proteins identified, five types of proteins were associated with the reproductive process. Among 11 proteins quantitatively identified by parallel reaction monitoring, angiotensinogen and fetuin-B were associated with reproduction. These differentially expressed proteins identified in this study involved multiple pathways according to the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Our study provides evidence that some differentially expressed proteins between TAI-positive women and controls were associated with the reproductive process and closely related to important physiologic effects, which could partially explain the underlying mechanism link between TAI and the adverse outcomes of assisted reproductive technology.

Enhanced autophagic retrograde axonal transport by dynein intermediate chain upregulation improves Aß clearance and cognitive function in APP/PS1 double transgenic mice.

Autophagosome accumulation is observed in the distal axons of Alzheimer disease (AD) patients and AD animal models, suggesting that deficient retrograde transport and impaired autophagic clearance of beta-amyloid (A ß) contribute to AD pathogenesis. Expression of the retrograde axonal transport-related protein dynein intermediate chain (DIC) is also reduced in AD patients, but the contributions of DIC to AD pathology remain elusive. This study investigated the effects of DIC expression levels on cognitive function, autophagosome axonal transport, and A ß clearance in the APP/PS1 double transgenic mouse model of AD. Autophagic activity was enhanced in the hippocampus of young (3-month-old) AD mice, as evidenced by greater expression of autophagosome markers, lysosome markers, axonal transport motors (including DIC), and dynein regulatory proteins. The expression levels of autophagosome markers remained elevated, whereas those of autophagic and axonal transport proteins decreased progressively with age, accompanied by spatial learning and memory deficits, axonal autophagosome accumulation, and A ß deposition. Knockdown of DIC exacerbated while overexpression improved axonal transport, autophagosome maturation, Aß clearance, and spatial learning and memory in aged AD mice. Our study provides evidence that age-dependent failure of axonal autophagic flux contributes to AD-associated neuropathology and cognitive deficits, suggesting DIC as a potential therapeutic target for AD.

Central Sfrp5 regulates hepatic glucose flux and VLDL-triglyceride secretion.

OBJECTIVE: Secreted frizzled-related protein 5 (Sfrp5) has been shown to be associated with energy homeostasis and insulin resistance in mouse models of obesity and diabetes. However, its central role in glucose and lipid metabolism is unknown. METHODS: HFD-fed rats received ICV infusions of vehicle or Sfrp5 during a pancreatic euglycemic clamp procedure. To delineate the pathway(s) by which ICV Sfrp5 modulates HGP and VLDL-TG secretion, we inhibited the hypothalamic KATP channel using glibenclamide, the DVC NMDA receptor with MK801, and selectively transected the hepatic branch of the vagal nerve while centrally infusing Sfrp5. RESULTS: ICV Sfrp5 in HFD-fed rats significantly increased the glucose infusion required to maintain euglycemia due to HGP inhibition during the clamp procedure; moreover, hepatic PEPCK and G6Pase expression was decreased, and InsR and Akt phosphorylation was increased in the liver. ICV Sfrp5 also decreased circulating triglyceride levels via inhibiting hepatic VLDL-TG secretion. These changes were accompanied by the inhibition of enzymes related to lipogenesis in the liver. ICV Sfrp5 significantly increased insulin-stimulated phosphorylation of InsR and Akt in the hypothalamus of HFD-fed rats, and insulin-stimulated immunodetectable PIP3 levels were higher in Sfrp5 group than in control group both in vitro and vivo. The glucose- and lipid-lowering effects of ICV Sfrp5 were eliminated by NMDA receptor or DVC KATP channel inhibition or HVAG. CONCLUSIONS: The present study demonstrates that central Sfrp5 signaling activates a previously unappreciated InsR-Akt-PI3k-KATP channel pathway in the hypothalamus and brain-hepatic vagus neurocircuitry to decrease HGP and VLDL-TG secretion.

Association between serum TSH levels and metabolic components in euthyroid subjects: a nationwide population-based study.

BACKGROUND: Whether a relationship exists between various metabolic factors and thyroid-stimulating hormone (TSH) levels in euthyroid persons remains unknown. This study aims to explore the relationship between TSH levels and metabolic factors in euthyroid individuals. METHODS: A total of 2,663 subjects were enrolled from a nationwide population-based cross-sectional survey of iodine nutrition, thyroid disease and diabetes in China (2014-2017). Euthyroid individuals were divided into four groups according to quartiles of TSH levels: group A (n=305, 0.3-1.3 mIU/L), group B (n=829, 1.3-2.2 mIU/L), group C (n=673, 2.2-3.2 mIU/L) and group D (n=349, 3.2-4.2 mIU/L). Anthropometric parameters, biochemical indicators and TSH levels were determined. RESULTS: A total of 2,156 euthyroid subjects with serum TSH levels within the normal range accounted for 86.8% of the sample. The systolic blood pressure (SBP) in group D was significantly higher than that in the other three groups. Group C displayed significantly lower thyroid peroxidase antibody (TPOAb) levels than the other three groups. Group C also had lower anti-thyroglobulin antibody (TgAb) levels than groups A and D, whereas the TgAb levels in group B were only lower than those in group A. Spearman's or Pearson's linear regression analysis showed that SBP (r=0.054; P=0.013) was positively correlated with TSH, but cholesterol (TC) (r=-0.043, P=0.047) was negatively correlated with TSH. Multiple stepwise regression analysis revealed that SBP, the urinary iodine concentration (UIC), waist circumference (WC), body mass index (BMI), TC, triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-C) were independent predictors of serum TSH levels. CONCLUSION: This large population-based study demonstrates a significant interaction between metabolic factors and TSH levels. An adverse weight status, high blood pressure levels, blood lipid metabolism disorder and excessive iodine intake may be early manifestations of thyroid disease in euthyroid subjects.