CLCF1 inhibits energy expenditure via suppressing brown fat thermogenesis.

Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis which plays an important role in thermogenesis and energy metabolism. However, the regulatory factors that inhibit BAT activity remain largely unknown. Here, cardiotrophin-like cytokine factor 1 (CLCF1) is identified as a negative regulator of thermogenesis in BAT. Adenovirus-mediated overexpression of CLCF1 in BAT greatly impairs the thermogenic capacity of BAT and reduces the metabolic rate. Consistently, BAT-specific ablation of CLCF1 enhances the BAT function and energy expenditure under both thermoneutral and cold conditions. Mechanistically, adenylate cyclase 3 (ADCY3) is identified as a downstream target of CLCF1 to mediate its role in regulating thermogenesis. Furthermore, CLCF1 is identified to negatively regulate the PERK-ATF4 signaling axis to modulate the transcriptional activity of ADCY3, which activates the PKA substrate phosphorylation. Moreover, CLCF1 deletion in BAT protects the mice against diet-induced obesity by promoting BAT activation and further attenuating impaired glucose and lipid metabolism. Therefore, our results reveal the essential role of CLCF1 in regulating BAT thermogenesis and suggest that inhibiting CLCF1 signaling might be a potential therapeutic strategy for improving obesity-related metabolic disorders.

Blocking coprophagy increases the levels of inflammation and depression in healthy mice as well as mice receiving fecal microbiota transplantation from disease model mice donors.

Rodents have been extensively used as animal models in microbiome studies. However, all rodents have a habitual nature called coprophagy, a phenomenon that they self-reinoculate feces into their gastrointestinal tract. Recent studies have shown that blocking coprophagy can alter rodents' diversity of gut microbiota, metabolism, neurochemistry, and cognitive behavior. However, whether rodents' coprophagy behavior affects the levels of inflammation and depression is unclear. In order to address this problem, we first blocked coprophagy in healthy mice. It displayed an increase in the levels of depression, verified by depressive-like behaviors and mood-related indicators, and inflammation, verified by the increased levels of the pro-inflammatory cytokine, in coprophagy-blocked mice. Furthermore, we transplanted fecal microbiota from chronic restraint stress (CRS) depression model mice and lipopolysaccharide (LPS) inflammation model mice to healthy recipient mice, respectively. It showed that the disease-like phenotypes in the coprophagy-blocked group were worse than those in the coprophagy-unblocked group, including severer depressive symptoms and higher levels of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α and IFN-γ) in serum, prefrontal cortex (PFC), and hippocampus (HIP). These findings showed that blocking coprophagy in mice not only increased the levels of inflammation and depression in healthy mice but also aggravated inflammation and depression induced by fecal microbiota from disease donors. The discovery may provide a vital reference for future research involving FMT in rodents.

Associations of Menstrual Cycle Regularity and Length With Cardiovascular Diseases: A Prospective Study From UK Biobank.

Background The association between menstrual cycle characteristics and cardiovascular outcomes remains unclear. This study was undertaken to evaluate whether menstrual cycle regularity and length throughout the life course are associated with cardiovascular outcomes. Methods and Results This cohort study included 58 056 women who had no cardiovascular disease (CVD) at baseline and reported their menstrual cycle regularity and length. Hazard ratios (HRs) and 95% CIs for CVD events were estimated using Cox proportional hazards models. During the median 11.8 years of follow-up, 1623 incident CVD cases were documented, including 827 incident cases of coronary heart disease, 199 myocardial infarctions, 271 strokes, 174 cases of heart failure, and 393 cases of atrial fibrillations. Compared with women with regular menstrual cycles, the HRs for women with irregular menstrual cycles were 1.19 (95% CI, 1.07-1.31) for CVD events and 1.40 (95% CI, 1.14-1.72) for atrial fibrillation. The multivariable-adjusted HRs for short (≤21 days) or long (35 days) menstrual cycles during follow-up were 1.29 (95% CI, 1.11-1.50) and 1.11 (95% CI, 0.98-1.56) for CVD events, respectively. Similarly, long or short cycle length were more likely to be associated with increased risk of atrial fibrillation (HR, 1.30 [95% CI, 1.01-1.66]; and HR, 1.38 [95% CI, 1.02-1.87]), and short cycle length was more likely to be associated with increased risk of coronary heart disease and myocardial infarction. However, these associations for stroke and heart failure were not significant. Conclusions Long or short menstrual cycle length was associated with increased risks of CVD and atrial fibrillation but not myocardial infarction, heart failure, or stroke. Short cycle length was associated with a greater risk of coronary heart disease and myocardial infarction.

Associations of fish oil supplementation with incident dementia: Evidence from the UK Biobank cohort study.

Background: Although numerous studies have investigated the association of dietary intake of omega-3 fatty acids with cognitive function and the risks of dementia, the relationship between fish oil supplementation and incident dementia in a large population-based cohort study has not yet well studied. Materials and methods: A total of 211,094 community-dwelling older persons over 60 years from the UK Biobank cohorts enrolled between 2006 and 2010 that reported regularly taking fish oil and had no dementia at baseline, was included in the present study. All participants completed an electronic questionnaire regarding habitual use of supplements including fish oil. Results: Overall, 83,283 (39.5%) participants reported regularly taking fish oil at baseline. Of 211,094 participants with the median age was 64.1 years, 5,274 participants developed dementia events during a median follow-up of 11.7 years, with 3,290 individuals derived from fish oil non-users. In the multivariable adjusted models, the adjusted hazard ratios (HRs) associated with fish oil supplementation for all-cause dementia, vascular dementia, frontotemporal dementia, and other dementia were 0.91 [CI = 0.84-0.97], 0.83 [CI = 0.71-0.97], 0.43 [CI = 0.26-0.72], 0.90 [CI = 0.82-0.98], respectively (all P < 0.05). However, no significant association between fish oil supplementation and Alzheimer's disease was found (HR = 1.00 [CI = 0.89-1.12], P = 0.977). In the subgroup analyses, the associations between use of fish oil and the risk of all-cause dementia (P for interaction = 0.007) and vascular dementia were stronger among men (P for interaction = 0.026). Conclusion: Among older adults, regular fish oil supplementation was significantly associated with a lower risks of incident all-cause dementia, as well as vascular dementia, frontotemporal dementia and other dementia but not Alzheimer's disease. These findings support that habitual use of fish oils may be beneficial for the prevention of dementia in clinical practice.

Leukemia inhibitory factor protects against liver steatosis in nonalcoholic fatty liver disease patients and obese mice.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. However, the molecular mechanisms that promote dysregulation of hepatic triglyceride metabolism and lead to NAFLD are poorly understood, and effective treatments are limited. Leukemia inhibitory factor (LIF) is a member of the interleukin-6 cytokine family and has been shown to regulate a variety of physiological processes, although its role in hepatic triglyceride metabolism remains unknown. In the present study, we measured circulating LIF levels by ELISA in 214 patients with biopsy-diagnosed NAFLD as well as 314 normal control patients. We further investigated the potential role and mechanism of LIF on hepatic lipid metabolism in obese mice. We found that circulating LIF levels correlated with the severity of liver steatosis. Patients with ballooning, fibrosis, lobular inflammation, and abnormally elevated liver injury markers alanine transaminase and aspartate aminotransferase also had higher levels of serum LIF than control patients. Furthermore, animal studies showed that white adipose tissue-derived LIF could ameliorate liver steatosis through activation of hepatic LIF receptor signaling pathways. Together, our results suggested that targeting LIF-LIF receptor signaling might be a promising strategy for treating NAFLD.

Association of Serum 25-Hydroxyvitamin D With Cardiovascular Outcomes and All-Cause Mortality in Individuals With Prediabetes and Diabetes: Results From the UK Biobank Prospective Cohort Study.

OBJECTIVE: To examine the associations of circulating 25-hydroxyvitamin D (25[OH]D) concentrations with cardiovascular disease (CVD) and all-cause mortality in individuals with prediabetes and diabetes from the large population-based UK Biobank cohort study. RESEARCH DESIGN AND METHODS: A total of 67,789 individuals diagnosed with prediabetes and 24,311 with diabetes who had no CVD or cancer at baseline were included in the current study. Serum 25(OH)D concentrations were measured at baseline. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs for cardiovascular outcomes and mortality after 10-14 years. RESULTS: After multivariable adjustment, higher serum 25(OH)D levels were significantly and nonlinearly associated with lower risk of cardiovascular outcomes and all-cause mortality among participants with prediabetes and diabetes (all P nonlinearity < 0.05). Compared with those in the lowest category of 25(OH)D levels (<25 nmol/L), participants with prediabetes in the highest category of 25(OH)D levels (≥75 nmol/L) had a significant association with lower risk of cardiovascular events (HR 0.78; 95% CI 0.71-0.86), coronary heart disease (CHD) (HR 0.79; 95% CI 0.71-0.89), heart failure (HR 0.66; 95% CI 0.54-0.81), stroke (HR 0.75; 95% CI 0.61-0.93), CVD mortality (HR 0.43; 95% CI 0.32-0.59), and all-cause mortality (HR 0.66; 95% CI 0.58-0.75). Likewise, these associations with cardiovascular events, CHD, heart failure, CVD mortality, and all-cause mortality were observed among participants with diabetes, except for stroke. CONCLUSIONS: These findings highlight the importance of monitoring and correcting vitamin D deficiency in the prevention of CVD and mortality among adults with prediabetes and diabetes.

Elevated Serum Tsukushi Levels in Patients With Hyperthyroidism.

Background: Tsukushi (TSK) is a secreted hepatokine recently identified as playing an important role in modulating glucose and lipid metabolism, and systemic energy homeostasis. However, information is not available regarding the association between circulating TSK and hyperthyroidism in humans. Methods: We measured serum TSK levels in 180 patients with hyperthyroidism and 82 healthy controls recruited from the clinic. Of them, 46 hyperthyroid patients received thionamide treatment for 3 months. Results: Hyperthyroid patients had higher levels of circulating TSK than healthy controls [186.67 (133.63-280.59) ng/ml vs. 97.27 (77.87-146.96) ng/ml, P < 0.001]. Subjects with higher level of serum free triiodothyronine (T3) and free thyroxine (T4) had higher levels of circulating TSK. In addition, serum TSK levels markedly declined with the improvement of thyroid function after thionamide treatment. In multivariable linear regression analyses, circulating TSK concentrations were significantly associated with serum free T3, free T4, thyroid stimulating hormone, thyrotropin receptor antibody, total cholesterol, low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein cholesterol (HDL-cholesterol), and basal metabolic rate (all P < 0.01), adjusting for age, gender, smoking, and body mass index (BMI). Importantly, circulating TSK was significantly associated with risks of hyperthyroidism in multivariable logistic regression analyses, adjusting for age, gender, smoking, BMI, fasting glucose, LDL-cholesterol, and insulin resistance (HOMA-IR) [OR (95% CI), 1.012(1.005-1.019), P = 0.001]. Conclusion: These findings indicate that circulating TSK concentrations are independently associated with hyperthyroidism, suggesting that circulating TSK may be a predictive factor of hyperthyroidism and can be used for therapeutic monitoring.

Elevated circulating Gpnmb levels are associated with hyperthyroidism.

BACKGROUND: Glycoprotein non-metastatic protein B (Gpnmb) has been identified as a new cytokine secreted by hepatocyte that plays an important role in balancing lipid homeostasis and development of obesity and metabolic disorders. However, information is not available regarding the association between circulating Gpnmb and hyperthyroid in humans. METHODS: We measured serum Gpnmb in 180 hyperthyroid patients and 82 healthy subjects that were recruited from the clinic. Of them, 46 hyperthyroid patients received thionamide treatment for 3 months. RESULTS: Hyperthyroid subjects had higher levels of circulating Gpnmb than healthy controls (47.8 ± 10.1 ng/mL vs 31.0 ± 4.9 ng/mL, P < 0.001). Subjects with higher levels of serum free triiodothyronine (T3) and free thyroxine (T4) had higher levels of circulating Gpnmb. After thionamide treatment, levels of circulating Gpnmb in hyperthyroid subjects remarkably declined with significant improvement of thyroid function (P < 0.001). Furthermore, the change of circulating Gpnmb levels was significantly associated with basal metabolic rate (BMR) and thyroid hormones, including free T3 and free T4, adjusting for age, gender, smoking and BMI before thionamide treatment. In multivariable logistic regression analyses, circulating Gpnmb was significantly associated with risks of hyperthyroidism (OR (95% CI): 1.44 (1.20-1.74), P < 0.001), adjusted for age, gender, BMI, fasting glucose, HOMA-IR, LDL-cholesterol, ALT and AST. CONCLUSIONS: These findings indicate that circulating Gpnmb concentrations are independently associated with hyperthyroid, suggesting that circulating Gpnmb may be a predictor of risk for hyperthyroidism and can be used for therapeutic monitoring.

Core-shell MOF@MOF composites for sensitive nonenzymatic glucose sensing in human serum.

The detection of blood glucose level receives much attention, because diabetes has become one of the significant threats to human health worldwide. In this paper, we described a novel core-shell MOF@MOF composite-based electrochemical sensor for nonenzymatic glucose sensing in alkaline media. The core-shell UiO-67@Ni-MOF composites were synthesized by internal extended growth of shell Ni-MOF on the core UiO-67 under polyvinylpyrrolidone (PVP) regulation. In the sensor system, UiO-67 with large specific surface area and good conductivity was used to accelerate the rate of electron transfer of UiO-67@Ni-MOF. Ni-MOF served as an electrocatalytic material due to excellent electrochemical activity toward glucose oxidation. The morphology, structure, and electrochemical performance of UiO-67@Ni-MOF composites were characterized. To demonstrate the detection performance of the UiO-67@Ni-MOF composite-based sensor, it was successfully used for nonenzymatic glucose sensing. The results indicated that UiO-67@Ni-MOF composites exhibited high electrocatalytic activity toward glucose oxidation compared with individual UiO-67 and Ni-MOF. Moreover, the sensor possessed high sensitivity and selectivity for real-time amperometric detection of glucose. It performed glucose level detection in human serum samples with acceptable reliability and accuracy. The present work suggested that the as-fabricated sensor is promising for nonenzymatic glucose sensing in real samples and holds great potential as an alternative tool for the rapid diagnosis of diabetes and for monitoring blood glucose levels daily.

Carboxyl hydrogel particle film as a local pH buffer for voltammetric determination of luteolin and baicalein.

Electrochemical determination of luteolin and baicalein always needs acidic supporting electrolyte to guarantee good sensitivity. Therefore, most of the reported electrochemical sensors of luteolin and baicalein are unsuitable for detection of neutral actual samples. It is necessary to design a highly sensitive sensor for direct determination of them in neutral conditions. In this study, poly(N-isopropylacrylamide-acrylic acid) hydrogel particles (NIPA/AA) and multiwall carbon nanotubes (MWCNTs) composite modified glassy carbon electrode (GCE) was fabricated by a simple casting method. The voltammetric results showed that the NIPA/AA particle film provided acidic environment for proton-electron coupled reaction in neutral mediums. The near-surface pH of the electrode was related on the loaded amount of the NIPA/AA particles in pH range from 4.2 to 5.9. The voltammetric behaviors of luteolin and baicalein at the NIPA/AA-MWCNTs-GCE were studied by cyclic voltammetry. The peak separations between cathodic and anodic peaks were decreased and peak currents were increased because of decrease in pH and increase in ion conductivity at the local electrode surface. The sensitivity of the electrode was investigated by differential pulse voltammetry. Even under neutral conditions, the plots of the oxidation currents of luteolin and baicalein were dependent linearly on their concentration with detection limit of 14.5 pM and 44.4 pM, respectively. Moreover, the proposed NIPA/AA-MWCNTs-GCE was also successfully applied for determination of luteolin and baicalein in peanut shell, Huang-qin and tomato samples.

Graphene Aerogel-Metal-Organic Framework-Based Electrochemical Method for Simultaneous Detection of Multiple Heavy-Metal Ions.

The development of an effective method for detecting heavy-metal ions remains a serious task because of their high toxicity to public health and environments. Herein, a new electrochemical method based on a graphene aerogel (GA) and metal-organic framework (MOF) composites was developed for simultaneous detection of multiple heavy-metal ions in aqueous solutions. The GA-MOF composites were synthesized via the in situ growth of the MOF UiO-66-NH2 crystal on the GA matrix. GA not only serves as the backbone for UiO-66-NH2 but also enhances the conductivity of the composites by accelerating the electron transfer in the matrix. UiO-66-NH2 worked as a binding site for heavy-metal ions because of the interaction between hydrophilic groups and metal cations. The detection performance of the GA-UiO-66-NH2 composite-modified electrodes was determined. The developed electrochemical method can be successfully applied for individual and simultaneous detection of heavy-metal ions, namely, Cd2+, Pb2+, Cu2+,and Hg2+, in aqueous solutions with high sensitivity and selectivity. The method can also be used for simultaneous detection of Cd2+, Pb2+, Cu2+, and Hg2+ in river water and the leaching solutions of soil and vegetable with high accuracy and reliability. This work provides a new approach for simultaneous detection of multiple heavy-metal ions in practical applications.

Role of Nox2 and p22phox in Persistent Postoperative Hypertension in Aldosterone-Producing Adenoma Patients after Adrenalectomy.

Adrenal aldosterone-producing adenoma (APA), producing the salt-retaining hormone aldosterone, commonly causes secondary hypertension, which often persists after unilateral adrenalectomy. Although persistent hypertension was correlated with residual hormone aldosterone, the in vivo mechanism remains unclear. NADPH oxidase is the critical cause of aldosterone synthesis in vitro. Nox2 and p22phox comprise the NADPH oxidase catalytic core, serving to initiate a reactive oxygen species (ROS) cascade that may participate in the pathology. mRNAs of seven NADPH oxidase isoforms in APA were evaluated by RT-PCR and Q-PCR and their proteins by immunohistochemistry and Western blotting. NADPH oxidase activity was also detected. Nox2 and p22phox were especially abundant in APA. Particularly higher Nox2 and p22phox gene and protein levels were seen in APA than controls. Significant correlations between Nox2 mRNA and aldosterone synthase (CYP11B2) mRNA (R = 0.66, P < 0.01) and Nox2 protein and baseline plasma aldosterone concentration (PAC) (R = 0.503, P < 0.01) were detected in APA; however, none were found between p22phox mRNA, CYP11B2 mRNA, p22phox protein, and baseline PAC. Importantly, we found that Nox2 localized specifically in hyperplastic zona glomerulosa cells. In conclusion, our results highlight that Nox2 and p22phox may be directly involved in pathological aldosterone production and zona glomerulosa cell proliferation after APA resection.

Mass preparation and novel visible light photocatalytic activity of C and Ag Co-modified ZnO nanocrystals.

A combustion method was developed to synthesize the C and Ag co-modified ZnO NCs to enhance its photocatalytic efficiency and practicability. The results showed that the doped Ag was significant to promote the photocatalytic activity, and the optimum content was 2% molar ratio of Ag to Zn atom. The degradation rate under visible light increased by 150% compared with C-ZnO NCs, while by more 1233.3% than pure ZnO photocatalyst. There were some new little particles with grain size about 10 nm on the C-ZnO NCs surface, which may state for the existence of Ag atoms. The synergy effect of Ag and carbon elements was proposed to explain the mechanism of enhanced photocatalytic performance under visible light irradiation.

Ultrasensitive electrochemical immunosensor for ochratoxin A using gold colloid-mediated hapten immobilization.

A convenient, specific, and highly sensitive electrochemical immunosensor based on an indirect competitive assay format was developed for the determination of ochratoxin A (OTA), a common toxic contaminant in various kinds of agricultural products. The sensing substrate was prepared using a gold electrode modified with a self-assembled monolayer of 1,6-hexanedithiol that mediated the assembly of a gold colloid layer, which could enhance the surface loading of OTA-ovalbumin conjugate and improve the sensitivity in electrochemical readouts. After competition of the limited anti-OTA mouse monoclonal antibody between immobilized hapten and OTA analyte in sample solution, alkaline phosphatase (ALP)-labeled horse anti-mouse immunoglobulin G (IgG) antibody was selectively bound onto the surface of the electrode, affording an indicator for OTA concentration in the sample. Electrochemical response arising from the oxidation of enzymatic product of 1-naphthyl phosphate was observed to be inversely proportional to OTA concentration in the range from 10 pg/ml to 100 ng/ml with a detection limit as low as 8.2 pg/ml. Furthermore, a negligible matrix effect and good recoveries were obtained in the determination of corn samples, evidencing the feasibility of the proposed method for accurate determination of OTA in corn samples.