The plasma level of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is a strong predictor of disease development and premature mortality in the general population. Unhealthy lifestyle habits such as smoking or unhealthy eating is known to elevate the suPAR level. We aimed to investigate whether change in lifestyle habits impact on the suPAR level, and whether the resultant levels are associated with mortality.
Results
Paired suPAR measurements from baseline- and the 5-year visit of the population-based Inter99 study were compared with the habits of diet, smoking, alcohol consumption, and physical activity. Paired suPAR measurements for 3225 individuals were analyzed by linear regression, adjusted for demographics and lifestyle habits. Compared to individuals with a healthy lifestyle, an unhealthy diet, low physical activity, and daily smoking were associated with a 5.9, 12.8, and 17.6% higher 5-year suPAR, respectively. During 6.1 years of follow-up after the 5-year visit, 1.6% of those with a low suPAR (mean 2.93 ng/ml) died compared with 3.8% of individuals with a high suPAR (mean 4.73 ng/ml), P < 0.001. In Cox regression analysis, adjusted for demographics and lifestyle, the hazard ratio for mortality per 5-year suPAR doubling was 2.03 (95% CI: 1.22–3.37).
Conclusion
Lifestyle has a considerable impact on suPAR levels; the combination of unhealthy habits was associated with 44% higher 5-year suPAR values and the 5-year suPAR was a strong predictor of mortality. We propose suPAR as a candidate biomarker for lifestyle changes as well as the subsequent risk of mortality.
Asymmetric dimethylarginine (ADMA) plays a vital role in the regulation of insulin sensitivity and has been shown as a potential marker for various disease, including type 2 diabetes mellitus (DM2). However, the correlation between ADMA and impaired glucose tolerance (IGT) and obesity has not been studied. A total of 195 subjects were involved in our study. The characteristics of the subjects in the study cohort were measured and analyzed. We found that the serum ADMA and C-reactive protein levels were significantly increased in IGT and diabetic patients, whereas the levels of lipoprotein A and adiponectin were decreased, especially in diabetic patients with obesity. The serum ADMA level was positively correlated to a homeostatic model assessment for insulin resistance, and multivariate regression analysis further indicated that ADMA was an independent factor for DM patients with obesity. Our study expands the understanding of the complicated relationship between obesity, insulin resistance, IGT, and ADMA. In addition, we demonstrated that the serum ADMA level could serve as a diagnositic biomarker of the early signs for IGT patients with obesity. 相似文献
Insulin resistance is associated with impaired glucose uptake and altered protein kinase B (Akt) signaling. Previous studies have suggested asymmetric dimethylarginine (ADMA) and inflammation are two distinguish factors that correlate with insulin resistance (IR). How ADMA and inflammation factors interact and synchronize in the regulation of IR in liver remain to be elucidated. In this study, we systematically investigated whether ADMA is involved in IR using primary hepatocytes, if yes, by via which molecular mechanism. Our results demonstrated that ADMA inhibits insulin sensitivity in a concentration-dependent manner by activating inflammation factors tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 in primary hepatocytes. Further analysis revealed that mitogen-activated protein kinase (MAPK) signaling pathway act downstream of ADMA and inflammation factors, and inhibition of MAPK pathway rescued the IR. Furthermore, metformin effects has been found which could reverse ADMA-induced IR by suppressing MAPK signaling pathway. To our knowledge, we, for the first time, unveiled the complicated regulatory network and interactions among ADMA, inflammation, and MAPK signaling pathway, which advanced current research on the development and regulation of IR in liver. This study also certainly provided novel insights on comprehensive diagonistics roles of ADMA as a potential biomarker. 相似文献
Hemoglobin cross-linked with small molecular modifiers turns out to be more stable. Modifications of proteins with polyethylene glycol (PEG) have been proven to enlarge the molecular size of proteins, to prolong their retention time in the circulation as well as blunt immune reactions. In the present study, the optimal conditions for porcine hemoglobin (pHb) modification with bis (3, 5-dibromosalicyl) fumarate (DBBF) and PEG were evaluated. The derivative of DBBF cross-linked pHb (DBBF-pHb) showed improved oxygen affinity and the ability to resist the dissociation of the alpha2beta2 tetramer compared with the natural protein. DBBF-pHb was then bound to the activated PEG. The results indicated that the pHb modified with DBBF and PEG had more stable tetrameric conformation with a molecular weight of 107000. Their oxygen half-saturation pressure (P50) is around 3.33 kPa, which approximates the physiological P50 of human red blood cells. Both routine and reinforced immunizing methods were adopted to study the immunogenicity of modified products and the results showed that the products had very low immunogenicity evaluated by enzyme-linked immunoadsordent assay (ELISA). Somewhat beneficial effects were shown in the treatment of hemorrhagic shock where modified hemoglobin solutions were used as resuscitation fluids in the hemorrhagic shock Sprague-Dawley (SD) rats model. 相似文献
Influenza viruses are a major cause of morbidity and mortality around the world. More recently, a swine-origin influenza A (H1N1) virus that is spreading via human-to-human transmission has become a serious public concern. Although vaccination is the primary strategy for preventing infections, influenza antiviral drugs play an important role in a comprehensive approach to controlling illness and transmission. In addition, a search for influenza-inhibiting drugs is particularly important in the face of high rate of emergence of influenza strains resistant to several existing influenza antivirals.
Methods
We searched for novel anti-influenza inhibitors using a cell-based neutralization (inhibition of virus-induced cytopathic effect) assay. After screening 20,800 randomly selected compounds from a library from ChemDiv, Inc., we found that BPR1P0034 has sub-micromolar antiviral activity. The compound was resynthesized in five steps by conventional chemical techniques. Lead optimization and a structure-activity analysis were used to improve potency. Time-of-addition assay was performed to target an event in the virus life cycle.
Results
The 50% effective inhibitory concentration (IC50) of BPR1P0034 was 0.42 ± 0.11 μM, when measured with a plaque reduction assay. Viral protein and RNA synthesis of A/WSN/33 (H1N1) was inhibited by BPR1P0034 and the virus-induced cytopathic effects were thus significantly reduced. BPR1P0034 exhibited broad inhibition spectrum for influenza viruses but showed no antiviral effect for enteroviruses and echovirus 9. In a time-of-addition assay, in which the compound was added at different stages along the viral replication cycle (such as at adsorption or after adsorption), its antiviral activity was more efficient in cells treated with the test compound between 0 and 2 h, right after viral infection, implying that an early step of viral replication might be the target of the compound. These results suggest that BPR1P0034 targets the virus during viral uncoating or viral RNA importation into the nucleus.
Conclusions
To the best of our knowledge, BPR1P0034 is the first pyrazole-based anti-influenza compound ever identified and characterized from high throughput screening to show potent (sub-μM) antiviral activity. We conclude that BPR1P0034 has potential antiviral activity, which offers an opportunity for the development of a new anti-influenza virus agent. 相似文献