Evidence for Renal Tubular Resorption of Collagen Fragments from Immunostaining of Rat Kidney with Antibodies Specific for Denatured Type I Collagen

Antibodies to rat collagens I and III were raised in sheep. The antisera to collagen I were separated by affinity chromatography into components specific for either native or denatured forms. Immunolabelling of rat kidney sections with antibodies to native collagen I showed staining only of the interstitial matrix. By contrast, antibodies to denatured collagen I revealed the presence of immunoreactive material primarily in the upper part of the proximal tubules, detected in both fixed and cryostat sections. In fixed material, the granular appearance of staining in the region of the brush border was shown to be distinct from the protein droplets counterstained by toluidine blue. Collagen III antibodies stained the interstitial matrix in a similar pattern to that for native collagen I, but no proximal tubule staining was observed despite the fact that antibodies to denatured collagen III were shown to be present. No material reactive with denatured collagen I antibodies was detected in urine or serum by an inhibition ELISA technique. The results are discussed in terms of renal tubular resorption of collagen degradation products.     

Comparison of the Absorption and Distribution of Cadmium via Cadmium Chloride and Cadmium-contaminated Rice in Rats

正Cadmium(Cd) is considered a toxic element of which food is the major source of acquisition,which can lead to diseases such as renal dysfunction,cancer and osteoporosis~([1]).Cd is classified as a group I carcinogen by the International Agency for Research on Cancer~([2]).The results of dietary exposure to cadmium in Europe in 2012 showed that the contribution rate from the broad food categories     

Taurine improves neuron injuries and cognitive impairment in a mouse Parkinson’s disease model through inhibition of microglial activation

Clinical and experimental findings support the view that activation of hippocampus microglia through NADPH oxidase contributes to cognitive impairment in Parkinson's disease (PD). Taurine, an antioxidant, displays an exclusive physical property on brain function, such as learning and memory. To date, the role of taurine in improving cognitive impairment in PD is not fully uncovered. Hence, we evaluated the protective effect of taurine on cognitive ability and explored the related mechanism in the model built by paraquat and maneb (P + M)-induced PD mice. Then the ability of learning and memory was observed by Morris water maze, neuron loss was evaluated by immunohistochemistry in hippocampus, the level of postsynaptic density 95 (PSD95) and microglia activation was assessed by immunostaining, the molecules (gp91^phox, p47^phox, mac1, p-Src/Src and p-Erk/Erk) were examined by western blot. The results showed that taurine could alleviate the impairments in learning and memory induced by P + M injection in mice (decreased escape latency on day 4, P < 0.01; decreased swimming distance on day 4, P < 0.05; increased percent time in target quadrant, P < 0.05), corresponding with activation of microglia (decreased IBa-1 density, P < 0.001; decreased the protein expression of p47^phox, P < 0.05; decreased protein expression of gp91^phox, P < 0.01; decreased p-Src/Src, P < 0.01; decreased p-Erk/Erk, P < 0.01; decreased mac 1, P < 0.01), decreased neuron loss (increased number of NeurN⁺ neuron, P < 0.001; increased protein expression of NeruN, P < 0.01; decreased protein expression of caspase 3, P < 0.01) and increased PSD95 level in hippocampus (P < 0.01). The results indicated that mac1 and Src-Erk signaling was involved in increased NADPH oxidase expression in hippocampus microglia of P + M mice, and taurine could improve injuries in learning and memory through mac1 reduction. The new findings in mac1 triggering hippocampal microglia NADPH oxidase through Src/Erk pathway of the present study might provide a therapy target for PD.     

Cognitive effects of the GSK-3 inhibitor “lithium” in LPS/chronic mild stress rat model of depression: Hippocampal and cortical neuroinflammation and tauopathy

Low-dose repeated lipopolysaccharide pre-challenge followed by chronic mild stress (LPS/CMS) protocol has been introduced as a rodent model of depression combining the roles of immune activation and chronic psychological stress. However, the impact of this paradigm on cognitive functioning has not been investigated hitherto.MethodsThis study evaluated LPS/CMS-induced cognitive effects and the role of glycogen synthase kinase-3β (GSK-3β) activation with subsequent neuroinflammation and pathological tau deposition in the pathogenesis of these effects using lithium (Li) as a tool for GSK-3 inhibition.ResultsLPS pre-challenge reduced CMS-induced neuroinflammation, depressive-like behavior and cognitive inflexibility. It also improved spatial learning but increased GSK-3β expression and exaggerated hyperphosphorylated tau accumulation in hippocampus and prefrontal cortex. Li ameliorated CMS and LPS/CMS-induced depressive and cognitive deficits, reduced GSK-3β over-expression and tau hyperphosphorylation, impeded neuroinflammation and enhanced neuronal survival.ConclusionThis study draws attention to LPS/CMS-triggered cognitive changes and highlights how prior low-dose immune challenge could develop an adaptive capacity to buffer inflammatory damage and maintain the cognitive abilities necessary to withstand threats. This work also underscores the favorable effect of Li (as a GSK-3β inhibitor) in impeding exaggerated tauopathy and neuroinflammation, rescuing neuronal survival and preserving cognitive functions. Yet, further in-depth studies utilizing different low-dose LPS challenge schedules are needed to elucidate the complex interactions between immune activation and chronic stress exposure.     

13C-caffeine breath test identifies single nucleotide polymorphisms associated with caffeine metabolism

We performed a caffeine (N-3-methyl-¹³C) breath test (CafeBT) to determine whether it can be employed to identify caffeine metabolism-associated single nucleotide polymorphisms. The study included 130 healthy adults (mean age: 21.9 years). Saliva was collected using an Oragene®•DNA saliva collection kit. Breath samples were collected from the subjects. The subjects orally ingested 100 mg ¹³C-caffeine dissolved in distilled water. Subsequently, breath samples were collected in bags every 10 min for a total of 90 min. An analysis of ¹³CO₂ in the expired breath was performed by infrared spectroscopy, and the sum of Δ¹³CO₂ over 90 min (S^90m) was calculated. DNA from saliva samples was genotyped using TaqMan® SNP Genotyping for the following genes: cytochrome P4501A2: rs762551, rs2472297, aryl-hydrocarbon receptor (rs4410790), and adenosine A_2A receptor (rs5751876). All subjects had the genotype CC in rs2472297 alleles. No significant difference was observed in S^90m among the genotypes of rs762551 and rs5751876; however, a significant difference was found in S^90m among the genotypes of rs4410790 (C > T). Our findings suggest that the N-3 demethylation of caffeine is dependent on the rs4410790 allele and that CafeBT may be used to determine rs4410790 genotypes.     

Extrapolation for a pharmacokinetic model for acetaminophen from adults to neonates: A Latin Hypercube Sampling analysis

Physiological and drug-specific parameters need to be adjusted when extrapolating a pharmacokinetic (PK) model from adults to neonates, so as to reproduce the time profiles of the studied drug(s) consistent with clinical, in vivo data or in vitro cell line measurements. In this paper we present a parameter analysis method, i.e. the Latin Hypercube Sampling (LHS) method for an acetaminophen (APAP) PK model. The original model consists of two compartments (the blood and the urine) with Michaelis-Menten kinetic parameters determined for APAP and its metabolites. The physiological parameters are scaled through allometric laws from adults to neonates, and APAP-specific parameters are adjusted for enzymatic maturational changes. The LHS method is used to statistically investigate the interplay between these parameters. The results for the extrapolated APAP model are consistent with published APAP PK data in neonates. We found the sulphation clearance parameter played a crucial role in the neonatal PK model, but its influence was weakened if the volume of distribution parameters were included. We suggest that this kind of in silico experiment could be valuable as the first step in PK model extrapolation between different ages.     

中国成年人吸烟与心血管疾病发病风险的关联及其性别差异分析

目的 分析中国成年人吸烟与不同心血管疾病发病风险的关联及其性别差异。方法 研究对象来自中国慢性病前瞻性研究,基线调查开展于2004年6月至2008年7月,剔除基线自报患有恶性肿瘤、冠心病、脑卒中的个体,最终纳入487 373名研究对象。随访人年数的计算从研究对象完成基线调查时开始,至最早出现以下任一事件的时间为止：心血管疾病（CVD）发病、死亡、失访或2015年12月31日。使用Cox比例风险模型计算吸烟行为特征和心血管疾病发病风险的关联。结果 研究对象平均随访8.9年。随访期间新发缺血性心脏病33 947人,急性冠心病事件6 048人,脑内出血7 794人,脑梗死31 722人。男性吸烟率（67.9%）远高于女性（2.7%）。与非吸烟者相比,吸烟能增加各类CVD结局的发病风险,风险效应值HR值 （95%CI）由大到小依次为急性冠心病事件1.54 （1.43～1.66）、缺血性心脏病1.28 （1.24～1.32）、脑梗死1.18 （1.14～1.22）、脑内出血1.07 （1.00～1.15）。当前吸烟者中,每天吸烟量和开始吸烟年龄与急性冠心病事件风险间的关联存在性别差异（性别交互作用P值分别为0.006、0.011）,主要表现为女性吸烟者风险高于男性。每天吸烟量和开始吸烟年龄与缺血性心脏病、脑内出血和脑梗死之间的关联均未见性别差异（性别交互作用P>0.05）。结论 吸烟能够增加各类CVD的发病风险,而女性吸烟者发生急性冠心病事件的风险远高于男性。     

中国成年人中心性肥胖与缺血性心脏病发病风险的前瞻性研究

目的 分析中心性肥胖评价指标腰围与发生缺血性心脏病（IHD）、急性冠心病事件（MCE）以及死于IHD风险的关联。方法 研究对象来自中国慢性病前瞻性研究,基线调查开展于2004年6月至2008年7月,剔除基线时患有冠心病、脑卒中、恶性肿瘤、慢性阻塞性肺疾病和糖尿病的个体,共纳入428 595人进行分析。统计学分析采用Cox比例风险模型。结果 研究人群平均随访9.1年,累积随访3 803 637人年,期间新发IHD 26 900例,MCE 4 320例,IHD死亡2 787例。调整了多种混杂因素和BMI后,与非中心性肥胖者（男性<85.0 cm,女性<80.0 cm）相比,中心性肥胖前期者（男性85.0～89.9 cm,女性80.0～84.9 cm）发生IHD、MCE和死于IHD的风险HR值（95% CI）分别为1.13（1.09～1.17）、1.15（1.05～1.26）、1.11（0.98～1.24）,中心性肥胖者（男性≥90.0 cm,女性≥85.0 cm）对应的风险效应值更高,HR值（95% CI）分别为1.29（1.24～1.34）、1.30（1.17～1.44）、1.32（1.16～1.51）。按BMI分层,即使在BMI正常的人群中,与非中心性肥胖者相比,中心性肥胖前期和中心性肥胖人群发生IHD、MCE或死于IHD的风险也会增加。结论 中心性肥胖是IHD风险独立的危险因素,IHD风险随中心性肥胖测量指标腰围的增加而增加。