The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans

FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity. The purpose of this study is to characterize alcohol preference and related phenotypes in Fkbp5 knockout (KO) mice and to examine the role of FKBP5 in human alcohol consumption. The following experiments were performed to characterize Fkpb5 KO mice. (1) Fkbp5 KO and wild-type (WT) EtOH consumption was tested using a two-bottle choice paradigm; (2) The EtOH elimination rate was measured after intraperitoneal (IP) injection of 2.0 g/kg EtOH; (3) Blood alcohol concentration (BAC) was measured after 3 h limited access of alcohol; (4) Brain region expression of Fkbp5 was identified using LacZ staining; (5) Baseline corticosterone (CORT) was assessed. Additionally, two SNPs, rs1360780 (C/T) and rs3800373 (T/G), were selected to study the association of FKBP5 with alcohol consumption in humans. Participants were college students (n = 1162) from 21–26 years of age with Chinese, Korean or Caucasian ethnicity. The results, compared to WT mice, for KO mice exhibited an increase in alcohol consumption that was not due to differences in taste sensitivity or alcohol metabolism. Higher BAC was found in KO mice after 3 h of EtOH access. Fkbp5 was highly expressed in brain regions involved in the regulation of the stress response, such as the hippocampus, amygdala, dorsal raphe and locus coeruleus. Both genotypes exhibited similar basal levels of plasma corticosterone (CORT). Finally, single nucleotide polymorphisms (SNPs) in FKBP5 were found to be associated with alcohol drinking in humans. These results suggest that the association between FKBP5 and alcohol consumption is conserved in both mice and humans.     

口服制剂掩味方法的研究进展

综述了药物掩味方法的研究进展,对不同的技术进行了总结.开发药物制剂时,正确运用这些方法与技术,不影响药物的物理、化学稳定性和生物利用度.     

Intranasal Administration of Rotenone Reduces GABAergic Inhibition in the Mouse Insular Cortex Leading to Impairment of LTD and Conditioned Taste Aversion Memory

The pesticide rotenone inhibits mitochondrial complex I and is thought to cause neurological disorders such as Parkinson’s disease and cognitive disorders. However, little is known about the effects of rotenone on conditioned taste aversion memory. In the present study, we investigated whether intranasal administration of rotenone affects conditioned taste aversion memory in mice. We also examined how the intranasal administration of rotenone modulates synaptic transmission and plasticity in layer V pyramidal neurons of the mouse insular cortex that is critical for conditioned taste aversion memory. We found that the intranasal administration of rotenone impaired conditioned taste aversion memory to bitter taste. Regarding its cellular mechanisms, long-term depression (LTD) but not long-term potentiation (LTP) was impaired in rotenone-treated mice. Furthermore, spontaneous inhibitory synaptic currents and tonic GABA currents were decreased in layer V pyramidal neurons of rotenone-treated mice compared to the control mice. The impaired LTD observed in pyramidal neurons of rotenone-treated mice was restored by a GABA_A receptor agonist muscimol. These results suggest that intranasal administration of rotenone decreases GABAergic synaptic transmission in layer V pyramidal neurons of the mouse insular cortex, the result of which leads to impairment of LTD and conditioned taste aversion memory.     

饮用水中嗅味物质的检测技术研究进展

随着近年来世界范围内饮用水嗅味事件的不断发生,水中嗅味问题成为人们关注的热点之一。从感官检测法、仪器检测法和其它检测方法三个方面,全面阐述了国内外嗅味物质的检测技术研究进展,介绍了发达国家及国内饮用水水质标准中对嗅味的限定,指出了我国与发达国家在饮用水嗅味研究方面的差异及今后发展的方向。     

猪牛鸡肉酶解液中游离氨基酸及呈味特性的对比分析

为对比分析猪肉、牛肉与鸡肉酶解液中游离氨基酸的组成及含量,采用氨基酸自动分析仪分析检测猪肉、牛肉与鸡肉酶解液中的游离氨基酸,通过计算味道强度值(TAV)确定各游离氨基酸对猪肉、牛肉与鸡肉酶解液滋味的贡献率。 结果表明,鸡肉酶解液中鲜味和甜味氨基酸质量分数以及味道强度值均大于猪肉和牛肉酶解液,3种酶解液中味道强度值最大的均为组氨酸,其次为苯丙氨酸,均为呈苦味氨基酸,可见猪、牛、鸡肉酶解液整体滋味以苦味为主。     

Selective Inhibition of PDE4B Reduces Binge Drinking in Two C57BL/6 Substrains

Cyclic AMP (cAMP)-dependent signaling is highly implicated in the pathophysiology of alcohol use disorder (AUD), with evidence supporting the efficacy of inhibiting the cAMP hydrolyzing enzyme phosphodiesterase 4 (PDE4) as a therapeutic strategy for drinking reduction. Off-target emetic effects associated with non-selective PDE4 inhibitors has prompted the development of selective PDE4 isozyme inhibitors for treating neuropsychiatric conditions. Herein, we examined the effect of a selective PDE4B inhibitor A33 (0–1.0 mg/kg) on alcohol drinking in both female and male mice from two genetically distinct C57BL/6 substrains. Under two different binge-drinking procedures, A33 pretreatment reduced alcohol intake in male and female mice of both substrains. In both drinking studies, there was no evidence for carry-over effects the next day; however, we did observe some sign of tolerance to A33’s effect on alcohol intake upon repeated, intermittent, treatment (5 injections of 1.0 mg/kg, every other day). Pretreatment with 1.0 mg/kg of A33 augmented sucrose intake by C57BL/6NJ, but not C57BL/6J, mice. In mice with a prior history of A33 pretreatment during alcohol-drinking, A33 (1.0 mg/kg) did not alter spontaneous locomotor activity or basal motor coordination, nor did it alter alcohol’s effects on motor activity, coordination or sedation. In a distinct cohort of alcohol-naïve mice, acute pretreatment with 1.0 mg/kg of A33 did not alter motor performance on a rotarod and reduced sensitivity to the acute intoxicating effects of alcohol. These data provide the first evidence that selective PDE4B inhibition is an effective strategy for reducing excessive alcohol intake in murine models of binge drinking, with minimal off-target effects. Despite reducing sensitivity to acute alcohol intoxication, PDE4B inhibition reduces binge alcohol drinking, without influencing behavioral sensitivity to alcohol in alcohol-experienced mice. Furthermore, A33 is equally effective in males and females and exerts a quantitatively similar reduction in alcohol intake in mice with a genetic predisposition for high versus moderate alcohol preference. Such findings further support the safety and potential clinical utility of targeting PDE4 for treating AUD.     

Molecular Mechanisms of Taste Recognition: Considerations about the Role of Saliva

The gustatory system plays a critical role in determining food preferences and food intake, in addition to nutritive, energy and electrolyte balance. Fine tuning of the gustatory system is also crucial in this respect. The exact mechanisms that fine tune taste sensitivity are as of yet poorly defined, but it is clear that various effects of saliva on taste recognition are also involved. Specifically those metabolic polypeptides present in the saliva that were classically considered to be gut and appetite hormones (i.e., leptin, ghrelin, insulin, neuropeptide Y, peptide YY) were considered to play a pivotal role. Besides these, data clearly indicate the major role of several other salivary proteins, such as salivary carbonic anhydrase (gustin), proline-rich proteins, cystatins, alpha-amylases, histatins, salivary albumin and mucins. Other proteins like glucagon-like peptide-1, salivary immunoglobulin-A, zinc-α-2-glycoprotein, salivary lactoperoxidase, salivary prolactin-inducible protein and salivary molecular chaperone HSP70/HSPAs were also expected to play an important role. Furthermore, factors including salivary flow rate, buffer capacity and ionic composition of saliva should also be considered. In this paper, the current state of research related to the above and the overall emerging field of taste-related salivary research alongside basic principles of taste perception is reviewed.     

饮用水中的高氯酸盐

本文参考了国内外大量关于饮用水中高氯酸盐对人体的毒理作用,在环境中的迁移转化特性,降解方法等方面的研究,总结和分析了研究现状,阐述了在我国开展相关研究的重要意义,提出有待深入研究的领域。     

ABCG5/G8 Deficiency in Mice Reduces Dietary Triacylglycerol and Cholesterol Transport into the Lymph

The adenosine triphosphate‐binding cassette (ABC) transporter G5/G8 is critical in protecting the body from accumulating dietary plant sterols. Expressed in the liver and small intestine, it transports plant sterols into the biliary and intestinal lumens, thus promoting their excretion. The extent to which G5/G8 regulates cholesterol absorption remains unclear. G5/G8 is also implicated in reducing the absorption of dietary triacylglycerols (TAG) by unknown mechanisms. We hypothesized that G5/G8 suppresses the production of chylomicrons, and its deficiency would enhance the absorption of both dietary TAG and cholesterol. The aim of this study was to investigate the effects of G5/G8 deficiency on lipid uptake and secretion into the lymph under steady‐state conditions. Surprisingly, compared with wild‐type mice (WT) (n = 9), G5/G8 KO (n = 13) lymph fistula mice given a continuous intraduodenal infusion of [3H]‐TAG and [14C]‐cholesterol showed a significant (P < 0.05) reduction in lymphatic transport of both [³H]‐TAG and [¹⁴C]‐cholesterol, concomitant with a significant (P < 0.05) increase of [³H]‐TAG and [¹⁴C]‐cholesterol accumulated in the intestinal lumen. There was no difference in the total amount of radiolabeled lipids retained in the intestinal mucosa between the two groups. G5/G8 KO mice given a bolus of TAG showed reduced intestinal TAG secretion compared with WT, suggesting an independent role for G5/G8 in facilitating intestinal TAG transport. Our data demonstrate that G5/G8 deficiency reduces the uptake and secretion of both dietary TAG and cholesterol by the intestine, suggesting a novel role for the sterol transporter in the formation and secretion of chylomicrons.     

饮用水中硝酸盐的去除

作为重要的饮用水源,地下水中硝酸盐的污染日趋严重,硝酸盐对人体健康有严重的危害。物化方法(离子交换、电渗析、反渗透等)、生物反硝化、化学反硝化等工艺都可不同程度地去除作为饮用水的地下水中的硝酸盐,这些方法各有优缺点。本文综述了地下水中硝酸盐去除方法的应用和研究现状,并对其发展趋势做了简单的讨论。     

Calcitriol Reduces the Inflammation,Endothelial Damage and Oxidative Stress in AKI Caused by Cisplatin

Cisplatin treatment is one of the most commonly used treatments for patients with cancer. However, thirty percent of patients treated with cisplatin develop acute kidney injury (AKI). Several studies have demonstrated the effect of bioactive vitamin D or calcitriol on the inflammatory process and endothelial injury, essential events that contribute to changes in renal function and structure caused by cisplatin (CP). This study explored the effects of calcitriol administration on proximal tubular injury, oxidative stress, inflammation and vascular injury observed in CP-induced AKI. Male Wistar Hannover rats were pretreated with calcitriol (6 ng/day) or vehicle (0.9% NaCl). The treatment started two weeks before i.p. administration of CP or saline and was maintained for another five days after the injections. On the fifth day after the injections, urine, plasma and renal tissue samples were collected to evaluate renal function and structure. The animals of the CP group had increased plasma levels of creatinine and of fractional sodium excretion and decreased glomerular filtration rates. These changes were associated with intense tubular injury, endothelial damage, reductions in antioxidant enzymes and an inflammatory process observed in the renal outer medulla of the animals from this group. These changes were attenuated by treatment with calcitriol, which reduced the inflammation and increased the expression of vascular regeneration markers and antioxidant enzymes.     

饮用水中草甘膦的离子色谱法测定

目的：建立一次进样同时测定饮用水中溴酸盐、草甘膦的离子色谱测定法。方法：选用DIONEX ICS-2000型离子色谱仪,用离子色谱法测定饮用水氟离子、溴酸盐、氯离子、溴离子、硝酸盐氮、硫酸盐、磷酸盐和草甘膦等离子,分离效果理想、灵敏度较高。进样量100μL。结果溴酸盐、溴离子、磷酸盐、草甘膦的检出限分别为：4.0μg/L、4.0μg/L、5.2μg/L、4.4μg/L;标准偏差〈5%;样品加标回收率在88.0%~104.0%之间。结论：该方法操作简单,分析快速,灵敏度高,重现性好,能够准确检测水中草甘膦含量。     

A Review of the Evidence Supporting the Taste of Non-esterified Fatty Acids in Humans

Dietary fats contribute to the flavor of foods by multiple mechanisms. A role for their taste has only recently gained credence. Current evidence indicates non‐esterified fatty acids (NEFA) are the effective stimuli for the taste component. CD36 and GPR120 are putative receptors, but may not fully account for the totality of the range of sensations elicited by fatty acids. The sensory quality of long‐chain NEFA is not adequately characterized by commonly accepted taste primary qualities and has been termed oleogustus. There is marked individual variability in sensitivity to the taste of NEFA prompting hypotheses of genetic and environmental determinants. Though an association with BMI has been proposed, the preponderance of evidence is not supportive. The importance of oleogustus has not been fully established, but likely contributes to flavor, which influences food choice as well as lipid metabolism and chronic disease risk. A better understanding of oleogustus may provide insights useful for product formulation.     

Berbamine Reduces Chloroquine-Induced Itch in Mice through Inhibition of MrgprX1

Chloroquine (CQ) is an antimalaria drug that has been widely used for decades. However, CQ-induced pruritus remains one of the major obstacles in CQ treatment for uncomplicated malaria. Recent studies have revealed that MrgprX1 plays an essential role in CQ-induced itch. To date, a few MrgprX1 antagonists have been discovered, but they are clinically unavailable or lack selectivity. Here, a cell-based high-throughput screening was performed to identify novel antagonists of MrgprX1, and the screening of 2543 compounds revealed two novel MrgprX1 inhibitors, berbamine and closantel. Notably, berbamine potently inhibited CQ-mediated MrgprX1 activation (IC₅₀ = 1.6 μM) but did not alter the activity of other pruritogenic GPCRs. In addition, berbamine suppressed the CQ-mediated phosphorylation of ERK1/2. Interestingly, CQ-induced pruritus was significantly reduced by berbamine in a dose-dependent manner, but berbamine had no effect on histamine-induced, protease-activated receptors 2-activating peptide-induced, and deoxycholic acid-induced itch in mice. These results suggest that berbamine is a novel, potent, and selective antagonist of MrgprX1 and may be a potential drug candidate for the development of therapeutic agents to treat CQ-induced pruritus.     

Formation of Ketoacids in Ozonated Drinking Water

Three ketoacids; glyoxylic acid, pyruvic acid and ketomalonic acid, were identified in ozonated drinking waters and fulvic acid solutions using gas chromatography-mass spectrometry. It was found that the concentrations of ketoacids were much higher than those of aldehydes in ozonated waters. The significance of ketoacids in finished drinking waters is discussed.     

活性炭在饮用水处理中的应用(一)

随着人们对生活饮用水水质要求的提高 ,活性炭在饮用水处理中的应用 ,受到广泛的重视。本文主要就活性炭在饮用水处理中的应用作些介绍。1　活性炭的吸附特性1 1活性炭的特性活性炭是用含炭为主的物质作原料 ,经高温炭化和活化制得的疏水性吸附剂 ,因此它具有良好的吸附性及稳定化学性能 ,可以耐强酸及强碱 ,能经受水浸、高温、高压的作用 ,不易破碎 ,便于在工业上使用。1 .1 .1细孔构造和细孔分布活性炭的细孔是在原料进行活化过程中 ,含炭有机物去除后使基本晶格间生成孔隙 ,形成很多的各种形状和大小的细孔 ,孔壁的总面积即为表面积 ,每…     

饮用水处理中的臭氧化技术

臭氧化技术是一种新型的消毒技术,与传统的消毒技术相比,该技术具有氧化能力强、杀菌效果好、接触时间短、受水中的pH值和氨氮影响小等优点。本文简述了臭氧的性质以及自来水的臭氧消毒工艺,并综述了臭氧与其他技术联用在饮用水处理中的应用,说明臭氧化技术存水处理中具有广泛的应用前景。     

Mechanisms of Systolic Cardiac Dysfunction in PP2A,PP5 and PP2AxPP5 Double Transgenic Mice

As part of our ongoing studies on the potential pathophysiological role of serine/threonine phosphatases (PP) in the mammalian heart, we have generated transgenic mice with cardiac muscle cell-specific overexpression of PP2Acα (PP2A) and PP5 (PP5). For further studies we crossbred PP2A and PP5 mice to obtain PP2AxPP5 double transgenic mice (PP2AxPP5, DT) and compared them with littermate wild-type mice (WT) serving as a control. The mortality of DT mice was greatly enhanced vs. other genotypes. Cardiac fibrosis was noted histologically and mRNA levels of collagen 1α, collagen 3α and fibronectin 1 were augmented in DT. DT and PP2A mice exhibited an increase in relative heart weight. The ejection fraction (EF) was reduced in PP2A and DT but while the EF of PP2A was nearly normalized after β-adrenergic stimulation by isoproterenol, it was almost unchanged in DT. Moreover, left atrial preparations from DT were less sensitive to isoproterenol treatment both under normoxic conditions and after hypoxia. In addition, levels of the hypertrophy markers atrial natriuretic peptide and B-type natriuretic peptide as well as the inflammation markers interleukin 6 and nuclear factor kappa B were increased in DT. PP2A enzyme activity was enhanced in PP2A vs. WT but similar to DT. This was accompanied by a reduced phosphorylation state of phospholamban at serine-16. Fittingly, the relaxation times in left atria from DT were prolonged. In summary, cardiac co-overexpression of PP2A and PP5 were detrimental to animal survival and cardiac function, and the mechanism may involve dephosphorylation of important regulatory proteins but also fibrosis and inflammation.     

Increase in Anticancer Drug-Induced Toxicity by Fisetin in Lung Adenocarcinoma A549 Spheroid Cells Mediated by the Reduction of Claudin-2 Expression

Claudin-2 (CLDN2), a component of tight junction, is involved in the reduction of anticancer drug-induced toxicity in spheroids of A549 cells derived from human lung adenocarcinoma. Fisetin, a dietary flavonoid, inhibits cancer cell growth, but its effect on chemosensitivity in spheroids is unknown. Here, we found that fisetin (20 μM) decreases the protein level of CLDN2 to 22.3%. Therefore, the expression mechanisms were investigated by real-time polymerase chain reaction and Western blotting. Spheroids were formed in round-bottom plates, and anticancer drug-induced toxicity was measured by ATP content. Fisetin decreased the phosphorylated-Akt level, and CLDN2 expression was decreased by a phosphatidylinositol 3-kinase (PI3K) inhibitor, suggesting the inhibition of PI3K/Akt signal is involved in the reduction of CLDN2 expression. Hypoxia level, one of the hallmarks of tumor microenvironment, was reduced by fisetin. Although fisetin did not change hypoxia inducible factor-1α level, it decreased the protein level of nuclear factor erythroid 2-related factor 2, a stress response factor, by 25.4% in the spheroids. The toxicity of doxorubicin (20 μM) was enhanced by fisetin from 62.8% to 40.9%, which was rescued by CLDN2 overexpression (51.7%). These results suggest that fisetin can enhance anticancer drug toxicity in A549 spheroids mediated by the reduction of CLDN2 expression.     

饮用水中高氯酸盐的检测技术进展

高氯酸盐是对人体有害的物质。近十年来,国外学者已经对其在饮用水中的来源、存在、检测、安全阈值及去除技术开展了大量的研究与调查。文章参考大量文献,较详细地介绍了国内外学者采用离子色谱法和离子色谱-质谱联用技术对饮用水中高氯酸盐进行检测的研究进展,同时阐述了饮用水中高氯酸盐标准制订的现状,以及在中国开展此方面研究的意义和内容。