高密度脂蛋白与载脂蛋白A1、低密度脂蛋白与载脂蛋白B的相关性分析

目的对高密度脂蛋白与载脂蛋白A1、低密度脂蛋白与载脂蛋白B之间的相关性进行分析探讨。方法随机抽取在2010年1月～2012年5月间在本院进行体检的500名受检者,对其进行血清高密度脂蛋白(HDL-C)、低密度脂蛋白(LDL-C)、载脂蛋白A1(apoA1)、载脂蛋白B(apoB)测定,并按照三酰甘油(TG)水平的不同进行分组,分析HDL-C与apoA1、LDL-C与apoB之间的相关性。结果在TG水平小于10.00mmol/L时,HDL-C与apoA1、LDL-C与apoB之间存在明显的相关性,在TG水平大于10.00mmol/L时,HDL-C与apoA1、LDL-C与apoB不具有明显的相关性。结论在一定条件下,HDL-C与apoA1、LDL-C与apoB存在比较明显的相关性,这将对临床诊断与治疗评价产生重要意义,值得关注。     

Doxorubicin-Bound Albumin Nanoparticles Containing a TRAIL Protein for Targeted Treatment of Colon Cancer

Purpose

We developed a new nanoparticle formulation comprised of human serum albumin (HSA) for co-delivery of doxorubicin (Dox) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with the goal of apoptotic synergy in the treatment of colon cancer.

Methods

TRAIL (0.2, 0.4, 1.0%)- and Dox-loaded HSA nanoparticles (TRAIL/Dox HSA NPs) were prepared by using the nab^TM technology. Morphological and physicochemical characterizations were investigated by dynamic light scattering and transmission electron microscopy. Synergistic cytotoxicity, apoptotic activity, and potential penetration into mass tumor were determined in HCT116 cell-based systems. Furthermore, antitumor efficacy and tumor targeting were also investigated.

Results

TRAIL/Dox HSA NPs were uniformly spherical with sizes of 60?~?120 nm. The encapsulation efficacy of Dox and TRAIL was 68.9–77.2% and 80.4–86.0%, respectively. TRAIL 1.0%/Dox HSA NPs displayed the best inhibition of HCT116 colon cancer cells; inhibition was 6 times higher than achieved with Dox HSA NPs. The TRAIL 1.0%/Dox HSA NPs formulation was studied further. Flow cytometry analysis and TUNEL assay revealed that TRAIL 1.0%/Dox HSA NPs had markedly greater apoptotic activity than Dox HSA NPs. In HCT116 tumor-bearing BALB/c nu/nu mice, TRAIL 1.0%/Dox HSA NPs had significantly higher antitumor efficacy than Dox HSA NPs (tumor volume; 933.4 mm³ vs. 3183.7 mm³, respectively). TRAIL 1.0%/Dox HSA NPs penetrated deeply into tumor masses in a HCT116 spheroid model and localized in tumor sites after tail vein injection.

Conclusions

Data indicate that TRAIL 1.0%/Dox HSA NPs offer advantages of co-delivery of Dox and TRAIL in tumors, with potential synergistic apoptosis-based anticancer therapy.

     

Strenuous exercise aggravates MDMA-induced skeletal muscle damage in mice

The aim of this study was to investigate the influence of ecstasy (MDMA) administration on body temperature and soleus muscle histology in exercised and non-exercised mice. Charles-River mice were distributed into four groups: Control (C), exercise (EX), MDMA treated (M), and M + EX. The treated animals received an i.p. injection (10 mg/kg) of MDMA (saline for C and EX), and the exercise consisted of a 90 min level run at a velocity of 900 m/h, immediately after the MDMA or saline administration. Body temperature was recorded every 30 min via subcutaneous implanted transponder. Animals were sacrificed 1.5, 25.5, and 49.5 h after i.p. injection and the soleus muscles were removed and processed for light and electron microscopy. The MDMA-treated animals showed a significant increase in body temperature (similar in M and M + EX groups), reaching the peak 90 min after i.p. administration; their temperature remained higher than control for more than 5 h. The EX group evidenced a similar and parallel, yet lower temperature increase during exercise and recovery. Morphological signs of damage were rarely encountered in the EX group; they were more pronounced in M group and even aggravated in M + EX group. In conclusion, MDMA and exercise per se increased body temperature but in conjunction did not have a cumulated effect. However, ecstasy and concomitant physical activity might severely accumulate with regard to skeletal muscle toxicity and may lead to rhabdomyolysis.     

Mutation of the DRY motif reveals different structural requirements for the CC chemokine receptor 5-mediated signaling and receptor endocytosis

CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor that governs migration of leukocytes and serves as a coreceptor for the R5 tropic strains of human immunodeficiency virus (HIV). CCR5-mediated signaling in response to CC chemokines relies on G protein activation. Desensitization, which rapidly turns off G protein-dependent signaling, involves phosphorylation of CCR5 that promotes interaction of the receptor with beta-arrestins for endocytosis. Whether coupling to G proteins, desensitization, and endocytosis of CCR5 require the same structural determinants remains a matter of investigation. Here, we show that CCR5 displayed agonist-independent coupling to G proteins. This constitutive activity of the receptor was abrogated by TAK779 (N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride), a nonpeptidic CCR5 ligand that inhibits HIV infection and was found to depend on the integrity of the Asp-Arg-Tyr (DRY) motif. Changing Arg-126 by the neutral residue Asn (R126N-CCR5 mutant) abolished CCR5-mediated activation of G proteins, either constitutively or in response to agonists. In contrast, R126N-CCR5 not only retained agonist-promoted phosphorylation and beta-arrestin-dependent endocytosis but also displayed a higher basal phosphorylation than wild-type CCR5. Expression of beta-arrestin in R126N-CCR5-expressing cells resulted in receptor down-regulation, thereby suggesting that R126N-CCR5 spontaneously interacts with beta-arrestins. However, although expression of beta-arrestin favored wild-type CCR5-mediated chemotaxis, it failed to promote migration of cells expressing R126N-CCR5. Overall, these data indicate that structural requirements for CCR5-mediated activation of G proteins, albeit not involved in receptor desensitization and internalization, are needed for beta-arrestin-mediated chemotaxis. These results have implications for how distinct biological responses of CCR5 might rely on a different set of receptor conformations.     

Assessment of the genotoxic and carcinogenic potentials of 3‐aminothiophene derivatives using in vitro and in silico methodologies

Thiophene derivatives, a class of compounds widely used in products such as pharmaceuticals, agrochemicals or dyestuffs, represent chemicals of concern. Indeed, the thiophene ring is often considered as a structural moiety that may be involved in toxic effects in humans. We primarily focus on the genotoxic/mutagenic and carcinogenic potentials of the methyl 3‐amino‐4‐methylthiophene‐2‐carboxylate (1), a precursor of the articaine local anesthetic (4) which falls within the scope of the European REACH (Registration, Evaluation, Authorisation and restriction of CHemicals) legislation. To discern some structure–toxicity relationships, we also studied two related compounds, namely the 3‐amino 4‐methylthiophene (2) and the 2‐acetyl 4‐chlorothiophene (3). Techniques employed to assess mutagenic and DNA‐damaging effects involved the Salmonella mutagenicity assay (or Ames test) and the single‐cell gel electrophoresis assay (or Comet assay). In the range of tested doses, none of these derivatives led to a positive response in the Ames tests and DNA damage was only observed in the Comet assay after high concentration exposure of 2. The study of their carcinogenic potential using the in vitro SHE (Syrian Hamster Embryo) cell transformation assay (CTA) highlighted the activity of compound 2. A combination of experimental data with in silico predictions of the reactivity of thiophene derivatives towards cytochrome P450 (CYP450), enabled us to hypothesize possible pathways leading to these toxicological profiles. Copyright © 2013 John Wiley & Sons, Ltd.     

Brain activation by short-term nicotine exposure in anesthetized wild-type and beta2-nicotinic receptors knockout mice: a BOLD fMRI study

Rationale

The behavioral effects of nicotine and the role of the beta2-containing nicotinic receptors in these behaviors are well documented. However, the behaviors altered by nicotine rely on the functioning on multiple brain circuits where the high-affinity beta2-containing nicotinic receptors (β2*nAChRs) are located.

Objectives

We intend to see which brain circuits are activated when nicotine is given in animals naïve for nicotine and whether the β2*nAChRs are needed for its activation of the blood oxygen level dependent (BOLD) signal in all brain areas.

Materials and methods

We used functional magnetic resonance imaging (fMRI) to measure the brain activation evoked by nicotine (1 mg/kg delivered at a slow rate for 45 min) in anesthetized C57BL/6J mice and beta2 knockout (KO) mice.

Results

Acute nicotine injection results in a significant increased activation in anterior frontal, motor, and somatosensory cortices and in the ventral tegmental area and the substantia nigra. Anesthetized mice receiving no nicotine injection exhibited a major decreased activation in all cortical and subcortical structures, likely due to prolonged anesthesia. At a global level, beta2 KO mice were not rescued from the globally declining BOLD signal. However, nicotine still activated regions of a meso-cortico-limbic circuit likely via alpha7 nicotinic receptors.

Conclusions

Acute nicotine exposure compensates for the drop in brain activation due to anesthesia through the meso-cortico-limbic network via the action of nicotine on β2*nAChRs. The developed fMRI method is suitable for comparing responses in wild-type and mutant mice.

     

Comparative studies of the neuro-excitatory behavioural effects of morphine-3-glucuronide and dynorphin A(2-17) following spinal and supraspinal routes of administration

Morphine-3-glucuronide (M3G) administered centrally produces dose-dependent neuro-excitatory behaviours in rodents via a predominantly non-opioid mechanism. The endogenous opioid peptide, dynorphin A (Dyn A) (1-17), is rapidly cleaved in vivo to the relatively more stable fragment Dyn A(2-17) which also produces excitatory behaviours in rodents via a non-opioid mechanism. This study investigated the possible contribution of Dyn A(2-17) to the neuro-excitatory behaviours evoked by supraspinally and spinally administered M3G in male Sprague–Dawley (SD) rats. Marked qualitative differences in behaviours were apparent following administration of M3G and Dyn A(2-17). Administration of 11 nmol i.c.v. doses of M3G produced intermittent myoclonic jerks, tonic–clonic convulsions, and ataxia, as well as postural changes, whereas i.c.v. Dyn A(2-17) at 15 nmol produced effects on body posture alone. Administration of 11 nmol i.t. doses of M3G produced intermittent explosive motor activity, and touch-evoked agitation, as well as postural changes, whereas i.t. Dyn A(2-17) at 15 nmol produced postural changes, touch-evoked agitation, and paralysis. Pre-treatment with Dyn A antiserum (200 µg) markedly attenuated total behavioural excitation following i.c.v. and i.t. administration of Dyn A(2-17) by  94% and 78%, respectively. However, total behavioural excitation following i.c.v. and i.t. administration of M3G was less markedly attenuated (both  27%) by pre-treatment with Dyn A antiserum, with reductions in tonic–clonic convulsions ( 43%), explosive motor behaviour ( 28%), and touch-evoked agitation ( 22%). The present findings discount a major role for Dyn A in mediating the neuro-excitatory effects of M3G, although it may contribute to maintaining some individual neuro-excitatory behaviours.     

2种修复膜材料用于牙种植引导骨再生的临床效果比较

目的：比较2种修复膜材料用于牙种植引导骨再生的临床效果。方法：选择上海市静安区牙病防治所2017年9月—2018年9月行牙种植引导骨再生治疗的患者139例,按随机表法分为对照组（68例）和试验组（71例）,对照组应用博特医用胶原修复膜引导骨再生,试验组应用海奥口腔修复膜引导骨再生,术后6个月随访记录修复情况,分别比较2组修复成功率和并发症发生率,并评价成骨厚度和高度、植骨厚度和高度,以及水平和垂直骨生长情况。采用SPSS 20.0软件包对数据进行统计学分析。结果：术后6个月,对照组修复成功率为85.29%（58/68）,试验组为95.77%（68/71）,差异有统计学意义(P<0.05);2组植骨厚度和植骨高度无显著差异(P>0.05),试验组成骨厚度、成骨高度、水平骨生长和垂直骨生长均显著高于对照组(P<0.05);对照组并发症发生率为25.00%,显著高于试验组的12.67%(P<0.05)。结论：海奥口腔修复膜引导骨再生的修复成功率优于博特医用胶原修复膜,可更好促进骨和植骨生长,疗效显著,安全性更高,更适合用于牙种植引导骨再生。     

Splinted and unsplinted overdenture attachment systems: A systematic review and meta‐analysis

Splinted and unsplinted overdenture attachment systems have unique advantages and disadvantages. The aim of the present systematic review was to determine the influence of splinted and unsplinted overdenture attachment systems on the marginal bone loss, prosthetic complications and implant survival rate. PubMed/MEDLINE , Scopus and Cochrane databases were searched for articles published up to October 2017, using the following search terms: “overdenture AND attachment OR overdenture AND bar OR overdenture splinted.” The PICO question “Do splinted overdenture attachment systems promote better clinical results in comparison to unsplinted systems?” was evaluated. Eligible studies included randomized controlled clinical trials, prospective studies with at least 10 participants and a minimum follow‐up of 6 months, and studies published in English that compared splinted and unsplinted attachment systems within the same study. The 95% confidence interval (CI ) was considered for all outcomes analysed. After completion of the different steps in the article selection process, nine articles were included in the qualitative and quantitative analyses. A total of 984 implants were placed in 380 patients (mean age: 62.8 years). The meta‐analysis demonstrated no statistically significant differences between splinted and unsplinted attachment systems with regard to marginal bone loss (P  = .39; MD : ?0.11; 95% CI : ?0.37 to 0.14), complications (P  = .31; RR : 1.26; CI : 0.80‐1.99) and implant survival rate (P  = .14; RR : 0.37% CI : 0.10‐1.36). In addition, splinted and unsplinted overdenture attachment systems achieved similar results with regard to marginal bone loss, prosthetic complications and implant survival rate.     

Stimulatory response of neutrophils from periodontitis patients with periodontal pathogens

OBJECTIVE: Neutrophils play a crucial role in the defense of invading bacteria by releasing biologically active molecules. The response of peripheral blood neutrophils was studied in periodontitis-affected patients and in healthy controls towards stimulation to Porphyromonas gingivalis (Pg) and Actinobacillus actinomycetemcomitans (Aa) extracts. MATERIALS AND METHODS: Peripheral venous blood was drawn from 23 adult patients with moderate to advanced chronic periodontitis (probing depth >or=5 mm, attachment loss >or=3 mm), and 30 healthy volunteers. Neutrophil response followed by metalloproteinase-9 (MMP-9) and interleukin-8 (IL-8) secretion was assayed by zymography and enzyme-linked immunosorbent assay, respectively, on both whole blood and purified neutrophils. In addition to periodontal pathogen extracts, known stimulating agents were tested, such as Escherichia coli-lipopolysaccharide (LPS), phytohemagglutinin, and zymosan A. RESULTS: Neutrophil response, expressed as a secretion ratio under stimulated and non-stimulated conditions, measured in whole blood, showed no differences between periodontitis and healthy controls. Instead, in purified neutrophils from patients, MMP-9 exhibited a significantly higher secretion ratio with LPS and Pg (1.5- to 2-fold), whereas IL-8 showed a larger increase in secretion ratio (3- to 7-fold) in the presence of Pg, Aa, LPS, and zymosan A. CONCLUSION: Peripheral neutrophils of periodontitis-affected patients are more reactive as suggested by their significantly higher response toward periodontal pathogen extracts and other stimulating agents.