Protein Effects on Surfactant Adsorption Suggest the Dominant Mode of Surfactant-Mediated Stabilization of Protein

Surfactants stabilize proteins through two major mechanisms: (1) their preferential location at nearby interfaces, in this way precluding protein adsorption; and/or (2) their association with protein into “complexes” that prevent proteins from interacting with surfaces as well as each other. However, selection of surfactants for protein stabilization currently is not typically made with benefit of any quantitative, predictive information to ensure that either mechanism will be enforced. We compared surface tension depression by poloxamer 188, polysorbate (PS) 80, and PS 20 in the presence and absence of lysozyme or a recombinant protein. The kinetic results were interpreted with reference to a mechanism for surfactant adsorption governed by the formation of a rate-limiting structural intermediate (i.e., an “activated complex”) composed of surfactant and protein. The presence of protein was seen to increase the rate of surfactant adsorption in relation to surfactant acting alone for the PSs, with very little change in kinetics owing to protein in the case of poloxamer 188. A simple thermodynamic analysis indicated the presence of protein caused a reduction in ΔG for the surfactant adsorption process, deriving entirely from a reduction in ΔH. Thus, protein likely accelerates the adsorption of these surfactants by disrupting their self-associations, increasing the concentration of surfactant monomers near the interface. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.     

A Case Study of Nondelamination Glass Dissolution Resulting in Visible Particles: Implications for Neutral pH Formulations

Visible particles were unexpectedly observed in a neutral-pH placebo formulation stored in glass vials but were not observed in the same formulation composition that contained protein. The particles were identified as silica gel (SiO₂) and polysorbate 20, suggesting dissolution of the glass vial. Time course studies were performed to assess the effect of variables such as pH, excipients, storage temperature, and duration on particle formation. Data suggest that glass dissolution occurred during the storage in the liquid state, as shown by increased Si levels in solution. Upon freezing, the samples underwent freeze concentration and likely became supersaturated, which resulted in the appearance of visible silica particles upon thawing. The glass degradation described here is unique and differs from the more commonly reported delamination, defined by the presence of reflective, shard-like glass flakes in solution that are often termed lamellae. This case study underscores the importance of an early assessment (during formulation development) of potential incompatibility of the formulation with the primary container. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1104–1114, 2014     

Species and gender differences in the carcinogenic activity of trimethylolpropane triacrylate in rats and mice

Trimethylolpropane triacrylate (TMPTA) is a multifunctional monomer with industrial applications. To determine the carcinogenic potential, male and female F344/N rats and B6C3F1/N mice were administered TMPTA (0, 0.3, 1.0, or 3.0 mg/kg) in acetone dermally for 2 years. There were no differences in the body weights and survival in the treated animals compared to controls. Nonneoplastic skin lesions at the site of application included epidermal hyperplasia and hyperkeratosis in both rats and mice. There were no incidences of tumors at the site of application in rats and mice. Rare malignant liver neoplasms were observed in female mice that included hepatoblastoma in the 0.3 and 3.0 mg/kg groups, and hepatocholangiocarcinoma in the 1.0 and 3.0 mg/kg groups. The incidences of uterine stromal polyp and stromal polyp or stromal sarcoma (combined) in female mice occurred with positive trends and the incidences were significantly increased in the 3.0 mg/kg group. A marginal increase in the incidences of malignant mesothelioma in male rats may have been related to TMPTA treatment. In conclusion, our studies show that TMPTA is a dermal irritant in both rats and mice of either sex. Increased incidences of tumor formation were observed in female mice and male rats.     

The organochlorine p,p′-dichlorodiphenyltrichloroethane induces colorectal cancer growth through Wnt/β-catenin signaling

Dichlorodiphenyltrichloroethane (DDT), an organochlorine pollutant, is associated with several types of cancer. However, the relationship between DDT and colorectal cancer is uncertain. In this study, the impact of p,p′-DDT on colorectal cancer growth was evaluated using both in vitro and in vivo models. Our results indicated that the proliferation of human colorectal adenocarcinoma DLD1 cells was significantly promoted after exposed to low concentrations of p,p′-DDT ranging from 10⁻¹² to 10⁻⁷ M for 96 h. Exposure to p,p′-DDT from 10⁻¹⁰ to 10⁻⁸ M led to upregulation of phospho-GSK3β (Ser9), β-catenin, c-Myc and cyclin D1 in DLD1 cells. RNA interference of β-catenin inhibited the proliferation of DLD1 cells stimulated by p,p′-DDT. Inhibiting of estrogen receptors (ERs) had no significant effect on the action of p,p′-DDT. Treatment with p,p′-DDT induced production of intracellular reactive oxygen species (ROS) and inhibited superoxide dismutase (SOD) activity in DLD1 cells. Treatment with N-acetyl-L-cysteine (NAC), a ROS inhibitor, suppressed the induction of Wnt/β-catenin signaling and DLD1 cell proliferation by p,p′-DDT. Moreover, in a mouse xenograft model, 5 nmol/kg p,p′-DDT resulted in increased tumor size, oxidative stress and Wnt/β-catenin signaling. These results indicated that low concentrations of p,p′-DDT promoted colorectal cancer growth through Wnt/β-catenin signaling, which was mediated by oxidative stress. The finding suggests an association between low concentrations of p,p′-DDT exposure and colorectal cancer progression.     

Oligomeric proanthocyanidins alleviate hexabromocyclododecane-induced cytotoxicity in HepG2 cells through regulation on ROS formation and mitochondrial pathway

Hexabromocyclododecane (HBCD), a type of brominated flame retardants (BFR), has become ubiquitous organic contaminants in recent years. However, studies on HBCD toxicity and the related molecular mechanisms are so far limited. The objective of the present study was to investigate the effects of oligomeric proanthocyanidins (OPCs) on cytotoxicity induced by HBCD and the underlying molecular mechanisms. HepG2 cells were treated with HBCD and/or OPCs at different concentrations, and cell viability, cell apoptosis, reactive oxygen species (ROS) production, cellular Ca²⁺ level, mitochondrial membrane potential (ΔΨ), cytochrome C (Cyt-c) release, and nuclear factor-erythroid 2-related factor 2 (Nrf2) proteins expression were evaluated. Results showed that HBCD induced toxic effects in HepG2 cells in a concentration-dependent manner. HBCD at high concentrations (40 and 60 μM) caused a significant decrease of cell viability and led to elevated cell apoptosis ratio, intracellular Ca²⁺ level, cytoplasmic Cyt-c level, and ROS production, together with a loss of ΔΨ and mobilization of Nrf2. Pretreatment with OPCs effectively attenuated the cytotoxic effects and ROS production, as well as mitochondrial responses induced by HBCD. Thus, OPCs could alleviate cytotoxicity in HepG2 cells induced by HBCD through regulation on intracellular Ca²⁺ level and ROS formation in a mitochondrial pathway.     

Genetic modification of the effect of maternal household air pollution exposure on birth weight in Guatemalan newborns

Low birth weight is associated with exposure to air pollution during pregnancy. The purpose of this study was to evaluate whether null polymorphisms of Glutathione S-transferases (GSTs), specifically GSTM1 and GSTT1 genes in infants or mothers, modify the association between high exposures to household air pollution (HAP) from cooking fires and birth weight. Pregnant women in rural Guatemala were randomized to receive a chimney stove or continue to use open fires for cooking. Newborns were measured within 48 h of birth. 132 mother–infant pairs provided infant genotypes (n = 130) and/or maternal genotypes (n = 116). Maternal null GSTM1 was associated with a 144 g (95% CI, −291, 1) and combined maternal/infant null GSTT1 was associated with a 155 g (95% CI, −303, −8) decrease in birth weight. Although there was a trend toward higher birth weights with increasing number of expressed GST genes, the effect modification by chimney stove use was not demonstrated.     

Estimation of bisphenol A (BPA) concentrations in pregnant women,fetuses and nonpregnant women in Eastern Townships of Canada

We determined bisphenol A (BPA) concentrations of 61 pregnant women (PW), their fetuses and 26 nonpregnant women (NPW) in Eastern Townships of Canada; and evaluated potential correlations between maternal and fetal blood, and between peripheral blood and peritoneal fluid. In PW, BPA levels were ranged from non-detected to 4.46 ng/ml and from non-detected to 4.60 ng/ml for maternal and fetal serum, respectively. In NPW, BPA levels were ranged from 1.30 to 8.17 ng/ml and from 0.19 to 13.45 ng/ml for serum and peritoneal fluid, respectively. Positive correlation was found between maternal and fetal serum, and between serum and peritoneal fluid. In conclusion, our findings highlight a continuous distribution of BPA between the mother and its fetus and reveal a role of pregnancy in underestimating the actual levels of blood BPA. Our study also provides a temporal-spatial reference on BPA exposure, which is a useful tool in monitoring, comparing and correcting.     

抑制JAK3激酶的免疫抑制剂托法替尼

JAK/STAT是一类重要的细胞因子信号传导通路,与类风湿性关节炎及银屑病等许多疾病相关。美国辉瑞公司研发的JAK抑制剂托法替尼（Tofacitinib,CP-690550）能选择性抑制JAK3激酶,美国食品和药物管理局（FDA）已于2012年11月批准其用于中至重度类风湿性关节炎的治疗。综述其作用机制、合成方法、药效与药动学、临床研究进展,为同类新药的研发提供参考。     

Nanostructured Iron Sulfide/N,S Dual-Doped Carbon Nanotube-Graphene Composites as Efficient Electrocatalysts for Oxygen Reduction Reaction

Nanostructured FeS dispersed onto N, S dual-doped carbon nanotube–graphene composite support (FeS/N,S:CNT–GR) was prepared by a simple synthetic method. Annealing an ethanol slurry of Fe precursor, thiourea, carbon nanotube, and graphene oxide at 973 K under N₂ atmosphere and subsequent acid treatment produced FeS nanoparticles distributed onto the N, S-doped carbon nanotube–graphene support. The synthesized FeS/N,S:CNT–GR catalyst exhibited significantly enhanced electrochemical performance in the oxygen reduction reaction (ORR) compared with bare FeS, FeS/N,S:GR, and FeS/N,S:CNT with a small half-wave potential (0.827 V) in an alkaline electrolyte. The improved ORR performance, comparable to that of commercial Pt/C, could be attributed to synergy between the small FeS nanoparticles with a high activity and the N, S-doped carbon nanotube–graphene composite support providing high electrical conductivity, large surface area, and additional active sites.     

Study on the fouling mechanism and cleaning method in the treatment of polymer flooding produced water with ion exchange membranes

The complex interactions between organic and inorganic foulants in polymer flooding produced water (PFPW) play a significant role in membrane fouling characteristics during the treatment processes with ion-exchange membranes (IEMs). In order to ensure the desalination capacity of IEMs during electrodialysis, this work systematically investigated the fouling mechanism and cleaning properties with different synthetic solutions as feed water. The results demonstrated that the desalination rates of the IEMs decreased by 39.73%, 43.05%, 45.81% and 52.72% when fouled by HPAM, HPAM-inorganic (i.e., CaCl₂ and NaHCO₃), oil emulsions and oil–HPAM-inorganic, respectively. The results of membrane resistances and SEM images indicated that organic foulant (i.e., HPAM) and inorganic components have a synergistic effect on the fouling of IEMs. The membrane cleaning method using acid–base-sodium dodecyl benzene sulfonate (SDBS) was proposed here to recover the performance of the IEMs after being fouled by feed solution containing oil–HPAM-inorganic compounds. The desalination rate of the IEMs after membrane cleaning increased from 39.62% to 81.39%. This indicated that the acid–base cleaning alone eliminated the inorganic precipitation and gel layer, and the subsequent SDBS cleaning removed the dominant oil emulsion layer.

The fouling and cleaning mechanism of ion exchange membranes in polymer flooding produced water treatment were investigated.