Investigating phase separation in amorphous solid dispersions via Raman mapping

The bioavailability of poorly-water-soluble active pharmaceutical ingredients (APIs) can be significantly improved by so-called amorphous solid dispersions (ASDs). However, the long-term stability of ASDs might be impaired by API recrystallization and/or amorphous phase separation (APS). So far, no methods have been reported to quantify APS in ASDs. In this work, phase-separation kinetics as well as the compositions of the two amorphous phases evolving due to APS were quantitatively determined for the first time using confocal Raman spectroscopy. Raman spectra were evaluated via non-linear multivariate Indirect Hard Modeling and verified by differential scanning calorimetry and hot-stage microscopy. APS in water-free ASDs of ibuprofen and poly (DL-lactic-co-glycolic acid) was investigated considering the influence of temperature and polymer architecture (linear vs. star-shaped). Water absorbed at 40?°C and 75% relative humidity (RH) promotes APS which was quantified for formulations of felodipine/poly(vinyl pyrrolidone) and ibuprofen/poly(vinyl pyrrolidone).     

Penta-block copolymer microspheres: Impact of polymer characteristics and process parameters on protein release

Here, we aimed to develop protein loaded microspheres (MSs) using penta-block PLGA-based copolymers to obtain sustained and complete protein release. We varied MS morphology and studied the control of protein release. Lysozyme was used as a model protein and MSs were prepared using the solid-in-oil-in-water emulsion solvent extraction method. We synthesized and studied various penta-block PLGA-based copolymers. Copolymer characteristics (LA/GA ratio and molecular weight of PLGA blocks) influenced MS morphology. MS porosity was influenced by process parameters (such as solvent type, polymer concentration, emulsifying speed), whereas the aqueous volume for extraction and stabilizer did not have a significant effect. MSs of the same size, but different morphologies, exhibited different protein release behavior, with porous structures being essential for the continuous and complete release of encapsulated protein. These findings suggest strategies to engineer the morphology of MSs produced from PLGA-based multi-block copolymers to achieve appropriate release rates for a protein delivery system.     

Gallic acid inhibits migration and invasion in human osteosarcoma U-2 OS cells through suppressing the matrix metalloproteinase-2/-9, protein kinase B (PKB) and PKC signaling pathways

Advanced cancer is a multifactorial disease which complicates treatment if the cancer cells have metastasized calling for the targeting of multiple cellular pathways. Gallic acid (GA) is known to possess multiple pharmacological activity including antitumor effects. This study investigated the mechanisms for the anticancer properties of GA on migration and invasion of human osteosarcoma U-2 OS cells. The migration and invasion in U-2 OS cells were determined by a Boyden chamber transwell assay. The expression levels and activities of MMP-2 and MMP-9 were measured by Western blotting, real-time PCR and gelatin zymography assays. All examined proteins levels from Western blotting indicated that GA decreased the protein levels of GRB2, PI3K, AKT/PKB, PKC, p38, ERK1/2, JNK, NF-κB p65 in U-2 OS cells. GA also inhibited the activities of AKT, IKK and PKC by in vitro kinase assay. GA suppressed the migration and invasive ability of U-2 OS cells, and it decreased MMP-2 and MMP-9 protein and mRNA levels and secreted enzyme activities in vitro. These results suggest that potential signaling pathways of GA-inhibited migration and invasion in U-2 OS cells may be due to down-regulation of PKC, inhibition of mitogen-activated protein kinase (MAPK) and PI3K/AKT, resulting in inhibition of MMP-2 and MMP-9 expressions.     

MTT法检测没食子酸对两种细胞的体外毒性

目的:探讨抗肿瘤单体没食子酸(GA)对体外培养的正常人肝细胞株LO2和肝癌细胞株SMMC-7721的毒性。方法:采用MTT实验分析GA对LO2和SMMC-7721的增殖抑制作用。结果:GA作用24h、48h、72h后,用药组均出现了不同程度的增殖抑制。结论:抗肿瘤单体GA对LO2和SMMC-7721细胞均有一定的毒性,表现为增殖抑制作用,作用早期(24h)对LO2的抑制大于对SMMC-7721的抑制,连续作用后(48h、72h),对SMMC-7721细胞的损伤明显超过对LO2的抑制。     

Minireview on the toxicity of dietary acrylamide.

Acrylamide is a commodity chemical with many industrial and laboratory uses. It is also formed from carbohydrate and amino acid containing food by heating (primarily in fried potato products, bread, coffee). Neurotoxicity was detected as the primary toxic effect after occupational exposure. In rats and mice AA is toxic for reproduction and development and to male germ cells, is genotoxic through a reactive metabolite, glycidamide, and carcinogenic to several organs. Epidemiological studies did not point to an association between either occupational or dietary exposure and an excess of cancer incidence. Health risks of the general population are based on an average exposure to 1 microg/kg bw/day increasing for high consumers to 4 microg/kg bw/day. For average consumers a margin of exposure of 200 for neurotoxicity can be regarded as sufficiently protective. However, a margin of 300 for carcinogenic risks appears not sufficient when applying a precautionary principle. This is also illustrated when the benchmark dose lower confidence limit for cancer is divided by an uncertainty factor of 300, which arrives at a tolerable daily intake of 1 microg/kg bw/day, and thus is in the range of average consumption. Further measures to minimize acrylamide formation in food should therefore be explored to reduce human exposure.     

一种改进的遗传算法及其在喜树碱和三唑醇类化合物的QSAR研究中的应用

目的 :考察改进的遗传算法 (GA)在QSAR中的变量优选能力。方法 :用自编程的改进的GA选择变量 ,PLS方法拟合模型 ,对 7,9,10 ,11取代的喜树碱衍生物和取代苯环双三氮唑醇类抗真菌化合物两个数据组进行QSAR研究。结果 :对两个数据组分别得到了一批较常规QSAR分析结果更优的方程。结论 :GA作为一种启发式搜索算法以其高效快速、并行性的特点尤其适合于QSAR研究 ,但因其仅以统计指标为进化依据 ,故需对其实施必要的预处理及结果检查     

Participatory research in Northwest Atlanta's Proctor Creek Watershed: Using photovoice to explore environmental health risks at the water's edge

In this study we used a participatory research method, photovoice, to explore community perceptions about environmental health risks, community assets, and strengths in and around an urban, degraded watershed in Northwest Atlanta, Georgia. This watershed, formed by Proctor Creek, is a focal point for redevelopment and infrastructure investments for years to come. Using a community-based participatory research approach, 10 Proctor Creek residents (watershed researchers), and a university partner, engaged in data collection; participatory data analysis; internal discussions; translation of research findings into watershed restoration, community revitalization, remedial action, and policy solutions; and dissemination of results to fellow watershed residents, stakeholders, and decision makers. We present a conceptual model linking the watershed researchers' understanding of urban policies and practice in the Proctor Creek Watershed to environmental, neighborhood and housing conditions and their influence on health outcomes and quality of life. Engaging community members in defining their own community environmental health challenges and assets yielded the following primary themes: 1) threats to the natural environment, 2) built environment stressors that influence health, 3) blight and divestment of public resources, and 4) hope for the future. Residents’ vision for the future of the watershed - a restored creek, revitalized neighborhoods, and restored people - is fueled by a strong connection to history, memory, and sense of place. We demonstrate the value of local knowledge in identifying previously unaddressed environmental health risks in the Proctor Creek Watershed as well as solutions to reduce or eliminate them.     

Phenols of virgin olive oil protects nuclear DNA against oxidative damage in HeLa cells

Oxidative DNA damage is an inescapable consequence for cells constantly exposed to oxidative stress derived from normal metabolic processes and from environmental factors. Phenolic compounds, which have strong antioxidant activity, prevent DNA damage by protecting the cells against harmful effects of oxidative stress. In this study, the effect of virgin olive oil phenolic extract (OOPE) was investigated on H₂O₂-induced mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage in HeLa cells. DNA damage was assessed in mitochondria and two nuclear regions by using quantitative PCR (QPCR) assay. The cells were pre-treated with non-cytotoxic doses of OOPE for 4 h, and DNA damage was determined. OOPE alone does not change the steady-state level of DNA damage. The oxidative stress generated with 750 μM H₂O₂ caused two times greater damages in mtDNA compared to nDNA, which included the nonexpressed β-globin region (1.507 ± 0.110 lesions/10 kb) and the expressed APEX1 gene (1.623 ± 0.243 lesions/10 kb) with respect to the control region. When cells were preincubated with OOPE for 4 h, nDNA damage under stress condition was completely inhibited; however, mtDNA damage was not affected by this procedure. These results suggest that OOPE has a protective effect against nDNA damage in HeLa cells.     

Biomonitoring of mercury and persistent organic pollutants in Michigan urban anglers and association with fish consumption

The 32-mile Detroit River and surrounding tributaries have been designated as a Great Lakes Area of Concern due to pollution from decades of municipal and industrial discharges, sewer overflows and urban development. Key pollutants in fish samples from the Detroit River include mercury, polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (DDE), dioxins and furans. A biomonitoring study was conducted to assess exposures to these persistent toxic substances in Detroit urban shoreline anglers who may be at high exposure risk due to consumption of locally caught fish. Using a modified venue-based sampling approach, 287 adult shoreline anglers along the Detroit River were recruited and participated in the program. Study participants provided blood and urine specimens and completed a questionnaire following informed consent. We examined percentile estimates for total blood mercury, PCBs, DDE, and dioxin-like total toxic equivalency (TEQ) concentrations among study participants. Multiple linear regression was used to identify important predictors of contaminant concentrations. Participants consumed a median of 64 Detroit River caught fish meals in the past year. The Detroit urban anglers’ median total blood mercury concentrations was 3.2 times higher than that for the general adult U.S. population. PCB concentrations among the Detroit anglers aged 18–39 years were higher than the U.S. population of the same race/ethnicity. Elevated levels of DDE and total TEQ concentrations were not observed in the cohort. Eating more locally caught fish was associated with higher total blood mercury and serum PCB concentrations. The biomonitoring data served to inform public health officials and help guide environmental public health actions to reduce harmful exposures.     

In vitro fermentation of gum acacia – impact on the faecal microbiota

Interest in the consumption of gum acacia (GA) has been associated with beneficial health effects, which may be mediated in part by prebiotic activity. Two doses of GA and fructooligosaccharide (FOS) (1 and 2%) were tested for their efficacy over 48?h in pH- and temperature-controlled anaerobic batch cultures inoculated with human faeces. Samples were taken after 0, 5, 10, 24 and 48?h of fermentation. The selective effects of GA (increases in Bifidobacterium spp. and Lactobacillus spp.) were similar to those of the known prebiotic FOS. The 1% dose of substrates showed more enhanced selectivity compared to the 2% dose. The fermentation of GA also led to SCFA production, specifically increased acetate after 10, 24 and 48?h of fermentation, propionate after 48?h and butyrate after 24 and 48?h. In addition, FOS led to significant increase in the main SCFAs. These results suggest that GA displays potential prebiotic properties.