Berberine inhibits proliferation and migration of colorectal cancer cells by downregulation of GRP78.

Human colorectal cancer (CRC), a highly malignant and metastatic carcinoma, is resistant to many present anticancer therapies. The inhibition of tumor survival and growth through receptor suppression is a promising way to treat CRC. The study aimed to investigate the effect of a natural plant triterpenoid, berberine (BBR), on SW480 cells and whether its role is mediated by Glucose-regulated protein 78 (GRP78). MTT assay, wound healing assay, and Annexin V-FITC assay were used to measure the effect of BBR on the proliferation, migration, and apoptosis of SW480 cells, respectively. Immunofluorescence and western blotting were used to evaluate both the downregulation of BBR on GRP78 and the role of GRP78 in the effect of BBR on SW480 cells. Our results revealed that BBR inhibited the proliferation and migration, as well as induced the apoptosis of SW480 cells, in a dose-dependent manner. BBR induced the dose-dependent inhibition of cell proliferation in HT-29 cells. BBR inhibited the expression of GRP78 and its localization on the cell surface. Moreover, BBR inhibited the expression of Bax, Bcl-2, c-Myc, and Vimentin and up-regulated the cytokeratin expression in SW480 cells. In addition, we found that the effects of BBR on cell proliferation, migration, and apoptosis in SW480 cells were reversed by the overexpression of GRP78. Our findings demonstrated that BBR inhibited the proliferation and migration and induced the apoptosis of SW480 cells by downregulating the expression of GRP78, and targeting GRP78 might be a potential way to develop the effective anticancer therapy.

Suppression of progesterone synthesis in human trophoblast cells by fine particulate matter primarily derived from industry.

Epidemiological studies have exhibited a positive association between fine particulate matter (PM2.5) exposure and adverse pregnancy outcome (APO). However, source-related effect and the potential mechanism have not been thoroughly elucidated in toxicology. In this study, PM2.5 was collected during a severe winter haze episode in an energy-base city of China. We coupled this approach with the source appointment by applying the Lagrangian Integrated Trajectory and Concentration Weighted Trajectory model. We observed that the primary trajectory with high polluted air mass came from the northwest of the sampling site. Approximately 90% or more of PM2.5 was derived from the industry at this haze period. Next, the sampled PM2.5 was used to study the classical hormone synthesis pathway on trophoblast JEG-3 cells. PM2.5 induced the secretion of human chorionic gonadotrophin (HCG) and the proliferation of JEG-3 cells at a noncytotoxic concentration. However, the synthesis of progesterone was significantly suppressed, even if both hCG and cyclic adenosine monophosphate (cAMP) were increased, suggesting that PM2.5 may interfere the downstream of cAMP. As expected, the phosphorylated activity of protein kinase A (PKA) was attenuated. Subsequently, the downstream molecules of steroidogenesis, such as ferredoxin reductase (FDXR), CYP11A1 (encoded P450scc), and 3ß-Hydroxysteroid dehydrogenase type 1 (3ß-HSD1), were inhibited. Therefore, PM2.5, primarily derived from industry, may directly inhibit the phosphorylation status of PKA in JEG-3 which, in turn, inhibited the proteins expression in progesterone-synthesis to suppress progesterone levels. Considering the pivotal role of progesterone in pregnancy maintenance, the mechanism on hormone synthesis may provide a better understanding for PM2.5-caused APO. Industry-emanated PM2.5, though not specific, could threaten the placenta, which needs to be verified by further epidemiological studies.

Enantioselective Phytotoxicity and the Relative Mechanism of Current Chiral Herbicides.

BACKGROUND: Regardless of the achievable of chiral switch, most of the chiral nature agrochemical is still sold as racemate or enantiomer-enriched pesticides. Herbicides, accounted for a large proportion in pesticide market, are of great concern due to the frequent occurrence in environment and the structure selective phyto-biochemical impact on plants. METHODS: We give a systematic search on the literature database and included approximately 50 papers which were related to the review. We do careful categories for the chiral herbicides according to their structure and listed out the acute phytotoxicity endpoints. The potential mechanism for the enantioselective toxicity was concluded into 5 main points. RESULTS: The enantiomer-specific toxicity on plant growth and flowers are limited on phenoxyalkanoic acid herbicide, aryloxyphenoxypropanoic acid, imidazolinone herbicide, and acetamide pesticide. Data available on the potential mechanism explanation of enantioselective phytotoxicity has been concerned on the genetic transcription, oxidative stress, and photosynthesis disruption, etc. A comparison between the two enantiomers' enantioselective effects identified an organ-specific and species-specific phenomenon for several herbicides. Moreover, a more herbicidal activity enantiomer is also displayed the more toxicity than its antipode. CONCLUSION: The review elucidated a paucity of information on the enantioselective effect research on various types of plants at the different life stages. It appealed us to conduct a more holistic approach to balance the benefit between herbicidal activity and phytotoxicity when try to develop an enantio-pure herbicide.

CLIC1 Inhibition Attenuates Vascular Inflammation, Oxidative Stress, and Endothelial Injury.

Endothelial dysfunction, which includes endothelial oxidative damage and vascular inflammation, is a key initiating step in the pathogenesis of atherosclerosis (AS) and an independent risk factor for this disorder. Intracellular chloride channel 1 (CLIC1), a novel metamorphic protein, acts as a sensor of cell oxidation and is involved in inflammation. In this study, we hypothesize that CLIC1 plays an important role in AS. Apolipoprotein E-deficient mice were supplied with a normal diet or a high-fat and high-cholesterol diet for 8 weeks. Overexpressed CLIC1 was associated with the accelerated atherosclerotic plaque development, amplified oxidative stress, and in vivo release of inflammatory cytokines. We subsequently examined the underlying molecular mechanisms through in vitro experiments. Treatment of cultured human umbilical vein endothelial cells (HUVECs) with H2O2 induced endothelial oxidative damage and enhanced CLIC1 expression. Suppressing CLIC1 expression through gene knocked-out (CLIC1-/-) or using the specific inhibitor indanyloxyacetic acid-94 (IAA94) reduced ROS production, increased SOD enzyme activity, and significantly decreased MDA level. CLIC1-/- HUVECs exhibited significantly reduced expression of TNF-α and IL-1ß as well as ICAM-1 and VCAM-1 at the protein levels. In addition, H2O2 promoted CLIC1 translocation to the cell membrane and insertion into lipid membranes, whereas IAA94 inhibited CLIC1 membrane translocation induced by H2O2. By contrast, the majority of CLIC1 did not aggregate on the cell membrane in normal HUVECs, and this finding is consistent with the changes in cytoplasmic chloride ion concentration. This study demonstrates for the first time that CLIC1 is overexpressed during AS development both in vitro and in vivo and can regulate the accumulation of inflammatory cytokines and production of oxidative stress. Our results also highlight that deregulation of endothelial functions may be associated with the membrane translocation of CLIC1 and active chloride-selective ion channels in endothelial cells.

Perturbation of metabonome of embryo/larvae zebrafish after exposure to fipronil.

The escalating demand for fipronil by the increasing insects' resistance to synthetic pyrethroids placed a burden on aquatic vertebrates. Although awareness regarding the toxicity of fipronil to fish is arising, the integral alteration caused by fipronil remains unexplored. Here, we investigated on the development toxicity of fipronil and the metabolic physiology perturbation at 120h post fertilization through GC-MS metabolomics on zebrafish embryo. We observed that fipronil dose-dependently induced malformations including uninflated swim bladder and bent spine. Further, the "omic" technique hit 26 differential metabolites after exposure to fipronil and five significant signaling pathways. We speculated that changes in primary bile acid synthesis pathway and the content of saturated fatty acid in the chemical-related group indicated the liver toxicity. Pathway of Aminoacyl-tRNA biosynthesis changed by fipronil may relate to the macromolecular synthesis. Concurrently, methane metabolism pathway was also identified while the role in zebrafish needs further determination. Overall, this study revealed several new signaling pathways in fipronil-treated zebrafish embryo/larval.