Zn-Mediated Fragmentation of N-Alkoxyphthalimides Enabling the Synthesis of gem-Difluoroalkenes.

Zn-mediated generation of alkoxyl radicals from N-alkoxyphthalimides emerged as an efficient approach for forming diverse and valuable alkyl radicals through ß-scission or a hydrogen atom transfer process. The alkyl radical species can be further trapped by α-trifluoromethyl alkenes to construct a series of gem-difluoroalkenes.

CCL2 overexpression is associated with paclitaxel resistance in ovarian cancer cells via autocrine signaling and macrophage recruitment.

Tumor cells can secret various cytokines and chemokines, which affect the tumor cells themselves and the neighboring cells. Here, we observed that human ovarian cancer (OC) cells developed resistance to paclitaxel treatment following culture with the conditioned medium (CM) derived from paclitaxel-resistant OC (OCTR) cells. A cytokine array revealed that both OCTR cells secreted large amounts of CC chemokine ligand 2 (CCL2). CCL2 and its receptor, CCR2, were overexpressed in OCTR cells. CCL2 expression was associated with worse progression-free survival in patients with ovarian cancer. The inhibition of the CCL2/CCR2 axis suppressed the chemoresistance induced by OCTR-CM. The enhanced expression and production of CCL2 in OC cells were mediated via the NF-κB pathway, and stimulated the activation of the PI3K/Akt pathway, which resulted in the development of paclitaxel resistance in OC cells. Additionally, the OCTR cells significantly increased the migration of macrophages, which was also associated with the overproduction of CCL2 in chemoresistant cancer cells. The macrophages stimulated by OCTR cells expressed high levels of markers of M2 phenotype, and their CM significantly decreased the paclitaxel responsiveness of OC cells. The administration of a CCR2 inhibitor to a murine model significantly improved the paclitaxel sensitivity. These data suggested that apart from inducing chemoresistance in OC cells by acting as an autocrine factor, CCL2 also functions as a chemokine that induces the chemotaxis of macrophages, which may contribute to chemoresistance. Therefore, targeting the CCL2/CCR2 signaling axis may improve the therapeutic response of patients with ovarian cancer to paclitaxel.

1'-Acetoxyeugenol Acetate Isolated from Thai Ginger Induces Apoptosis in Human Ovarian Cancer Cells by ROS Production via NADPH Oxidase.

The rhizomes of Alpinia galanga (Thai ginger) have been used extensively as a spice in Southeast Asian and Arabian cuisines and reported to possess a wide range of biological properties, such as antioxidant, antimicrobial, and antibacterial. However, the specific molecular and cellular mechanisms underlying the anti-tumor effects induced by Thai ginger and its corresponding active compounds have been poorly characterized. We found that upon EtOH extraction, Thai ginger extract exhibits cytotoxic activity (IC50 < 10 µg/mL) and triggers cell death via caspase-dependent apoptosis in human ovarian cancer cells. Among the three major compounds isolated from the extract, 1'-acetoxyeugenol acetate (AEA) exhibited potent cytotoxic activity in human ovarian cancer cells, SKOV3 and A2780. AEA induced apoptotic cell death through the activation of caspases-3 and -9. Notably, AEA enhanced the intracellular levels of reactive oxygen species (ROS), and the application of an antioxidant markedly reversed AEA-induced apoptosis of ovarian cancer cells. The knockdown of p47phox, a subunit of NADPH oxidase, suppressed both the pro-apoptotic and ROS-inducing effects of AEA. Additionally, the activation of the mitogen-activated protein kinase (MAPK) pathway by AEA through ROS regulation was found to be involved in AEA-induced apoptosis. Altogether, these results suggest that AEA exhibits potent apoptosis-inducing activity through the activation of the intrinsic pathway via ROS-mediated MAPK signaling in human ovarian cancer cells.

CC Chemokine Ligand 7 Derived from Cancer-Stimulated Macrophages Promotes Ovarian Cancer Cell Invasion.

In the tumor microenvironment, macrophages have been suggested to be stimulated by tumor cells, becoming tumor-associated macrophages that promote cancer development and progression. We examined the effect of these macrophages on human ovarian cancer cell invasion and found that conditioned medium of macrophages stimulated by ovarian cancer cells (OC-MQs) significantly increased cell invasion. CC chemokine ligand 7 (CCL7) expression and production were significantly higher in OC-MQs than in the control macrophages. Peritoneal macrophages from patients with ovarian cancer showed higher CCL7 expression levels than those from healthy controls. Inhibition of CCL7 using siRNA and neutralizing antibodies reduced the OC-MQ-CM-induced ovarian cancer cell invasion. CC chemokine receptor 3 (CCR3) was highly expressed in human ovarian cancer cells, and a specific inhibitor of this receptor reduced the OC-MQ-CM-induced invasion. Specific signaling and transcription factors were associated with enhanced CCL7 expression in OC-MQs. CCL7-induced invasion required the expression of matrix metalloproteinase 9 via activation of extracellular signal-related kinase signaling in human ovarian cancer cells. These data suggest that tumor-associated macrophages can affect human ovarian cancer metastasis via the CCL7/CCR3 axis.

Capacity for clonal integration in introduced versus native clones of the invasive plant Hydrocotyle vulgaris.

Clonal plants can make up a disproportionately high number of the introduced, invasive plant species in a region. Physiological integration of connected ramets within clones is a key ecological advantage of clonal growth. To ask whether clonal integration underlies the invasiveness of clonal plants, we tested the hypothesis that introduced clones of an invasive species will show higher capacity for integration than native clones of the same species. We conduct a greenhouse experiment on the widespread, perennial herb Hydrocotyle vulgaris. Clonal fragments consisting of pairs of connected ramets from seven sites in northwestern Spain where the species is native and seven sites in southeastern China where the species is introduced and invasive were grown for 79 days with the younger, apical ramet shaded to 30% of ambient light and the connection between ramets either severed or left intact. Severance decreased the final dry mass and ramet number of the apical ramet and its offspring in nearly all clones and increased the mass or ramet number of the basal portion of the fragment in about half of the clones, but these effects did not differ consistently between native and introduced clones. Severance did affect allocation more in introduced than in native clones, decreasing root/total mass more in apical portions and increasing it more in basal portions. Maintaining the connection between ramets caused introduced, but not native, clonal fragments to produce more leaf and less root mass and thus to lower allocation to roots. Regardless of severance, introduced clones accumulated about twice as much mass as native clones. Results suggest that introduced clones of a species can show greater effects of integration on allocation than native clones. In species such as H. vulgaris, this might increase competitiveness for light.

TRPV1 Antagonist DWP05195 Induces ER Stress-Dependent Apoptosis through the ROS-p38-CHOP Pathway in Human Ovarian Cancer Cells.

In addition to their analgesic activity, transient receptor potential vanilloid 1 (TRPV1) agonists and antagonists demonstrate profound anti-cancer activities in various human cancers. In the present study, we investigated the anti-cancer activity of a novel TRPV1 antagonist, DWP05195, and evaluated its molecular mechanism in human ovarian cancer cells. DWP05195 demonstrated potent growth inhibitory effects in all five ovarian cancer cell lines examined. DWP05195 induced apoptosis through the activation of caspase-3, -8, and -9. DWP05195 induced C/EBP homologous protein (CHOP) expression and endoplasmic reticulum (ER) stress. Sodium phenylbutyrate (4-PBA), an ER-stress inhibitor, and CHOP knockdown significantly suppressed DWP5195-induced cell death. DWP05195-enhanced CHOP expression stimulated intrinsic and extrinsic apoptotic pathways through the regulation of Bcl2-like11 (BIM), death receptor 4 (DR4), and DR5. DWP05195-induced cell death was associated with increased reactive oxygen species (ROS) levels and p38 pathway activation. Pre-treatment with the antioxidant N-acetyl-L-cysteine (NAC) significantly suppressed DWP05195-induced CHOP expression and p38 activation. Inhibition of NADPH oxidase (NOX) through p47phox knockdown abolished DWP05195-induced CHOP expression and cell death. Taken together, the findings indicate that DWP05195 induces ER stress-induced apoptosis via the ROS-p38-CHOP pathway in human ovarian cancer cells.

Isoflavones Isolated from the Seeds of Millettia ferruginea Induced Apoptotic Cell Death in Human Ovarian Cancer Cells.

The seeds of Millettia ferruginea are used in fishing, pesticides, and folk medicine in Ethiopia. Here, the anti-cancer effects of isoflavones isolated from M. ferruginea were evaluated in human ovarian cancer cells. We found that isoflavone ferrugone and 6,7-dimethoxy-3',4'-methylenedioxy-8-(3,3-dimethylallyl)isoflavone (DMI) had potent cytotoxic effects on human ovarian cancer cell A2780 and SKOV3. Ferrugone and DMI treatment increased the sub-G1 cell population in a dose-dependent manner in A2780 cells. The cytotoxic activity of ferrugone and DMI was associated with the induction of apoptosis, as shown by an increase in annexin V-positive cells. Z-VAD-fmk, a broad-spectrum caspase inhibitor, and z-DEVD-fmk, a caspase-3 inhibitor, significantly reversed both the ferrugone and DMI-induced apoptosis, suggesting that cell death stimulated by the isoflavones is mediated by caspase-3-dependent apoptosis. Additionally, ferrugone-induced apoptosis was found to be caspase-8-dependent, while DMI-induced apoptosis was caspase-9-dependent. Notably, DMI, but not ferrugone, increased the intracellular levels of reactive oxygen species (ROS), and antioxidant N-acetyl-L-cysteine (NAC) attenuated the pro-apoptotic activity of DMI. These data suggest that DMI induced apoptotic cell death through the intrinsic pathway via ROS production, while ferrugone stimulated the extrinsic pathway in human ovarian cancer cells.

[Detection and significance of IL-6 and TNF-α in patients with Graves disease and periodontitis].

PURPOSE: To investigate the expression of IL-6 and TNF-α in gingival crevicular fluid (GCF) and serum of patients with Graves' disease(GD) and periodontitis (CP), and to analyze the correlation between Graves' disease and periodontitis. METHODS: One hundred and twenty subjects were selected and divided into 4 groups: 30 healthy participants as the control group, 30 patients with CP, 30 patients with GD, and 30 patients with GD and CP. The serum and GCF level of IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA), and clinical periodontal parameters including probing depth (PD), clinical attachment level (CAL) and sulcus bleeding indexes (SBI) were examined. The date was analyzed with SPSS19.0 software package. RESULTS: The concentration of IL-6 and TNF-α in serum and GCF of patients with GD+CP group was significantly higher than that in CP group and GD group (P<0.05). The level of IL-6 and TNF-α in serum and GCF of patients in GD+CP group and GD group was positively correlated with FT3 and FT4 (P<0.05), and the correlation between GD+CP group was significantly higher than that in GD group. CONCLUSIONS: The level of IL-6 and TNF-α in GD+CP group were significantly higher than those in CP group and GD group, indicating that there is an interaction between periodontitis and Graves' disease in immune mechanism.

Cellular and biochemical parameters following autotomy and ablation-mediated cheliped loss in the Chinese mitten crab, Eriocheir sinensis.

In the pond culture of juvenile Eriocheir sinensis, various factors have frequently led to a high rate of autotomy and limb impairments. This study evaluated the differential effects of cheliped loss with autotomy and ablation on the short-term cellular and biochemical parameters of juvenile E. sinensis. In this study, compared with the crabs before treatment, the total hemocyte counts (THC), granulocyte counts (GC), hemocyte agglutination, phosphatase activity and glucose metabolism levels were significantly increased, while hyalinocyte counts (HC) and total antioxidant capacity (T-AOC) were significantly decreased within 3 h. However, the THC levels, hemocyte agglutination and hemocyte proliferation were significantly higher in the ablation group within 3 h compared to the autotomy group. Moreover, the changes of glucose metabolism and immune-related enzymes activities in ablation groups were later than autotomy groups. The bacterial challenge showed that the mortality rate of the ablation group was significantly higher than that of the autotomy group. Therefore, the observations in this study indicate that compared with the passive trauma response of ablation, autotomy is a congenital, efficient, and active trauma response mechanism, which is of great significance to the survival and growth of E. sinensis.

[The expression and clinical significance of IL-35 in periodontitis and oral lichen planus].

PURPOSE: To investigate the influence of IL-35 in the pathogenesis of periodontitis and oral lichen planus, and the correlation between periodontitis and oral lichen planus patients. METHODS: The gingival crevicular fluid（GCF） and serum were collected from patients with oral lichen planus (n=20), periodontitis (n=20), periodontitis and oral lichen planus (n=20) and healthy controls (n=12). The patients' basic information, probing depth, clinical attachment loss, gingival index, sulcus bleeding index were measured and collected. The expression of IL-35 in GCF and serum was detected by ELISA. SPSS19.0 software package was used for statistical analysis. RESULTS: The concentration of IL-35 in patients with periodontitis and oral lichen planus was significantly higher than that of other groups(P<0.05). There was significantly positive correlation between IL-35 level and periodontal clinical parameters. CONCLUSIONS: Periodontitis and oral lichen planus may increase the concentration of IL-35 both in serum and GCF. The expression of IL-35 was positively correlated with periodontitis and oral lichen planus.