CXCR2-Driven Ovarian Cancer Progression Involves Upregulation of Proinflammatory Chemokines by Potentiating NF-κB Activation via EGFR-Transactivated Akt Signaling

Ovarian cancer is an inflammation-associated malignancy with a high mortality rate. CXCR2 expressing ovarian cancers are aggressive with poorer outcomes. We therefore investigated molecular mechanisms involved in CXCR2-driven cancer progression by comparing CXCR2 positive and negative ovarian cancer cell lines. Stably CXCR2 transfected SKOV-3 cells had a faster growth rate as compared to control cells transfected with empty vector. Particularly, tumor necrosis factor (TNF), abundantly expressed in ovarian cancer, enhanced cell proliferation by decreasing the G0-G1 phase in CXCR2 transfected cells. TNF increased nuclear factor-κB (NF-κB) activity to a greater degree in CXCR2 transfected cells than control cells as well as provided a greater activation of IκB. CXCR2 transfected cells expressed higher levels of its proinflammatory ligands, CXCL1/2 and enhanced more proliferation, migration, invasion and colony formation. CXCR2 positive cells also activated more EGFR, which led to higher Akt activation. Enhanced NF-κB activity in CXCR2 positive cells was reduced by a PI3K/Akt inhibitor rather than an Erk inhibitor. CXCL1 added to CXCR2 positive cells led to an increased activation of IκB. CXCL1 also led to a significantly greater number of invasive cells in CXCR2 transfected cells, which was blocked by the NF-κB inhibitor, Bay 11-7082. In addition, enhanced cell proliferation in CXCR2 positive cells was more sensitive to CXCL1 antibody or an NF-κB inhibitor. Finally, CXCR2 transfection of parental cells increased CXCL1 promoter activity via an NF-κB site. Thus augmentation of proinflammatory chemokines CXCL1/2, by potentiating NF-κB activation through EGFR-transactivated Akt, contributes to CXCR2-driven ovarian cancer progression.     

Adipose Vascular Endothelial Growth Factor Regulates Metabolic Homeostasis through Angiogenesis

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Highlights? Two-way modulations of adipose VEGF were generated with aP2-Cre transgene ? Adipose VEGF KO reduces vasculature, increases hypoxia and inflammation in fat ? Adipose VEGF KO accelerates the development of metabolic disease in high-fat diet ? Induced adipose VEGF has opposite effect on fat and restores metabolic homeostasis     

Antifatigue Effects of Panax ginseng C.A. Meyer: A Randomised,Double-Blind,Placebo-Controlled Trial

The present study investigated the antifatigue effects of Panax ginseng C.A. Meyer in 90 subjects (21 men and 69 women) with idiopathic chronic fatigue (ICF) in a randomised, double-blind, placebo-controlled and parallel designed trial. A bespoke 20% ethanol extract of P. ginseng (1 g or 2 g day^–1) or a placebo was administered to each group for 4 weeks, and then fatigue severity was monitored using a self-rating numeric scale (NRS) and a visual analogue scale (VAS) as a primary endpoint. Serum levels of reactive oxygen species (ROS), malondialdehyde (MDA), total glutathione (GSH) contents and glutathione reductase (GSH-Rd) activity were determined. After 4-week, P. ginseng administration decreased the total NRS score, but they were not statistically significant compared with placebo (P>0.05). Mental NRS score was significantly improved by P. ginseng administrations as 20.4±5.0 to 15.1±6.5 [95% CI 2.3∼8.2] for 1 g and 20.7±6.3 to 13.8±6.2 [95% CI −0.1∼4.2] for 2 g compared with placebo 20.9±4.5 to 18.8±2.9 [95% CI 4.1∼9.9, P<0.01]. Only 2 g P. ginseng significantly reduced the VAS score from 7.3±1.3 to 4.4±1.8 [95% CI 0.7∼1.8] compared with the placebo 7.1±1.0 to 5.8±1.3 [95% CI 2.2 ∼3.7, P<0.01]. ROS and MDA levels were lowered by P. ginseng compared to placebo. P. ginseng 1 g increased GSH concentration and GSH-Rd activity. Our results provide the first evidence of the antifatigue effects of P. ginseng in patients with ICF, and we submit that these changes in antioxidant properties contribute in part to its mechanism.

Trial Registration

Clinical Research Information Service (CRIS) KCT0000048     

Biocompatibility of a Novel Cyanoacrylate Based Tissue Adhesive: Cytotoxicity and Biochemical Property Evaluation

Cyanoacrylate (CA) is most widely used as a medical and commercial tissue adhesive because of easier wound closure, good cosmetic results and little discomfort. But, CA-based tissue adhesives have some limitations including the release of cytotoxic chemicals during biodegradation. In previous study, we made prepolymerized allyl 2-CA (PACA) based tissue adhesive, resulting in longer chain structure. In this study, we investigated a biocompatibility of PACA as alternative tissue adhesive for medical application, comparing with that of Dermabond® as commercial tissue adhesive. The biocompatibility of PACA was evaluated for short-term (24 hr) and long-term (3 and 7 days) using conventional cytotoxicity (WST, neutral red, LIVE/DEAD and TUNEL) assays, hematoxylin-eosin (H&E) and Masson trichrome (MT) staining. Besides we examined the biochemical changes in cells and DNA induced by PACA and Dermabond® utilizing Raman spectroscopy which could observe the denaturation and conformational changes in protein, as well as disintegration of the DNA/RNA by cell death. In particular, we analyzed Raman spectrum using the multivariate statistical methods including principal component analysis (PCA) and support vector machine (SVM). As a result, PACA and Dermabond® tissue adhesive treated cells and tissues showed no difference of the cell viability values, histological analysis and Raman spectral intensity. Also, the classification analysis by means of PCA-SVM classifier could not discriminate the difference between the PACA and Dermabond® treated cells and DNA. Therefore we suggest that novel PACA might be useful as potential tissue adhesive with effective biocompatibility.     

Genetic analysis of ORF5 porcine reproductive and respiratory syndrome virus isolated in Vietnam

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important swine pathogens because it is highly infectious and causes economic losses due to decreased pig productivity. In this study, the 603 bp complete major envelope protein encoding gene (ORF5) of 32 field PRRSV isolates from Vietnam collected during 2008–2012 were sequenced and analyzed. Multiple nucleotide (nt) and deduced amino acid (aa) alignments of ORF5 were performed on the 32 isolates: the representative strains (European and North American genotypes), Chinese strains available in GenBank and vaccine strains licensed for use in Vietnam. The results showed 94.8–100.0% nt identity and 94.0–100% aa similarity among the 32 isolates. These isolates shared similarities with the prototype of the North American PRRSV strain (VR‐2332; nt 87.8–89.3%, aa 87.5–90.0%), and Lelystat virus, the prototype of the European PRRSV strain (LV; nt 61.1–61.9%, aa 55.1‐57.0%). There was greater similarity with QN07 (nt 96.5‐98.5%, aa 96.0‐99.0%) from the 2007 PRRS outbreak in QuangNam Province, CH‐1a (nt 93.2–95.1%, 91.5–93.5%) isolated in China in 1995 and JXA1 (nt 96.5–98.6%, aa 95.0–98.0%), the highly pathogenic strain from China isolated in 2006. The Vietnamese isolates were more similar to JXA1‐R (nt 96.5–98.6%, aa 95.0–98.0%), the strain used in Chinese vaccines, than to Ingelvac MLV/BSL‐PS (nt 87.2–89.0%, aa 86.0–89.0%). Phylogenetic analysis showed that the 32 isolates were of the North American genotype and classified into sub‐lineage 8.7. This sub‐lineage contains highly pathogenic Chinese PRRSV strains. This study documents genetic variation in circulating PRRSV strains and could assist more effective use of PRRS vaccines in Vietnam.     

Unravelling mitochondrial retrograde regulation in the abiotic stress induction of rice ALTERNATIVE OXIDASE 1 genes

Mitochondrial retrograde regulation (MRR) is the transduction of mitochondrial signals to mediate nuclear gene expression. It is not clear whether MRR is a common regulation mechanism in plant abiotic stress response. In this study, we analysed the early abiotic stress response of the rice OsAOX1 genes, and the induction of OsAOX1a and OsAOX1b (OsAOX1a/b) was selected as a working model for the stress‐induced MRR studies. We found that the induction mediated by the superoxide ion (O_2·^‐)‐generating chemical methyl viologen was stronger than that of hydrogen peroxide (H₂O₂). The addition of reactive oxygen species (ROS) scavengers demonstrated that the stress induction was reduced by eliminating O_2·^‐. Furthermore, the stress induction did not rely on chloroplast‐ or cytosol‐derived O_2·^‐. Next, we generated transgenic plants overexpressing the superoxide dismutase (SOD) gene at different subcellular locations. The results suggest that only the mitochondrial SOD, OsMSD, attenuated the stress induction of OsAOX1a/b specifically. Therefore, our findings demonstrate that abiotic stress initiates the MRR on OsAOX1a/b and that mitochondrial O_2·^– is involved in the process.     

The HEX1 Gene of Fusarium graminearum Is Required for Fungal Asexual Reproduction and Pathogenesis and for Efficient Viral RNA Accumulation of Fusarium graminearum Virus 1

The accumulation of viral RNA depends on many host cellular factors. The hexagonal peroxisome (Hex1) protein is a fungal protein that is highly expressed when the DK21 strain of Fusarium graminearum virus 1 (FgV1) infects its host, and Hex1 affects the accumulation of FgV1 RNA. The Hex1 protein is the major constituent of the Woronin body (WB), which is a peroxisome-derived electron-dense core organelle that seals the septal pore in response to hyphal wounding. To clarify the role of Hex1 and the WB in the relationship between FgV1 and Fusarium graminearum, we generated targeted gene deletion and overexpression mutants. Although neither HEX1 gene deletion nor overexpression substantially affected vegetative growth, both changes reduced the production of asexual spores and reduced virulence on wheat spikelets in the absence of FgV1 infection. However, the vegetative growth of deletion and overexpression mutants was increased and decreased, respectively, upon FgV1 infection compared to that of an FgV1-infected wild-type isolate. Viral RNA accumulation was significantly decreased in deletion mutants but was significantly increased in overexpression mutants compared to the viral RNA accumulation in the virus-infected wild-type control. Overall, these data indicate that the HEX1 gene plays a direct role in the asexual reproduction and virulence of F. graminearum and facilitates viral RNA accumulation in the FgV1-infected host fungus.     

Effects of oral deoxynivalenol exposure on immune-related parameters in lymphoid organs and serum of mice vaccinated with porcine parvovirus vaccine

Mice were exposed to deoxynivalenol (DON) via drinking water at a concentration of 2 mg/L for 36 days. On day 8 of treatment, inactivated porcine parvovirus vaccine (PPV) was injected intraperitoneally. The relative and absolute weight of the spleen was significantly decreased in the DON-treated group (DON). Antibody titers to parvovirus in serum were 47.9?±?2.4 in the vaccination group (Vac), but 15.2?±?6.5 in the group treated with DON and vaccine (DON?+?Vac). The IgA and IgG was not different in the DON, Vac an,d DON?+?Vac groups. IgM was significantly lower only in the DON?+?Vac group. However IgE was significantly increased in the Vac and DON?+?Vac group, but no change was observed between the Vac and DON?+?Vac groups. The concentrations of IL-2, IL-4, GM-CSF, MCP-1 and Rantes in serum, and IL-1α in mesenteric lymph node and MIP-1β in spleen were significantly increased by DON treatment compared to control. The concentrations of IL-2, IL-5, IL-6, IL-9, IL-12, IL-13 and Rantes in thymus, of IL-2 in spleen, and of IL-1α, IL-1β, IL-3, IL-5, IL-10, IL-17, G-CSF, GM-CSF and MCP-1 in mesenteric lymph nodes were significantly decreased in mice compared to those in the Vac group, while concentrations of IL-1α, IL-2, IL-9, IL-13,G-CSF, GM-CSF, IFN-γ, MCP-1, MIP-1α and TNF-α were significantly increased in serum compared to the Vac group. In conclusion, the results presented here indicate that exposure to DON at 2.0 mg/L via drinking water can disrupt the immune response in vaccinated mice by modulating cytokines and chemokines involved in their immune response to infectious disease.