Narrow Results

We evaluated the in vivo anti-inflammatory and analgesic activities of orally administered paeonol in mice, and also investigated the anti-inflammatory activity of paeonol in a cell line. Paeonol significantly reduced the edema induced by arachidonic acid in rats. The analgesic effects were assayed using 2 different models, i.e., by acetic acid-induced writhing response and by formalin induced licking and biting time. Moreover, we examined the effects of paeonol on the release of inflammatory mediators such as NO, PGE₂ and IL-6. Our results demonstrated that paeonol inhibited LPS induced expression of NO, PGE₂ and IL-6. Paeonol prevented LPS induced iNOS, COX-2 and ERK activation. Therefore, paeonol appears to have potential as a treatment for inflammatory disease and analgesic.

Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway occurs commonly in cancer cells and endothelial cells, and contributes to angiogenesis. Wogonin is a compound with many biologically relevant properties. We previously reported that wogonin blocked IL-6-induced angiogenesis through suppression of VEGF expression, an important regulator of angiogenesis. However, the pathway involved in the suppressive effect of wogonin on IL-6-induced VEGF has not been completely clarified. This study aimed to investigate the molecular mechanisms participating in the suppression of wogonin on IL-6-induced VEGF in vitro, focusing on IL-6R/JAK1/STAT3/VEGF pathway. Both STAT3 siRNA and wogonin treatment resulted in an abolition of the expression of VEGF. Moreover, our data revealed that wogonin treatment after STAT3 knock-down did not further suppress VEGF expression. The addition of IL-6R siRNA or wogonin resulted in a decrease in the expression level of the phosphorylated JAK1 protein. Furthermore, wogonin significantly decreased the amount of phosphorylated STAT3. Finally, by EMSA, wogonin suppressed IL-6-induced STAT3 binding activity in a concentration-dependent manner. Taken together, our results show that wogonin suppresses IL-6-induced VEGF by modulating the IL-6R/JAK1/STAT3 signaling pathway. Based on this study, we suggest that wogonin may provide a new potential therapeutic option for treatment of IL-6-related pathological angiogenesis.

Traditionally, Phyllanthus acidus (Phyllanthaceae) has been used for the treatment of rheumatism, bronchitis, asthma, respiratory disorders, and hepatitis. Recently, we showed that a methanol extract of Phyllanthaceae (Pa-ME) has a potent anti-inflammatory activity in RAW264.7 cells and strongly ameliorates HCl/EtOH-induced gastric ulcers in mice by targeting the Src/Syk of NF-κB. In the present study, we explored the molecular mechanism of Pa-ME on the AP-1 activation pathway and evaluated its potential hepatoprotective effects. To do this, we employed lipopolysaccharide (LPS)-stimulated RAW264.7 cells and U937 cells and an LPS/D-galactosamine (D-GaIN)-induced acute hepatitis mouse model. We utilized a multitude of assays, including immunoblotting analysis, reporter gene assays, and mRNA expression analysis, to determine the effect of Pa-ME on the AP-1 pathway. Pa-ME strikingly suppressed the production of LPS-induced pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). Furthermore, Pa-ME also strongly inhibited activator protein-1 (AP-1) activation and mitogen-activated protein kinase (MAPK) phosphorylation in LPS-stimulated RAW264.7 macrophages cells and the U937 monocyte like human cell line. Moreover, pre-treatment with Pa-ME exhibited strong hepatoprotective and curative effects in an LPS/D-Gal-induced mouse hepatitis model as evidenced by a decrease in elevated serum AST and ALT levels and the amelioration of histological damage. Taken together, our data suggest that Pa-ME might play a crucial ethnopharmacological role as a hepatoprotective herbal remedy by suppressing MAPK signaling and the activity of the downstream transcription factor AP-1.

Gliomas are the mostly observed form of primary brain tumor, and glioblastoma multiforme (GBM) shows the highest incidence. The survival rate of GBM is fairly poor; thus, discovery of effective treatment options is required. Among several suggested targets for therapy, the Axl/IL-6/STAT3 signaling pathway has gained recent interest because of its important role within cancer microenvironment. Quercetin, a plant flavonoid, is well known for its anticancer action. However, the effect of quercetin on Axl has never been reported. Quercetin treatment significantly reduced cell viability in two GBM cell lines of U87MG and U373MG while keeping 85% of normal astrocytes alive. Further western blot assays suggested that quercetin induces apoptosis but does not affect Akt or mitogen-activated protein kinases, factors related to cell proliferation. Quercetin also decreased IL-6 release and phosphorylation of STAT3 in GBM cells. In addition, gene expression, protein expression, and half-life of synthesized Axl protein were all suppressed by quercetin. By applying shRNA for knockdown of Axl, we could confirm that the role of Axl was crucial in the apoptotic effect of quercetin on GBM cells. In conclusion, we suggest quercetin as a potential anticancer agent, which may improve cancer microenvironment of GBM via the Axl/IL-6/STAT3 pathway.

This study was undertaken to elucidate the cytokine response in chicken infected with strains of avian reovirus (ARV) S1133 and 2408. The expression levels of cytokine mRNA in the spleen and viral S1 RNA in various tissues at 1.5 and 2.5 days post inoculation (dpi) were examined using real-time quantitative PCR. Among the cytokines examined, the mRNA expression levels of IL-6, IFN-γ, IL-10 and iNOS at 2.5 dpi were significantly upregulated and higher in chickens infected with strain 2408 than in chickens infected with strain S1133, particularly IL-6 and IFN-γ. A significantly higher levels of viral S1 RNA were detected in the examined tissues from chickens infected with strain 2408 than with strain S1133 over the experimental course, among which the foot pad and spleen were more predominant. The highest levels of IL-6 and IFN-γ mRNA expression correlated with the viral S1 RNA levels in the spleen and the marked clinical diseases and gross lesions, suggesting that IL-6 and IFN-γ may play a role in the pathogenesis of ARV infection.

Canine transmissible venereal tumor (CTVT) is a tumor which can be transmitted naturally through mucosa contact between dogs. When CTVT cells are experimentally inoculated on dogs, they will grow rapidly (Progressive/P phase) and then regress (Regressive/R phase) spontaneously. Therefore, it is a good model to investigate the interactions between tumor cells and host immune system. Previous studies have shown that CTVT cells cannot grow in the dogs restored from CTVT inoculation. To investigate the possible mechanism, this study characterized the CTVT-specific immune response of the peripheral blood mononuclear cells (PBMCs) which isolated from the blood of "naïve" or "CTVT-restored" dogs. The phenotypes (CD3, CD4, CD8, or CD21) of PBMCs were examined by flowcytometry. In response to CTVT stimulation, proliferation, IFN-γ secretion, and cytotoxicity of PBMCs were analyzed. Expression level of proinflammatory cytokines (TNF-α, IL-1β, IL-6, TGF-β), Th1 (IL-2, IFN-γ), and Th2 cytokines (IL-4, IL-10) and cytotoxic proteins (Granzyme B, Perforin) in PBMCs was also evaluated by real-time RT-PCR. The results indicated that there is no significant difference between two groups on lymphocyte phenotypes. Proliferation, IFN-γ secretion, and cytotoxicity of PBMCs between two groups showed no significant difference, except naïve PBMCs present higher proliferation after Con-A stimulation. Production of IL-1β and IL-6 in naïve PBMCs was higher than that in CTVT-restored PBMCs (p < 0.05). The production difference of IL-1β and IL-6 between two groups might be the reason why CTVT cannot be reinoculated on CTVT-restored dog. However, further investigations are necessary to explore the exact role of these cytokines in CTVT growth.

Most neurodegenerative diseases are characterized by a prominent inflammatory response (often called neuroinflammation), which consists mainly of elements of the innate immune response. Whether neuroinflammation is a cause or simply a consequence of the neuropathological events seen during neurodegenerative diseases is unclear, but it is undisputed that chronic inflammation normally leads to permanent scarring and tissue damage. In order to understand this complex biological response, it is essential to identify all factors involved in it. There is a clear consensus that a number of cytokines orchestrate the brain inflammatory response, in terms of both inducing and limiting it, but also control the expression of proteins important for coping with the potential tissue damage. One such protein is metallothionein (MT). Results obtained in MT-1/MT-2–null mice and in MT-1–overexpressing mice strongly suggest that these MT isoforms are important antioxidant, anti-inflammatory, and antiapoptotic proteins in the brain. Results in MT-3–null mice show a very different pattern, with no support for MT-1/MT-2-like functions; rather, MT-3 could be involved in neuronal sprouting and survival.