The fungal metabolite, citrinin, inhibits lipopolysaccharide/interferon-γ-induced nitric oxide production in glomerular mesangial cells
Department of Biomedical Sciences, Chung Shan Medical University, Taichung 40203, Taiwan, ROC. International immunopharmacology
(Impact Factor: 2.47).
10/2010; 10(12):1608-15. DOI: 10.1016/j.intimp.2010.09.017
The mycotoxin, citrinin (CTN), is a secondary metabolite of the fermented products of Monascus. The mycotoxin can either suppress or stimulate immune responses. In the present study, the immunomodulatory role of CTN in nitric oxide (NO) production, a proinflammatory mediator in the process of inflammation, was investigated. NO is well known as a mediator of immune responses. Overproduction of NO catalyzed by inducible nitric oxide synthase (iNOS) protects host cells against microbial invasion, while aberrant iNOS induction is associated with the pathophysiology of inflammatory events. Herein, we report that CTN significantly suppressed lipopolysaccharide (LPS)/interferon (IFN)-γ-induced NO production in MES-13 cells, a glomerular mesangial cell line. The percentage of NO reduction caused by CTN was far greater than that of the decline in cell viability. CTN decreased iNOS gene and protein expressions in concentration-dependent manners. CTN caused declines in LPS/IFN-γ-induced signal transducer and activator of transcription-1α (STAT-1α) phosphorylation. Furthermore, LPS/IFN-γ's induction of interferon response factor-1 (IRF-1) mRNA expression was inhibited by CTN. Moreover, CTN attenuated IκB-α phosphorylation and reduced NF-κB's translocation to the nuclear fraction. Taken together, our data indicated that CTN significantly suppressed NO and iNOS expressions in MES-13 cells via inhibition of the JAK/STAT-1α and NF-κB signaling pathways.
Available from: Jing Nan
- "Quantitative real-time PCR was finished with Roche Cyber Green PCR mix kit on Biorad C1000 Thermal Cycler. The primer pairs for RT-PCR were as follows: gapdh forward 5′-TGGCAAATTCCATGGCAC-3′, reverse 5′-CCATGGTGGTGAAGACGC-3′; socs3 forward 5′-CCATGGTGGTGAAGACGC-3′, reverse 5′-CCTGTCCAGCCCAATACCTGA-3′
; IRF-1 forward5′-CGATACAAAGCAGGGGAAAA-3′, reverse 5′-TAGCTGCTGTGGTCATCAGG-3′
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ABSTRACT: Signal abnormalities in human cells usually cause unexpected consequences for individual health. We focus on these kinds of events involved in JAK-STAT signal pathways, especially the ones triggered by aberrant activated STAT3, an oncoprotein which participates in essential processes of cell survival, growth and proliferation in many types of tumors, as well as immune diseases. By establishing a STAT3 signal based high-throughput drug screening system in human lung cancer A549 cells, we have screened a library from natural products which contained purified compounds from medicinal herbs. One compound, named Brevilin A, exhibited both strong STAT3 signal inhibition and STAT3 signal dependent cell growth inhibition. Further investigations revealed that Brevilin A not only inhibits STAT3 signaling but also STAT1 signaling for cytokines induced phosphorylation of STAT3 and STAT1 as well as the expression of their target genes. In addition, we found Brevilin A could attenuate the JAKs activity by blocking the JAKs tyrosine kinase domain JH1. The levels of cytokine induced phosphorylation of STATs and other substrates were dramatically reduced by treatment of Brevilin A. The roles of Brevilin A targeting on JAKs activity indicate that Brevilin A may not only be used as a STAT3 inhibitor but also a compound blocking other JAK-STAT hyperactivation. Thus, these findings provided a strong impetus for the development of selective JAK-STAT inhibitors and therapeutic drugs in order to improve survival of patients with hyperactivated JAKs and STATs.
PLoS ONE 05/2013; 8(5):e63697. DOI:10.1371/journal.pone.0063697 · 3.23 Impact Factor
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ABSTRACT: Inflammation is a complex protective process that can become -dysregulated and can lead to a large number of diseases, the most common being rheumatoid arthritis, inflammatory bowel diseases, psoriasis and multiple sclerosis. Inflammation also plays a key role in other complex diseases such as alzeihmers, cardiovascular disease and cancer. A range of therapies exists for the treatment of inflammation-driven diseases such as steroids, non-steroidal anti-inflammatory drugs and anti-histamines. Despite some notable success, there is still major unmet medical need in the treatment of inflammatory diseases. Current therapeutic approaches for the treatment of inflammatory diseases are centered on cyclooxygenases (both COX-1 and 2) proinflammatory enzymes but present available drugs of this category are associated with undesirable gastrointestinal and cardiovascular side effects. Recent advances in drug research are focusing on bio-molecules such as proinflammatory cytokines, components of signal transduction and matrix degrading enzymes which are playing major roles in resolving inflammatory responses, might be new targets for treatment of chronic inflammatory diseases. In the present review several metabolites obtained from fungi with potential as anti-inflammatory agents are listed. The targets covered in this chapter are inhibitor of iNOS, NF-κB, AP-1, JAK, STAT, cytokines, cyclooxygenase (COX-1 and COX-2), 3α-HSD, XO and PLA2. The mode of action of some of the metabolites and a short description of some leads discovered is reviewed. © 2012 Springer Science+Business Media B.V. All rights reserved.
Microorganisms in Sustainable Agriculture and Biotechnology, 01/2012: pages 613-645; , ISBN: 978-94-007-2213-2
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ABSTRACT: The mycotoxin citrinin can cause mycotoxic nephropathy, cytotoxicity and genotoxicity. To investigate the immune modulatory effects, CTN was orally administered to female BALB/c mice at the dose of 1, 5, or 10mg/kg body weight for 14days, and several immunotoxicity tests were performed. The populations of F4/80(+) cells and CD19(+) cells were significantly decreased in spleen and MLN. In MLN, CD4(+), CD8(+), and CD4(+)CD25(+)Foxp3(+) cell populations were increased. CD8 (+) cells were increased but CD19(+) cells were decreased in intra-epithelial, lamina propria and Peyer's patches lymphocytes. In a cell proliferation assay, along with the increased proliferative capacities of ConA-induced splenocytes and MLN cells, IFN-γ production was increased. The expression of TLR 2 was increased in spleen, but TLR 3 expression in MLN was decreased. The level of serum IgM was reduced. Furthermore, apoptosis was induced in spleen, MLN and Peyer's patches and promoted by the change in the ratio of Bax/Bcl-2 activities. Autophagy gene Atg5 and Beclin-1 were up-regulated in spleen. The expressions of IL-1β, IL-10, and TNF-α were inhibited in murine macrophage cells pre-exposed with TLR ligands. These results indicate that CTN has multiple immune modulatory effects in mice that may alter normal functions of immune system.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 07/2012; 50(10):3537-47. DOI:10.1016/j.fct.2012.06.050 · 2.90 Impact Factor
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