Sulforaphene enhances radiosensitivity of hepatocellular carcinoma through suppression of the NF‐κB pathway

Sulforaphene (SFE), a naturally occurring isothiocyanate found in cruciferous vegetables, has attracted increasing attention for its anti‐cancer effect in many cancers, including hepatocellular carcinoma (HCC). However, the precise role of SFE in the radiosensitivity of HCC is still unclear. Here, cell proliferation and apoptosis were detected by MTT and flow cytometry assay, respectively. The activity of NF‐κB was further evaluated by ELISA. We also observed the effect of SFE and/or radiation on tumor growth. The results showed that SFE inhibited cell proliferation and induced apoptosis in HCC cells. Radiation increased NF‐kB activity, while PDTC, a NF‐kB inhibitor, enhanced radiation‐induced cell death. SFE inhibited NF‐kB activity and the downstream gene expressions of the NF‐kB pathway in HCC cells. Moreover, SFE enhanced the inhibitory effect of radiation on tumor growth both in vitro and in vivo. This study indicated that SFE sensitized the radiosensitivity of HCC by blocking the NF‐kB pathway.     

Anemonin attenuates osteoarthritis progression through inhibiting the activation of IL‐1β/NF‐κB pathway

The osteoarthritis (OA) progression is now considered to be related to inflammation. Anemonin (ANE) is a small natural molecule extracted from various kinds of Chinese traditional herbs and has been shown to inhibiting inflammation response. In this study, we examined whether ANE could attenuate the progression of OA via suppression of IL‐1β/NF‐κB pathway activation. Destabilization of the medial meniscus (DMM) was performed in 10‐week‐old male C57BL/6J mice. ANE was then intra‐articularly injected into joint capsule for 8 and 12 weeks. Human articular chondrocytes and cartilage explants challenged with interleukin‐1β (IL‐1β) were treated with ANE. We found that ANE delayed articular cartilage degeneration in vitro and in vivo. In particular, proteoglycan loss and chondrocyte hypertrophy were significantly decreased in ANE ‐treated mice compared with vehicle‐treated mice. ANE decreased the expressions of matrix metalloproteinase‐13 (MMP13), A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), collagen X (Col X) while increasing Aggrecan level in murine with DMM surgery. ANE treatment also attenuated proteoglycan loss in human cartilage explants treated with IL‐1β ex vivo. ANE is a potent protective molecule for OA; it delays OA progression by suppressing ECM loss and chondrocyte hypertrophy partially by suppressing IL‐1β/NF‐κB pathway activation.     

Optineurin suppression causes neuronal cell death via NF‐κB pathway

Mutations in more than 10 genes are reported to cause familial amyotrophic lateral sclerosis (ALS). Among these genes, optineurin (OPTN) is virtually the only gene that is considered to cause classical ALS by a loss‐of‐function mutation. Wild‐type optineurin (OPTN^WT) suppresses nuclear factor‐kappa B (NF‐κB) activity, but the ALS‐causing mutant OPTN is unable to suppress NF‐κB activity. Therefore, we knocked down OPTN in neuronal cells and examined the resulting NF‐κB activity and phenotype. First, we confirmed the loss of the endogenous OPTN expression after siRNA treatment and found that NF‐κB activity was increased in OPTN‐knockdown cells. Next, we found that OPTN knockdown caused neuronal cell death. Then, overexpression of OPTN^WT or OPTN^E50K with intact NF‐κB‐suppressive activity, but not overexpression of ALS‐related OPTN mutants, suppressed the neuronal death induced by OPTN knockdown. This neuronal cell death was inhibited by withaferin A, which selectively inhibits NF‐κB activation. Lastly, involvement of the mitochondrial proapoptotic pathway was suggested for neuronal death induced by OPTN knockdown. Taken together, these results indicate that inappropriate NF‐κB activation is the pathogenic mechanism underlying OPTN mutation‐related ALS.

     

Alkannin attenuates lipopolysaccharide‐induced lung injury in mice via Rho/ROCK/NF‐κB pathway

We investigated the effects and associated mechanism of alkannin (AL) on lipopolysaccharide (LPS)‐induced acute lung injury in a mouse model. Pretreatment with AL in vivo significantly reduced the lung wet/dry weight ratio and inhibited lung myeloperoxidase activity and malondialdehyde content, while increasing superoxide dismutase activity. Hematoxylin and eosin staining demonstrated that AL attenuated lung histopathological changes. In addition, AL‐inhibited overproduction of proinflammatory cytokines in bronchoalveolar lavage fluid and lung tissues in LPS‐injured mice and LPS‐exposed A549 cells. Further analysis showed that AL‐inhibited induction of the Rho/ROCK/NF‐κB pathway via LPS‐induced inflammation in mice and A549 cells. Fasudil, a selective ROCK inhibitor, showed similar effects. Overall, the findings indicate that AL suppresses the expression of messenger RNAs and proteins associated with Rho/ROCK/NF‐κB signaling to effectively ameliorate lung injury.     

Eriodictyol ameliorates lipopolysaccharide‐induced acute lung injury by suppressing the inflammatory COX‐2/NLRP3/NF‐κB pathway in mice

The purpose of this paper is to observe the protective action and its effective mechanism of eriodictyol on lipopolysaccharide (LPS)‐induced acute lung injury (ALI). In this study, our results indicated that eriodictyol could dramatically suppress the inflammatory mediators, including interleukin‐6 (IL‐6), IL‐1β, prostaglandin E2, and tumor necrosis factor‐α in bronchoalveolar lavage fluid of LPS‐challenged mice. Eriodictyol also alleviated the wet/dry ratio and improved pathological changes of the lung. In addition, eriodictyol significantly decreased myeloperoxidase activity and malondialdehyde content as well as increased superoxide dismutase activity. Moreover, eriodictyol inhibited the COX‐2/NLRP3/NF‐κB signaling pathway in the lung tissues of ALI mice. In conclusion, our observations validated that eriodictyol processed the protective effects on ALI mice, which was related to the regulation of the COX‐2/NLRP3/NF‐κB signaling pathway.     

Gastrokine 1 regulates NF‐κB signaling pathway and cytokine expression in gastric cancers

Gastrokine 1 (GKN1) plays an important role in the gastric mucosal defense mechanism and also acts as a functional gastric tumor suppressor. In this study, we examined the effect of GKN1 on the expression of inflammatory mediators, including NF‐κB, COX‐2, and cytokines in GKN1‐transfected AGS cells and shGKN1‐transfected HFE‐145 cells. Lymphocyte migration and cell viability were also analyzed after treatment with GKN1 and inflammatory cytokines in AGS cells by transwell chemotaxis and an MTT assay, respectively. In GKN1‐transfected AGS cells, we observed inactivation and reduced expression of NF‐κB and COX‐2, whereas shGKN1‐transfected HFE‐145 cells showed activation and increased expression of NF‐κB and COX‐2. GKN1 expression induced production of inflammatory cytokines including IL‐8 and ‐17A, but decreased expression of IL‐6 and ‐10. We also found IL‐17A expression in 9 (13.6%) out of 166 gastric cancer tissues and its expression was closely associated with GKN1 expression. GKN1 also acted as a chemoattractant for the migration of Jurkat T cells and peripheral B lymphocytes in the transwell assay. In addition, GKN1 significantly reduced cell viability in both AGS and HFE‐145 cells. These data suggest that the GKN1 gene may inhibit progression of gastric epithelial cells to cancer cells by regulating NF‐κB signaling pathway and cytokine expression. J. Cell. Biochem. 114: 1800–1809, 2013. © 2013 Wiley Periodicals, Inc.     

Pseudolaric acid B suppresses T lymphocyte activation through inhibition of NF‐κB signaling pathway and p38 phosphorylation

Pseudolaric acid B (PAB) is a major bioactive component of the medicinal plant Pseudolarix kaempferi. Traditional medicine practitioners in Asia have been using the roots of this plant to treat inflammatory and microbial skin diseases for centuries. In the current study, in vitro immunosuppressive effect of PAB and the underlying mechanisms have been investigated. The results showed that PAB dose‐dependently suppressed human T lymphocyte proliferation, IL‐2 production and CD25 expression induced by co‐stimulation of PMA plus ionomycin or of anti‐OKT‐3 plus anti‐CD28. Mechanistic studies showed that PAB significantly inhibited nuclear translocation of NF‐κB p65 and phosphorylation and degradation of IκB‐α evoked by co‐stimulation of PMA plus ionomycin. PAB could also suppress the phosphorylation of p38 in the MAPKs pathway. Based on these evidences, we conclude that PAB suppressed T lymphocyte activation through inhibition of NF‐κB and p38 signaling pathways; this would make PAB a strong candidate for further study as an anti‐inflammatory agent. J. Cell. Biochem. 108: 87–95, 2009. © 2009 Wiley‐Liss, Inc.     

Yes‐associated protein promotes tumour necrosis factor α–treated cementoblast mineralization partly by inactivating NF‐κB pathway

Cementum regeneration, as one of the most difficult challenges of periodontal regeneration, is influenced by inflammatory factors. Inflammation may hamper or promote periodontal tissue repair under different circumstances, as it is found to do in dentin‐pulp complex and bone tissue. Our team demonstrated that YAP promotes mineralization of OCCM, a cementoblast cell line. However, the effect of YAP on its mineralization under inflammatory microenvironment is unclear. In this study, cementogenesis in vitro was up‐regulated after transient TNF‐α treatment for 30 minutes. YAP expression also was increased by TNF‐α treatment. YAP overexpression promoted OCCM mineralization after the cells were transiently treated with TNF‐α because YAP overexpression inhibited NF‐κB pathway activity, while YAP knockdown elevated it. The inhibited mineralization potential and activated NF‐κB pathway activity by YAP knockdown also were partly rescued by the application of the NF‐κB inhibitor Bay 11‐7082. These results demonstrated that YAP plays a positive role in the mineralization of TNF‐α transiently treated cementoblast, partly by inhibiting the NF‐κB pathway activity.