Serratia marcescens has long been recognized as an important opportunistic pathogen, but the underlying pathogenesis mechanism is not completely clear. Here, we report a key pathogenesis pathway in S. marcescens comprising the RssAB two-component system and its downstream elements, FlhDC and the dominant virulence factor hemolysin ShlBA. Expression of shlBA is under the positive control of FlhDC, which is repressed by RssAB signaling. At 37°C, functional RssAB inhibits swarming, represses hemolysin production, and promotes S. marcescens biofilm formation. In comparison, when rssBA is deleted, S. marcescens displays aberrant multicellularity favoring motile swarming with unbridled hemolysin production. Cellular and animal infection models further demonstrate that loss of rssBA transforms this opportunistic pathogen into hypervirulent phenotypes, leading to extensive inflammatory responses coupled with destructive and systemic infection. Hemolysin production is essential in this context. Collectively, a major virulence regulatory pathway is identified in S. marcescens.The Gram-negative bacterium Serratia marcescens is an important opportunistic pathogen that causes a wide range of diseases and clinical presentations with high morbidity (25). S. marcescens frequently causes outbreaks in intensive and neonatal care units, and the occurrence of multiple-antibioticresistant strains has further exacerbated clinical treatment difficulties (3, 39). Despite years of study, the mechanism of pathogenesis of S. marcescens and why it behaves as an opportunistic pathogen remain poorly understood. Unraveling the underlying mechanism of pathogenesis is thus very important for developing strategies to prevent and treat S. marcescens infection.The hemolysin ShlA was shown to be a dominant virulence factor in S. marcescens pathogenesis using a murine lung infection model (35). ShlA is responsible for the hemolytic and cytotoxic effects on erythrocytes and cultured cells, with the aid of an outer membrane protein, ShlB (28,29,47,53,54). ShlA also contributes to the release of inflammatory mediators, increases uropathogenicity, and triggers microtubule-dependent invasion of S. marcescens into epithelial cells (27,30,34,40). However, the mechanism by which the expression of shlA is regulated, especially in response to any bacterial signaling system control, remains uncharacterized. Only one reported study has indicated that iron is involved in the regulation of shlBA expression in S. marcescens (46). S. marcescens exhibits swarming, which is recognized as a highly coordinated multicellular surface migration behavior (24,51,62) that is correlated with virulence capability, antibiotic resistance, and hemolysin production in other bacteria (1,17,44). S. marcescens swarms on Luria-Bertani (LB) agar surfaces at 30°C, but not at 37°C (36). Our previous studies showed that activation of a bacterial two-component system, RssAB, comprising a sensor kinase, RssA, and a response regulator, RssB, inhibited swarming and reduced hemolysin productio...

Resveratrol, a naturally occurring dietary compound with chemopreventive properties has been reported to trigger a variety of cancer cell types to apoptosis. Whether resveratrol shows any activity on human nasopharyngeal carcinoma (NPC) cells remained to be determined. The aim of this study was to investigate the effect and mechanism of resveratrol on human NPC cells. Treatment of resveratrol resulted in significant decrease in cell viability of NPC cell lines in a dose- and time-dependent manner. A dose-dependent apoptotic cell death was also measured by flow cytometery analysis. Molecular mechanistic studies of apoptosis unraveled resveratrol treatment resulted in a significant loss of mitochondrial transmembrane potential, release of cytochrome c, enhanced expression of Fas ligand (FasL), and suppression of glucose-regulated protein 78 kDa (GRP78). These were followed by activation of caspases-9, -8, -4, and -3, subsequently leading to DNA fragmentation and cell apoptosis. Furthermore, up-regulation of proapoptotic Bax and down-regulation of antiapoptotic Bcl-2 protein were also observed. Taken together, resveratrol induces apoptosis in human NPC cells through regulation of multiple apoptotic pathways, including death receptor, mitochondria, and endoplasmic reticulum (ER) stress. Resveratrol can be developed as an effective compound for human NPC treatment.

Osajin is a prenylated isoflavone showing antitumor activity in different tumor cell lines. The underlying mechanism of osajin-induced cancer cell death is not clearly understood. In the present study, the mechanisms of osajin-induced cell death of human nasopharyngeal carcinoma (NPC) cells were explored. Osajin was found to significantly induce apoptosis of NPC cells in a dose- and time-dependent manner. Multiple molecular effects were observed during osajin treatment including a significant loss of mitochondrial transmembrane potential, release of cytochrome c into the cytosol, enhanced expression of Fas ligand (FasL), suppression of glucose-regulated protein 78 kDa (GRP78), and activation of caspases-9, -8, -4 and -3. In addition, up-regulation of proapoptotic Bax protein and down-regulation of antiapoptotic Bcl-2 protein were also observed. Taken together, osajin induces apoptosis in human NPC cells through multiple apoptotic pathways, including the extrinsic death receptor pathway, and intrinsic pathways relying on mitochondria and endoplasmic reticulum stress. Thus, osajin could be developed as a new effective and chemopreventive compound for human NPC.

2,3-BTD activates NK cells cytotoxicity by NKG2D/NCRs pathways. The natural compound 2,3-BTD has diverse physiological effects in a range of organisms, including acting as a detoxifying product of liver alcohol metabolism in humans and ameliorating endotoxin-induced acute lung injury in rats. In this study, we reveal that 2,3-BTD enhances NK cell cytotoxic activity in human pNK cells and NK92 cells. Treatment of NK cells with 2,3-BTD increased perforin expression in a dose-dependent manner. This was accompanied by elevated JNK and ERK1/2 MAPK activities and enhanced expression of NKG2D/NCRs, upstream signaling molecules of the MAPK pathways. The 2,3-BTD effect was inhibited by pretreatment with inhibitors of JNK (SP) or ERK1/2 (PD) or by depleting NKG2D/NCRs or JNK1 or ERK2 with siRNA. These results indicate that 2,3-BTD activates NK cell cytotoxicity by NKG2D/NCR pathways and represent the first report of the 2,3-BTD effect on activation of innate immunity cells.

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