Cilostazol improves the prognosis after hepatectomy in rats with sinusoidal obstruction syndrome.

BACKGROUND AND AIM: Safe radical hepatectomy is important for patients with colorectal liver metastases complicated by sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy. This study aimed to investigate the impact of preoperative administration of cilostazol (CZ), an oral selective phosphodiesterase III inhibitor, on hepatectomy in rat SOS model. MATERIAL AND METHODS: Rats were divided into NL (normal liver), SOS (monocrotaline [MCT]-treated), and SOS + CZ (MCT + CZ-treated) groups. MCT or CZ was administered orally, and a 30% partial hepatectomy was performed 48 h after MCT administration. Postoperative survival rates were evaluated (n = 9, for each). Other rats were sacrificed on postoperative days (POD) 1 and 3 and evaluated histologically, immunohistochemically, biochemically, and using transmission electron microscopy (TEM), focusing particularly on SOS findings, liver damage, and liver sinusoidal endothelial cell (LSEC) injury. RESULTS: The cumulative 10-day postoperative survival rate was significantly higher in the SOS + CZ group than in the SOS group (88.9% vs 33.3%, P = 0.001). Total SOS scores were significantly lower in the SOS + CZ group than in the SOS group on both POD 1 and 3. Serum biochemistry and immunohistochemistry showed that CZ reduced liver damage after hepatectomy. TEM revealed that LSECs were significantly preserved morphologically in the SOS + CZ group than in the SOS group on POD 1 (86.1 ± 8.2% vs 63.8 ± 9.3%, P = 0.003). CONCLUSION: Preoperative CZ administration reduced liver injury by protecting LSECs and improved the prognosis after hepatectomy in rats with SOS.

Hypoxia-Induced CD36 Expression in Gastric Cancer Cells Promotes Peritoneal Metastasis via Fatty Acid Uptake.

BACKGROUND: The lipid scavenger receptor cluster of differentiation 36 (CD36) has been shown to have a pro-metastatic function in several cancers. Adipose tissue, a favorable site for peritoneal metastasis (PM) from gastric cancer (GC), promotes this process by providing free fatty acids (FFAs); however, the role of CD36 in PM progression from GC remains to be elucidated. MATERIALS AND METHODS: We evaluated CD36 expression in the GC cells under various conditions. CD36 overexpressing (CD36OE) MKN45 cells were prepared and their migration and invasive properties were assessed. A PM mouse model was used to investigate the biological effects of palmitic acid (PA) and CD36. Furthermore, we examined the clinical role of CD36 expression in 82 human PM samples by immunohistochemical staining. RESULTS: Hypoxia markedly increased CD36 expression in GC cells. In normoxia, only CD36OE MKN45 cells treated with PA showed an increase in migration and invasion abilities. An increased expression of active Rac1 and Cdc42 was observed, which decreased following etomoxir treatment. Conversely, hypoxia increased those capacities of both vector and CD36OE MKN45 cells. In a mouse model transplanted with CD36OE MKN45 cells, more peritoneal tumors were observed in the high-fat diet group than those in the normal diet group. In clinical samples, 80% of PM lesions expressed CD36, consistent with hypoxic regions, indicating a significant association with prognosis. CONCLUSION: Our findings indicate that a hypoxia in the peritoneal cavity induces CD36 expression in GC cells, which contributes to PM through the uptake of FFAs.

Assaying ADAMTS13 Activity as a Potential Prognostic Biomarker for Sinusoidal Obstruction Syndrome in Mice.

Sinusoidal obstruction syndrome (SOS) is a serious liver disorder that occurs after liver transplantation, hematopoietic stem cell transplantation, and the administration of anticancer drugs. Since SOS is a life-threatening condition that can progress to liver failure, early detection and prompt treatment are required for the survival of patients with this condition. In this study, female CD1 mice were divided into treatment and control groups after the induction of an SOS model using monocrotaline (MCT, 270 mg/kg body weight intraperitoneally). The mice were analyzed at 0, 12, 24, and 48 h after MCT administration, and blood and liver samples were collected for assays and histopathology tests. SOS was observed in the livers 12 h after MCT injection. In addition, immunohistochemical findings demonstrated CD42b-positive platelet aggregations, positive signals for von Willebrand factor (VWF), and a disintegrin-like metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) in the MCT-exposed liver sinusoid. Although ADAMTS13's plasma concentrations peaked at 12 h, its enzyme activity continuously decreased by 75% at 48 h and, inversely and proportionally, concentrations in the VWF-A2 domain, in which the cleavage site of ADAMTS13 is located, increased after MCT injection. These findings suggest that the plasma concentration and activity of ADAMTS13 could be useful biomarkers for early detection and therapeutic intervention in patients with SOS.

Dynamic switch of immunity and antitumor effects of metformin in rat spontaneous esophageal carcinogenesis.

Chronic inflammation contributes to tumor development by creating a local microenvironment that facilitates neoplastic transformation and potentiates the progression of cancer. Esophageal cancer (EC) is an inflammation-associated malignancy with a poor prognosis. The nature of the switch between chronic inflammation of the esophagus and EC-related immunological changes remains unclear. Here, we examined the dynamic alterations of immune cells at different stages of chronic esophagitis, Barrett's esophagus (BE) and EC using an esophageal spontaneous carcinogenesis rat model. We also investigated the anticancer effects of metformin. To stimulate EC carcinogenesis, chronic gastroduodenal reflux esophagitis via esophagojejunostomy was induced in 120 rats in metformin-treated and non-treated (control) groups. After 40 weeks, BE and EC developed in 96.7% and 63.3% of the control group, and in 66.7% and 23.3% of the metformin-treated group, respectively. Flow cytometric analysis demonstrated that the balance of M1/M2-polarized or phospho-Stat3-positive macrophages, regulatory T, cytotoxic T, natural killer (NK), NK T cells, and Th17 T cells was dynamically changed at each stage of the disease and were resolved by metformin treatment. These findings clarify the immunity in esophageal carcinogenesis and suggest that metformin could suppress this disease by improving the immunosuppressive tumor microenvironment and immune evasion.

Inhibitory Effects of Saururus chinensis Extract on Receptor for Advanced Glycation End-Products-Dependent Inflammation and Diabetes-Induced Dysregulation of Vasodilation.

Advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) are implicated in inflammatory reactions and vascular complications in diabetes. Signaling pathways downstream of RAGE are involved in NF-κB activation. In this study, we examined whether ethanol extracts of Saururus chinensis (Lour.) Baill. (SE) could affect RAGE signaling and vascular relaxation in streptozotocin (STZ)-induced diabetic rats. Treatment with SE inhibited AGEs-modified bovine serum albumin (AGEs-BSA)-elicited activation of NF-κB and could compete with AGEs-BSA binding to RAGE in a dose-dependent manner. Tumor necrosis factor-α (TNF-α) secretion induced by lipopolysaccharide (LPS)-a RAGE ligand-was also reduced by SE treatment in wild-type Ager+/+ mice as well as in cultured peritoneal macrophages from Ager+/+ mice but not in Ager-/- mice. SE administration significantly ameliorated diabetes-related dysregulation of acetylcholine-mediated vascular relaxation in STZ-induced diabetic rats. These results suggest that SE would inhibit RAGE signaling and would be useful for the improvement of vascular endothelial dysfunction in diabetes.

Dual Nature of RAGE in Host Reaction and Nurturing the Mother-Infant Bond.

Non-enzymatic glycation is an unavoidable reaction that occurs across biological taxa. The final products of this irreversible reaction are called advanced glycation end-products (AGEs). The endogenously formed AGEs are known to be bioactive and detrimental to human health. Additionally, exogenous food-derived AGEs are debated to contribute to the development of aging and various diseases. Receptor for AGEs (RAGE) is widely known to elicit biological reactions. The binding of RAGE to other ligands (e.g., high mobility group box 1, S100 proteins, lipopolysaccharides, and amyloid-ß) can result in pathological processes via the activation of intracellular RAGE signaling pathways, including inflammation, diabetes, aging, cancer growth, and metastasis. RAGE is now recognized as a pattern-recognition receptor. All mammals have RAGE homologs; however, other vertebrates, such as birds, amphibians, fish, and reptiles, do not have RAGE at the genomic level. This evidence from an evolutionary perspective allows us to understand why mammals require RAGE. In this review, we provide an overview of the scientific knowledge about the role of RAGE in physiological and pathological processes. In particular, we focus on (1) RAGE biology, (2) the role of RAGE in physiological and pathophysiological processes, (3) RAGE isoforms, including full-length membrane-bound RAGE (mRAGE), and the soluble forms of RAGE (sRAGE), which comprise endogenous secretory RAGE (esRAGE) and an ectodomain-shed form of RAGE, and (4) oxytocin transporters in the brain and intestine, which are important for maternal bonding and social behaviors.

RAGE signaling antagonist suppresses mouse macrophage foam cell formation.

The engagement of the receptor for advanced glycation end-products (receptor for AGEs, RAGE) with diverse ligands could elicit chronic vascular inflammation, such as atherosclerosis. Binding of cytoplasmic tail RAGE (ctRAGE) to diaphanous-related formin 1 (Diaph1) is known to yield RAGE intracellular signal transduction and subsequent cellular responses. However, the effectiveness of an inhibitor of the ctRAGE/Diaph1 interaction in attenuating the development of atherosclerosis is unclear. In this study, using macrophages from Ager+/+ and Ager-/- mice, we validated the effects of an inhibitor on AGEs-RAGE-induced foam cell formation. The inhibitor significantly suppressed AGEs-RAGE-evoked Rac1 activity, cell invasion, and uptake of oxidized low-density lipoprotein, as well as AGEs-induced NF-κB activation and upregulation of proinflammatory gene expression. Moreover, expression of Il-10, an anti-inflammatory gene, was restored by this antagonist. These findings suggest that the RAGE-Diaph1 inhibitor could be a potential therapeutic drug against RAGE-related diseases, such as chronic inflammation and atherosclerosis.

Glycation reaction and the role of the receptor for advanced glycation end-products in immunity and social behavior.

The receptor for advanced glycation end-products (receptor for AGEs, RAGE) is a pattern recognition receptor. The interaction of RAGE with its ligands, such as AGEs, S100 proteins, high mobility group box-1 (HMGB1), and lipopolysaccharides (LPS), is known to play a pivotal role in the propagation of immune responses and inflammatory reactions. The ligand-RAGE interaction elicits cellular responses, for example, in myeloid and lymphoid cells, through distinct pathways by activating NF-κB and Rac1/cdc42, which lead to cytokine production, cell migration, phagocytosis, maturation, and polarization. Recently, oxytocin, a peptide hormone and neuropeptide, was identified as a novel binding molecule for the RAGE; however, it cannot compete with the interaction of RAGE with other ligands or induce RAGE intracellular signaling. The RAGE transports oxytocin from the blood into the brain and regulates brain functions. In this review, we summarize the current understanding of glycation reaction, AGEs, and the RAGE-mediated biological responses as well as the physiological role of RAGE in immunity and social behaviors, particularly, maternal bonding.

Citrullinated Histone H3: Early Biomarker of Neutrophil Extracellular Traps in Septic Liver Damage.

BACKGROUND: Neutrophil extracellular traps (NETs) play a crucial role in host defense, but excess and prolonged interaction of NETs with platelets can cause severe inflammation and host organ damage. Modification of histone H3 by citrullination is involved in in vitro NET formation. The phosphodiesterase III inhibitor, cilostazol (Ciz), which has a protective effect on liver sinusoidal endothelial cells and inhibits platelet aggregation, may prevent organ damage caused by excess NETosis. In this study, we investigated whether citrullinated histone H3 (H3Cit) could serve as a biomarker for the detection of critical liver damage in sepsis and the efficacy of phosphodiesterase-III inhibition for preventing the liver dysfunction induced by NETosis. MATERIALS AND METHODS: Mice injected with lipopolysaccharide (LPS; 1 mg/kg) were used as a sepsis model with or without treatment with Ciz (200 mg/kg). H3Cit, myeloperoxidase, and neutrophil elastase levels were measured by immunohistochemistry. We evaluated H3Cit-positive neutrophils in the peripheral blood by flow cytometry. RESULTS: Immunohistochemistry revealed that H3Cit-, neutrophil elastase-, and myeloperoxidase-positive cell numbers in the livers peaked at 12 h after LPS administration. However, flow cytometry showed a significant increase in H3Cit-positive neutrophils in the peripheral blood only 4 h after LPS injection. Treatment with Ciz significantly ameliorated all parameters. CONCLUSIONS: H3Cit is a useful biomarker for early detection of NETosis or liver dysfunction, and Ciz may be an effective treatment for septic liver damage.

Clinical relevance of peroxisome proliferator-activated receptor-gamma expression in myxoid liposarcoma.

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. PPARγ is essential in adipocyte differentiation from precursor cells. Its antitumorigenic effects are reported in certain malignancies; however, its effects in liposarcoma are unclear. METHODS: We analyzed PPARγ expression using immunohistochemistry (IHC) in 46 patients with myxoid liposarcoma [MLS; median age, 47 years (range, 14-90 years) and mean follow-up period, 91 months (range, 13-358 months)]. PPARγ mRNA expression levels were measured by quantitative reverse transcription polymerase chain reaction. Further, we evaluated the correlation of PPARγ expression with clinical outcomes. RESULTS: We found that the metastasis-free survival rate was significantly higher in lower PPARγ expressers [34 patients with labeling index (LI) <50 %] than in higher expressers (12 patients with LI ≥50 %; p = 0.01). Cox multivariate analysis revealed that a higher PPARγ level was an independent predictor of metastasis (relative risk = 6.945, p = 0.026). Furthermore, using 28 fresh MLS specimens, we confirmed an increased PPARγ mRNA expression level in the higher LI group (p = 0.001). CONCLUSIONS: In this study, higher PPARγ expression in MLS was a risk factor associated with distant metastasis; therefore, it would be a novel prognostic marker for MLS. Further analyses will help to understand the correlation between PPARγ expression and tumor malignancy in liposarcoma.

Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination.

BACKGROUND: Tumor-associated macrophages (TAMs) of the M2 phenotype are known to promote tumor proliferation and to be associated with a poor prognosis in numerous cancers. Here, we investigated whether M2 macrophages participate in the development of peritoneal dissemination in gastric cancer. METHODS: The characteristics of peritoneal macrophages in gastric cancer patients with or without peritoneal dissemination were examined by flow cytometry and the real-time quantitative polymerase chain reaction. The effects of M2 macrophages on phenotypic changes of the gastric cancer cell line MKN45 were assessed with a direct or indirect co-culture system in vitro and an in vivo mouse xenograft model. RESULTS: The number of peritoneal macrophages with the M2 phenotype (CD68(+)CD163(+) or CD68(+)CD204(+)) was significantly higher in gastric cancer patients with peritoneal dissemination than in those without peritoneal dissemination. Higher expression of the M2-related messenger RNAs (IL-10, vascular endothelial growth factor A, vascular endothelial growth factor C, matrix metalloproteinase 1, and amphiregulin) and lower expression of M1-related messenger RNAs (TNF-α, CD80, CD86, and IL-12p40) were also confirmed in the TAMs. Macrophage co-culture with gastric cancer cells converted M1 phenotype into M2 phenotype. Moreover, the coexistence of MKN45 cells with M2 macrophages resulted in cancer cell proliferation and an acceleration of tumor growth in the xenograft model. CONCLUSIONS: Intraperitoneal TAMs in gastric cancer patients with peritoneal dissemination were polarized to the M2 phenotype, and could contribute to tumor proliferation and progression. Therefore, intraperitoneal TAMs are expected to be a promising target in the treatment of peritoneal dissemination in gastric cancer.

cAMP ameliorates inflammation by modulation of macrophage receptor for advanced glycation end-products.

Clarification of the roles of PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) is indispensable for therapeutic strategies against various inflammatory diseases. RAGE (receptor for advanced glycation end-products) is one of the PRRs (pattern recognition receptors) and has been implicated in autoimmune and inflammatory diseases. Effective remedies targeting RAGE are required for the diseases. In the present study, we show that cAMP-induced modulation of the RAGE isoform in macrophages can control the inflammatory state in both in vitro and in vivo experimental conditions. The RAGE ligand S100B stimulated MCP-1 (monocyte chemoattractant protein-1) secretion from peritoneal macrophages, but cAMP elevation suppressed it by converting the RAGE isoform from a membrane-bound into a soluble form. This shedding is the result of ectodomain cleavage of mRAGE (membrane-bound RAGE) by MMP9 (matrix metalloproteinase 9). Furthermore, forskolin significantly inhibited peritoneal macrophage accumulation in a mouse S100B-induced peritonitis model. These results suggest that cAMP serves as a negative regulator of ligand-RAGE signalling and macrophage recruitment by mRAGE down-regulation and formation of decoys as soluble receptors. The present study should deepen our understanding of the pathogenesis of RAGE-mediated tissue derangement and provide new clues for overcoming RAGE-related inflammatory diseases.

Induction of receptor for advanced glycation end products by insufficient leptin action triggers pancreatic ß-cell failure in type 2 diabetes.

Glucolipotoxicity, which is exerted by free fatty acids (FFA) and prolonged hyperglycemia, is implicated in pancreatic ß-cell failure in diabetes. Pattern recognition receptors such as receptor for advanced glycation end products (RAGE) and toll-like receptors 2 and 4 could mediate danger signals in ß-cells. We examined whether RAGE contributes to ß-cell failure in a type 2 diabetes mouse model. Pancreatic islets were isolated from ob/ob, db/db, diet-induced obesity (DIO), RAGE-null (RAGE(-/-) ), and RAGE(+/+) wild-type (WT) control mice and dispersed into single cells for flow cytometry. RAGE expression was detected in insulin-positive ß-cells of ob/ob and db/db mice, but not of WT, DIO, or RAGE(-/-) mice: thus, inadequate leptin receptor signaling and RAGE expression may be linked. Compared with RAGE(+/+) db/db mice, RAGE(-/-) db/db mice showed higher ß-cell number and mass with less apoptosis as well as glucose tolerance with higher insulin secretion without any differences in serum levels of FFA and adiponectin. Palmitate or oleate pretreatment combined with a leptin antagonist induced RAGE expression, AGE-elicited apoptosis, and impaired glucose-stimulated insulin secretion by advanced glycation end products (AGE) in MIN6 cells. FFA elevation with concomitant AGE formation during prolonged hyperglycemia could cause ß-cell damage through insufficient leptin action and subsequent RAGE induction in type 2 diabetes.

Sivelestat sodium hydrate inhibits neutrophil migration to the vessel wall and suppresses hepatic ischemia-reperfusion injury.

BACKGROUND: Sivelestat sodium hydrate (sivelestat) is a specific neutrophil elastase inhibitor that is effective in treating acute lung injury associated with systemic inflammatory response syndrome. As such, it may be useful in treating hepatic ischemia-reperfusion injury (IRI), a condition in which neutrophils transmigrate into the interstitium, leading to release of neutrophil elastase from neutrophils and consequent damage to the affected tissue, particularly in cases of hepatic failure after liver transplantation or massive liver resection. AIMS: The purpose of this study was to examine whether treatment with sivelestat inhibits neutrophil adhesion and migration to the vessel wall and suppresses hepatic IRI. METHODS: Whether and, if so, the extent to which sivelestat suppresses the adhesion and migration of neutrophils and reduces liver damage in hepatic IRI was examined in a human umbilical vein endothelial cell (HUVEC) model and a rat hepatic IRI model. RESULTS: In the HUVEC model, the extent of the adhesion and migration of neutrophils stimulated by platelet-activating factor were found to be dose-dependently inhibited by sivelestat treatment (p < 0.05). In the rat model, serum liver enzyme levels were significantly lower at 12 h after reperfusion, and the number of neutrophils that had migrated to extravascular sites was significantly less in the treatment group compared to the control group (p < 0.05). CONCLUSION: Sivelestat inhibits the adhesion and migration of neutrophils to vascular endothelium in hepatic IRI, thereby suppressing liver injury.

Thrombomodulin modulates dendritic cells via both antagonism of high mobility group protein B1 and an independent mechanism.

BACKGROUND: Thrombomodulin treatment modulates the properties of dendritic cells (DCs) converting them from immunogenic to tolerogenic and inducing its own expression on DCs. Thrombomodulin binds to the inflammatory mediator, high mobility group protein B1 (HMGB1), antagonizing signalling through its receptor, receptor for advanced glycation end products (RAGE). METHODS: To test if soluble thrombomodulin could antagonize HMGB1 signaling via RAGE on DCs. DCs were prepared from mouse bone marrow cells or human monocytes. In some experiments dendritic cells were sorted into thrombomodulin+ and thrombomodulin- populations. Expression of surface maturation markers was determined by flow cytometry following treatment with thrombomodulin in the presence or absence of HMGB1. RESULTS: Thrombomodulin+ dendritic cells secrete less HMGB1 into the medium. HMGB1 reduces the effects of thrombomodulin on expression of DC maturation markers. Treatment with thrombomodulin reduces the expression of maturation markers such as CD80 and CD86 and increases the expression of thrombomodulin on the DC surface. Treatment of DCs with neutralizing anti-HMGB1 antibody acted synergistically with thrombomodulin in increasing thrombomodulin expression on DCs. Treatment with thrombomodulin can still reduce the expression of surface markers on DCs derived from mice that are deficient in RAGE showing that thrombomodulin can affect DCs by an alternative mechanism. CONCLUSIONS: The results of this study show that thrombomodulin modulates DCs both by antagonizing the interaction of HMGB1 with RAGE and by an independent mechanism.

Low molecular weight heparin suppresses receptor for advanced glycation end products-mediated expression of malignant phenotype in human fibrosarcoma cells.

The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor and its engagement by ligands such as high mobility group box 1 (HMGB1) is implicated in tumor growth and metastasis. Low molecular weight heparin (LMWH) has an antagonistic effect on the RAGE axis and is also reported to exert an antitumor effect beyond the known activity of anticoagulation. However, the link between the anti-RAGE and antitumor activities of LMWH has not yet to be fully elucidated. In this study, we investigated whether LMWH could inhibit tumor cell proliferation, invasion, and metastasis by blocking the RAGE axis using in vitro and in vivo assay systems. Stably transformed HT1080 human fibrosarcoma cell lines were obtained, including human full-length RAGE-overexpressing (HT1080(RAGE)), RAGE dominant-negative, intracellular tail-deleted RAGE-overexpressing (HT1080(dnRAGE)), and mock-transfected control (HT1080(mock)) cells. Confocal microscopy showed the expression of HMGB1 and RAGE in HT1080 cells. The LMWH significantly inhibited HMGB1-induced NFκB activation through RAGE using an NFκB-dependent luciferase reporter assay and the HT1080 cell lines. Overexpression of RAGE significantly accelerated, but dnRAGE expression attenuated HT1080 cell proliferation and invasion in vitro, along with similar effects on local tumor mass growth and lung metastasis in vivo. Treatment with LMWH significantly inhibited the migration, invasion, tumor formation, and lung metastasis of HT1080(RAGE) cells, but not of HT1080(mock) or HT1080(dnRAGE) cells. In conclusion, this study revealed that RAGE exacerbated the malignant phenotype of human fibrosarcoma cells, and that this exacerbation could be ameliorated by LMWH. It is suggested that LMWH has therapeutic potential in patients with certain types of malignant tumors.

Septic shock is associated with receptor for advanced glycation end products ligation of LPS.

Septic shock is a severe systemic response to bacterial infection. Receptor for advanced glycation end products (RAGE) plays a role in immune reactions to recognize specific molecular patterns as pathogen recognition receptors. However, the interaction between LPS, the bioactive component of bacterial cell walls, and RAGE is unclear. In this study, we found direct LPS binding to RAGE by a surface plasmon resonance assay, a plate competition assay, and flow cytometry. LPS increased TNF-α secretion from peritoneal macrophages and an NF-κB promoter-driven luciferase activity through RAGE. Blood neutrophils and monocytes expressed RAGE, and TLR2 was counterregulated in RAGE(-/-) mice. After LPS injection, RAGE(+/+) mice showed a higher mortality, higher serum levels of IL-6, TNF-α, high mobility group box 1, and endothelin-1, and severe lung and liver pathologies compared with RAGE(-/-) mice without significant differences in plasma LPS level. Administration of soluble RAGE significantly reduced the LPS-induced cytokine release and tissue damage and improved the LPS-induced lethality even in RAGE(-/-) as well as RAGE(+/+) mice. The results thus suggest that RAGE can associate with LPS and that RAGE system can regulate inflammatory responses. Soluble RAGE would be a therapeutic tool for LPS-induced septic shock.

A nonsteroidal anti-inflammatory drug, zaltoprofen, inhibits the growth of extraskeletal chondrosarcoma cells by inducing PPARγ, p21, p27, and p53.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and master transcription factor of adipogenesis-related genes, and has been reported as an antitumor target for chondrosarcomas. Herein, we show that the nonsteroidal anti-inflammatory drug, zaltoprofen, induces the expression of PPARγ at the mRNA and protein levels, following the induction of PPARγ-activating factors, such as Krox20, C/EBPß, and C/EBPα, in human extraskeletal chondrosarcoma H-EMC-SS cells. Upregulation of the cell cycle checkpoint proteins, p21, p27, and p53, was observed upon treatment of H-EMC-SS cells with zaltoprofen, which probably resulted in the inhibition of proliferation of these cells observed in vitro. Zaltoprofen treatment inhibited tumor growth, induced tumor cell apoptosis, and was well tolerated in a mouse model of extraskeletal myxoid chondrosarcoma. Our results provide mechanistic insights into the therapeutic effect of zaltoprofen that should promote further studies on the rational use of this drug for the effective treatment of sarcomas.