Treatment strategies for metastatic gastric cancer: chemotherapy, palliative surgery or radiotherapy?

Aim: This study explored whether chemotherapy combined with palliative surgery and/or radiotherapy is a possible treatment for metastatic gastric cancer. Materials & methods: Patients were divided into groups according to treatments. COX models were used to explore prognostic factors. Kaplan-Meier models and log-rank tests were used to analyze outcomes. Outcomes were analyzed before and after propensity score matching. Results: Chemotherapy combined with gastrectomy or metastasectomy prolongs the survival time compared with chemotherapy alone (p < 0.05). Chemotherapy combined with gastrectomy plus metastasectomy and/or radiation therapy also prolongs the survival time (p < 0.05). Conclusion: Chemotherapy combined with gastrectomy could be a more effective treatment for metastatic gastric cancer. Chemotherapy combined with gastrectomy plus metastasectomy and/or radiation therapy could also be a promising treatment.

[Effects of saikosaponin b_2 on inflammation and energy metabolism in mice with acute liver injury induced by LPS/GalN].

To study the effects of saikosaponin b2( SS-b2) on inflammatory factors and energy metabolism against lipopolysaccharide/galactosamine( LPS/Gal N) induced acute liver injury in mice. Mice were randomly divided into normal group( equal amount of normal saline),model group( 100 g·kg~(-1) LPS and 400 mg·kg~(-1) Gal N),low,medium,high dose group of SS-b2( SS-b25,10,20 mg·kg~(-1)·d-1) and positive control group( dexamethasone,10 mg·kg~(-1)). All of the groups except for the normal group were treated with LPS/Gal N though intraperitoneally injection to establish the acute liver injury model. The organ indexes were calculated. The levels of serum transaminases( ALT and AST) and the activities of ATPase( Na+-K+-ATPase,Ca2+-Mg2+-ATPase) in liver were detected. The activity of tumor necrosis factor-α( TNF-α),interleukin-1ß( IL-1ß) and interleukin-6( IL-6) were determined by the enzyme-linked immunosorbent assay( ELISA). The contents of lactate dehydrogenase( LDH) in liver were determined by micro-enzyme method. HE staining was used to observe the histopathological changes of the liver. Histochemical method was used to investigate the protein expression of liver lactate dehydrogenase-A( LDH-A). The protein expressions of Sirt-6 and NF-κB in the liver were detected by Western blot. According to the results,compared with the model group,there were significant changes in organ indexes in the high-dose group of SS-b2( P<0. 05). The level of ALT,AST,TNF-α,IL-1ß,IL-6 and the activities of LDH in serum of mice with liver injury were significantly reduced in the medium and high dose groups of SS-b2( P<0. 01). With the increase of the concentration of SS-b2,the range of hepatic lesions and the damage in mice decreased. The activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase in liver of mice were significantly enhanced in each dose group( P<0. 01). The expression of NF-κB in liver tissues was significantly down-regulated in the medium and high dose group( P<0. 01). Meanwhile,the expression of Sirt-6 protein in the liver of mice with acute liver injury was significantly increased in each dose group( P<0. 01).In summary,SS-b2 has a significant protective effect on LPS/Gal N-induced acute liver injury in mice,which may be related to the down-regulation of NF-κB protein expression and up-regulation of Sirt-6 protein expression to improve inflammatory injury and energy metabolism.

CXCL8 is associated with the recurrence of patients with acute myeloid leukemia and cell proliferation in leukemia cell lines.

Acute myeloid leukemia (AML) blasts release a wide range of chemokines in which CXCL8 has recently been recognized to be important for tumor progression. To find out the function of CXCL8 in AML, we compared blood serum of AML patients and healthy donors and found that the average level of CXCL8 was higher in AML patients. Among patients, higher expression of CXCL8 was also a positive recurrence indicator which illustrated the critical role of CXCL8 in AML. Knocking down of CXCL8 in leukemic cell lines led to significant reduction of proliferation via inducing G0/G1 cell cycle arrest and apoptosis, which was accompanied by the inactivation of ERK1/2. Furthermore, inhibition of ERK1/2 by specific chemical inhibitors reconstructed the CXCL8 knocking down phenomenon. Overall, we demonstrated that expression level of CXCL8 had a positive relationship with recurrence probability in AML. And CXCL8 was strongly implicated in AML cells growth by activating the ERK1/2 signal pathway.

Omethoate induces pharyngeal cancer cell proliferation and G1/S cell cycle progression by activation of Akt/GSK-3ß/cyclin D1 signaling pathway.

Omethoate is a broad category of organophosphorous pesticides (OPs) and has toxic effects on human health under long-term, low-dose exposure. However, the role of omethoate in cancer development remains elusive. The incidence of global head and neck squamous cell carcinomas (HNSCC) has markedly increased in recent years. Thus, we examined whether omethoate induced the proliferation of FaDu cells (a cell line of HNSCC) and if so, what the underlying mechanism was. The study revealed that omethoate induced FaDu cell growth in a dose- and time-dependent manner. Omethoate stimulated FaDu cell proliferation was mainly due to enhancing the G1 to S phase transition by flow cytometry analysis. We also found that omethoate up-regulated cyclin D1, a key gene controlling the G1-S transition. Furthermore, we showed that omethoate was capable of activating the Akt/GSK-3ß signaling pathway. Blockage of Akt by siRNA or small molecule inhibitor significantly suppressed omethoate-induced cyclin D1 expression and cell proliferation. Collectively, these findings demonstrated for the first time that omethoate could induce the pharyngeal cancer cell proliferation by activation of the Akt/GSK-3ß/cyclin D1 signaling pathway.

Simonkolleite Coating on Poly(Amino Acids) to Improve Osteogenesis and Suppress Osteoclast Formation in Vitro.

Zinc can enhance osteoblastic bone formation and stimulate osteogenic differentiation, suppress the differentiation of osteoclast precursor cells into osteoclasts, and inhibit pathogenic bacterial growth in a dose-dependent manner. In this study, simonkolleite, as a novel zinc resource, was coated on poly (amino acids) (PAA) via suspending PAA powder in different concentrations of zinc chloride (ZnCl2) solution, and the simonkolleite-coated PAA (Zn-PAA) was characterized by SEM, XRD, FT-IR and XPS. Zinc ions were continuously released from the coating, and the release behavior was dependent on both the concentration of the ZnCl2 immersing solution and the type of soak solutions (SBF, PBS and DMEM). The Zn-PAA was cultured with mouse bone marrow stem cells (BMSCs) through TranswellTM plates, and the results indicated that the relative cell viability, alkaline phosphatase (ALP) activity and mineralization of BMSCs were significantly higher with Zn-PAA as compared to PAA. Moreover, the Zn-PAA was cultured with RAW264.7 cells, and the results suggested an inhibiting effect of Zn-PAA on the cell differentiation into osteoclasts. In addition, Zn-PAA exhibited an antibacterial activity against both S. aureus and E. coli. These findings suggest that simonkolleite coating with certain contents could promote osteogenesis, suppress osteoclast formation and inhibit bacteria, indicating a novel way of enhancing the functionality of synthetic bone graft material and identifying the underline principles for designing zinc-containing bone grafts.

Sam68 affects cell proliferation and apoptosis of human adult T-acute lymphoblastic leukemia cells via AKT/mTOR signal pathway.

Sam68 (Src associated in mitosis, 68kDa) belongs to the signal，transduction and activation of RNA (STAR) family and its function has been linked to the onset and progression of many tumors. However, the role of Sam68 in T-acute lymphoblastic leukemia (T-ALL) remains unclear. This present study aimed to investigate whether and how Sam68 involved in T-ALL. Our results showed high expression of Sam68 in adult T-ALL cases, Jurkat and CCRF-CEM cell lines. Knockdown of Sam68 repressed cell proliferation, increased apoptosis, induced S arrest along with upregulation of p21, Bad, cleaved caspase-9, caspase-3, PARP and downregulation of CDK2 and Bcl-xl. Furthermore, the data indicated that the expression change of Sam68 went with the changes of AKT/mTOR signaling pathway in T-ALL cell lines. Our findings demonstrated that Sam68 possibly participated in the progresses of T-ALL at least partially via AKT/mTOR signaling pathway.

SIRT2 mediates multidrug resistance in acute myelogenous leukemia cells via ERK1/2 signaling pathway.

SIRT2, one of nicotinamide adenine dinucleotide (NAD+)-dependent class Ⅲ histone deacetylase family proteins, has been found to be involved in the proliferation and survival of acute myeloid leukemia (AML) cells. However, its effect on drug resistance on chemoresistant AML cells is unclear. In the present study, we first found that SIRT2 was expressed at higher level in the relapsed AML patients than the newly diagnosed patients. Consistent with this observation, the expression level of SIRT2 was higher in HL60/A cells than that in HL60 cells. Depletion of SIRT2 by shRNAs in HL60/A cells resulted in decreased MRP1 level, enhanced drug accumulation and triggered more apoptosis. By contrast, overexpression of SIRT2 in HL60 cells led to increased MRP1 level, drug efflux and attenuated drug sensitivity. Moreover, the decreased expression of phosphorylated ERK1/2 was detected in SIRT2-depleted HL60/A cells and increased expression of phosphorylated ERK1/2 was observed in SIRT2 overexpressed HL60 cells. Furthermore, blockage of ERK1/2 signaling pathway with the chemical inhibitor PD98059, further induced apoptosis of HL60/A cells conferred by SIRT2 depletion. Importantly, ERK1/2 inhibition was able to reverse the drug resistance of HL60 conferred by SIRT2 overexpression. Thus, our findings collectively suggested that the expression level of SIRT2 has a positive relationship with DNR/Ara-C resistance and activity of ERK1/2 signaling pathway. SIRT2 might regulate DNR/Ara-C sensitivity in AML cells at least partially through the ERK1/2 pathway.

Tumor Necrosis Factor Alpha Stimulates Proliferation of Dental Pulp Stem Cells via Akt/Glycogen Synthase Kinase-3ß/Cyclin D1 Signaling Pathway.

INTRODUCTION: It has been widely accepted that dental pulp stem cells (DPSCs), which are a class of self-renewal and differentiation potential of adult stem cells, play an important role in the repair procession of pulp's inflammation. We investigated whether tumor necrosis factor alpha (TNF-α) could induce the proliferation of DPSCs and clarified the potential mechanism of this proliferation. METHODS: Cell Counting Kit-8 assay (Dojindo Laboratories, Mashiki-machi, Kumamoto, Japan) and 5-ethynyl-2'-deoxyuridine-based proliferation assays were determined to investigate various concentrations or hours of TNF-α inducing a cell number change of DPSCs. Next, flow cytometry analysis was performed to investigate the main cell cycle phase process of DPSCs. Furthermore, the signaling pathway of TNF-α-induced proliferation of DPSCs was analyzed using Western blot analysis. Then, inhibitors were added to confirm the mechanism of this signaling pathway. RESULTS: TNF-α induced the proliferation of DPSCs in a dose- and time-dependent manner. Cyclin D1, which controlled the cell cycle process from the G1 to the S phase, was up-regulated by TNF-α in a time-dependent manner, whereas its overexpression alone increased DPSC proliferation. Furthermore, TNF-α was capable of inducing Akt/GSK-3ß signaling pathway activation. Blockage of phosphoinositide 3-kinase/Akt by their kinase or genetic inhibitors could significantly reduce TNF-α-induced proliferation of DPSCs. CONCLUSIONS: This study confirmed that TNF-α induced the proliferation of DPSCs by regulating the Akt/GSK-3ß/cyclin D1 signaling pathway and then provided a suitable number for the requirements of cell differentiation.

2,3,7,8-Tetrachlorodibenzo-p-dioxin stimulates proliferation of HAPI microglia by affecting the Akt/GSK-3ß/cyclin D1 signaling pathway.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental toxin that induces apoptosis of neurons and a pro-inflammatory response in microglial cells. First, we found that TCDD induced proliferation of HAPI microglial cells in a dose- and time-dependent manner. Flow cytometry analysis showed that this proliferation by TCDD was due to mainly enhancing the G1 to S phase transition. Next, it was found that TCDD treatment led to up-regulation of cyclin D1, which induces cell cycle progression from G1 to S phase, in a time-dependent manner. As for molecular mechanism, we revealed that TCDD was capable of inducing Akt phosphorylation and activation, resulting in phosphorylation and inactivation of glycogen synthase kinase-3ß (GSK-3ß). Inactivated GSK-3ß attenuated proteasomal degradation of cyclin D1 by reducing Thr(286)-phosphorylated cyclin D1 levels. Moreover, inactivated GSK-3ß increased cyclin D1 gene transcription by increasing its transcription factor ß-catenin in the nucleus. Further, blockage of phosphoinositide 3-kinase/Akt kinase with their specific inhibitors, LY294002 and Akt 1/2 kinase inhibitor, significantly reduced TCDD-enhanced proliferation of HAPI microglial cells. In conclusion, TCDD stimulates proliferation of HAPI microglial cells by affecting the Akt/GSK-3ß/cyclin D1 signaling pathway.

2,3,7,8-TCDD induces neurotoxicity and neuronal apoptosis in the rat brain cortex and PC12 cell line through the down-regulation of the Wnt/ß-catenin signaling pathway.

TCDD exposure has various toxic effects on in the human nervous system resulting in various developmental and behavioral deficits. However the underlying molecular mechanism of TCDD-induced adverse effects on the CNS and associated signaling pathways remains largely unknown. Herein we analyzed acute TCDD exposure in the rat brain cortex to investigate whether misregulation of the Wnt/ß-catenin signaling pathway plays a role in neurotoxicity. Western blot and immunohistochemical experiments revealed a significant down-regulation of ß-catenin and phospho-glycogen synthase kinase-3ß (pSer9-GSK-3ß) after TCDD exposure. TUNEL assay results showed apoptosis occurs mainly at day 7 after TCDD treatment. Immunofluorescent labeling indicated that ß-catenin was localized mainly in the neurons; co-localization of ß-catenin and active caspase-3 was found following TCDD exposure. Further, TCDD exposure decreased the level of pSer9-GSK-3ß and ß-catenin, and increased apoptosis in the PC12 neuronal cell line in a dose-dependent manner. Interestingly the application of lithium chloride, a GSK-3ß inhibitor, reversed the suppressive effect of TCDD on ß-catenin in PC12 cells and primary cortical neurons restoring cell viability and protecting cells from apoptosis as compared to untreated controls. Taken together, these results indicate that the canonical Wnt/ß-catenin signaling pathway may play an important role in TCDD-induced neurotoxicity and neuronal apoptosis.

2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced inflammatory activation is mediated by intracellular free calcium in microglial cells.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been known to induce inflammatory signaling in a number of cell types and tissues. However, the adverse effects of TCDD on the central nervous system (CNS) have not been entirely elucidated. In this study, using reverse transcriptase PCR (RT-PCR) and ELISA, we showed that TCDD up-regulated the expression and secretion of tumor necrosis factor-alpha (TNF-α) in a time-dependent manner in cultured HAPI microglial cells. TCDD also caused a fast (within 30min as judged by the increase in its mRNA level) activation of cytosolic phospholipase A2 (cPLA2). This initial action was accompanied by up-regulation of cyclooxygenase-2 (COX-2), an important inflammation marker within 1h after TCDD treatment. These pro-inflammatory responses were inhibited by two types of Ca(2+) blockers, bis-(o-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester (BAPTA-AM) and nifedipine, thus, indicating that the effects are triggered by initial increase in the intracellular concentration of free Ca(2+) ([Ca(2+)]i). Further, TCDD exposure could induce phosphorylation- and ubiquitination-dependent degradation of IкBα, and the translocation of NF-κB p65 from the cytosol to the nucleus in this microglial cell line. Thus, the NF-κB signaling pathway can be activated after TCDD treatment. However, Ca(2+) blockers also obviously attenuated NF-κB activation and transnuclear transport induced by TCDD. In concert with these results, we highlighted that the secretion of pro-inflammatory cytokine and NF-κB activation induced by TCDD can be mediated by elevation of [Ca(2+)]i in HAPI microglial cells.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces microglial nitric oxide production and subsequent rat primary cortical neuron apoptosis through p38/JNK MAPK pathway.

It has been widely accepted that microglia, which are the innate immune cells in the brain, upon activation can cause neuronal damage. In the present study, we investigated the role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in regulating microglial nitric oxide production and its role in causing neuronal damage. The study revealed that TCDD stimulates the expression of inducible nitric oxide synthase (iNOS) as well as the production of nitric oxide (NO) in a dose- and time-dependent manner. Further, a rapid activation of p38 and JNK MAPKs was found in HAPI microglia following TCDD treatment. Blockage of p38 and JNK kinases with their specific inhibitors, SB202190 and SP600125, significantly reduced TCDD-induced iNOS expression and NO production. In addition, it was demonstrated through treating rat primary cortical neurons with media conditioned with TCDD treated microglia that microglial iNOS activation mediates neuronal apoptosis. Lastly, it was also found that p38 and JNK MAPK inhibitors could attenuate the apoptosis of rat cortical neurons upon exposure to medium conditioned by TCDD-treated HAPI microglial cells. Based on these observations, we highlight that the p38/JNK MAPK pathways play an important role in TCDD-induced iNOS activation in rat HAPI microglia and in the subsequent induction of apoptosis in primary cortical neurons.