OBJECTIVE: Cellular, animal, and human epidemiological studies suggested that benzodiazepines increase the risk of cancer and cancer mortality. Obesity is also clearly linked to carcinogenesis. However, no human studies have examined benzodiazepine-associated carcinogenesis as assessed by changes in cancer biomarkers. METHODS: A total of 19 patients were recruited, and received a 6-week treatment of 0.5 mg lorazepam. The measured cancer biomarkers were angiopoietin-2 (ANG-2), soluble CD40 ligand, epidermal growth factor, endoglin, soluble Fas ligand (sFASL), heparin-binding EGF-like growth factor (HB-EGF), insulin-like growth factor binding protein, interleukin (IL)-6, IL-8, IL-18, plasminogen activator inhibitor (PLGF), placental growth factor, transforming growth factor (TGF)-α, tumor necrosis factor (TNF)-α, urokinase-type plasminogen (uPA), vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D. RESULTS: Six cancer biomarkers were significantly increased in all patients as a whole. The subgroup analysis revealed a distinct pattern of change. Overweight patients showed a significant increase in 11 cancer biomarkers, including ANG-2, sFASL, HB-EGF, IL-8, PLGF, TGF-α, TNF-α, uPA, VEGF-A, VEGF-C, and VEGF-D. However, normal-weight patients did not show any changes in cancer biomarkers. CONCLUSION: Adiposity may have primed the carcinogenic potential, leading to lorazepam-associated carcinogenesis in overweight patients. Epidemiological studies addressing this issue should consider the potential modulator contributing to benzodiazepine-associated carcinogenesis.
Adiposity ; Angiopoietin-2 ; Animals ; Benzodiazepines ; Biomarkers, Tumor ; Carcinogenesis* ; Carrier Proteins ; CD40 Ligand ; Epidemiologic Studies ; Epidermal Growth Factor ; Fas Ligand Protein ; Heparin-binding EGF-like Growth Factor ; Humans ; Interleukin-18 ; Interleukin-8 ; Interleukins ; Lorazepam ; Mortality ; Obesity ; Overweight* ; Plasminogen ; Plasminogen Activators ; Transforming Growth Factors ; Tumor Necrosis Factor-alpha ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor C ; Vascular Endothelial Growth Factor D

PURPOSE: Expression levels of tumor necrosis factor (TNF)-alpha expression on the mucosa of the small intestine is increased in patients with villous atrophy in food protein-induced enterocolitis syndrome (FPIES). TNF-alpha has been reported to induce apoptotic cell death in the epithelial cells. We studied the TNF family and TNF-receptor family apoptosis on the duodenal mucosa to investigate their roles in the pathogenesis of FPIES. METHODS: Fifteen infants diagnosed as having FPIES using standard oral challenge test and 5 controls were included. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining was performed to identify the apoptotic cell death bodies. Immunohistochemical staining of TNF-alpha, Fas ligand (FasL) for TNF family and TNF-related apoptosis-including ligand (TRAIL) receptor 1 (DR4), TRAIL receptor 2 (DR5), and Fas for TNF-receptor family were performed to determine the apoptotic mechanisms. RESULTS: TUNEL+ was significantly more highly expressed in the duodenal mucosa of FPIES patients than in controls (P=0.043). TNF-alpha (P=0.0001) and DR4 (P=0.003) were significantly more highly expressed in FPIES patients than in controls. Expression levels of FasL, Fas, and DR5 were low in both groups and were not significantly different between the 2 groups. CONCLUSION: These results suggest that FPIES pathogenesis is induced by apoptosis, and that TNF-alpha expression and DR4 pathway may have an important role in apoptosis.
Apoptosis ; Atrophy ; Cell Death ; Enterocolitis ; Epithelial Cells ; Fas Ligand Protein ; Humans ; Infant ; Intestine, Small ; Mucous Membrane ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; Tumor Necrosis Factor-alpha ; Up-Regulation

Osteoclasts are multinucleated cells formed mainly on bone surfaces in response to cytokines by fusion of bone marrow-derived myeloid lineage precursors that circulate in the blood. Major advances in understanding of the molecular mechanisms regulating osteoclast formation and functions have been made in the past 20 years since the discovery that their formation requires nuclear factor-kappa B (NF-kappaB) signaling and that this is activated in response to the essential osteoclastogenic cytokine, receptor activator of NF-kappaB ligand (RANKL), which also controls osteoclast activation to resorb (degrade) bone. These studies have revealed that RANKL and some pro-inflammatory cytokines, including tumor necrosis factor, activate NF-kappaB and downstream signaling, including c-Fos and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), and inhibition of repressors of NFATc1 signaling, to positively regulate osteoclast formation and functions. However, these cytokines also activate NF-kappaB signaling that can limit osteoclast formation through the NF-kappaB signaling proteins, TRAF3 and p100, and the suppressors of c-Fos/NFATc1 signaling, IRF8, and RBP-J. This paper reviews current understanding of how NF-kappaB signaling is involved in the positive and negative regulation of cytokine-mediated osteoclast formation and activation.
Cytokines ; NF-kappa B ; NFATC Transcription Factors ; Osteoclasts ; RANK Ligand ; Receptor Activator of Nuclear Factor-kappa B ; TNF Receptor-Associated Factor 3 ; Tumor Necrosis Factor-alpha

BACKGROUND: The ligand for CD137 (CD137L; also called 4-1BBL) is mainly expressed on activated APCs such as dendritic cells, B cells and macrophages. Even though CD137L functions as a trigger of the CD137 signaling pathway for T cell activation and expansion, engagement of CD137L can deliver a signal leading to the production of proinflammatory cytokines in macrophages. METHODS: We generated cell-permeable TAT-CD137L cytoplasmic domain fusion protein (TAT-CD137Lct) and examined its ability to initiate the CD137L reverse signaling pathway. RESULTS: Treatment of TAT-CD137Lct induced the production of high levels of IL-6 and TNF-alpha mRNAs and proteins in peritoneal macrophages. TAT-CD137Lct increased phosphorylation of Erk, p38 MAPK and Jnk, and activated transcription factors C/EBP and CREB. However, TAT-CD137Lct did not visibly affect the degradation of the inhibitor of NF-kB (IkBalpha). We further demonstrated that JNK activation was required for TAT-CD137Lct-induced production of TNF-alpha, while activation of Erk and p38 MAPK were involved in IL-6 and TNF-alpha production. CONCLUSION: Our results suggest that TAT-CD137Lct is an effective activator for the CD137L reverse signaling pathway.
4-1BB Ligand ; B-Lymphocytes ; Cytokines ; Cytoplasm ; Dendritic Cells ; Interleukin-6 ; Macrophages ; Macrophages, Peritoneal ; NF-kappa B ; p38 Mitogen-Activated Protein Kinases ; Phosphorylation ; Proteins ; RNA, Messenger ; Transcription Factors ; Tumor Necrosis Factor-alpha

<b>OBJECTIVEb>To investigate the effect of Astragalus injection (AI) on plasma levels of apoptosis-related factors in aged patients with chronic heart failure (CHF).

<b>METHODSb>Seventy-two CHF patients were randomly divided into the AI group (36 cases) treated with AI and the control group (36 cases) treated with conventional treatment. Plasma levels of soluble Fas (sFas), soluble Fas ligand (sFasL), tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assays (ELISA) with monoclonal anti-human antibodies. Besides, New York Heart Association (NYHA) grading was assessed according to improved symptoms and left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV) and left ventricular ejection fraction (LVEF) were assessed by echocardiogram after 4 weeks of treatment.

<b>RESULTSb>After 4 weeks of treatment, NYHA grading was markedly improved in the two groups, but it was significantly better in AI group than that in the control group (P < 0.05). As compared with the control group, sFas, sFasL, TNF-alpha and IL-6 in the AI group were obviously lower, the difference between the two groups and between before and after treatment were significant (P < 0.05 or P < 0.01). Moreover, in AI group, LVESV and LVEDV decreased, LVEF increased, which was significantly different than that before treatment (P < 0.05), respectively.

<b>CONCLUSIONb>AI could lower plasma levels of apoptosis-related factors, and is one of the effective drugs in improving cardiac function in the aged patients with CHF.

Age Factors ; Aged ; Apoptosis ; immunology ; Astragalus Plant ; Fas Ligand Protein ; Female ; Heart Failure ; blood ; drug therapy ; immunology ; Humans ; Injections ; Interleukin-6 ; blood ; Male ; Membrane Glycoproteins ; blood ; Middle Aged ; Phytotherapy ; Plant Preparations ; administration & dosage ; Tumor Necrosis Factor-alpha ; analysis ; Tumor Necrosis Factors ; blood ; fas Receptor ; blood

To investigate the tumoricidal activity of dendritic cell (DC) stimulated by interferon-gamma (IFN-gamma) against freshly isolated myeloid leukemia cells and its mechanism, the peripheral blood monocytes collected from healthy donors were cocultured with interleukin-4 and granulocyte-macrophage colony-stimulating factor in medium to induce DC for 7 days. After 12 hour culture in the absence or presence of IFN-gamma, the changes of costimulatory molecules were analyzed with flow cytometry. To assay the cytotoxicity of DC against freshly isolated acute myeloid cells, they were cocultured at various effector-to-target ratio for 18 hours, then the percentage of tumoricidal activity was measured with (51)Cr release assay. To explore the mechanism of DC-mediated cytotoxicity, the change of DC surface or intracellular protein expression of Fas ligand (Fas L), TNF-alpha and TNF related apoptosis-inducing ligand (TRAIL) were analyzed with flow cytometry. The results showed that IFN-gamma enhanced cytotoxicity of DC against AML cells was (33.8 +/- 1.6)% at E:T as 20:1, compared with unstimulated DC (P < 0.05); IFN-gamma up-regulated expression of costimulatory molecules of DC surface such as CD86 and CD83; after stimulation with IFN-gamma, expression of intracellular TRAIL of DC was significantly enhanced, but expression of TRAIL on cell surface of DC was low; while the significant changes of Fas L and TNF-alpha expression neither on cell surface or in cells were not observed before or after stimulation with IFN-gamma. It is concluded that DC stimulated by IFN-gamma exhibit tumoricidal activity against AML cells. The cytotoxicity is partially related to maturation of DC and TRAIL inducing apoptosis, but not associated with death domain-independent mechanism of Fas L and TNF-alpha.
Acute Disease ; Antigens, CD ; analysis ; B7-2 Antigen ; analysis ; Coculture Techniques ; Cytotoxicity, Immunologic ; drug effects ; immunology ; Dendritic Cells ; drug effects ; immunology ; metabolism ; Fas Ligand Protein ; analysis ; Flow Cytometry ; Humans ; Immunoglobulins ; analysis ; Interferon-gamma ; pharmacology ; Leukemia, Myeloid ; immunology ; pathology ; Membrane Glycoproteins ; analysis ; TNF-Related Apoptosis-Inducing Ligand ; analysis ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha ; analysis

Humans ; Mucocutaneous Lymph Node Syndrome ; drug therapy ; Tumor Necrosis Factor-alpha ; antagonists & inhibitors ; Tumor Necrosis Factors

Aspergillus fumigatus ; Cytokines ; Humans ; Interleukin-1beta ; Keratitis ; Receptors, IgE ; Tumor Necrosis Factor-alpha ; Tumor Necrosis Factors

<b>OBJECTIVEb>To investigate the levels of tumor necrosis factor-&alpha; (TNF-&alpha;) in tissue or plasma and its clinical implications in different types of lymphoma.

<b>METHODSb>The levels of TNF-&alpha; in paraffin tissue or plasma samples were detected by immunohistochemistry or ELISA assay in 88 lymphoma patients and 88 healthy controls. Univariate and multivariate Cox regression analysis were used to identify the correlation between Ann Ardor stage, blood cells count, bone marrow abnormalities, erythrocyte sedimentation rate (ESR), serum ferritin and TNF-&alpha; expression.

<b>RESULTSb>The levels of TNF-&alpha; had significant difference in different types of lymphoma (P<0.05). High positive and levels in Hodgkin lymphoma [HL, 72.72% and (43.12±15.28) ng/L], aggressive non-HL [NHL, 67.86% and (40.73±16.65) ng/L], and indolent NHL [57.14% and (53.18±20.47) ng/L]. Cox regression analysis showed that Ann Ardor stage, bone marrow abnormalities, ESR, and the levels of TNF-&alpha; were independent risk factors for lymphoma with poor prognosis.

<b>CONCLUSIONb>As an independent factor, TNF-&alpha; may play a role in the development of lymphoma and is an important prognostic factor.

Humans ; Immunohistochemistry ; Lymphoma ; Prognosis ; Risk Factors ; Tumor Necrosis Factor-alpha

OBJECTIVE: To investigate the effect of lycium barbarum polysaccharide (LBP) alone or combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the apoptosis of leukemia cell lines with MLL gene-rearrangement, and to explore the cell apoptotic pathway after the combined action. METHODS: MLL-ALL cell line KOCL44 and KOCL45 were selected as the research object, then the control and experimental groups were set up. The cell survival rate was measured by the trypan blue dye exclusion method, the cell early apoptosis and expression of death receptors on the cell surface were detected by flow cytometry with Annexin-V/PI double staining. The protein level of caspase-8, BID, caspase-3, caspase-9, BAD, BCL-2, as well as mitochondrial and cytosol Cyto-C were detected by Western blot. RESULTS: LBF combined with TRAIL inhibited the growth of KOCL44 and KOCL-45 cells and showed the synergistic effect, the results of flow cytometry with Amnexiu V/PI double staining were consistent with above-mentioned results. After treatment of KOCL44 and KOCL45 cells with LBF plus TRAIL, the significant expression of DR4 on cell surface was not found, while the expression of DR4 receptor was enhanced significantly, the pro-apoptotic proteins including caspase-8, BID, caspase-3, caspase-9 and BAD were activated significantly and BCL-2 was suppressed significantly with time-dependent manner. The expression of mitochondria cyto-C in KOCL44 and KOCL45 decreased along with prolonging of treatment time (r=-0.95, r=-0.866), while the expression of cytosol cyto-C in KOCL44 and KOCL45 increased along with prolonging of treatment time (r=0.883, r=0.903). CONCLUSION The combination of LBP and TRAIL significantly increases the apoptosis of KOCL44 and KOCL45, and the LBP and TRAIL can up-regulate the expression of TRAIL death receptor-DR5 on the cell surface, activate the pathway of caspase and mito-chrondia mitachondria, thus enhance the sensitivity of KOCL44 and KOCL45 to TRAIL induced apoptosis through both mitochondrial and apoptotic pathway.
Apoptosis ; Caspase 8 ; Drugs, Chinese Herbal ; Leukemia, Myeloid, Acute ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; TNF-Related Apoptosis-Inducing Ligand ; Tumor Necrosis Factor-alpha