OBJECTIVES: To investigate the expression of soluble factor-related apoptosis ligand (sFasL) in peripheral blood and microRNA-147b (miR-147b) in monocytes in children with sepsis and their value in assessing prognosis. METHODS: A prospective study was conducted on 124 children with sepsis (sepsis group), 60 children with common infections (infection group), and 60 healthy children undergoing physical examinations (healthy control group). The independent risk factors for poor prognosis in children with sepsis were analyzed, and the value of serum sFasL and monocyte miR-147b in predicting poor prognosis in children with sepsis was assessed. RESULTS: The serum level of sFasL and the relative expression of miR-147b in monocytes were highest in the sepsis group, followed by the infection group and the healthy control group (P<0.05). The multivariate logistic regression analysis showed that the serum level of sFasL and the relative expression of miR-147b in monocytes were closely associated with the poor prognosis of children with sepsis (P<0.05). The receiver operating characteristic curve analysis showed that the combination of serum sFasL level and relative expression of miR-147b in monocytes had a larger area under the curve compared to each indicator alone in predicting the prognosis of children with sepsis (P<0.05). CONCLUSIONS There are significant increases in the level of sFasL in peripheral blood and the relative expression of miR-147b in monocytes in children with sepsis. The combined use of these two indicators has relatively high clinical value in assessing the prognosis of children with sepsis.
Humans ; Sepsis/diagnosis* ; MicroRNAs/blood* ; Male ; Female ; Monocytes/metabolism* ; Prognosis ; Child, Preschool ; Prospective Studies ; Child ; Infant ; TNF-Related Apoptosis-Inducing Ligand/blood* ; Logistic Models

Malignant glioma is the most frequent type in brain tumors. The prognosis of this tumor has not been significantly improved for the past decades and the average survival of patients is less than one year. Thus, an effective novel therapy is urgently needed. TNF-related apoptosis inducing ligand (TRAIL), known to have tumor cell-specific killing activity, has been investigated as a novel therapeutic for cancers. We have developed Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy and demonstrated the potential to treat malignant gliomas. Currently, this Ad-stTRAIL gene therapy is under phase I clinical trial for malignant gliomas. Here, we report preclinical studies for Ad-stTRAIL carried out using rats. We delivered Ad-stTRAIL intracranially and determined its pharmacokinetics and biodistribution. Most Ad-stTRAIL remained in the delivered site and the relatively low number of viral genomes was detected in the opposite site of brain and cerebrospinal fluid. Similarly, only small portion of the viral particles injected was found in the blood plasma and major organs and tissues, probably due to the brain-blood barrier. Multiple administrations did not lead to accumulation of Ad-stTRAIL at the injection site and organs. Repeated delivery of Ad-stTRAIL did not show any serious side effects. Our data indicate that intracranially delivered Ad-stTRAIL is a safe approach, demonstrating the potential as a novel therapy for treating gliomas.
Adenoviridae/genetics ; Animals ; Blood-Brain Barrier ; Brain/drug effects/*metabolism/pathology ; Brain Neoplasms/genetics/metabolism/pathology/*therapy ; Clinical Trials, Phase I as Topic ; DNA, Viral/metabolism ; Disease Models, Animal ; Drug Delivery Systems ; Drug Evaluation, Preclinical ; *Gene Therapy ; Glioma/genetics/metabolism/pathology/*therapy ; Humans ; Liver/drug effects/metabolism/pathology ; Protein Multimerization/genetics ; Rats ; Spleen/drug effects/metabolism/pathology ; TNF-Related Apoptosis-Inducing Ligand/genetics/*pharmacokinetics

Malignant glioma is the most frequent type in brain tumors. The prognosis of this tumor has not been significantly improved for the past decades and the average survival of patients is less than one year. Thus, an effective novel therapy is urgently needed. TNF-related apoptosis inducing ligand (TRAIL), known to have tumor cell-specific killing activity, has been investigated as a novel therapeutic for cancers. We have developed Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy and demonstrated the potential to treat malignant gliomas. Currently, this Ad-stTRAIL gene therapy is under phase I clinical trial for malignant gliomas. Here, we report preclinical studies for Ad-stTRAIL carried out using rats. We delivered Ad-stTRAIL intracranially and determined its pharmacokinetics and biodistribution. Most Ad-stTRAIL remained in the delivered site and the relatively low number of viral genomes was detected in the opposite site of brain and cerebrospinal fluid. Similarly, only small portion of the viral particles injected was found in the blood plasma and major organs and tissues, probably due to the brain-blood barrier. Multiple administrations did not lead to accumulation of Ad-stTRAIL at the injection site and organs. Repeated delivery of Ad-stTRAIL did not show any serious side effects. Our data indicate that intracranially delivered Ad-stTRAIL is a safe approach, demonstrating the potential as a novel therapy for treating gliomas.
Adenoviridae/genetics ; Animals ; Blood-Brain Barrier ; Brain/drug effects/*metabolism/pathology ; Brain Neoplasms/genetics/metabolism/pathology/*therapy ; Clinical Trials, Phase I as Topic ; DNA, Viral/metabolism ; Disease Models, Animal ; Drug Delivery Systems ; Drug Evaluation, Preclinical ; *Gene Therapy ; Glioma/genetics/metabolism/pathology/*therapy ; Humans ; Liver/drug effects/metabolism/pathology ; Protein Multimerization/genetics ; Rats ; Spleen/drug effects/metabolism/pathology ; TNF-Related Apoptosis-Inducing Ligand/genetics/*pharmacokinetics

OBJECTIVETo investigate the effects of interferon (IFN) on the natural killer (NK) cytotoxicity and the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and other apoptosis-inducing genes in peripheral blood mononuclear cells (PBMNC) from polycythemia rubra vera (PV).

METHODSPBMNC were collected from 12 PV patients. The NK cytotoxicity was assessed by lactate dehydrogenase release assay and lytic units (LU) were calculated based on specific lysis. The TRAIL mRNA and other apoptosis-inducing genes were determined by RNase protection assay.

RESULTSThe NK cytotoxicity of untreated PBMNC from PV was (152.0 +/- 146.6) LU. And of IFNalpha1b- and IFNalpha2b-treated PBMNC were up to (250.9 +/- 197.4) LU and (355.9 +/- 249.9) LU, respectively (P < 0.05 and P < 0.01, respectively). The expression of TRAIL mRNA was upregulated in IFNalpha1b and IFNalpha2b stimulated-PBMNC. Up-regulation of mRNA levels of FLICE, DR3, DR4 and TNFRp55 genes was observed in PBMNC after stimulated with IFNalpha, which also induced the mRNA expressions of FasL, Fas, TRADD and RIP. To explore the role of TRAIL in IFNalpha-augmented NK cytotoxicity, neutralizing assay was used and the results showed that IFNalpha-augmented NK activity could be blocked partially by peptides DR4-Fc and DR5-Fc.

CONCLUSIONIFNalpha induced/upregulated the expression of TRAIL and other apoptosis-inducing genes in PBMNC from PV patients, which partially contribute to the IFNalpha-augmented NK cytotoxicity augmentation. This may be one of the mechanisms of IFNalpha therapy for PV.

Adult ; Aged ; Cells, Cultured ; Female ; Humans ; Interferon-alpha ; pharmacology ; K562 Cells ; Killer Cells, Natural ; drug effects ; immunology ; Leukocytes, Mononuclear ; cytology ; drug effects ; metabolism ; Male ; Middle Aged ; Polycythemia Vera ; blood ; immunology ; pathology ; Reverse Transcriptase Polymerase Chain Reaction ; TNF-Related Apoptosis-Inducing Ligand ; genetics ; Up-Regulation ; drug effects ; genetics

OBJECTIVETo explore the levels of DR4 and DR5, the death receptor of soluble tumor necrosis factor-related apoptosis inducing ligand (TRAIL) in the patients with congestive heart failure (CHF) and the effect of shengmai injection (SI) on them.

METHODSSixty-four CHF patients were randomized into two groups, the SI group treated by SI and the control group treated with conventional treatment. Another 30 healthy persons were enrolled as the healthy control group. The serum levels of sDR4 and sDR5 were determined by sandwich ELISA before and after treatment.

RESULTSThe serum levels of sDR4 and sDR5 were obviously higher in CHF patients than in the healthy control subjects (P < 0.01), showing a rising trend with the aggravation of the degree of cardiac function impairment. Levels of sDR4 and sDR5 were lowered in the two treated groups after treatment, with better effects gotten in the SI group.

CONCLUSIONClose relationship presents between cardiac function status and levels of DR4 and DR5 in patients with CHF. DR4 and DR5 might play an important role in the occurrence and progression of myocardial cell apoptosis in patients with CHF, and SI may acts vitally to slow down the progress of CHF and improve patients' heart function by decreasing the levels of sDR4 and sDR5.

Adult ; Aged ; Aged, 80 and over ; Apoptosis ; Drug Combinations ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Heart Failure ; blood ; drug therapy ; Humans ; Injections, Intravenous ; Male ; Middle Aged ; Phytotherapy ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; blood

OBJECTIVETo explore the role of sTRAIL in the pathogenesis of HBV infection in human being.

METHODSsTRAIL in 153 patients' sera was examined with ELISA. Correlations between sTRAIL and liver functional parameters were analysed.

RESULTSThe levels of sTRAIL in patients with various clinical types of hepatitis B as well as primary hepatocellular carcinoma were all higher than that in normal persons and became almost normal in recovering stage cases. In acute and chronic HBV infection, sTRAIL level was negatively correlated with ALT, AST and total bilirubin levels, and positively correlated with serum albumin.

CONCLUSIONThe results indicated that higher level of sTRAIL expression is correlated with liver damage, and apoptosis induced by sTRAIL is one of the mechanisms of liver damage in HBV infection.

Adolescent ; Adult ; Aged ; Alanine Transaminase ; blood ; Aspartate Aminotransferases ; blood ; Enzyme-Linked Immunosorbent Assay ; Female ; Hepatitis B ; blood ; Hepatitis B, Chronic ; blood ; Humans ; Liver Cirrhosis ; blood ; virology ; Liver Neoplasms ; blood ; virology ; Male ; Middle Aged ; Serum Albumin ; analysis ; TNF-Related Apoptosis-Inducing Ligand ; blood ; Young Adult

In order to investigate the effect of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) on acute myeloid leukemic (AML) cells, BMMNC or PBMNC of 39 cases of AML (patient group) and 21 normal persons (control group) were isolated; the cytotoxic effects of TRAIL at various concentration on the cells were evaluated by MMT, apoptosis were detected by flow cytometry. The results showed that TRAIL of various concentration could kill AML cells in various degrees, but had no killing effect on normal cells. It is concluded that TRAIL can kill AML cells through inducing apoptosis, and TRAIL has a promising prospect in clinical use.
Adult ; Apoptosis ; drug effects ; Cell Survival ; drug effects ; Dose-Response Relationship, Drug ; Female ; Flow Cytometry ; Humans ; Leukemia, Myeloid, Acute ; blood ; pathology ; Male ; Middle Aged ; Recombinant Proteins ; pharmacology ; TNF-Related Apoptosis-Inducing Ligand ; genetics ; metabolism ; pharmacology ; Tumor Cells, Cultured

OBJECTIVETo describe a novel mechanism for TRAIL up-regulation of CD4+, CD8+ T cells to participate in the pathophysiological process in patients with chronic hepatitis B (CHB).

METHODSThe serum levels of soluble TRAIL (sTRAIL), IFN-gamma and membrane bound TRAIL expression on peripheral leucocytes from 58 CHB patients were examined by ELISA and flow cytometry respectively. The levels of TRAIL were compared with the baseline levels of 15 healthy controls, and correlation analysis were performed between ALT, TBil and PT, morphological change in hepatic tissues.

RESULTSThe results showed that TRAIL levels on membranes of CD4+, CD8+ T cells in CHB patients were much higher than the healthy controls (P < 0.001), which of CD4+ T cells positively correlated with serum TBil (r=0.354, P = 0.008), Serum IFN-gamma level (r=0.302, P = 0.011) and which of CD8+ T cells positively correlated with serum TBil (r=0.522, P = 0.000), ALT (r=0.393, P = 0.003), PT (r=0.385, P = 0.004), serum IFN-gamma level (r=0.307, P = 0.009). The serum levels of soluble TRAIL only correlated with serum HBeAg expression (r=0.695, P = 0.001).

CONCLUSIONThese findings suggest that the expression of TRAIL on the membranes of lymphocytes was up-regulated, which may take part in the immunopathogenesis in CHB patients. TRAIL expression can be induced either by virus-specific protein expression or by inflammation cytokine IFN-gamma

Adult ; Aged ; Apoptosis Regulatory Proteins ; CD4-Positive T-Lymphocytes ; chemistry ; CD8-Positive T-Lymphocytes ; chemistry ; DNA, Viral ; blood ; Female ; Hepatitis B, Chronic ; immunology ; pathology ; Humans ; Interferon-gamma ; blood ; Male ; Membrane Glycoproteins ; biosynthesis ; blood ; Middle Aged ; TNF-Related Apoptosis-Inducing Ligand ; Tumor Necrosis Factor-alpha ; biosynthesis ; Up-Regulation

BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to induce apoptosis in various tumor cells but not in normal cells, which suggests its potential use as a tumor-specific antineoplastic agent. In the present study, we examined here that the treatment of TRAIL-resistant leukemia cells with a low dose doxorubicin in combination of TRAIL induces a synergistic apoptotic response. METHODS: Cell growth inhibition was assessed by MTT assay, and the induction of apoptosis was examined using flow cytometry after stained with Annexin V. To find out the molecular change of the TRAIL receptors and caspase expression in acute leukemia cell lines and human umbilical cord blood (UCB) mononuclear cells, RT-PCR for TRAIL receptors and western blot analysis for DR4, DR5, and caspase 3, 7, 8, and 9 were performed. RESULTS: The Jurkat cell line was TRAIL sensitive and TRAIL-resistant Molt-4 cell line became sensitive after treatment with TRAIL and a low dose of doxorubicin (0.1micrometer), but UCB mononuclear cells remained resistant. DR4 expression was increased when TRAIL-sensitive Jurkat cells were treated with TRAIL. DR5 expression was increased after exposing TRAIL- resistant Molt-4 cell line to TRAIL plus a low dose of doxorubicin for 24 hours. The expression of DR4 and DR5 in UCB mononuclear cells was unchanged after treatment with TRAIL, a low dose doxorubicin, or TRAIL plus a low dose of doxorubicin. Activated caspase 3 expression was augmented by TRAIL plus a low dose of doxorubicin than TRAIL or a low dose of doxorubicin alone in TRAIL-resistant Molt-4 cells. CONCLUSION: A low dose doxorubicin in combination with TRAIL may effectively promote caspase activation in TRAIL-resistant leukemia cells. Apoptosis synergistically induced by the combination of a low dose doxorubicin and TRAIL might be considered as an effective and safe tool in treating TRAIL-resistant acute leukemia.
Annexin A5 ; Apoptosis ; Blotting, Western ; Caspase 3 ; Cell Line* ; Doxorubicin* ; Fetal Blood ; Flow Cytometry ; Humans ; Jurkat Cells ; Leukemia* ; Necrosis ; Receptors, TNF-Related Apoptosis-Inducing Ligand