Natural Killer (NK) cell activity of 47 operable stomach cancer patients was sequentially studied before and after chemotherapy in association with polyadenylic. polyuridylic acid [poly(A).poly(U)]. NK activity was determined by an in vitro 4 h chromium release assay using nonadherent mononuclear cells isolated from peripheral bloods as effectors and human myeloblastic cells (K562) as targets. The following results were obtained: 1) The mean NK activity of the 47 patients tested before chemotherapy was significantly lower than that of 14 healthy controls. 2) The patents who received chemotherapy consisting of 5 FU (12 mg/kg) and adriamycin (40 mg/M2) showed an increase in NK activity 5 days after injection as compared to that of the same patients tested before chemotherapy. 3) In these patients, an additional administration of poly(A) poly(U) (100mg) resulted in a further significant increase of NK activity 2 days later, whereas the control patients who received placebo showed no change of NK activity.
Adult ; Aged ; Combined Modality Therapy ; Doxorubicin/therapeutic use ; Female ; Fluorouracil/therapeutic use ; Human ; Killer Cells, Natural/drug effects* ; Male ; Middle Age ; Poly A-U/pharmacology ; Poly A-U/therapeutic use* ; Stimulation, Chemical ; Stomach Neoplasms/drug therapy* ; Stomach Neoplasms/surgery

The effects of polyadenylic.polyuridylic acid [poly(A).poly(U)] on in vitro proliferations of thymus and spleen cells from C57BL/6 mice were investigated. Mice were injected intravenously with 30 micrograms of poly(A).poly(U) or placebo. Two days later, thymus, spleen and peritoneal cells from these mice were prepared and cultured in pooled or non-pooled conditions. Cell proliferations were assessed by the technique of incorporation of tritiated thymidine. It has been revealed that the in vitro proliferations of thymus and spleen cells as well as the productions of interleukin-1 by peritoneal adhering cells and interleukin-2 by spleen cells were significantly enhanced in the cultures of cells from poly(A).poly(U)-treated mice. These enhancing effects were observed only in the cultures of pooled cells from mice whose genetic homogeneity is suspected. Furthermore, thymus cells from poly(A).poly(U)-treated mice acted as strong responder cells but not as stimulators in one way mixed cultures. Thus, the enhanced cellular responsiveness may be mediated by the increased production of cytokines and antigen recognitions of thymus-derived cells following activations via the adjuvant effect of poly(A).poly(U).
Animal ; Cell Division/drug effects ; Cells, Cultured ; Female ; Interleukin-1/biosynthesis ; Interleukin-2/biosynthesis ; Male ; Mice ; Mice, Inbred C57BL ; Poly A-U/administration & dosage/*pharmacology ; Spleen/*cytology ; Support, Non-U.S. Gov't ; Thymus Gland/*cytology

We have investigated in vitro proliferative responses of peripheral blood mononuclear cells and productions of interferon-gamma and soluble interleukin-2 receptors by these cells from 6 patients with chronic active hepatitis B immediately before and 24 hours after a single intravenous injection of 100 mg of polyadenylic.polyuridylic acid. Cell proliferations were assessed by the technique of tritiated-thymidine incorporation and productions of interferon-gamma and soluble interleukin-2 receptors were measured by enzyme-linked immunosorbent assay. The administration of polyadenylic.polyuridylic acid to the patients has resulted in significant increases of in vitro proliferations of their peripheral blood mononuclear cells as well as productions of interferon-gamma by these cells. However, in vitro productions of soluble interleukin-2 receptors were not changed significantly. These results suggest that the enhanced cellular responses by polyadenylic.polyuridylic acid might be due to the increased sensitivity rather than the increased expression of cellular interleukin-2 receptor.
Adult ; Hepatitis B/*immunology ; Hepatitis, Chronic/*immunology ; Human ; Immunity, Cellular/drug effects ; Interferon Type II/biosynthesis ; Leukocytes, Mononuclear/*drug effects/immunology ; Male ; Middle Age ; Poly A-U/*pharmacology ; Receptors, Interleukin-2/biosynthesis ; Solubility

The morbidity of neurodegenerative diseases are increased in recent years, however, the treatment is limited. Poly ADP-ribosylation (PARylation) is a post-translational modification of protein that catalyzed by poly(ADP-ribose) polymerase (PARP). Studies have shown that PARylation is involved in many neurodegenerative diseases such as stroke, Parkinson's diseases, Alzheimer's disease, amyotrophic lateral sclerosis and so on, by affecting intracellular translocation of protein molecules, protein aggregation, protein activity, and cell death. PARP inhibitors have showed neuroprotective efficacy for neurodegenerative diseases in pre-clinical studies and phase Ⅰ clinical trials. To find new PARP inhibitors with more specific effects and specific pharmacokinetic characteristics will be the new direction for the treatment of neurodegenerative diseases. This paper reviews the recent progress on PARylation in neurodegenerative diseases.
ADP-Ribosylation ; Humans ; Neurodegenerative Diseases ; physiopathology ; Poly Adenosine Diphosphate Ribose ; Poly(ADP-ribose) Polymerases ; metabolism

No abstract available.
Animals ; Antibody Formation* ; Immunoglobulin E* ; Mice* ; Poly I-C*

DNA Methylation ; Humans ; Poly(ADP-ribose) Polymerases ; genetics ; metabolism

Cardiovascular Diseases ; enzymology ; metabolism ; Humans ; Poly(ADP-ribose) Polymerases

The common adverse reactions caused by poly (ADP-ribose) polymerase (PARP) inhibitors include hematological toxicity, gastrointestinal toxicity and fatigue. The main prevention and treatment of hematological toxicity include: regular blood tests, referral to hematology department when routine treatment is ineffective, and being alert of myelodysplastic syndrome/acute myeloid leukemia. The key points to deal with gastrointestinal toxicity include: taking medicine at the right time, light diet, appropriate amount of drinking water, timely symptomatic treatment, prevention of expected nausea and vomiting, and so on. For fatigue, full assessment should be completed before treatment because the causes of fatigue are various; the management includes massage therapy, psychosocial interventions and drugs such as methylphenidate and Panax quinquefolius according to the severity. In addition, niraparib and fluzoparib can cause hypertension, hypertensive crisis and palpitation. Blood pressure and heart rate monitoring, timely symptomatic treatment, and multidisciplinary consultation should be taken if necessary. When cough and dyspnea occur, high resolution CT and bronchoscopy should be performed to exclude pneumonia. If necessary, PARP inhibitors should be stopped, and glucocorticoid and antimicrobial therapy should be given. Finally, more attention should be paid to drug interaction management, patient self-management and regular monitoring to minimize the risk and harm of adverse reactions of PARP inhibitors.
Humans ; Poly(ADP-ribose) Polymerase Inhibitors/adverse effects* ; Phthalazines/pharmacology* ; Poly(ADP-ribose) Polymerases ; Fatigue/drug therapy*

To construct the pharmacophore model of the poly (ADP-ribose) polymerase-1 inhibitor and to investigate the possible inhibitory mechanisms, ten pharmacophore models of PARP-1 inhibitor were established from the training set of thirty-eight PARP-1 inhibitors with conformer analysis and pharmacophore mapping by using the Catalyst software. Based on the mechanism of action and the known structure-activity relationship of PARP-1 inhibitor, an optimal pharmacophore model including two hydrogen-bonding acceptors and two aromatic hydrophobic core was confirmed. The reliability of the optimal pharmacophore model is preferably with RMS = 0.46, Correl = 0.91, Weight = 2.06, and Config = 15.97. This pharmacophore model not only provided some information about the interaction between enzyme and compound, but also showed excellent forecast ability and contributes to design the PARP-1 inhibitors with undiscovered structure.
Computer-Aided Design ; Drug Design ; Enzyme Inhibitors ; chemistry ; pharmacology ; Models, Molecular ; Molecular Structure ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases ; chemistry ; Protein Conformation

The study aimed to investigate the effect of inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) activity on tau phosphorylation in HEK293/tau441 cells and its mechanism. HEK293/tau441 cells were treated with 3-aminobenzamide (3-AB), a PARP-1 inhibitor, at different doses (0.5, 1, 2, 4 mmol/L). After 24 h, the cell morphology was observed under phase contrast microscope, tau phosphorylation level in different sites (tau-1, tau-5, Thr231) and the activity of glycogen synthase kinase 3 (GSK-3) were detected by Western blotting. The results showed: (1) 3-AB at different doses failed to change the morphology of cells; (2) The 3-AB-induced decrease in activity of PARP-1 resulted in increase of unphosphorylation level in tau-1(Ser195/198/199/202) sites; (3) The phosphorylation of tau was decreased in Thr231 site, while the total tau was slightly changed after 3-AB treatment; (4) With the increased phosphorylation of GSK-3 at Ser9 site, the activity of GSK-3 was decreased after 3-AB treatment. The results suggest that the inhibition of PARP-1 by 3-AB could decrease tau phosphorylation in HEK293/tau441 cells probably through decreasing GSK-3 activity.
Benzamides ; pharmacology ; Depression, Chemical ; Glycogen Synthase Kinase 3 ; metabolism ; HEK293 Cells ; Humans ; Phosphorylation ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases ; metabolism ; tau Proteins ; metabolism