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

BACKGROUND: ADP-ribosyl pyrophosphatases (ADPRase) has been known to catalyze the hydrolysis of ADP-ribose to ribose-5-phosphate and AMP. The role of ADPRase has been suggested to sanitize the cell by removing potentially toxic ADP-ribose. In this study, we examined the effect of nitric oxide on ADPRase activity in macrophages. METHODS: ADPRase activity was measured in NO-inducing J774 cells. For in vitro experiments, recombinant human ADPRase was prepared in bacteria. RESULTS: ADPRase activity was increased by the treatment of exogenous NO generating reagent, sodium nitroprusside (SNP), in J774 cells. The increased ADPRase activity was mediated by the post-translational modification, likely to cause cADP-ribosylation via nitrosylation of cysteine residue on the enzyme. The stimulation with endogeneous NO inducers, TNF-alpha/IFN-gamma, also increased ADPRase activity through NO synthesis. Futhermore, ADPRase activity may be mediated by the post-translational modification of ADPRase, ADP-ribosylation. CONCLUSION: These results indicate that NO synthesized by macrophage activation plays a critical role in the increase in ADPRase activity following ADP-ribose metabolism.
Adenosine Diphosphate Ribose* ; Bacteria ; Cysteine ; Humans ; Hydrolysis ; Macrophage Activation ; Macrophages ; Metabolism ; Nitric Oxide* ; Nitroprusside ; Protein Processing, Post-Translational ; Pyrophosphatases

OBJECTIVE: There are some evidences that some epithelial ovarian cancer cells respond to hormonal therapy. And in vitro studies have revealed that treatment of various human cancer cell lines with selective cyclooxygenase 2 (COX-2) inhibitors induces apoptotic cell death. The goal of this article is to evaluate the effects of tamoxifen and celecoxib, a selective COX-2 inhibitor, on the ovarian cancer cells and the benefits of combining these agents in the management of ovarian cancer. METHODS: SK-OV-3 epithelial ovarian cancer cells were exposed to increasing concentration of tamoxifen (10(-8) M, 10(-7) M, 10(-6) M, 10(-5) M and 10(-4) M) and celecoxib (10(-8) M, 10(-7) M, 10(-6) M, 10(-5) M and 10(-4) M) as well as a combination of both drugs. The activity of apoptosis was evaluated by the morphologic examination and the MTT assay. The pattern of apoptosis was also assessed by the caspase-3 activity and the fraction of cleaved PARP (poly ADP-ribose polymerase) protein. RESULTS: Single application of both drugs could significantly increase the rate of apoptosis after 24 h of continuous exposure. Concomitant treatment of SK-OV-3 cells with tamoxifen and celecoxib induced significant increase in apoptosis, comparing with single drug exposure. The pattern of apoptosis induced by these agents on SK-OV-3 cells seemed to be caspase-3 dependent. CONCLUSION: Our data suggest that combining tamoxifen with selective COX-2 inhibitor seems to have at least an additive tumoricidal effect. A more definitive role for this combination therapy in clinical settings in ovarian cancer will need to be defined through the conduct of clinical trials.
Adenosine Diphosphate Ribose ; Apoptosis ; Caspase 3 ; Cell Death ; Cell Line* ; Cyclooxygenase 2 ; Humans ; Ovarian Neoplasms* ; Tamoxifen* ; Celecoxib

OBJECTIVE: In vitro studies have revealed that treatment of various human cancer cell lines with specific cyclooxygenase 2 (COX-2) inhibitors induces apoptotic cell death. The goal of this article is to investigate the benefits of combining COX-2 inhibitors with existing treatment modalities in the management of ovarian cancer. METHODS: In this study we sought to determine the effects of combining paclitaxel and the COX-2 inhibitor celecoxib on apoptosis of epithelial ovarian cancer (EOC) cells. SK-OV-3 cells were exposed to increasing concentrations of paclitaxel (10(-7) M, 10(-6) M and 10(-5) M) and celecoxib (10(-8) M, 10(-7) M, 10(-6) M, 10(-5) M and 10(-4) M) as well as a combination of both drugs. The activity of apoptosis was evaluated by the morphologic examination and the MTT assay. The pattern of apoptosis was also assessed by the caspase-3 activity and the fraction of cleaved PARP (poly ADP-ribose polymerase) protein. RESULTS: Single application of both drugs could significantly increase the rate of apoptosis after 24 hours of continuous exposure. But concomitant treatment of SK-OV-3 EOC cell line with paclitaxel and celecoxib resulted in marked impairment of paclitaxel-induced apoptosis. The pattern of apoptosis induced by paclitaxel on SK-OV-3 EOC cell line was caspase-3 independent. CONCLUSION: Combining COX-2 inhibitors and paclitaxel does not have an additive or synergistic tumoricidal effect. On the contrary, celecoxib treatment markedly inhibited the apoptotic effects of paclitaxel in SK-OV-3 EOC cell line.
Adenosine Diphosphate Ribose ; Apoptosis* ; Caspase 3 ; Cell Death ; Cell Line* ; Cyclooxygenase 2 ; Cyclooxygenase 2 Inhibitors ; Humans ; Ovarian Neoplasms* ; Paclitaxel ; Celecoxib

Extracellular nicotinamide adenine dinucleotide (NAD) cleaving activity of a particular cell type determines the rate of the degradation of extracellular NAD with formation of metabolites in the vicinity of the plasma membrane, which has important physiological consequences. It is yet to be elucidated whether intact human neutrophils have any extracellular NAD cleaving activity. In this study, with a simple fluorometric assay utilizing 1,N6-ethenoadenine dinucleotide (etheno-NAD) as the substrate, we have shown that intact peripheral human neutrophils have scant extracellular etheno-NAD cleaving activity, which is much less than that of mouse bone marrow neutrophils, mouse peripheral neutrophils, human monocytes and lymphocytes. With high performance liquid chromatography (HPLC), we have identified that ADP-ribose (ADPR) is the major extracellular metabolite of NAD degradation by intact human neutrophils. The scant extracellular etheno-NAD cleaving activity is decreased further by N-formyl-methionine-leucine-phenylalanine (fMLP), a chemoattractant for neutrophils. The fMLP-mediated decrease in the extracellular etheno-NAD cleaving activity is reversed by WRW4, a potent FPRL1 antagonist. These findings show that a much less extracellular etheno-NAD cleaving activity of intact human neutrophils compared to other immune cell types is down-regulated by fMLP via a low affinity fMLP receptor FPRL1.
Adenosine Diphosphate Ribose ; Animals ; Bone Marrow ; Cell Membrane ; Chromatography, Liquid ; Humans ; Lymphocytes ; Mice ; Monocytes ; NAD* ; Neutrophils* ; Receptors, Formyl Peptide

ADP-ribosyltransferase (ADPRT) catalyzes the reaction in which the ADP-ribose moiety of beta-NAD+ is transferred to specific amino acid residues in target proteins. The ADPRT of Mycobacterium smegmatis has been known to inactivate rifampin through ADP-ribosylation. However, the enzymatic characteristics and functions of the enzyme have not been elucidated yet. In this study, the ADPRT-glutathione S-transferase (GST) fusion protein was expressed in Escherichia coli and enzymatic characteristics of the fusion protein were investigated. ADPRT-GST fusion protein was an ADPribosyltransferase that had no NAD glycohydrolase activity. ADPRT-GST fusion protein showed no self-inactivation phenomenon that is a universal nature for all NAD glycohydrolases and is important in regulating its activity. ADPRT activity of the enzyme was decreased by novobiocin and isonicotinic acid hydrazide. These results suggest that Mycobacterium smegmatis ADPRT could be regulated by a different way from other NADases and involved in bacterial physiological process through a post-translational modification of cytosolic proteins.
Adenosine Diphosphate Ribose ; ADP Ribose Transferases* ; Cytosol ; Escherichia coli ; Isoniazid ; Mycobacterium smegmatis* ; Mycobacterium* ; NAD+ Nucleosidase ; Novobiocin ; Physiological Processes ; Protein Processing, Post-Translational ; Rifampin

Poly ADP-ribose polymerase inhibitors (PARPi), which approved in recent years, are recommended for ovarian cancer, breast cancer, pancreatic cancer, prostate cancer and other cancers by The National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines. Because most of PARPi are metabolized by cytochrome P450 enzyme system, there are extensive interactions with other drugs commonly used in cancer patients. By setting up a consensus working group including pharmaceutical experts, clinical experts and methodology experts, this paper forms a consensus according to the following steps: determine clinical problems, data retrieval and evaluation, Delphi method to form recommendations, finally formation expert opinion on PARPi interaction management. This paper will provide practical reference for clinical medical staff.
Male ; Female ; Humans ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology* ; Consensus ; Ovarian Neoplasms/drug therapy* ; Drug Interactions ; Adenosine Diphosphate Ribose/therapeutic use*

BACKGROUND AND OBJECTIVES: In oral cavity cancer (OCC) cells, the effects of interleukin-4 (IL-4) are various according to the cell specificity. However, if IL-4 induces apoptosis on OCC cells, the mediator of this apoptosis is uncertain. Therefore, we investigated whether apoptosis of OCC cells occurs by IL-4 and whether 15-lipoxygenase-1 (15-LO-1) induced by IL-4 is the possible mediator of this apoptosis. MATERIALS AND METHODS: SCC 1483 cells were used. Flow cytometry and poly ADP-ribose polymerase cleavage were used to examine apoptosis. Western blot analysis and reverse transcription-polymerase chain reaction were used to measure 15-LO-1 protein and mRNA. RESULTS: The inhibition of cell proliferation by more than 50% was noted from 10 ng/ml of IL-4. At this dose, apoptosis was observed and this apoptosis was inhibited by 2.2 microM caffeic acid. 15-LO-1 expression was observed from the 8 hour treatment of IL-4 and apoptosis increased after the 24 hour treatment of IL-4. In this apoptosis, caspase cascade, cyclooxygenase-2, and non-steroidal anti-inflammatory drugs-activated gene-1 (NAG-1) were not involved. CONCLUSION: IL-4 induced apoptosis in SCC 1483 OCC cells and 15-LO-1 induced by IL-4 may mediate this apoptotic pathway.
Adenosine Diphosphate Ribose ; Apoptosis* ; Arachidonate 15-Lipoxygenase ; Blotting, Western ; Cell Proliferation ; Cyclooxygenase 2 ; Flow Cytometry ; Interleukin-4* ; Mouth Neoplasms ; Mouth* ; RNA, Messenger ; Sensitivity and Specificity

Transient receptor potential (TRP) superfamily is a superfamily of cation channels that can be divided into seven subfamilies. TRPM2 is the second member of the TRPM subfamily, which includes eight members, namely TRPM1-8. TRPM2 is widely expressed in excitable and non-excitable cells, where it forms a Ca(2+)-permeable cation channel and performs diverse cellular functions. TRPM2 channels are activated by ADP-ribose (ADPR), Ca(2+), H2O2 and other reactive oxygen species (ROS). It is established that TRPM2 serves as a cellular sensor for oxidative stress, mediating oxidative stress-induced [Ca(2+)]i increase and contributing to pathological processes in many cell types. Accumulating evidence has indicated that TRPM2 is a potential therapeutic target for oxidative stress-related diseases. This review will highlight recent progress in this field.
Adenosine Diphosphate Ribose ; metabolism ; Calcium ; physiology ; Calcium Channels ; physiology ; Humans ; Hydrogen Peroxide ; metabolism ; Oxidative Stress ; Reactive Oxygen Species ; metabolism ; TRPM Cation Channels ; physiology

PURPOSE: To evaluate the anti-fibrotic effects of nilotinib on the survival of cultured human Tenon's capsule fibroblasts (HTFs). METHODS: HTF primary cultures were obtained from samples following glaucoma surgery. Primarily cultured HTFs were exposed to 1, 5, 10, and 20 µM nilotinib for 24 hours. The effects of nilotinib on HTF proliferation and cell viability were determined using the 3-(4,5-dimethylthiazone-2-yl)-2,5-diphenyl tetrazolium (MTT) assay, and apoptosis was determined by flow cytometry using annexin-V/propidium iodide (PI) double staining. Apoptosis-related proteins were detected by western blotting. RESULTS: The MTT assay showed that nilotinib induced an inhibition of HTF proliferation at concentrations of 10 and 20 µM (p < 0.001 and p < 0.001, respectively). Annexin V/PI double staining showed significantly increased apoptosis in cells treated with nilotinib. Nilotinib activated caspase-3, -9, and poly adenosine diphosphate ribose polymerase cleavage, and downregulated the expression of B-cell lymphoma-extra large and Bax, which indicated that nilotinib-induced apoptosis was partly mediated through the mitochondrial pathway. In addition, treatment with nilotinib decreased the expression of α-smooth muscle actin and transforming growth factor-β. CONCLUSIONS: Nilotinib decreased cell survival of cultured HTFs and induced mitochondria-mediated apoptosis. The results suggested that nilotinib may exert antiproliferative effects on HTFs, making it a possible agent to control postoperative fibrosis in patients undergoing glaucoma surgery.
Actins ; Apoptosis ; B-Lymphocytes ; Blotting, Western ; Caspase 3 ; Cell Survival ; Fibroblasts ; Fibrosis ; Flow Cytometry ; Glaucoma ; Humans ; In Vitro Techniques ; Poly Adenosine Diphosphate Ribose ; Tenon Capsule