1.Poly adenosine diphosphate-ribosylation and neurodegenerative diseases.
Journal of Zhejiang University. Medical sciences 2020;49(1):100-106
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
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Humans
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Neurodegenerative Diseases
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physiopathology
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Poly Adenosine Diphosphate Ribose
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Poly(ADP-ribose) Polymerases
;
metabolism
4.Determination of ribose and phosphorus contents in Haemophilus influenzae type b capsular polysaccharide by a quantitative NMR method using a single internal standard.
Chun-Jun QIN ; Jing HU ; Wei TONG ; Teng-Teng ZHANG ; Guang-Zong TIAN ; Xiao-Peng ZOU ; Jian-Kai LIU ; Jian YIN
Chinese Journal of Natural Medicines (English Ed.) 2022;20(8):633-640
The ribose and phosphorus contents in Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) are two important chemical indexes for the development and quality control of Hib conjugate vaccine. A quantitative 1H- and 31P-NMR method using a single internal standard was developed for simultaneous determination of ribose and phosphorus contents in Hib CPS. Hexamethylphosphoramide (HMPA) was successfully utilized as an internal standard in quantitative 1H-NMR method for ribose content determination. The ribose and phosphorus contents were found to be affected by the concentration of polysaccharide solution. Thus, 15-20 mg·L-1 was the optimal concentration range of Hib CPS in D2O solution for determination of ribose and phosphorus contents by this method. The ribose and phosphorus contents obtained by the quantitative NMR were consistent with those obtained by traditional chemical methods. In conclusion, this quantitative 1H- and 31P-NMR method using a single internal standard shows good specificity, accuracy and precision, providing a valuable approach for the quality control of Hib glycoconjugate vaccines.
Haemophilus Vaccines
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Haemophilus influenzae type b
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Phosphorus
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Polysaccharides, Bacterial
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Ribose
5.Guidance on the management of adverse reactions induced by poly(ADP-ribose) polymerase inhibitors.
Of Zhejiang Medical Association SOCIETY OF OBSTETRICS AND GYNECOLOGY ; Of Zhejiang Medical Association SOCIETY OF UROLOGY ; Of Zhejiang Anticancer Association COMMITTEE OF BREAST CANCER ; Of Zhejiang Anticancer Association Preparation COMMITTEE OF CLINICAL PHARMACY ON ONCOLOGY ; Of Zhejiang Society For Mathematical Medicine COMMITTEE OF UROLOGY
Journal of Zhejiang University. Medical sciences 2023;51(6):765-774
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
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Poly(ADP-ribose) Polymerase Inhibitors/adverse effects*
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Phthalazines/pharmacology*
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Poly(ADP-ribose) Polymerases
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Fatigue/drug therapy*
6.Construction of pharmacophore model of PARP-1 inhibitor.
Wen-Ting ZHANG ; Hao YAN ; Feng-Chao JIANG
Acta Pharmaceutica Sinica 2007;42(3):279-285
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
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Drug Design
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Enzyme Inhibitors
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chemistry
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pharmacology
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Models, Molecular
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Molecular Structure
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerase Inhibitors
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Poly(ADP-ribose) Polymerases
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chemistry
;
Protein Conformation
7.Suppressing poly(ADP-ribose)polymerase-1 inhibits tau phosphorylation in HEK293/tau441 cells.
Qin-Hao CHEN ; Xiao-Mei LIAO ; Shao-Hui WANG
Acta Physiologica Sinica 2011;63(6):511-516
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
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pharmacology
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Depression, Chemical
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Glycogen Synthase Kinase 3
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metabolism
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HEK293 Cells
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Humans
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Phosphorylation
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerase Inhibitors
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Poly(ADP-ribose) Polymerases
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metabolism
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tau Proteins
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metabolism
8.Enzymatic characterization of Mycobacterium smegmatis ADP-ribosyltransferase.
Eun Kyung SONG ; Sun Young LEE ; Jung Kil CHO ; Myung Kwan HAN ; Hwang Ho LEE
Journal of Bacteriology and Virology 2003;33(4):293-300
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
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ADP Ribose Transferases*
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Cytosol
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Escherichia coli
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Isoniazid
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Mycobacterium smegmatis*
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Mycobacterium*
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NAD+ Nucleosidase
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Novobiocin
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Physiological Processes
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Protein Processing, Post-Translational
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Rifampin
9.Design, synthesis and biological evaluation of novel 3-(2-oxo-2-substituted acetamido)benzamides as PARP-1 inhibitors.
Yu-wen YIN ; Ming JI ; Ran CAO ; Xiao-guang CHEN ; Bai-ling XU
Acta Pharmaceutica Sinica 2015;50(6):738-745
Poly(ADP-ribose)polymerase-1 (PARP-1) plays a significant role in the DNA repair process by catalyzing the transfer of ADP-ribose from NAD+ to its receptors. It is a promising anticancer drug target and many PARP-1 inhibitors have been developed and used in the clinical trial. In this work, a series of 3-(2-oxo-2-substituted acetamido)benzamides have been synthesized and their inhibitory activities against PARP-1 were evaluated. Of all the tested compounds, six compounds displayed inhibitory activities with IC50 values ranging from 0.23 to 5.78 µmol.L-1 . The binding pose of compound 5a was predicted using molecular docking to facilitate further structural modification.
Antineoplastic Agents
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Benzamides
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chemistry
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DNA Repair
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Drug Design
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Humans
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Molecular Docking Simulation
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Poly(ADP-ribose) Polymerase Inhibitors
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chemical synthesis
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chemistry
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Poly(ADP-ribose) Polymerases
10.Expression and purification of hPARP1 by baculovirus system.
Haiyan ZHOU ; Jun MA ; Xueli YANG ; Xiaohai GONG ; Qiuping LI ; Jian JIN
Chinese Journal of Biotechnology 2013;29(7):998-1005
PARP1 is an important part of DNA repair machinery. In recent years, PARP1 as novel anti-cancer therapeutic target has been broadly explored. In this study, we expressed hPARP1 enzyme in the baculovirus system and tested its activity. We inserted hPARP1 gene into the pFastBac1, a baculovirus transfer vector and then transformed it into DH10Bac containing a shuttle vector of Bacmid. After co-transfecting the recombinant plasmid into Sf9 insect cells, the expressed hPARP1 was purified by 3-aminobezamide affinity chromatography. The expression of hPARPI was visualized by SDS-PAGE and Western blotting; the activity of expressed and purified hPARP1 was confirmed by the reaction of consumption of NAD+ by hPARP1 in vitro. After the purification by 3-aminobezamide affinity column, 3.2 mg protein was obtained and its specific activity was 1.988 nmol/(min x microg).
Animals
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Baculoviridae
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genetics
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Blotting, Western
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Electrophoresis, Polyacrylamide Gel
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Genetic Vectors
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Humans
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Insecta
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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biosynthesis
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Recombinant Proteins
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Sf9 Cells
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Transfection