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

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

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

OBJECTIVES: To investigate the effect of borneol on cutaneous toxicity of gilteritinib and to explore possible compounds that can intervene with the cutaneous toxicity. METHODS: C57BL/6J male mice were given gilteritinib by continuous gavage for 28 d and the damage to keratinocytes in the skin tissues was observed with hematoxylin and eosin (HE) staining, TUNEL assay and immunohistochemistry. Human keratinocytes HaCaT were treated with gilteritinib, and cell death and morphological changes were examined by SRB staining and microscopy; apoptosis of HaCaT cells was examined by Western blotting, flow cytometry with propidium iodide/AnnexinⅤ double staining and immunofluorescence; the accumulation of cellular reactive oxygen species (ROS) was examined by flow cytometry with DCFH-DA. Compounds that can effectively intervene the cutaneous toxicity of gilteritinib were screened from a natural compound library using SRB method, and the intervention effect of borneol on gilteritinib cutaneous toxicity was further investigated in HaCaT cells and C57BL/6J male mice. RESULTS: In vivo studies showed pathological changes in the skin with apoptosis of keratinocytes in the stratum spinosum and stratum granulosum in the modeling group. Invitro studies showed apoptosis of HaCaT cells, significant up-regulation of cleaved poly (ADP-ribose) polymerase (c-PARP) and gamma-H2A histone family member X (γ-H2AX) levels, and increased accumulation of ROS in gilteritinib-modeled skin keratinocytes compared with controls. Screening of the natural compound library revealed that borneol showed excellent intervention effects on the death of HaCaT cells. In vitro, cell apoptosis was significantly reduced in the borneol+gilteritinib group compared to the gilteritinib control group. The levels of c-PARP, γ-H2AX and ROS in cells were significantly decreased. In vivo, borneol alleviated gilteritinib-induced skin pathological changes and skin cell apoptosis in mice. CONCLUSIONS Gilteritinib induces keratinocytes apoptosis by causing intracellular ROS accumulation, resulting in cutaneous toxicity. Borneol can ameliorate the cutaneous toxicity of gilteritinib by reducing the accumulation of ROS and apoptosis of keratinocytes in the skin tissue.
Male ; Humans ; Animals ; Mice ; Reactive Oxygen Species/metabolism* ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology* ; Mice, Inbred C57BL ; Apoptosis ; Poly(ADP-ribose) Polymerases/metabolism*

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

PARP [poly(ADP-ribose)polymerase] represents a novel potential target in cancer therapy. It is involved in a DNA repair process by catalyzing the transfer of ADP-ribose units from NAD to a number of its substrate proteins. In this work, a series of novel azaindole derivatives was designed and synthesized. Moreover, 16 target molecules were screened and 8 compounds displayed inhibitory activity against PARP-1. It has been demonstrated that these azaindoles bearing cycloamine substituents at 2-position were active to both PARP-1 and PARP-2.
Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Aza Compounds ; chemical synthesis ; chemistry ; pharmacology ; Indoles ; chemical synthesis ; chemistry ; pharmacology ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; metabolism

BACKGROUNDSevere sepsis and septic shock are the leading causes of morbidity and mortality in hospitalized patients. This study aimed to investigate the association of poly (ADP-ribose) polymerase-1 (PARP-1) activity in circulating mononuclear cells with myocardial dysfunction in patients with septic shock.

METHODSA total of 64 patients with septic shock were divided into the survival group (n = 41) and the nonsurvival group (n = 23) according to mortality at 28 days after enrollments. PARP-1 activity in circulating mononuclear cells, brain natriuretic peptide, Acute Physiology and Chronic Health Evaluation II score, the cardiac index (CI), the cardiac function index (CFI), global ejection fraction (GEF), and the left ventricular contractility index (dp/dt max) were measured after admission to the intensive care unit.

RESULTSPARP-1 activity in circulating mononuclear cells of nonsurvival patients with septic shock was significantly higher than that in survival patients. PARP-1 activity in circulating mononuclear cells was strongly, negatively correlated with the CI, the CFI, GEF, and dp/dt max. Multiple Logistic regression analysis showed that PARP-1 activity in circulating mononuclear cells was an independent risk factor of myocardial dysfunction. The optimal cutoff point of PARP-1 activity for predicting 28-day mortality was 942 nmol/L with a sensibility of 78.2% and specificity of 65.1%.

CONCLUSIONPARP-1 activity in circulating mononuclear cells is significantly associated with myocardial dysfunction and may have prognostic value in patients with septic shock.

Aged ; Aged, 80 and over ; Female ; Humans ; Leukocytes, Mononuclear ; enzymology ; Male ; Middle Aged ; Poly(ADP-ribose) Polymerases ; metabolism ; Shock, Septic ; enzymology

Erythropoietin (EPO) is the major means of treating anemia of chronic disease (ACD) through stimulating hematopoiesis, inhibiting hepcidin and decreasing proinflammatory factors. Recently, it has been found that monocytes are another source of hepcidin. EPO can reduce the hepcidin stimulated by IL-6 in monocytes, it is assumed that EPO can reduce hepcidin indirectly by reducing IL-6. However, the specific mechanism of EPO inhibiting the proinflammatory cytokines in monocytes is unclear now. This study was purposed to investigate the effect of EPO on monocyte proinflammatory factors and its molecular mechanism. IL-6 mRNA and TNF-α mRNA were detected by real time PCR, level of signaling molecule PARP-1 protein was detected by Western blot. THP-1 monocytes were stimulated by 1 µg/ml lipopolysaccharide (LPS) to observe the impact of EPO at different concentrations (0.5, 1, 2, 5, 10 U/ml) for different time (0, 3, 6, 12, 24 hours) on the expression of IL-6 mRNA, TNF-α mRNA and PARP-1 protein. 1 µg/ml or 5 µg/ml EPO receptor (EPOR) antibody and/or 3-aminobenzamide (3-AB, PARP-1 inhibitor) were added to observe the antagonistic effect on EPO and the impact on PARP-1. The results showed that LPS could stimulate the THP-1 cells. EPO could decrease the levels of IL-6 and TNF-α stimulated by LPS in a dose- and time-dependent manners. The most significant decrease in IL-6 mRNA expression was observed in 2 U/ml EPO for 6 hours. And down-regulation of TNF-α mRNA expression was pronounced at 10 U/ml EPO for 3 hours. IL-6 mRNA expression could be stimulated by LPS, PARP-1 protein was induced at the same time. EPO inhibited the expression of IL-6 mRNA, while PARP-1 protein also decreased. Down-regulation of IL-6 mRNA and PARP-1 protein level was pronounced at 2 U/ml EPO for 6 hours. 3AB is a direct inhibitor of PARP-1. Similar to 3AB, EPO receptor antibody could antagonize the decline of IL-6 induced by EPO. It is concluded that EPO can inhibit the expression of IL-6 and TNF-α in monocytes, and the inhibition of IL-6 expression may be associated with decrease of PARP level.
Anemia ; metabolism ; Cell Line ; Erythropoietin ; pharmacology ; Humans ; Interleukin-6 ; metabolism ; Monocytes ; drug effects ; metabolism ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism

OBJECTIVETo investigate the effect of Actinidia chinensis Planch polysaccharide (ACPS) on the growth and apoptosis of human gastric cancer SGC-7901 cells, and to explore the effect of SGC-7901 cells on p-p38 expression.

METHODSThe inhibition rates at different concentrations of ACPS on SGC-7901 cells at 24, 48, and 72 h were detected using CCK-8 method. Apoptosis ratios in SGC-7901 were determined by flow cytometry after 48-h treatment of different concentrations of ACPS. The expression of pro-caspase-9, PARP, and p-p38 in SGC-7901 cells after treated by different concentrations of ACPS was detected using Western blot. The expression of pro-caspase-9, PARP, and p-p38 was detected after SGC-7901 cells were pre-treated by p38 specific inhibitor.

RESULTSCompared with the control group, the optical density of SGC-7901 cells decreased after treated by 1, 2.5, 5, and 10 mg/mL ACPS (P < 0.05). Meanwhile, the longer the acting time, the lower the optic density (P < 0.01). IC50 was 7.43 mg/mL at 24 h; 3.88 mg/mL at 48 h, and 1.32 mg/mL at 72 h respectively. ACPS suppressed the protein expression of pro-caspase-9 (P < 0.01) and up-regulated the expression of PARP (89KD) (both P < 0.01). Further study showed that the protein expression of p-p38 was up-regulated in SGC-7901 cells treated by ACPS of different concentrations at 24 h (P < 0.05). The expression of phosphorylation p38 and the ACPS induced apoptosis of SGC-7901 cells could be inhibited after treated by specific inhibitor for 2 h.

CONCLUSIONSACPS could inhibit the growth of SGC-7901 cells and induce apoptosis. The underlying mechanism of inducing apoptosis was partially due to activating the p38MAPK path and further activating Caspase9 and PARP, finally leading to cell death.

Actinidia ; chemistry ; Apoptosis ; drug effects ; Caspase 9 ; metabolism ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Humans ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; metabolism ; Polysaccharides ; pharmacology ; Stomach Neoplasms ; metabolism ; pathology ; p38 Mitogen-Activated Protein Kinases ; metabolism

This study was purposed to explore the inhibitory effect of Curcumin on growth of retinoic acid-resistant acute promyelocytic leukemia (APL) cells and its mechanism. The NB4-R1, an APL cell line resistant to retinoic acid, was used as a model. The growth level of NB4-R1 was detected by MTT assay, the morphologic features of cells were observed by light microscopy, the mitochondrial transmembrane potential was determined by flow cytometry, the expressions of apoptosis-related proteins procaspase 3, caspase 3, PARP and BCL-XL were measured by Western blot. The results indicated that the sensitivity of NB4-R1 to Curcumin was consistent with NB4 though NB4-R1 was resistant to retinoic acid, Curcumin displayed inhibitory effect on growth of NB4-R1 in time-and concentration-dependent manners. The morphologic observation showed existence of apoptotic bodies in NB4-R1 cells treated with 20 micromol/L of Curcumin. The flow cytometry indicated that the mitochondrial transmembrane potential in NB4-R1 cells treated with 20 micromol/L of Curcumin obviously decreased. The Western blot detection revealed that expressions of pro-caspase 3 and BCL-XL were down-regulated, expressions of caspase 3 and sheared PAPP were up-regulated in NB4-R1 cells treated with 20 micromol/L of Curcumin. It is concluded that the Curcumin can inhibit the growth and induce the apoptosis of NB4-R1.
Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Cell Line, Tumor ; Curcumin ; pharmacology ; Humans ; Leukemia, Promyelocytic, Acute ; metabolism ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; metabolism ; Tretinoin ; pharmacology ; bcl-X Protein ; metabolism