Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Necrotic lesions and necrotic cell death characterize severe autoimmune nephritides, and contribute to local inflammation and to progression of the disease. Poly(ADP-ribose) polymerase-1 (PARP-1), a DNA repair enzyme, is involved in the induction of necrosis and is a key player in the acute and chronic inflammation. Therefore, we hypothesized that PARP-1 controls the severity of nephritis by mediating the induction of necrosis in the kidney. We used lupus and anti-glomerular basement membrane models of nephritis to determine the effects of PARP-1 on the inflammatory response in the kidney. We show in this study that PARP-1 is indeed activated during the course of glomerulonephritis. We also show that the absence of PARP-1 or its pharmacological inhibition results in milder nephritis, with lower blood urea nitrogen levels, reduced necrotic lesions, and higher survival rates. The relevance of PARP-1 showed a strong male sex specificity, and treatment of male mice with 17beta-estradiol prolonged their survival during the course of nephritis. PARP-1 also regulated TNF-alpha expression and up-regulation of adhesion molecules, further supporting a role of PARP-1 in the inflammatory process within the kidney. Our results demonstrate that PARP-1 activation and consequent necrotic cell death play an important role in the pathogenesis of male nephritis, and suggest that PARP-1 can be a novel therapeutic target in glomerulonephritis.
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PMID:Poly(ADP-ribose) polymerase-1 regulates the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation. 1945 27

Management of fulminant hepatic failure (FHF) continues to be one challenging problem, and experimental animal models resembling its clinical conditions are still needed. Rabbit hemorrhagic disease (RHD) fullfils many requirements of an animal model of FHF. This work investigated changes in MAPK, NF-kappaB, AP-1 and STAT pathways during RHD-induced liver injury. Rabbits were infected with 2 x 10(4) hemagglutination units of an RHD virus isolate. Apoptosis was documented by the presence of caspase-3 activity and substantial PARP proteolysis at 36 and 48 h postinfection (pi). Infection induced a marked and maintained expression of TNF-alpha from 12 h pi, while there was only a transitory increase in IL-6 expression. Expression of phosphorylated (p)-JNK, p-p38 and p-ERK1/2 was significantly elevated at 12 h pi. At 48 h pi p-JNK expression was maintained at a maximum level, while that of p-p38 returned to normality and there was no p-ERK1/2 expression. Activation of NF-kappaB and AP-1 and increased expression of VCAM-1 and COX-2 were observed. No significant changes were detected in activation of STAT1 and STAT3, while SOCS3 expression increased significantly. The current findings suggest that activation of JNK is an essential component in liver injury mediated by the RHD virus and that lack of activation of STAT3, probably mediated by SOCS3 over-expression, would contribute to the inhibition of the regenerative response. Data show the presence of molecular mechanisms contributing to liver damage and the lack of regeneration and they support the usefulness of this model to investigate novel therapeutical modalities in FHF.
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PMID:Signaling pathways involved in liver injury and regeneration in rabbit hemorrhagic disease, an animal model of virally-induced fulminant hepatic failure. 1972 19

Minocycline exerts anti-inflammatory and anti-apoptotic effects distinct from its antimicrobial function. In this study we investigated the effect of this drug on chemotherapy-induced gut damage. Body weight loss results, diarrhea scores, and villi measurements showed that minocycline attenuated the severity of intestinal mucositis induced by 5-fluorouracil (5-FU). Minocycline repressed the expression of TNF-alpha, IL-1beta, and iNOS, decreased the apoptotic index, and inhibited poly(ADP-ribose) polymerase-1 (PARP-1) activity in the mouse small intestine. In vitro experiments showed that minocycline suppressed the upregulation of PARP-1 activity in enterocyte IEC-6 cells treated with 5-FU. In addition, minocycline treatment appeared to enhance the antitumor effects of 5-FU in tumor CT-26 xenograft mice. Our results indicate that minocycline protects mice from gut injury induced by 5-FU and enhances the antitumor effects of 5-FU in xenograft mice. These observations suggest that minocycline treatment may benefit patients undergoing standard cancer chemotherapy by alleviating chemical-associated intestinal mucositis.
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PMID:Minocycline attenuates 5-fluorouracil-induced small intestinal mucositis in mouse model. 1976 44

This study was aimed at evaluating the role for poly(ADP-ribose) polymerase (PARP) in early nephropathy associated with type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with one of two structurally unrelated PARP inhibitors, 1,5-isoquinolinediol (ISO) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15427), at 3 mg/kg(-1) x d(-1) ip and 30 mg/kg(-1) x d(-1), respectively, for 10 wk after the first 2 wk without treatment. PARP activity in the renal cortex was assessed by immunohistochemistry and Western blot analysis of poly(ADP-ribosyl)ated proteins. Variables of diabetic nephropathy in urine and renal cortex were evaluated by ELISA, Western blot analysis, immunohistochemistry, and colorimetry. Urinary albumin excretion was increased about 4-fold in diabetic rats, and this increase was prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-associated increase in poly(ADP-ribose) immunoreactivities in renal glomeruli and tubuli and poly(ADP-ribosyl)ated protein level. Renal concentrations of TGF-beta(1), vascular endothelial growth factor, endothelin-1, TNF-alpha, monocyte chemoattractant protein-1, lipid peroxidation products, and nitrotyrosine were increased in diabetic rats, and all these changes as well as an increase in urinary TNF-alpha excretion were completely or partially prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-induced up-regulation of endothelin (B) receptor, podocyte loss, accumulation of collagen-alpha1 (IY), periodic acid-Schiff-positive substances, fibronectin, and advanced glycation end-products in the renal cortex. In conclusion, PARP activation is implicated in multiple changes characteristic for early nephropathy associated with type 1 diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies.
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PMID:Poly(Adenosine 5'-diphosphate-ribose) polymerase inhibition counteracts multiple manifestations of experimental type 1 diabetic nephropathy. 1985 69

Although peripheral immune cells infiltrate ischemic infarct tissue and elicit immune injury, the role of Cytotoxic T Lymphocytes (CTLs) and the toxins they release in mediating neuronal death is not well understood. Granzyme-b (Gra-b), a serine protease found in the cytoplasmic granules of CTLs and natural killer cells, plays an important role in inducing target cell death by activating several caspases and by initiating caspase-independent pathways that contribute to target cell death. To determine if CTLs and Gra-b are involved in post-ischemic cerebral cell death; we investigated the role of CD8(+) CTLs and Gra-b in ischemic rat brain infarct after transient middle cerebral artery occlusion (tMCAO) and in sham-operated animals. We observed that CTLs infiltrate the ischemic infarct within 1 h of reperfusion. There was a significant increase in Gra-b levels in the ischemic region starting from 1 h until 3 day which correlated with increased levels of chemokines (IP-10/CXCL10, IL-2) and TNF-alpha. Co-immunoprecipitation experiments show that Gra-b interacts with Bid, PARP, and caspase-3 in ischemic samples. Immunofluorescence analysis of Gra-b and TUNEL showed that Gra-b is present both in apoptotic and necrotic cells. Triple immunostaining further confirmed that the Gra-b positive degenerating cells were neurons. CTLs in close spatial proximity to degenerating neurons, increased levels of Gra-b, localization in neurons positive for TUNEL, and interaction with other pro-apoptotic proteins indicate that Gra-b and CTLs play a significant role in neuronal death following cerebral ischemia in the rat brain after tMCAO. Based on the above findings we support our hypothesis that Gra-b secreted from activated CTLs might be involved in aggravating post-ischemic damage by mediating neuronal death.
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PMID:Granzyme-b is involved in mediating post-ischemic neuronal death during focal cerebral ischemia in rat model. 1989 73

Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD(+) synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD(+) depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-gamma and TNF-alpha production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD(+)-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD(+) depletion. In addition, we relate defective IFN-gamma and TNF-alpha production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.
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PMID:Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE. 1993 64

The nuclear enzyme poly(ADP-ribose) polymerse-1 (PARP-1) has previously been reported to play an important role in lipopolysaccharide (LPS)-induced pulmonary inflammation and is highly activated in COPD patients. In the present study, the anti-inflammatory efficacy of a previously identified poly(ADP-ribose) polymerase-1 (PARP-1) inhibiting caffeine metabolite, 1,7-dimethylxanthine, was both in vivo as well as ex vivo evaluated. Orally administered 1,7-dimethylxanthine significantly attenuated lung myeloperoxidase-levels, transcription of IL-6, TNF-alpha, MIP1alpha and MIP2 genes as well as PAR-polymer formation in a mouse model of intratracheally LPS-induced acute pulmonary inflammation. Serum amyloid P component and plasma IL-6 were also lowered in 1,7-dimethylxanthine treated mice, indicating a reduced systemic inflammatory response. In addition, at 24h after LPS administration anti-inflammatory effects of 1,7-dimethylxanthine appeared more pronounced than those of the orally administered PARP-1 inhibitor 3-aminobenzamide. In the second model, in blood of COPD-patients and healthy controls ex vivo pre-incubated with a physiological concentration of 1,7-dimethylxanthine (10microM), LPS-induced production of the cytokines IL-6 and TNF-alpha was significantly suppressed. 1,7-Dimethylxanthine exerts anti-inflammatory effects, both in vivo mouse as well as ex vivo human. These results suggest that the PARP-1 inhibiting caffeine metabolite 1,7-dimethylxanthine may have therapeutic potential in pulmonary inflammatory diseases such as COPD.
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PMID:Inhibition of acute pulmonary and systemic inflammation by 1,7-dimethylxanthine. 1996 77

In this study, we demonstrate that human cardiomyocytes (AC16) produce reactive oxygen species (ROS) and inflammatory cytokines in response to Trypanosoma cruzi. ROS were primarily produced by mitochondria, some of which diffused to cytosol of infected cardiomyocytes. These ROS resulted in an increase in 8-hydroxyguanine lesions and DNA fragmentation that signaled PARP-1 activation evidenced by poly(ADP-ribose) (PAR) modification of PARP-1 and other proteins in infected cardiomyocytes. Phenyl-alpha-tert-butylnitrone blocked the mitochondrial ROS (mtROS) formation, DNA damage, and PARP-1 activation in infected cardiomyocytes. Further inhibition studies demonstrated that ROS and PARP-1 signaled TNF-alpha and IL-1beta expression in infected cardiomyocytes. ROS directly signaled the nuclear translocation of RelA (p65), NF-kappaB activation, and cytokine gene expression. PARP-1 exhibited no direct interaction with p65 and did not signal its translocation to nuclei in infected cardiomyocytes. Instead, PARP-1 contributed to PAR modification of p65-interacting nuclear proteins and assembly of the NF-kappaB transcription complex. PJ34 (PARP-1 inhibitor) also prevented mitochondrial poly(ADP-ribosyl)ation (PARylation) and ROS formation. We conclude that T. cruzi-mediated mtROS provide primary stimulus for PARP-1-NF-kappaB activation and cytokine gene expression in infected cardiomyocytes. PAR modification of mitochondrial membranes then results in a feedback cycle of mtROS formation and DNA damage/PARP-1 activation. ROS, either through direct modulation of cytosolic NF-kappaB, or via PARP-1-dependent PAR modification of p65-interacting nuclear proteins, contributes to cytokine gene expression. Our results demonstrate a link between ROS and inflammatory responses in cardiomyocytes infected by T. cruzi and provide a clue to the pathomechanism of sustained inflammation in Chagas disease.
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PMID:Trypanosoma cruzi induces the reactive oxygen species-PARP-1-RelA pathway for up-regulation of cytokine expression in cardiomyocytes. 2014 42

Honeybee (Apis mellifera) venom (BV) has a broad array of therapeutic applications in traditional medicine to treat variety of diseases. It is also known that BV possesses anti-inflammatory and anticancer effect and that it can inhibit proliferation and induces apoptosis in cancer cells, but there is no evidence of information regarding anti-apoptosis of BV on hepatocytes. In the present study, we investigated the anti-apoptotic effect of BV on tumor necrosis factor (TNF)-alpha with actinomycin (Act) D induces apoptosis in hepatocytes. TNF-alpha/Act D-treated hepatocytes were exposed to different low concentration (1, 10 and 100 ng/mL) of BV. Our results showed statistically significant inhibition in DNA damage caused by BV treatment compared to corresponding TNF-alpha/Act D-treated hepatocytes. BV suppressed TNF-alpha/Act Dtreated activation of bcl-2 family and caspase family, which resulted in inhibition of cytochrome c release and PARP cleavage. These results demonstrate that low concentration BV possess a potent suppressive effect on anti-apoptotic responses of TNF-alpha/Act D-treated hepatocytes and suggest that these compounds may contribute substantial therapeutic potential for the treatment of liver diseases.
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PMID:Bee venom protects hepatocytes from tumor necrosis factor-alpha and actinomycin D. 2019 21

This study evaluated poly(ADP-ribose) polymerase (PARP) inhibition as a new therapeutic approach for peripheral diabetic neuropathy using clinically relevant animal model and endpoints, and nitrotyrosine (NT), TNF-alpha, and nitrite/nitrate as potential biomarkers of the disease. Control and streptozotocin-diabetic rats were maintained with or without treatment with orally active PARP inhibitor 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one (GPI-15,427), 30 mg kg(-1) d(-1), for 10 wk after first 2 wk without treatment. Therapeutic efficacy was evaluated by poly(ADP-ribosyl)ated protein expression (Western blot analysis), motor and sensory nerve conduction velocities, and tibial nerve morphometry. Sciatic nerve and spinal cord NT, TNF-alpha, and nitrite/nitrate concentrations were measured by ELISA. NT localization in peripheral nervous system was evaluated by double-label fluorescent immunohistochemistry. A PARP inhibitor treatment counteracted diabetes-induced motor and sensory nerve conduction slowing, axonal atrophy of large myelinated fibers, and increase in sciatic nerve and spinal cord NT and TNF-alpha concentrations. Sciatic nerve NT and TNF-alpha concentrations inversely correlated with motor and sensory nerve conduction velocities and myelin thickness, whereas nitrite/nitrate concentrations were indistinguishable between control and diabetic groups. NT accumulation was identified in endothelial and Schwann cells of the peripheral nerve, neurons, astrocytes, and oligodendrocytes of the spinal cord, and neurons and glial cells of the dorsal root ganglia. The findings identify PARP as a compelling drug target for prevention and treatment of both functional and structural manifestations of peripheral diabetic neuropathy and provide rationale for detailed evaluation of NT and TNF-alpha as potential biomarkers of its presence, severity, and progression.
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PMID:New therapeutic and biomarker discovery for peripheral diabetic neuropathy: PARP inhibitor, nitrotyrosine, and tumor necrosis factor-{alpha}. 2035 21


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