scholarly journals Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 41 ◽  
Author(s):  
Simonetta Pazzaglia ◽  
Claudio Pioli
Keyword(s):  
Dna Repair ◽  
Inflammatory Responses ◽  
Parp Inhibitors ◽  
Protective Role ◽  
Therapeutic Implications ◽  
Inflammatory Processes ◽  
Clinical Conditions ◽  
Cancer And Inflammation ◽  
Parp 1

PARP-1 (poly(ADP-ribose)-polymerase 1), mainly known for its protective role in DNA repair, also regulates inflammatory processes. Notably, defects in DNA repair and chronic inflammation may both predispose to cancer development. On the other hand, inhibition of DNA repair and inflammatory responses can be beneficial in cancer therapy and PARP inhibitors are currently used for their lethal effects on tumor cells. Furthermore, excess of PARP-1 activity has been associated with many tumors and inflammation-related clinical conditions, including asthma, sepsis, arthritis, atherosclerosis, and neurodegenerative diseases, to name a few. Activation and inhibition of PARP represent, therefore, a double-edged sword that can be exploited for therapeutic purposes. In our review, we will discuss recent findings highlighting the composite multifaceted role of PARP-1 in cancer and inflammation-related diseases.

scholarly journals The Role of Poly(ADP-ribose) Polymerase-1 in Rheumatoid Arthritis

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Samuel García ◽  
Carmen Conde
Keyword(s):  
Rheumatoid Arthritis ◽  
Septic Shock ◽  
Dna Repair ◽  
Beneficial Effect ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Genomic Stability ◽  
Inflammatory Processes ◽  
Parp 1

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme with a crucial role in the maintenance of genomic stability. In addition to the role of PARP-1 in DNA repair, multiple studies have also demonstrated its involvement in several inflammatory diseases, such as septic shock, asthma, atherosclerosis, and stroke, as well as in cancer. In these diseases, the pharmacological inhibition of PARP-1 has shown a beneficial effect, suggesting that PARP-1 regulates their inflammatory processes. In recent years, we have studied the role of PARP-1 in rheumatoid arthritis, as have other researchers, and the results have shown that PARP-1 has an important function in the development of this disease. This review summarizes current knowledge on the effects of PARP-1 in rheumatoid arthritis.

scholarly journals PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression

2018 ◽  
Vol 115 (17) ◽  
pp. E4061-E4070 ◽  
Author(s):  
Bastian Dörsam ◽  
Nina Seiwert ◽  
Sebastian Foersch ◽  
Svenja Stroh ◽  
Georg Nagel ◽  
...  
Keyword(s):  
Cell Death ◽  
Dna Repair ◽  
Tumor Progression ◽  
Dna Methyltransferase ◽  
Intestinal Inflammation ◽  
Colorectal Tumor ◽  
Colorectal Carcinogenesis ◽  
Dependent Manner ◽  
Parp 1

Colorectal cancer (CRC) is one of the most common tumor entities, which is causally linked to DNA repair defects and inflammatory bowel disease (IBD). Here, we studied the role of the DNA repair protein poly(ADP-ribose) polymerase-1 (PARP-1) in CRC. Tissue microarray analysis revealed PARP-1 overexpression in human CRC, correlating with disease progression. To elucidate its function in CRC, PARP-1 deficient (PARP-1−/−) and wild-type animals (WT) were subjected to azoxymethane (AOM)/ dextran sodium sulfate (DSS)-induced colorectal carcinogenesis. Miniendoscopy showed significantly more tumors in WT than in PARP-1−/− mice. Although the lack of PARP-1 moderately increased DNA damage, both genotypes exhibited comparable levels of AOM-induced autophagy and cell death. Interestingly, miniendoscopy revealed a higher AOM/DSS-triggered intestinal inflammation in WT animals, which was associated with increased levels of innate immune cells and proinflammatory cytokines. Tumors in WT animals were more aggressive, showing higher levels of STAT3 activation and cyclin D1 up-regulation. PARP-1−/− animals were then crossed with O6-methylguanine-DNA methyltransferase (MGMT)-deficient animals hypersensitive to AOM. Intriguingly, PARP-1−/−/MGMT−/− double knockout (DKO) mice developed more, but much smaller tumors than MGMT−/− animals. In contrast to MGMT-deficient mice, DKO animals showed strongly reduced AOM-dependent colonic cell death despite similar O6-methylguanine levels. Studies with PARP-1−/− cells provided evidence for increased alkylation-induced DNA strand break formation when MGMT was inhibited, suggesting a role of PARP-1 in the response to O6-methylguanine adducts. Our findings reveal PARP-1 as a double-edged sword in colorectal carcinogenesis, which suppresses tumor initiation following DNA alkylation in a MGMT-dependent manner, but promotes inflammation-driven tumor progression.

scholarly journals A Review on DNA Repair Inhibition by PARP Inhibitors in Cancer Therapy

Folia Medica ◽  
2018 ◽  
Vol 60 (1) ◽  
pp. 39-47 ◽  
Author(s):  
Ashish P. Shah ◽  
Chhagan N. Patel ◽  
Dipen K. Sureja ◽  
Kirtan P. Sanghavi
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Therapy ◽  
Repair Process ◽  
Parp Inhibitors ◽  
Brca Mutations ◽  
Development Of Resistance ◽  
Damage Repair ◽  
Future Therapy

AbstractThe DNA repair process protects the cells from DNA damaging agent by multiple pathways. Majority of the cancer therapy cause DNA damage which leads to apoptosis. The cell has natural ability to repair this damage which ultimately leads to development of resistance of drugs. The key enzymes involved in DNA repair process are poly(ADP-ribose) (PAR) and poly(ADP-ribose) polymerases (PARP). Tumor cells repair their defective gene via defective homologues recombination (HR) in the presence of enzyme PARP. PARP inhibitors inhibit the enzyme poly(ADP-ribose) polymerases (PARPs) which lead to apoptosis of cancer cells. Current clinical data shows the role of PARP inhibitors is not restricted to BRCA mutations but also effective in HR dysfunctions related tumors. Therefore, investigation in this area could be very helpful for future therapy of cancer. This review gives detail information on the role of PARP in DNA damage repair, the role of PARP inhibitors and chemistry of currently available PARP inhibitors.

scholarly journals Protective Role of C3aR (C3a Anaphylatoxin Receptor) Against Atherosclerosis in Atherosclerosis-Prone Mice

2020 ◽  
Vol 40 (9) ◽  
pp. 2070-2083
Author(s):  
Lin-Lin Wei ◽  
Ning Ma ◽  
Kun-Yi Wu ◽  
Jia-Xing Wang ◽  
Teng-Yue Diao ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Protective Role ◽  
Plaque Burden ◽  
Aortic Tissue ◽  
M2 Macrophage ◽  
Proinflammatory Mediators ◽  
Anti Inflammatory

Objective: Emerging evidence suggests that C3aR (C3a anaphylatoxin receptor) signaling has protective roles in various inflammatory-related diseases. However, its role in atherosclerosis has been unknown. The purpose of the study was to investigate the possible protective role of C3aR in aortic atherosclerosis and explore molecular and cellular mechanisms involved in the protection. Approach and Results: C3ar −/− /Apoe −/− mice were generated by cross-breeding of atherosclerosis-prone Apoe −/− mice and C3ar −/− mice. C3ar −/− /Apoe −/− mice and Apoe −/− mice (as a control) underwent high-fat diet for 16 weeks were assessed for (1) atherosclerotic plaque burden, (2) aortic tissue inflammation, (3) recruitment of CD11b + leukocytes into atherosclerotic lesions, and (4) systemic inflammatory responses. Compared with Apoe −/− mice, C3ar −/− /Apoe −/− mice developed more severe atherosclerosis. In addition, C3ar −/− /Apoe −/− mice have increased local production of proinflammatory mediators (eg, CCL2 [chemokine (C-C motif) ligand 2], TNF [tumor necrosis factor]-α) and infiltration of monocyte/macrophage in aortic tissue, and their lesional macrophages displayed an M1-like phenotype. Local pathological changes were associated with enhanced systemic inflammatory responses (ie, elevated plasma levels of CCL2 and TNF-α, increased circulating inflammatory cells). In vitro analyses using peritoneal macrophages showed that C3a stimulation resulted in upregulation of M2-associated signaling and molecules, but suppression of M1-associated signaling and molecules, supporting the roles of C3a/C3aR axis in mediating anti-inflammatory response and promoting M2 macrophage polarization. Conclusions: Our findings demonstrate a protective role for C3aR in the development of atherosclerosis and suggest that C3aR confers the protection through C3a/C3aR axis–mediated negative regulation of proinflammatory responses and modulation of macrophage toward the anti-inflammatory phenotype.

scholarly journals A Protective Role of Aryl Hydrocarbon Receptor Repressor in Inflammation and Tumor Growth

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 589 ◽  
Author(s):  
Christoph F. A. Vogel ◽  
Yasuhiro Ishihara ◽  
Claire E. Campbell ◽  
Sarah Y. Kado ◽  
Aimy Nguyen-Chi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Aryl Hydrocarbon Receptor ◽  
Inflammatory Responses ◽  
Environmental Pollutants ◽  
Protective Role ◽  
Potential Therapeutic Target ◽  
Embryonic Fibroblasts ◽  
Aryl Hydrocarbon ◽  
Enhancer Binding Protein

The aryl hydrocarbon receptor (AhR) is known for mediating the toxicity of environmental pollutants such as dioxins and numerous dioxin-like compounds, and is associated with the promotion of various malignancies, including lymphoma. The aryl hydrocarbon receptor repressor (AhRR), a ligand-independent, transcriptionally inactive AhR-like protein is known to repress AhR signaling through its ability to compete with the AhR for dimerization with the AhR nuclear translocator (ARNT). While AhRR effectively blocks AhR signaling, several aspects of the mechanism of AhRR’s functions are poorly understood, including suppression of inflammatory responses and its putative role as a tumor suppressor. In a transgenic mouse that overexpresses AhRR (AhRR Tg) we discovered that these mice suppress 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)- and inflammation-induced tumor growth after subcutaneous challenge of EL4 lymphoma cells. Using mouse embryonic fibroblasts (MEF) we found that AhRR overexpression suppresses the AhR-mediated anti-apoptotic response. The AhRR-mediated inhibition of apoptotic resistance was associated with a suppressed expression of interleukin (IL)-1β and cyclooxygenase (COX)-2, which was dependent on activation of protein kinase A (PKA) and the CAAT-enhancer-binding protein beta (C/EBPβ). These results provide mechanistic insights into the role of the AhRR to suppress inflammation and highlight the AhRR as a potential therapeutic target to suppress tumor growth.

scholarly journals Prototypical anti-inflammatory cytokine IL-10 prevents loss of IGF-I-induced myogenin protein expression caused by IL-1β

2008 ◽  
Vol 294 (4) ◽  
pp. E709-E718 ◽  
Author(s):  
Klemen Strle ◽  
Robert H. McCusker ◽  
Rodney W. Johnson ◽  
Samantha M. Zunich ◽  
Robert Dantzer ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Muscle Wasting ◽  
Inflammatory Responses ◽  
Mapk Signaling ◽  
Protective Role ◽  
Igf I ◽  
Anti Inflammatory ◽  
Kinase Pathway ◽  
Anti Inflammatory Cytokine

Prolonged and excessive inflammation is implicated in resistance to the biological actions of IGF-I and contributes to the pathophysiology of neurodegenerative, metabolic, and muscle-wasting disorders. IL-10 is a critical anti-inflammatory cytokine that restrains inflammatory responses in macrophages and T cells by inhibiting cytokine and chemokine synthesis and reducing expression of their receptors. Here we demonstrate that IL-10 plays a protective role in nonhematopoietic cells by suppressing the ability of exogenous IL-1β to inhibit IGF-I-induced myogenin and myosin heavy chain expression in myoblasts. This action of IL-10 is not caused by impairment of IL-1β-induced synthesis of IL-6 or the ability of IL-1β to activate two members of the MAPK family, ERK1/2 and p38. Instead, this newly defined protective role of IL-10 occurs by specific reversal of IL-1β activation of the JNK kinase pathway. IL-10 blocks IL-1β-induced phosphorylation of JNK, but not ERK1/2 or p38, indicating that only the JNK component of the IL-1β-induced MAPK signaling pathway is targeted by IL-10. This conclusion is supported by the finding that a specific JNK inhibitor acts similarly to IL-10 to restore IGF-I-induced myogenin expression, which is suppressed by IL-1β. Collectively, these data demonstrate that IL-10 acts in a novel, nonclassical, protective manner in nonhematopoietic cells to inhibit the IL-1β receptor-induced JNK kinase pathway, resulting in prevention of IGF-I resistance.

scholarly journals Role of Nicotinamide in DNA Damage, Mutagenesis, and DNA Repair

2010 ◽  
Vol 2010 ◽  
pp. 1-13 ◽  
Author(s):  
Devita Surjana ◽  
Gary M. Halliday ◽  
Diona L. Damian
Keyword(s):  
Dna Repair ◽  
Cellular Responses ◽  
Water Soluble ◽  
Vitamin B3 ◽  
Atp Production ◽  
Amide Form ◽  
Parp 1

Nicotinamide is a water-soluble amide form of niacin (nicotinic acid or vitamin B3). Both niacin and nicotinamide are widely available in plant and animal foods, and niacin can also be endogenously synthesized in the liver from dietary tryptophan. Nicotinamide is also commercially available in vitamin supplements and in a range of cosmetic, hair, and skin preparations. Nicotinamide is the primary precursor of nicotinamide adenine dinucleotide (NAD+), an essential coenzyme in ATP production and the sole substrate of the nuclear enzyme poly-ADP-ribose polymerase-1 (PARP-1). Numerousin vitroandin vivostudies have clearly shown that PARP-1 and NAD+status influence cellular responses to genotoxicity which can lead to mutagenesis and cancer formation. This paper will examine the role of nicotinamide in the protection from carcinogenesis, DNA repair, and maintenance of genomic stability.

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