Poly(ADP-Ribose)Polymerase-1 in Lung Inflammatory Disorders: A Review.

Asthma, acute lung injury (ALI), and chronic obstructive pulmonary disease (COPD) are lung inflammatory disorders with a common outcome, that is, difficulty in breathing. Corticosteroids, a class of potent anti-inflammatory drugs, have shown less success in the treatment/management of these disorders, particularly ALI and COPD; thus, alternative therapies are needed. Poly(ADP-ribose)polymerases (PARPs) are the post-translational modifying enzymes with a primary role in DNA repair. During the last two decades, several studies have reported the critical role played by PARPs in a good of inflammatory disorders. In the current review, the studies that address the role of PARPs in asthma, ALI, and COPD have been discussed. Among the different members of the family, PARP-1 emerges as a key player in the orchestration of lung inflammation in asthma and ALI. In addition, PARP activation seems to be associated with the progression of COPD. Furthermore, PARP-14 seems to play a crucial role in asthma. STAT-6 and GATA-3 are reported to be central players in PARP-1-mediated eosinophilic inflammation in asthma. Interestingly, oxidative stress-PARP-1-NF-κB axis appears to be tightly linked with inflammatory response in all three-lung diseases despite their distinct pathophysiologies. The present review sheds light on PARP-1-regulated factors, which may be common or differential players in asthma/ALI/COPD and put forward our prospective for future studies

CLUSTERING LARGE APPLICATION USING METAHEURISTICS (CLAM) FOR GROUPING DISTRICTS BASED ON PRIMARY SCHOOL DATA ON THE ISLAND OF SUMATRA

K-medoids is one of the partitioning methods with the medoid as its center cluster, where medoid is the most centrally located object in a cluster, which is robust to outliers. The k-medoids algorithm used in this study is Clustering Large Application Using Metaheuristics (CLAM), where CLAM is a development of the Clustering Large Application based on Randomized Search (CLARANS) algorithm in improving the quality of cluster analysis by using hybrid metaheuristics between Tabu Search (TS) and Variable Neighborhood Search (VNS). In the case study, the best cluster analysis method for classifying sub-districts on the island of Sumatra based on elementary school availability and elementary school process standards is the CLAM method with k=6, num local = 2, max neighbor = 154, tls = 50 and set radius = 100-10:5. It can be seen that based on the overall average silhouette width value, the CLAM method is better than the CLARANS method

Beneficial effects of Caesalpinia digyna extract against acid aspiration-Induced acute lung injury in mice

Objective: Caesalpinia digyna belongs to the genus Caesalpinia, which is known since ancient times for its medicinal properties. The present work was designed to evaluate the beneficial potential of hydroalcoholic extract of the roots of C. dignea against hydrochloric acid (HCl)-induced acute lung injury in mice. Materials and Methods: Ethanolic extract of C. dignea roots at a dose of 50, 100, or 200 mg/kg boy weight was given once orally 90 min before HCl administration. Mice were then analyzed for infiltration of inflammatory cells in bronchoalveolar lavage fluid (BALF) and oxidative stress markers in the lung tissue. Further, the effects of the extract were compared with bergenin isolated from the extract. Results: Our results showed that an oral administration of the extract 90 min before HCl instillation reduced the infiltration of neutrophils in the lungs in a dose-dependent manner. Reduction in lung inflammation was associated with decline in pulmonary edema as the total protein content in the BALF was found to be decreased substantially. The drug also restored the redox balance in the lungs toward normal on HCl treatment as assessed by measuring the levels of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and catalase activity. Bergenin, isolated from the plant, was able to suppress the neutrophils but increased the macrophage number in BALF when administered before HCl instillation, suggesting immunoregulatory properties of the key constituent of the extract. Conclusion: Our data suggest that hydroalcoholic extract of Caesalpinia digyna roots constitute the phytochemicals that can protect against HCl-induced acute lung injury in mice.

PARP-1 inhibition ameliorates elastase induced lung inflammation and emphysema in mice.

COPD is associated with high morbidity and mortality and no effective treatment is available till date. We have previously reported that PARP-1 plays an important role in the establishment of airway inflammation associated with asthma and ALI. In the present work, we have evaluated the beneficial effects of PARP-1 inhibition on COPD pathogenesis utilizing elastase induced mouse model of the disease. Our data show that PARP-1 inhibition by olaparib significantly reduced the elastase-induced recruitment of inflammatory cells particularly neutrophils in the lungs of mice when administered at a dose of 5 mg/kg b.wt (i.p.). Reduction in the lung inflammation was associated with suppressed myeloperoxidase activity. Further, the drug restored the redox status in the lung tissues towards normal as reflected by the levels of ROS, GSH and MDA. Olaparib administration prior to elastase instillation blunted the phosphorylation of P65-NF-κB at Ser 536 without altering phosphorylation of its inhibitor IκBα in the lungs. Furthermore, olaparib down regulated the elastase-induced expression of NF-κB dependent pro-inflammatory cytokines (TNF-A, IL-6), chemokine (MIP-2) and growth factor (GCSF) severely both at the mRNA and protein levels. Additionally, PARP-1 heterozygosity suppressed the recruitment of inflammatory cells and production of TNF-A, IL-6, MIP-2 and GCSF in the BALF to the similar extent as exhibited by olaparib administration. Finally, PARP-1 inhibition by olaparib or gene deletion protected against elastase-induced emphysema markedly. Overall, our data strongly suggest that PARP-1 plays a critical role in elastase induced lung inflammation and emphysema, and thus may be a new drug target candidate in COPD

Gallic acid protects against the COPD-linked lung inflammation and emphysema in mice.

Objective and designGallic acid (GA) a naturally occurring phenolic compound, known to possess antioxidant/anti-inflammatory activities. The aim of the present work was to investigate the beneficial effects of GA against COPD-linked lung inflammation/emphysema by utilizing elastase (ET) and cigarette smoke (CS)-induced mice model.MaterialsMale BALB/c mice were treated with ET (1U/mouse) or exposed to CS (9 cigarettes/day for 4 days). GA administration was started 7 days (daily) prior to ET/CS exposure. Broncho-alveolar lavage was analyzed for inflammatory cells and pro-inflammatory cytokines. Lung homogenate was assessed for MPO activity/GSH/MDA/protein carbonyls. Further, Lung tissue was subjected to semi-quantitative RT-PCR, immunoblotting, and histological analysis.ResultsGA suppressed the ET-induced neutrophil infiltration, elevated MPO activity and production of pro-inflammatory cytokines (IL-6/TNF-α/IL-1β) at 24 h. Reduced inflammation was accompanied with normalization of redox balance as reflected by ROS/GSH/MDA/protein carbonyl levels. Further, GA suppressed phosphorylation of p65NF-κB and IκBα along with down-regulation of IL-1β/TNF-α/KC/MIP-2/GCSF genes. Furthermore, GA offered protection against ET-induced airspace enlargement and ameliorated MMP-2/MMP-9. Finally, GA suppressed the CS-induced influx of neutrophils and macrophages and blunted gene expression of TNF-α/MIP-2/KC.ConclusionOverall, our data show that GA effectively modulates pulmonary inflammation and emphysema associated with COPD pathogenesis in mice

Gallic acid ameliorates COPD-associated exacerbation in mice.

COPD is an inflammatory lung disease, which is often exacerbated with microbial infections resulting in worsening of respiratory symptoms. Gallic acid (GA), a naturally occurring phenolic compound is known to possess anti-oxidant/anti-inflammatory activity. We have recently reported that GA protects against the elastase (ET) induced lung inflammation and emphysema and the present work was designed to investigate the beneficial effects of Gallic acid against ET + Lipopolysachharide (LPS) induced COPD exacerbation like condition in mice model. Our data showed that i.t. administration of LPS at 21 days after ET instillation resulted in significant infiltration of inflammatory cells particularly neutrophils (p < 0.0001) into the lungs along with elevated levels of pro-inflammatory cytokines like TNF-α, IL-1β and IL-6 (p < 0.0001). Interestingly, daily administration of GA (200 mg/Kg b. wt.) starting 7 days before ET instillation, significantly blunted the ET + LPS induced inflammation as indicated by reduced number of inflammatory cells particularly neutrophils (p < 0.0001) in BALF along with suppression of myeloperoxidase activity (p = 0.0009) and production of pro-inflammatory cytokines (p < 0.0001). Further, GA also restored the redox imbalance in the lungs towards normal. Additionally, phosphorylation of p65-NF-κB was found to be reduced (p = 0.015), which was associated with downregulation in the gene expression of IL-1β (p = 0.022) and TNF-α (p = 0.04). Conversely, GA treatment resulted in increased protein levels of Nrf2 (p = 0.021) with concomitant increase in transcription of its downstream target genes HO-1 (p = 0.033) and Prdx-1 (p = 0.006). Overall, our data show that GA effectively modulates COPD exacerbation manifestations in mice potentially by restoring redox imbalance in lungs

Cordycepin Blocks Lung Injury-Associated Inflammation and Promotes BRCA1-Deficient Breast Cancer Cell Killing by Effectively Inhibiting PARP

Cordycepin has been shown to interfere with a myriad of molecular processes from RNA elongation to kinase activity, and prevents numerous inflammatory processes in animal models. Here we show in a mouse model of LPS-induced acute lung injury that cordycepin prevents airway neutrophilia via a robust blockade of expression of several inflammatory genes, including the adhesion molecule ICAM-1 and VCAM-1, the cytokine/chemokine MCP-1, MIP-1α, MIP-2 and KC, and the chemokine receptor CXCR2. Such a blockade appears to be related to a severe reduction in TNF-α expression. Interestingly, in an in vitro system of A549 epithelial cell inflammation, cordycepin effectively blocked LPS-induced, but not TNF-α-induced, VCAM-1 expression. Such effects correlated with a marked reduction in p65-NF-κB activation as assessed by its phosphorylation at serine-536 but without an apparent effect on its nuclear translocation. The effects of cordycepin on the expression of VCAM-1 and ICAM-1, and of NF-κB activation and nuclear translocation upon TNF-α stimulation resembled the effects achieved upon poly(ADP-ribose) polymerase (PARP) inhibition, suggesting that cordycepin may function as a PARP inhibitor. Indeed, cordycepin blocked H2O2-induced PARP activation in A549 cells. In a cell-free system, cordycepin inhibited PARP-1 activity at nanomolar concentrations. Similar to PARP inhibitors, cordycepin significantly induced killing of breast cancer susceptibility gene (BRCA1)-deficient MCF-7 cells, supporting its therapeutic use for the treatment of BRCA-deficient breast cancers. With added antiinflammatory characteristics, therapies that include cordycepin may prevent potential inflammation triggered by traditional chemotherapeutic drugs. Cordycepin, to the best of our knowledge, represents the first natural product possessing PARP inhibitory traits