Ozone alleviates MSU-induced acute gout pain via upregulating AMPK/GAS6/MerTK/SOCS3 signaling pathway.

BACKGROUND: Gout pain seriously affects the quality of patients' life. There is still no effective treatment. The inflammatory response is the main mechanism of gout. Here, we found that ozone can reduce the inflammatory reaction in the joints of gouty mice and relieve gout pain, and we further explore its protective mechanism. METHODS: MSU was used to establish the gouty mice model. Nociception was assessed by Von Frey hairs. Cell signaling assays were performed by western blotting and immunohistochemistry. The mouse leukemia cells of monocyte macrophage line RAW264.7 were cultured to investigate the effects of ozone administration on macrophage. RESULTS: Ozone reduced inflammation, relieved gout pain and improved the paw mean intensity and duty cycle of the gouty mice. Ozone increased the phosphorylation of AMP-activated protein kinase (AMPK), induced suppressor of cytokine signaling 3 (SOCS3) expression and inhibited metallopeptidase 9 (MMP9) expression. In vivo, ozone activated AMPK to induce Gas6 release, and upregulated MerTK/SOCS3 signaling pathway to reduce inflammation in mouse macrophage line RAW264.7. Inhibitors of AMPK and MerTK, respectively abolished the analgesic and anti-inflammatory effects of ozone in vivo and in vitro. Gas6 knockout cancelled the protectively effects of ozone on gout pain and the paw mean intensity and duty cycle of gouty mice. Additionally, the level of Gas6 and protein S in plasma of patients with hyperuricemia was significantly higher than that of healthy contrast group. CONCLUSION: Ozone reduces inflammation and alleviates gout pain by activating AMPK to up-regulate Gas6/MerTK/SOCS3 signaling pathway.

Trends and projections of inflammatory bowel disease at the global, regional and national levels, 1990-2050: a bayesian age-period-cohort modeling study.

BACKGROUND: Inflammatory bowel disease (IBD) is a global health concern with varying levels and trends across countries and regions. Understanding these differences is crucial for effective prevention and treatment strategies. METHODS: Using data from the 2019 Global Burden of Disease study, we examine IBD incidence, mortality, and disability-adjusted life years (DALYs) rates in 198 countries from 1990 to 2019. To assess changes in the burden of IBD, estimated annual percentage changes (EAPC) were calculated, and a Bayesian age-period-cohort model was used to predict the future 30-year trends of IBD. RESULTS: In 2019, there were 405,000 new IBD cases globally (95% uncertainty interval (UI) 361,000 to 457,000), with 41,000 deaths (95% UI 35,000 to 45,000) and 1.62million DALYs (95% UI 1.36-1.92million). The global age-standardized incidence rate in 2019 was 4.97 per 100,000 person-years (95% UI 4.43 to 5.59), with a mortality rate of 0.54 (95% UI 0.46 to 0.59) and DALYs rate of 20.15 (95% UI 16.86 to 23.71). From 1990 to 2019, EAPC values for incidence, mortality, and DALYs rates were - 0.60 (95% UI - 0.73 to - 0.48), - 0.69 (95% UI - 0.81 to - 0.57), and - 1.04 (95% UI - 1.06 to - 1.01), respectively. Overall, the burden of IBD has shown a slow decline in recent years. In SDI stratification, regions with higher initial SDI (high-income North America and Central Europe) witnessed decreasing incidence and mortality rates with increasing SDI, while regions with lower initial SDI (South Asia, Oceania, and Latin America) experienced a rapid rise in incidence but a decrease in mortality with increasing SDI. Predictions using a Bayesian model showed lower new cases and deaths from 2020 to 2050 than reference values, while the slope of the predicted incidence-time curve closely paralleled that of the 2019 data. CONCLUSION: Increasing cases, deaths, and DALYs highlight the sustained burden of IBD on public health. Developed countries have stabilized or declining incidence rates but face high prevalence and societal burden. Emerging and developing countries experience rising incidence. Understanding these changes aids policymakers in effectively addressing IBD challenges in different regions and economic contexts.

DBP exposure induces thyroid inflammatory impairment through activating AKT/NF-κB/NLRP3 signaling.

Previous studies exhibited reproductive and neurodevelopmental toxicity in rats exposed to Di-n-butyl phthalate (DBP). However, the effects of DBP exposure on the other endocrine organ are still unclear. This study aimed to assess the impact of DBP exposure on the thyroid of male rats and the associated mechanisms. Here, rats were respectively treated with DBP at 0 (control), 50 (low dose), 250 (medium dose), or 500 (high dose) mg/kg/day dissolved in 1 ml quantity of corn oil by intragastrical administration for two weeks. The results demonstrated that the proliferation and inflammatory response changes were significantly different compared to the control. In vivo DBP is mainly converted to mono-n-butyl phthalate (MBP), an active form producing untoward reactions of DBP exposure. Therefore, for in vitro experiments, we treated the thyroid follicular epithelial cell line (Nthy-ori 3-1) in a temporal gradient using 1 mM MBP. Further in vitro studies showed that MBP exposure upregulated tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), as well as interleukin-1ß (IL-1ß) by activating AKT/NF-κB/NLRP3 signaling. Meanwhile, we detected that Pellino2 (Peli2) played an essential role in promoting the activation of NLRP3 inflammasome. Briefly speaking, this study confirmed that DBP exposure caused impaired thyroid structure and thyroid inflammation in male rats, which offered new views into the harm of DBP exposure on the endocrine organ.

Significance of the FGFR3 mutation in Chinese patients with bladder cancer.

Background: Bladder cancer (BC) is the 10th most common malignancy worldwide. The high recurrence rates of BC lead to significant treatment challenges. With the development of molecular biology techniques, research has shown that gene abnormalities are closely related to the occurrence and development of BC. This study analyzed the detection results of gene mutations in the tissue samples of BC patients and explored the relationship between fibroblast growth factor receptor 3 (FGFR3) and the prognosis and recurrence of BC. Methods: This study examined 82 Chinese patients with BC. Of these patients, 34 underwent radical cystectomy (RC), and 48 underwent transurethral resection with intravesical instillation. In addition, multi-gene panel targeted next-generation sequencing (NGS) of the samples was performed. Results: The mutational spectra revealed that C > T was the most common base substitution. Single nucleotide polymorphism (SNP) and deletion (DEL) were the common variant types in our cohort. The top 10 mutant genes were ROS1 (37%), PIK3CA (35%), FGFR3 (34%), BRAF (34%), ERBB2 (32%), ALK (27%), RET (27%), NTRK1 (24%), MET (23%), and EGFR (18%). FGFR3 mutations were detected more frequently in non-muscle-invasive bladder cancer (stages 0a, I) patients than in muscle-invasive bladder cancer (stage II, III, and IV) patients. The top 3 altered types of FGFR3 were p.Ser249Cys, p.Tyr375Cys, and p.Arg248Cys. Conclusions: This study examined the mutated types and frequency of FGFR3 and the prognosis of Chinese BC patients with FGFR mutations. We hope that our findings will enable clinical individualization strategies for BC patients to be optimized.

Embryonic 6:2 FTOH exposure causes reproductive toxicity by disrupting the formation of the blood-testis barrier in offspring mice.

Previous studies have revealed nephrotoxicity, hepatotoxicity, subchronic developmental and reproductive toxicity in rats exposed to fluorotelomer alcohol (FTOH). However, the effects of embryonic 6:2 FTOH exposure on the reproductive system of offspring mice remain unclear. The purpose of this study is to explore the reproductive toxic effects of embryonic 6:2 FTOH exposure on offspring male mice and the related molecular mechanisms. Therefore, the pregnant mice were given corn oil or 6:2 FTOH by gavage from gestational days 12.5-21.5. The results demonstrated that embryonic 6:2 FTOH exposure resulted in disrupted testicular structure, low expression of tight junction protein between Sertoli cells (SCs), impaired blood-testis barrier (BTB) formation and maturation, reduced sperm viability and increased malformation, and induced testicular inflammation in the offspring of mice. Further in vitro studies showed that 6:2 FTOH treatment upregulated MMP-8 expression by activating AKT/NF-κB signaling pathway, which in turn enhanced occludin cleavage leading to the disruption of SCs barrier integrity. In summary, this study demonstrated that 6:2 FTOH exposure caused reproductive dysfunction in male offspring through disruption of BTB, which provided new insights into the effects of 6:2 FTOH exposure on the offspring.

Opening KATP channels induces inflammatory tolerance and prevents chronic pain.

Current treatments for chronic pain are unsatisfactory, therefore, new therapeutics are urgently needed. Our previous study indicated that KATP channel openers have analgesic effects, but the underlying mechanism has not been elucidated. We speculated that KATP channel openers might increase suppressor of cytokine signaling (SOCS)-3 expression to induce inflammatory tolerance and attenuate chronic pain. Postoperative pain was induced by plantar incision to establish a chronic pain model. Growth arrest-specific 6 (Gas6)-/- and Axl-/- mice were used for signaling studies. The microglia cell line BV-2 was cultured for the in vitro experiments. The KATP channel opener significantly attenuated incision-induced mechanical allodynia in mice associated with the upregulated expression of SOCS3. Opening KATP channels induced the expression of SOCS3 in the Gas6/Axl signaling pathway in microglia, inhibited incision-induced mechanical allodynia by activating the Gas6/Axl-SOCS3 signaling pathway, and induced inflammatory tolerance to relieve neuroinflammation and postoperative pain. We demonstrated that opening of the KATP channel opening activated Gas6/Axl/SOCS3 signaling to induce inflammatory tolerance and relieve chronic pain. We explored a new target for anti-inflammatory and analgesic effects by regulating the innate immune system and provided a theoretical basis for clinical preemptive analgesia.

A novel SGLT2 inhibitor, SU-011, improves glycaemic control in rodents without the risk of hypoglycaemia and weight gain.

OBJECTIVE: To evaluate the pharmacological characteristics of SU-011, a novel sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor. METHODS: The in vitro activities of SU-011 were investigated in cell-based assays. The urinary glucose excretion, glucose tolerance and the risk of hypoglycaemia were evaluated in mice. Moreover, the dose-response relationship and chronic pharmacological studies of SU-011 were assessed in streptozotocin (STZ)-induced diabetic model, a STZ-treated model with impaired insulin secretion. KEY FINDINGS: SU-011 is a potential SGLT2 inhibitor with 5.6 nm inhibitory activity for SGLT2 and 1137-fold selectivity for SGLT1. In healthy mice, SU-011 improves the tolerance to a glucose load and promotes the urinary glucose excretion. Besides, SU-011 (10 mg/kg) still exhibited less risk of hypoglycaemia. During chronic treatment, SU-011 exhibited sustained glucose-lowering effect without the side effect of weight gain in STZ-induced diabetic mice. The levels of non-fasting and fasting plasma glucose, glycosylated haemoglobin, food and water intake were significantly decreased in SU-011-treated group. Moreover, SU-011 decreases the plasma levels of interleukin-1ß, tumour necrosis factor-α and C-reactive protein even better than that of dapagliflozin. CONCLUSIONS: All of these results indicated that SU-011 may be effective for the management of diabetes.

Gefitinib inhibits retina angiogenesis by affecting VEGF signaling pathway.

Gefitinib, a small-molecule multitargeted tyrosine kinase inhibitor, is reported to be as a new oral antiangiogenic molecule. However, it is unknown whether Gefitinib inhibits retina angiogenesis. In this study, we aimed to investigate the effect of Gefitinib on oxygen-induced retinal angiogenesis and the correlation between Gefitinib and VEGF signaling pathway. 12 cases of mice models of oxygen-induced retinopathy were obtained by exposing to 75% oxygen for 7 days. Then, these models were randomly assigned to two groups, and treated with Gefitinib and DMSO, respectively. Retinal vascular morphology was evaluated by Ink staining, HE staining and isolectin staining. Finally, the expression levels of VEGF, Cyclin E, CDK2, CD31 were detected in retinal tissues. Results shown that newborn retinal vessels and oxygen-induced vaso-obliteration were easily to be observed in oxygen-induced groups compared with controls. Meanwhile, the number of nonganglion cells and neovascular nuclei in oxygen-induced groups was significantly increased compared with those in control groups. However, when treated with Gefitinib, newborn retinal vessels in mice models of oxygen-induced retinopathy were significantly reduced. Further investigation confirmed that Gefitinib treatment affected the VEGF/Cyclin E/CDK2/CD31 pathway. In conclusion, these findings indicate that Gefitinib is critical for the treatment of retina angiogenesis, which is associated with VEGF/Cyclin E/CDK2/CD31 pathway.

Aberrant default mode network in amnestic mild cognitive impairment: a meta-analysis of independent component analysis studies.

Independent component analysis (ICA) is one of the most popular and valid methods to investigate the default mode network (DMN), an intrinsic network which attracts particular attention in amnestic mild cognitive impairment (aMCI). However, previous studies present inconsistent results regarding the topographical organization of the DMN in aMCI. Therefore, we conducted a quantitative, voxel-wise meta-analysis of resting-state ICA studies using Seed-based d Mapping to establish the most consistent pattern of DMN functional connectivity alterations in aMCI. Twenty studies, comprising 23 independent datasets involving 535 patients and 586 healthy controls, met the inclusion criteria. Patients with aMCI exhibited reliably lower DMN functional connectivity than the healthy controls in the bilateral precuneus/posterior cingulate cortices and medial temporal lobes, which are implicated in episodic memory deficits. Moreover, an exploratory meta-regression analysis revealed that greater severity of global cognitive impairment in the patient groups was associated with stronger functional connectivity in the bilateral medial frontal cortices (including the anterior cingulate cortices), left angular gyrus, and right temporal pole extending to the middle temporal gyrus, likely reflecting a compensatory mechanism for maintaining cognitive efficiency. This meta-analysis identifies a consistent pattern of aberrant DMN functional connectivity in aMCI, which facilitates understanding of the neurobiological substrates of this disease.

Activation of KGFR-Akt-mTOR-Nrf2 signaling protects human retinal pigment epithelium cells from Ultra-violet.

Ultra-violet (UV) radiation causes oxidative injuries to human retinal pigment epithelium (RPE) cells. We tested the potential effect of keratinocyte growth factor (KGF) against the process. KGF receptor (KGFR) is expressed in ARPE-19 cells and primary human RPE cells. Pre-treatment with KGF inhibited UV-induced reactive oxygen species (ROS) production and RPE cell death. KGF activated nuclear-factor-E2-related factor 2 (Nrf2) signaling in RPE cells, causing Nrf2 Ser-40 phosphorylation, stabilization and nuclear translocation as well as expression of Nrf2-dependent genes (HO1, NOQ1 and GCLC). Nrf2 knockdown (by targeted shRNAs) or S40T mutation almost reversed KGF-induced RPE cell protection against UV. Further studies demonstrated that KGF activated KGFR-Akt-mTORC1 signaling to mediate downstream Nrf2 activation. KGFR shRNA or Akt-mTORC1 inhibition not only blocked KGF-induced Nrf2 Ser-40 phosphorylation and activation, but also nullified KGF-mediated RPE cell protection against UV. We conclude that KGF-KGFR activates Akt-mTORC1 downstream Nrf2 signaling to protect RPE cells from UV radiation.

microRNA-503 contribute to pancreatic beta cell dysfunction by targeting the mTOR pathway in gestational diabetes mellitus.

Loss of pancreatic ß cells is involved in pathogenesis of gestational diabetes mellitus (GDM). Recently, several studies have elucidated the connection between microRNAs (miRNAs) and diabetes mellitus (DM), but the role of miRNAs in GDM remains unclear. The aim of this study was to evaluate the potential functions of miRNAs in GDM and to investigate the underlying mechanisms of action. First, we explored the expression profile of miRNAs in placenta tissue from GDM patients using microarray. Validation analysis was performed in peripheral blood specimens using quantitative reverse transcription PCR (qRT-PCR). Then the role and regulating mechanism of miR-503 in weaken the function of pancreatic ß cell was investigated. We found that miR-503 was markedly upregulated in placenta tissue from GDM patients, as elevated in peripheral blood specimens, and the high level was positively correlated to blood glucose concentration. Knockdown of miR-503 enhanced insulin secretion of pancreatic ß-cells, promoted cell proliferation and protected cells from apoptosis, whereas overexpression of miR-503 showed the opposite effects. Furthermore, mammalian target of rapamycin (mTOR) was identified as a direct target of miR-503 and mTOR silencing could reverse the improving effects of miR-503 knockdown on insulin secretion and pancreatic ß-cells proliferation. High expression of miR-503 in peripheral blood may be acted as a diagnosis biomarker of GDM. MiR-503 regulated functions of pancreatic ß-cells by targeting the mTOR pathway, suggesting that targeting miR-503/mTOR axis could serve as a novel therapeutic target for GDM.

Low dose of Bisphenol A enhance the susceptibility of thyroid carcinoma stimulated by DHPN and iodine excess in F344 rats.

Thyroid carcinoma (TC) is the most common endocrine neoplasm. The risk of TC as a second primary malignancy (SPM) of breast cancer is significantly increased. Bisphenol A (BPA) is a widely contacted xenoestrogen and increases susceptibility to breast cancer through binding to estrogen receptor alpha (ERα). However, the effect of BPA on thyroid carcinogenesis has not been fully demonstrated. This present study aimed to characterize the effects of BPA on the development of TC using a Fischer 344 (F344) rat model. In this study, we established a TC model using female F344 rats pretreated with N-Bis (2-hydroxypropyl) nitrosamine (DHPN) at a single dose of 2800 mg/kg (the DA group) or without DHPN (the DN group), followed by stimulation with BPA at the level of 250 µg/kg (BPA250) or 1000 µg/kg (BPA1000) and a basic diet containing potassium iodine (KI, 1000 µg/L) for 64 weeks. We demonstrated that the incidence of TC in the BPA250 + KI of DA groups reached the highest at 50%, the incidence of thyroid hyperplasia lesions (including both tumors and focal hyperplasia lesions) in the BPA1000 + KI of DA groups reached 100% (P < 0.05). ERα protein and immunochemistry expression was upregulated in the BPA-exposed groups and the immunochemistry scores were positively correlated with PCNA. Thus, the present results indicate that BPA could enhance the susceptibility to TC stimulated by DHPN and iodine excess. ERα is probably involved in the proliferation effect of BPA. BPA or KI alone could not increase TC incidence.

Bisphenol A and estrogen induce proliferation of human thyroid tumor cells via an estrogen-receptor-dependent pathway.

OBJECTIVE: To determine the relationship between papillary thyroid carcinoma and environmental exposure to bisphenol A (BPA) or 17-ß estrogen (E2) by assessing the effects of these compounds on estrogen receptor expression and AKT/mTOR signaling. METHODS: The effects of low levels of BPA (1mM-10nM) and 17ß-estradiol (E2, 0.1mM-1nM) on ER expression and cellular proliferation were determined in human thyroid papillary cancer BHP10-3 cells. Protein and mRNA levels of estrogen nuclear receptors (ERα/ERß) and membrane receptors (GPR30) were determined by immunofluorescence assay, Western blotting, and RT-PCR, respectively, and proliferation was assessed by CCK-8 assay. RESULTS: The proliferative effects of BPA and E2 were both concentration- and time-dependent. Expression of ERα/ERß and GPR30 were enhanced by BPA and E2. BPA and E2 could quickly phosphorylate AKT/mTOR. Moreover, ICI suppressed ERα expression and activated GPR30 as did G-1. G-15 reversed the effects of E2 on GPR30 and AKT/mTOR, but did not alter the effect of BPA. CONCLUSIONS: BPA influences thyroid cancer proliferation by regulating expression of ERs and GPR30, a mechanism that differs from E2. In addition, ICI and G-15 may have the potential to be used as anti-thyroid cancer agents.

Prognostic implication and functional role of long noncoding RNA IGF2AS in human non-small cell lung cancer.

PURPOSE: Emerging evidence shows that long noncoding RNAs (lncRNAs) play important roles in human cancer. In this work, we examined the expression, prognostic implication and functional mechanisms of a lncRNA, insulin growth factor 2 antisense (IGF2AS) in non-small cell lung cancer (NSCLC). METHODS: IGF2AS gene expression was examined by qPCR in both in situ NSCLC clinical samples and in vitro NSCLC cell lines. In patients with NSCLC, postoperative overall survival was estimated according to endogenous IGF2AS expression in their cancerous lung tissues. In NSCLC cell lines A549 and H226 cells, IGF2AS was upregulated to examine its effect on cancer proliferation, migration, cisplatin chemoresistance in vitro, and tumorigenicity in vivo. Related signaling pathways, including IGF2, VEGF and bFGF were also examined in IGF2AS upregulated NSCLC cells. RESULTS: IGF2AS is downregulated in both NSCLC human tumors and NSCLC cell lines, as well as in stage III or IV tumors. Downregulated IGF2AS was significantly correlated with NSCLC patients' short overall survival. In NSCLC A549 and H226 cell lines, IGF2AS upregulation had anti-cancer effects by inhibiting cancer cell proliferation, migration and cisplatin chemoresistance in vitro, and explant growth in vivo. Moreover, IGF2AS upregulation markedly reduced oncogenic factors of IGF2, VEGF and bFGF at both mRNA and protein levels. CONCLUSION: IGF2AS may be a prognostic biomarker for NSCLC. Upregulating IGF2AS may be considered as a novel molecular pathway to fight NSCLC. This article is protected by copyright. All rights reserved.

Oncogene LSD1 is epigenetically suppressed by miR-137 overexpression in human non-small cell lung cancer.

PURPOSE: We examined the epigenetic regulation of microRNA-137 (miR-137) on lysine-specific demethylase 1 (KDM1A, or LSD1) induced oncogenic effects in NSCLC. METHODS: NSCLC cell lines, A549 and H460 cells were transfected with a mammalian LSD1 overexpression plasmid. It's effects on endogenous KDM1A gene and LSD1 protein expressions were examined by qRT-PCR and western blot assays. NSCLC proliferation and migration were also examined by MTT proliferation and wound-scratch assays, respectively. In LSD1-overexpeseed NSCLC cells, lentiviral transfection was conducted to upregulated miR-137 expression. The subsequent effects of miR-137 upregulation on LSD1-mediated cancer regulations were also examined. In addition, key components of histone deacetylases-associated signaling pathways, including EZH2, HDAC1 and HDAC2 were also examined by western blot in LSD1-and miR-137-mediated NSCLC cells. RESULTS: Mammalian LSD1 overexpression plasmid was efficient in upregulating KDM1A gene and LSD1 protein in A549 and H460 cells. It also exerted oncogenic effects in NSCLC by promoting cancer proliferation and migration. MiR-137 was inversely correlated with LSD1 in NSCLC, as lentivirus-mediated miR-137 upregulation suppressed KDM1A/LSD1 productions and inhibited proliferation or migration in LSD1-overexpressed A549 and H460 cells. Further western blot analysis demonstrated EZH2, HDAC1 and HDAC2 were activated by LSD1, but inhibited by miR-137 in NSCLC. CONCLUSION: Oncogenic effects of LSD1 were reversely regulated by its upstream epigenetic modulator miR-137 in NSCLC. The interaction between LSD1 and miR-137 may very well involve the regulation on histone deacetylases-associated signaling pathways.

Effect of bisphenol a on occurrence and progression of prolactinoma and its underlying mechanisms.

OBJECTIVE: To investigate the effects of Bisphenol A (BPA) on prolactin (PRL) release, pituitary cell proliferation, prolactinoma formation in estrogen-sensitive Fischer 344 (F344) rats. MATERIALS AND METHODS: Four-week-old female F344 rats were orally administered with different concentrations of BPA or intraperitoneal injection of estradiol benzoate (estradiolbenzoate, E2) for 12 weeks. Bodyweight, blood RPL level and pituitary weights were observed and recorded. Real-time PCR, western blot and immunohistochemistry analysis were used to detect the mRNA and protein levels of the proliferation markers, including proliferating cell neclear antigen (PCNA), pituitary tumor-transforming gene (PTTG) and its relevant marker ERα. Plasma and urine BPA concentration in patients with prolactinoma and healthy participants were measured as well. RESULTS: Body weights of the rats treated with BPA were significantly decreased compared with those in the control group. The plasma PRL level and the pituitary weights of the rats were higher than those in the control group after BPA treatment. Compared with the control group, the pituitary mRNA and protein expression levels of PCNA and PTTG were significantly increased after BPA treatment. Moreover, ERα expression level was enhanced by the treatment of BPA in comparison with that of the control group. Finally, the plasma BPA concentration in the prolactin tumor patients was significantly higher than that in the healthy participants. CONCLUSION: BPA can significantly promote pituitary cell proliferation and prolactin secretion in F344 rats, which may have impact on the proliferation and secretion of pituitary cell function through the ERα pathway.

[Inhibitory effect of 5-aminoisoquinolinone on PARP activity in colon carcinoma cell line HT-29].

BACKGROUND & OBJECTIVE: 5-Aminoisoquinolinone(5-AIQ),a poly(adenosine 5'-diphosphate ribose) polymerase (PARP) inhibitor, plays an important role in inflammation, but its role in tumors is unclear. This study was to investigate the biological role of 5-AIQ-induced PARP inhibition in colon carcinoma cell line HT-29. METHODS: The expression of poly(adenosine 5'-diphosphate ribose) (PAR) and co-expression of PAR with P-selectin and intercellular adhesion molecule-1 (ICAM-1) in 45 specimens of colorectal carcinoma and 10 specimens of adjacent normal colorectal mucosa were detected by SP immunohistochemistry and double immunofluorescence staining. After treatment of 5-AIQ, the adhesion of colon carcinoma cell line HT-29 to human umbilical vein endothelial cells (HUVEC) was detected by adhesion experimentû the expression of PAR, P-selectin, and ICAM-1 in HT-29 cells was detected by SP immunohistochemistry. RESULTS: The positive rate of PAR was significantly higher in colorectal carcinoma than in control colorectal mucosa (77.8% vs. 10.0%, P < 0.05), and higher in colorectal carcinomas with metastasis than in colorectal carcinomas without metastasis (86.7% vs. 60.0%). PAR expression was correlated to P-selectin and ICAM-1 expression. Cell adhesion rate was significantly lower in 100, 300, and 500 mumol/L 5-AIQ-treated HT-29 cells than in control cells (55.79%, 46.31%, and 39.77% vs. 100%, P < 0.05). The protein levels of PAR, P-selectin, and ICAM-1 were significantly lower in 5-AIQ-treated HT-29 cells than in control cells (1.41+/-0.12 vs. 2.61+/-0.10, 1.57+/-0.13 vs. 2.73+/-0.16, 1.23+/-0.13 vs. 2.30+/-0.12, P < 0.05). CONCLUSIONS: PARP activity is enhanced in colorectal carcinoma. PARP inhibitor 5-AIQ can inhibit the adhesion of HT-29 cells to HUVECs, and the expression of PAR, P-selectin, and ICAM-1 in HT-29 cells.