The poly(ADP-ribosyl)ation of BRD4 mediated by PARP1 promoted pathological cardiac hypertrophy

The bromodomain and extraterminal (BET) family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy. BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin, facilitating the phosphorylation of RNA polymerases II (Pol II) and leading to transcription elongation. The present study identified a novel post-translational modification of BRD4: poly(ADP-ribosyl)ation (PARylation), that was mediated by poly(ADP-ribose)polymerase-1 (PARP1) in cardiac hypertrophy. BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol (ISO), whereas overexpression of BRD4 promoted cardiac hypertrophy, confirming the critical role of BRD4 in pathological cardiac hypertrophy. PARP1 was activated in ISO-induced cardiac hypertrophy and facilitated the development of cardiac hypertrophy. BRD4 was involved in the prohypertrophic effect of PARP1, as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses, and that BRD4 overexpression suppressed the anti-hypertrophic effect of PARP1 inhibitors. Interactions of BRD4 and PARP1 were observed by co-immunoprecipitation and immunofluorescence. PARylation of BRD4 induced by PARP1 was investigated by PARylation assays. In response to hypertrophic stimuli like ISO, PARylation level of BRD4 was elevated, along with enhanced interactions between BRD4 and PARP1. By investigating the PARylation of truncation mutants of BRD4, the C-terminal domain (CTD) was identified as the PARylation modification sites of BRD4. PARylation of BRD4 facilitated its binding to the transcription start sites (TSS) of hypertrophic genes, resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes. The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.

Targeting castration-resistant prostate cancer with a novel ROR

Prostate cancer (PCa) patients who progress to metastatic castration-resistant PCa (mCRPC) mostly have poor outcomes due to the lack of effective therapies. Our recent study established the orphan nuclear receptor ROR

Chrysophanol protects against doxorubicin-induced cardiotoxicity by suppressing cellular PARylation

The clinical application of doxorubicin (DOX) in cancer chemotherapy is limited by its life-threatening cardiotoxic effects. Chrysophanol (CHR), an anthraquinone compound isolated from the rhizome of L., is considered to play a broad role in a variety of biological processes. However, the effects of CHR׳s cardioprotection in DOX-induced cardiomyopathy is poorly understood. In this study, we found that the cardiac apoptosis, mitochondrial injury and cellular PARylation levels were significantly increased in H9C2 cells treated by Dox, while these effects were suppressed by CHR. Similar results were observed when PARP1 activity was suppressed by its inhibitors 3-aminobenzamide (3AB) and ABT888. Ectopic expression of PARP1 effectively blocked this CHR׳s cardioprotection against DOX-induced cardiomyocyte injury in H9C2 cells. Furthermore, pre-administration with both CHR and 3AB relieved DOX-induced cardiac apoptosis, mitochondrial impairment and heart dysfunction in Sprague-Dawley rat model. These results revealed that CHR protects against DOX-induced cardiotoxicity by suppressing cellular PARylation and provided critical evidence that PARylation may be a novel target for DOX-induced cardiomyopathy.

Clinical efficacy of etoposide soft capsules oral monotherapy in second-line treatment of elderly patients with recurrent small cell lung cancer / 中国生化药物杂志

Objective To observe the clinical efficacy and safety of etoposide capsule (VP16) in the treatment of recurrent small cell lung cancer. Methods Retrospective analysis 39 patients,aged≥65, with relapsed small cell lung cancer, who were at least three months after the end of the first-line treatment since January 2012 to January 2014 in Tianjin fifth central hospital.Etoposide was administered by daily oral at 100 mg/day for seven consecutive days and withdraw for 14 days,21 days as a therapeutic cycle,repeat treatment until disease progression or intolerable side effects occur, analyze the progression-free survival and overall survival.Observe the clinical benefit rate,the overall response rate and safety.Results The clinical benefit rate (DCR) and overall response rate (ORR) after the treatment were 61.5% and 30.77%.The progression-free survival (PFS) was 2.8 months, and the overall survival (OS) was 7.3 months.Neutropenia is the most common toxicities, and grade Ⅲ or Ⅳ occurred in 7.7% of the patients.No grade Ⅲ or Ⅳ thrombocytopenia, or grade Ⅲ or Ⅳ non-hematologic toxicity was occured.Conclusion Etoposide oral capsules monotherapy may be considered as one of the safe and effective choice of the second-line treatment of elderly patients with relapsed small cell lung cancer.

Postoperative quality of life of cervical cancer patients treated by laparoscopic surgery / 中国内镜杂志

Objectives To investigate the postoperative quality of life of cervical cancer patients treated by laparo-scopic surgery. Methods 27 cases of cervical cancer treated by laparoscopic surgery from May 2009 to September 2010 as observation group, 27 cases of cervical cancer treated by laparotomy treatment in the same period as control group. Observe and analyzed the clinical data, operation, postoperative recurrence and survival rates and postopera-tive FACT-G score between the two groups. Results Age, body mass index has no statistical difference between the two groups ( > 0.05), the blood loss in observation group was less than that in control group ( < 0.05), the lymph node dissection number in observation group was more than that in control group ( < 0.05), the exhaust time and hospital stay in observation group were less than that in control group ( <0.05), the 1-year, 3-year and 5-year re-currence rate and survival rate in observation group showed no significant difference compared with control group ( < 0.05). The 1-year, 3-year and 5-year FACT-G score in control group were higher than that in control group ( < 0.05). Conclusion Laparoscopic surgery for cervical cancer patients can reduce bleeding, shorten exhaust time and hospitalization time, improve postoperative FACT-G score and postoperative quality of life of cervical cancer pa-tients.

Comparison of topographic changes in optic nerve head parameters after intraocular pressure reduction and lamina cribrosa compliance between POAG and PACG / 眼科

Objective To compare the changes in optic disc parameters after intraocular pressure (lOP) reduction between primary angle-closure glaucoma (PACG) and primary open angle glaucoma (POAG) eyes, and to determine if there is a difference of lamina eribrosa compliance between POAG and PACG. Design Prospective comparative study. Participants 36 PACG (49 eyes) and 35 POAG (49 eyes). Methods Patients underwent Heidelberg Retina Tomography (HRT Ⅱ) and Humphrey visual field test before IOP reduction. HRT and Humphrey visual field test were repeated one month after the IOP was reduced by laser, anti-glaucomatous medications or surgery treatment. Factors that affected the change in IOP were assessed including age, pretreatment IOP, IOP reduction, initial cup: disc ratio and diagnosis (POAG/PACG). Main outcome measures Changes of HRT parameters including cup area, mean cup depth, cup volume, and rim area after IOP reduction. Results The cup area, mean cup depth and cup volume decreased, and rim area in-creased significantly when the IOP was reduced (P<0.05), but there were no significant differences in the changes between PACG and POAG patients (P>0.05). Changes of these four HRT parameters were related to the amount of IOP reduction and the baseline ratio of cup to disc(P>0.05), but not related to age and pre-treatment IOP (P<0.05). Conclusions The cup became smaller and the rim area in-creased after IOP lowering with treatment in both POAG and PACG, and the magnitude of the change was similar in both groups. The lamina cribrosa compliance may not be different between POAG and PACG. (Ophthalmol CHN, 2009, 18: 264-269)