Pin1 aggravates renal injury induced by ischemia and reperfusion in rats via Nrf2/HO-1 mediated endoplasmic reticulum stress

Purpose: To investigate the role of peptidyl-prolyl cis/trans isomerase 1 (Pin1) on renal ischemia-reperfusion (I/R) injury and underlying mechanism. Methods: By establishing the in vitro and in vivo models of renal I/R, the role of Pin1 was explored by using molecular assays. Results: In renal I/R, endogenous Pin1 level was up-regulated in I/R-impaired kidney. Suppression of Pin1 with juglone afforded protection against I/R-mediated kidney dysfunction, and reduced I/R-induced endoplasmic reticulum (ER) stress in vivo. Consistent with the in vivo results, repression of Pin1 with juglone or gene knockdown with si-Pin1 conferred cytoprotection and restricted hypoxia/reoxygenation (H/R)-driven ER stress in HK-2 cells. Simultaneously, further study uncovered that Nrf-2/HO-1 signals was the association between Pin1 and ER stress in response to renal I/R. In addition, Nrf-2/HO-1 signal pathway was inactivated after kidney exposed to I/R, as indicated by the down-regulation of Nrf-2/HO-1 levels. Furthermore, inhibition of Pin1 remarkably rescued the inactivation ofNrf-2/HO-1. Conclusions: Pin1 modulated I/R-mediated kidney injury in ER stress manner dependent on Nrf2-HO-1 pathway in I/R injury.

The Role of Exportin-5 in MicroRNA Biogenesis and Cancer / 基因组蛋白质组与生物信息学报·英文版

MicroRNAs (miRNAs) are conserved small non-coding RNAs that play an important role in the regulation of gene expression and participate in a variety of biological processes. The biogenesis of miRNAs is tightly controlled at multiple steps, such as transcription of miRNA genes, processing by Drosha and Dicer, and transportation of precursor miRNAs (pre-miRNAs) from the nucleus to the cytoplasm by exportin-5 (XPO5). Given the critical role of nuclear export of pre-miRNAs in miRNA biogenesis, any alterations of XPO5, resulting from either genetic mutation, epigenetic change, abnormal expression level or posttranslational modification, could affect miRNA expression and thus have profound effects on tumorigenesis. Importantly, XPO5 phosphorylation by ERK kinase and its cis/trans isomerization by the prolyl isomerase Pin1 impair XPO5's nucleo-to-cytoplasmic transport ability of pre-miRNAs, leading to downregulation of mature miRNAs in hepatocellular carcinoma. In this review, we focus on how XPO5 transports pre-miRNAs in the cells and summarize the dysregulation of XPO5 in human tumors.

Silencing of Pin1 suppresses hyperoxia-induced apoptosis of A549 cells / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To explore the effect of silence of Pin1 expression on hyperoxia-induced apoptosis in alveolar epithelial cells A549.</p><p><b>METHODS</b>A549 cells were divided into four groups: control, hyperoxia, negative lentivirus and Pin1-shRNA hyperoxia. The hyperoxia group was exposed to a mixture of 95%O2 and 5%CO2 for 10 minutes. Then cells were cultured in a closed environment. After 24 hours, the changes of morphology were observed under an inverted microscope. Cell apoptosis was detected by flow cytometry (FCM). The expression of X-linked inhibitor of apoptosis protein (XIAP) and Caspase-9 were detected by immunohistochemistry. The production of reactive oxygen species (ROS) and cellular mitochondria membrane potential (△Ψm) were determined by fluorescence microscopy.</p><p><b>RESULTS</b>Under the inverted microscope, the A549 cells grew slowly and the changes in morphology of the cells were most obvious in the hyperoxia and negative lentivirus groups. The changes in morphology of A549 cells were obviously improved in the Pin1-shRNA hyperoxia group. The FCM results showed that the apoptosis rate of A549 cells increased, Caspase-9 expression increased, XIAP expression decreased, mitochondrial ROS production increased and mitochondrial membrane potential decreased in the hyperoxia and negative lentivirus groups compared with the control group (P<0.05). Compared with the hyperoxia and negative lentivirus groups, the apoptosis rate of A549 cells decreased, Caspase-9 expression decreased, XIAP expression increased, mitochondrial ROS production decreased and mitochondrial membrane potential increased in the Pin1-shRNA hyperoxia group (P<0.05), although the levels of the indexes did not reach to those of the control group.</p><p><b>CONCLUSIONS</b>Silencing of Pin1 could suppress hyperoxia-induced apoptosis of A549 cells.</p>

Effect of Pin1 inhibitor juglone on proliferation, migration and angiogenic ability of breast cancer cell line MCF7Adr / 华中科技大学学报（医学）（英德文版）

This study aimed to evaluate the effects of Pin1 inhibitor Juglone on proliferation, migration and the angiogenic ability of breast cancer cell line MCF7Adr. MCF7Adr cells were cultured and separately treated with Pin1 inhibitor Juglone (treatment group) and DMEM without drug (control group). The cell cycle was examined by flow cytometry. Cell migration was measured by wound-healing assay. Cyclin E protein content was detected by Western blotting. The angiogenesis factor vascular endothelial growth factor (VEGF) in cell media was determined by enzyme linked immunosorbent assay. The results showed that the percentage of cells in G2/M phase in treatment group was significantly higher than that in control group (25.5% vs. 10.1%, P<0.05), and that in G0/G1 phase and S stage in treatment group was significantly lower than that in control group (40.5% vs. 48.2%, and 33.7% vs. 41.7%, P<0.05). Cyclin E protein content in treatment group was significantly lower than that in control group (39.2 ± 7.4 vs. 100 ± 23.1, P<0.05). (A0-A24)/A0 value in treatment group was significantly lower than that in control group (23.9 ± 3.8 vs. 100 ± 14.4, P<0.05). VEGF-A, -B, and -C contents in cell media of treatment group were significantly lower than those in control group (P<0.05). It was suggested that Pin1 inhibitor Juglone can effectively inhibit the proliferation, migration and the angiogenic ability of MCF7Adr cells, and can be used as an alternative drug therapy for breast cancer.

Application of temperature sensitive yeast models with definite target in the screening of potential human Pin1 inhibitors / 药学学报

This study is to explore new lead compounds by inhibition of Pin1 for anticancer therapy using temperature sensitive mutants. As Pin1 is conserved from yeast to human, we established a high-throughput screening method for Pin1 inhibitors, which employed yeast assay. This method led to the identification of one potent hits, 8-11. In vitro, 8-11 inhibited purified Pin1 enzyme activity with IC50 of (10.40 +/- 1.68) micromol x L(-1), induced G1 phase arrest and apoptosis, showed inhibitory effects on a series of cancer cell proliferation, reduced Cyclin D1 expression, was defined as reciprocally matched for protein-ligand complex in virtual docking analysis and reduced cell migration ability. In vivo, we could observe reduction of tumor volume after treatment with 8-11 in xenograft mice compared with vehicle DMSO treatment. Altogether, these results provide for the first time the involvement of 8-11 in the anticancer activity against Pin1.

Expression of pin1 in endometrial carcinoma and its relation with PR / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the clinicopathologic significance of pin1 and PR in patients with endometrial adenocarcinoma.</p><p><b>METHODS</b>The expression of pin1 and PR were investigated by immunohistochemistry in a total of 50 endometrial adenocarcinoma specimens.</p><p><b>RESULTS</b>Pin1 was over expressed in 66% (33/50) of the cases. The expression rate decreased gradually with tumor differentiation(P<0.05). In addition, pin1 expression was negatively correlated with lymph node metastasis and invasive depth of myometrium. Moreover, pin1 was positively correlated with PR expression.</p><p><b>CONCLUSION</b>Our results suggest that pin1 may play important roles in the tumorigenesis and migration of endometrial cancer. Pin1 expression may be considered as a prognostic marker as PR in patients with endometrial cancer.</p>

Design, synthesis and biological evaluation of novel diaryl ethers bearing a pyrimidine motif as human Pin1 inhibitors / 药学学报

Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) belongs to peptidyl-prolyl cis-trans isomerase (PPIase) and is a novel promising anticancer target. Based on the lead structure of benzophenone, a series of novel diarylether derivatives containing a pyrimidine ring were designed and synthesized. The inhibitory activities on Pin1 of compounds 5a-5d and 6a-6i were evaluated by a protease-coupled enzyme assay. Of all the evaluated compounds, 6 compounds displayed inhibitory activities. Molecular docking was performed using FlexX algorithm to explore the binding mode of the active molecules.

Recent advance in the study of novel anti-tumor targets and drugs--aurora kinase and Pin1 / 药学学报

Malignant tumor, one of the most refractory diseases, plays a threaten role in human health, the therapy and research on malignant tumor have taken a long way to go. The anti-tumor drugs which are the essential therapy strategies upgrade with the development of new anti-tumor targets and the research on tumor pathogenesis. Aurora kinase and Pin1, the novel anti-tumor targets, maintain the important relationship with tumor. Many new compounds designed on these targets have excellent anti-tumor effects and also enter into phase I or phase II clinical trial.

The expression and significance of Pin1 and CyclinD1 in adult papilloma of larynx / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To study the expression and relationship of Pin1 and CyclinD1 in adult papilloma of larynx, and the effect of both in laryngeal papilloma's canceration.@*METHOD@#Ninety-two cases of paraffin section with immunoperoxidase (SP) staining method was used to detect the distribution of Pin1 and CyclinD1 in 10 cases of laryngeal normal epithelial tissue, 39 cases of laryngeal papilloma, 27 cases of laryngeal papilloma with middle, severe atypical hyperplasia and 16 cases of laryngeal carcinoma.@*RESULT@#The distribution of Pin1 and CyclinD1 increased gradually from laryngeal normal epithelial tissue to laryngeal carcinoma (P0.0125), but there had significant difference of the expression of Pin1 and CyclinD1 among the rest groups; There was significantly direct correlation between the expression of Pin1 and CyclinD1 (P<0.05).@*CONCLUSION@#The hyper-expressions of Pin1 and CyclinD1 may play a key role in laryngeal papilloma's malignant change. Pin1 up-regulating the expressions of cyclinD1 possibly participate in its malignant change.

Effect of yizhi jiannao granules on the expression of Pin1 and HMGB1 mRNA in the hippocampus of SAMP8 mice / 中南大学学报(医学版)

OBJECTIVE@#To investigate the effect of yizhi jiannao granule concentration fluid (YCF) on the expression of peptidyl-prolyl-cis-trans isomerase A (Pin1) and high mobility group box 1 (HMGB1) mRNA in the hippocampus of senescence accelerated mice Senile-Prone8(SAMP8).@*METHODS@#Six-month old SAMP8 mice were randomly divided into a YCF group and a model group. Six-month old SAMP8 mice were served as a normal control group. The YCF group was ravaged, while the model group and the normal control group were gavaged with double-distilled water for 8 weeks. The hippocampus was taken out for examination. The expression of Pin1 and HMGB1 mRNA was measured by RT-PCR.@*RESULTS@#In the YCF group, the level of Pin1 mRNA increased, and the level of HMGB1 mRNA decreased compared with that of the model group.@*CONCLUSION@#Yizhi jiannao granules can prevent Alzheimer's disease by increasing the Pin1 level and decreasing the HMGB1 level.

Recent advances in the study of pin1 and its inhibitors / 药学学报

Pin1 is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase, which specifically catalyzes the amide bond isomerization of phosphoserine-proline or phosphothreonine-proline in mitotic phosphoproteins. Pin1 induces the conformational changes to control the function of phosphoproteins. Depletion of Pinl on various human cancer cell lines cause mitotic arrest and apoptosis. Pin1 is an attracting therapeutic target for anticancer and its inhibitors might be potential anticancer drug. In this review, Pin1 inhibitors and the catalytic mechanism, the biological function of Pin1 and its role in oncogenesis are summarized.

Expression of pin1 mRNA in the circulation of non-small cell lung cancer patients and influence of sequence of vessel ligation / 中南大学学报(医学版)

OBJECTIVE@#To detect the expression of peptidylprolyl cis/trans isomerase NIMA-interacting l (pin1 mRNA) in the circulation of non-small cell lung cancer (NSCLC) and to investigate the effect of ligating pulmonary vein first or ligating pulmonary artery first during operation on haematogenous dissemination of cancer cells.@*METHODS@#Twenty-six consecutive patients with NSCLC who underwent surgical resection with curative intention were randomly assigned into pulmonary artery first-ligation group (PA group) and pulmonary vein first-ligation group (PV group). Blood samples were collected just before and 7 days after the operation. During the lobectomy, blood samples of the proximal part and distal part of the pulmonary vein when it was ligated were collected. Another 10 patients with benign lung disease served as control subjects undergoing surgical resection, and 10 healthy persons served as negative controls. All blood samples were subjected to real-time RT-PCR with pin1 mRNA as the marker.@*RESULTS@#Compared with the benign lung disease and healthy persons, pin1 mRNA in NSCLC was overexpressed (1.45 to approximately 29.86 vs.0.83 to approximately 1.26 vs 1, P0.05; 16.84+/-2.36 vs.13.36+/-1.78, P>0.05).@*CONCLUSION@#pin1 mRNA was overexpressed in the circulation of NSCLC. Ligation of pulmonary vein before the ligation of the pulmonary artery may decrease the expression of pin1 mRNA in the circulation, which can prevent the release of tumor cells into the bloodstream.

Expression of Pin1, beta-catenin and cyclin D1 in salivary adenoid cystic carcinoma and its significance / 中华口腔医学杂志

<p><b>OBJECTIVE</b>To investigate the expression of Pin1, beta-catenin and cyclin D1 in salivary adenoid cystic carcinomas (SACC) and to evaluate the role of beta-catenin and Pin1 in SACC carcinogenesis.</p><p><b>METHODS</b>The expressions of Pin1, beta-catenin and cyclin D1 were examined in the specimens of 65 patients with SACC by immunohistochemistry, and Pin1 protein and mRNA expressions detected by Western blot and RT-PCR in four SACC cell lines.</p><p><b>RESULTS</b>Pin1 was overexpressed in 51 cases of ACC (78%), and 41 (63%) cases showed positive immunoreactivity for cyclin D1 protein in the nuclear fraction in tumor tissues. Fourteen (22%) cases showed positive immunoreactivity for beta-catenin protein in the nuclear/cytoplasmic fraction in tumor tissues, 6 of which exhibited quite evident expression of beta-catenin in nucleolus. The expression of membranous beta-catenin was down-regulated in most of the patients with lymph node metastasis (11/14).</p><p><b>CONCLUSIONS</b>The results suggest that Pin1 and beta-catenin signalling pathway were activated in SACC and might play a pivotal role in SACC carcinogenesis and metastasis.</p>