ABSTRACT
Pulmonary fibrosis (PF) is the pathological structure of incurable fibroproliferative lung diseases that are attributed to the repeated lung injury-caused failure of lung alveolar regeneration (LAR). Here, we report that repetitive lung damage results in a progressive accumulation of the transcriptional repressor SLUG in alveolar epithelial type II cells (AEC2s). The abnormal increased SLUG inhibits AEC2s from self-renewal and differentiation into alveolar epithelial type I cells (AEC1s). We found that the elevated SLUG represses the expression of the phosphate transporter SLC34A2 in AEC2s, which reduces intracellular phosphate and represses the phosphorylation of JNK and P38 MAPK, two critical kinases supporting LAR, leading to LAR failure. TRIB3, a stress sensor, interacts with the E3 ligase MDM2 to suppress SLUG degradation in AEC2s by impeding MDM2-catalyzed SLUG ubiquitination. Targeting SLUG degradation by disturbing the TRIB3/MDM2 interaction using a new synthetic staple peptide restores LAR capacity and exhibits potent therapeutic efficacy against experimental PF. Our study reveals a mechanism of the TRIB3-MDM2-SLUG-SLC34A2 axis causing the LAR failure in PF, which confers a potential strategy for treating patients with fibroproliferative lung diseases.
ABSTRACT
The cell cycle inhibitor P21 has been implicated in cell senescence and plays an important role in the injury-repair process following lung injury. Pulmonary fibrosis (PF) is a fibrotic lung disorder characterized by cell senescence in lung alveolar epithelial cells. In this study, we report that P21 expression was increased in alveolar epithelial type 2 cells (AEC2s) in a time-dependent manner following multiple bleomycin-induced PF. Repeated injury of AEC2s resulted in telomere shortening and triggered P21-dependent cell senescence. AEC2s with elevated expression of P21 lost their self-renewal and differentiation abilities. In particular, elevated P21 not only induced cell cycle arrest in AEC2s but also bound to P300 and β-catenin and inhibited AEC2 differentiation by disturbing the P300-β-catenin interaction. Meanwhile, senescent AEC2s triggered myofibroblast activation by releasing profibrotic cytokines. Knockdown of P21 restored AEC2-mediated lung alveolar regeneration in mice with chronic PF. The results of our study reveal a mechanism of P21-mediated lung regeneration failure during PF development, which suggests a potential strategy for the treatment of fibrotic lung diseases.
ABSTRACT
Objective To investigate the correlation betw een the cerebral w atershed infarction (WSI) types and cerebrovascular stenosis. Methods Patients w ith WSI diagnosed by MRI and diffusion -w eighted imaging w ere enroled. Color Doppler ultrasound w as used to conduct extracranial internal carotid artery (ICA) examination. Magnetic resonance angiography w as used to conduct intracranial vascular examination. The patients w ith WSI w ere divided into cortical w atershed infarction (CWSI), internal w atershed infarction (IWSI), and mixed-type w atershed infarction (MWSI). The correlation betw een the different types of WSI and cerebral vascular stenosis w ere analyzed. Results A total of 120 patients w ith WSI w ere enroled, including 18 w ith CWSI, 48 w ith IWSI, and 54 w ith MWSI. Ipsilateral vascular stenosis: 48 patients w ere in ICA (40.0%, 22 of them in the extracranial segment, 39 in the intracranial segment), 24 (20 .0%) w ere in the anterior cerebral artery, 86 (71.7%) w ere in the middle cerebral artery, 40 (33.3%) w ere in the posterior cerebral artery, 35 (29.2%) w ere in the vertebral basilar artery, and 36 (30.0%) w ere in ICA +MCA. There w ere significant differences in the detection rates of ipsilateral ICA, MCA and ICA + MCA stenosis among different types of WSI. Multivariate logistic regression analysis show ed that CWSI often accompanied by the ipsilateral ICA stenosis (odds ratio [ OR] 0.022; 95% confidence interval [ CI] 0.002 -0.230; P =0.001); IWSI often accompanied by the MCA stenosis ( OR 40.164; 95% CI 3.861 -417.810; P =0.002), w hile MWSI often accompanied by the ipsilateral MCA stenosis ( OR 9.586; 95% CI 2.776 -33.126; P <0.001) and ipsilateral ICA + MCA stenoses ( OR 7.481; 95% CI 2.541 -22.022; P <0.001). Conclusion There w ere significant differences in the incidence of the ipsilateral ICA, MCA, and ICA + MCA stenosis among the different types of WSI. CWSI often accompanied by the ipsilateral ICA stenosis, IWSI often accompanied by the ipsilateral MCA stenosis, and MWSI often accompanied by the ipsilateral ICA + MCA stenosis.
ABSTRACT
Aim ToconstructHEK293cellsstablyex-pressing corticotropin releasing factor receptor 1 ( CRFR1 ) , and evaluate its function by the cAMP as-say.Methods CulturedHEK293cellsweretransfect-ed with CRFR1-expressing vector by Lipofectamine 2000 and were selected by using G418 . CRFR1 ex-pression was detected by Western blot, RT-PCR and immunofluorescence.Results Westernblot,RT-PCR and immunofluorescence data revealed that the HEK293 cells expressed CRFR1 protein stably. The dose-responsive relationship experiment revealed that CRF induced a CRFR1-mediated cAMP production in HEK293 cells with EC50 =(5. 64 ± 0. 05) × 10 -10 mol ·L-1.Conclusion HEK293celllinesstablyex-pressing CRFR1 were constructed successfully, which would provide a cellular model to facilitate the research on the biological function of CRFR1 and CRFR1-targe-ted drug screening.
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Objective To investigate the changes in ovarian function and the radiotheraputic influence on ovarian function on patients with cervical squamous cell carcinoma.Methods We retrospectively analyzed 53 cases of cervical cancer patients FIGO staging Ⅰ B1-Ⅱ B who had received ovarian transposition surgery at the Maternal and Child Health Hospital of Jiangxi province from January 2009 to June 2012.All the patients included in the study were FIGO staging Ⅰ B1-Ⅱ B and had undergone radiation therapy,including 38 staging Ⅰ B1-Ⅱ A2 cervical cancer patients receiving chemo-therapy after radical radiotherapy due to the presence of risk factors and other 15 patients with stage Ⅱ B to radical concurrent chemoradiotherapy ovarian transposition.Ovarian transposition methods would include laparoscopic ovarian transposition and transabdominal ovarian transposition.15 concurrent patients with stage Ⅱ B who currently receiving chemo-radiotherapy were under laparoscopic ovarian transposition.Among the 38 radical hysterectomy patients,31 were having abdominal ovarian transposition,and the remaining 7 cases were laparoscopic.All the 53 patients had undergone radiotherapy.The levels of serum female hormones FSH,LH,E2 were determined to monitor the ovarian endocrine function.Results According to FIGO staging,18 cases were stage Ⅰ B 1,15 cases Ⅰ B2,3 cases Ⅱ A1,2 cases Ⅱ A2 and 15 cases Ⅱ B.Patients' age range was from 28 to 44 years old,with an average of 37.7 years,median age as 38 years.14 patients (63.6％) were still normal ovarian function after radiotherapy by laparoscopic ovarian transposition,which was 100.0％before radiotherapy.There was a significant difference (P＜0.05) compared with before radiotherapy.After transabdominal ovarian transposition surgery and radiotherapy,normal ovarian function 22 cases (71.0％),and there was a significant difference (P＜0.05) compared with before radiotherapy.No significant difference was found with regard to the proportion of normal ovarian function after radiotherapy between the two groups of patients with laparoscopic and transabdominal ovarian transposition (P＞0.05).Conclusion For the young cervical cancer patients,even with ovarian transposition,ovarian dysfunction was still evident after radiotherapy.There was no significant difference between laparoscopic and transabdominal ovarian transposition.
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Objective Toinvestigatetherelationshipbetweendifferenttypesofinternalwatershed infarctionandtandemstenosesofinternalcarotidartery(ICA).Methods Atotalof55patientswith internal watershed infarction confirmed by head MRI and diffusion-weighted imaging (DWI )examination were enrolled. They all underwent the extracranial internal carotid artery (ICA ) ultrasonography and intracranial cerebral artery MR angiography (MRA)examinations. According to the findings of imaging,the 55 patients with internal watershed infarction were divided into a simple internal watershed infarction (IWSI)group and an internal watershed infarction accompanied with ipsilateral cortical watershed infarction (C-IWSI)group. The relationship between the two types of internal watershed infarction and tandem stenoses of ICA was analyzed. Results (1 ) Of the 55 patients with internal watershed infarction,24 cases (43. 6%)were in the internal watershed infarction group and 31 cases (56. 4%)were in the C-IWSI group. The ipsilateral vascular stenosis were ICA 20 cases (36. 4%,including extracranial segment 11 cases and intracranial segment 17 cases),middle cerebral artery (MCA)44 cases (80. 0%), and tandem stenoses of ICA 15 cases (27. 3%). (2)Ipsilateral tandem stenoses of ICA:2 cases were in the IWSI group (intracranial ICA+MCA 2 cases);13 cases were in the C-IWSI group (extracranial ICA+intracranial ICA +MCA 4 cases,extracranial ICA + intracranial ICA 1 case,extracranial ICA + MCA 2 cases,and intracranial ICA+MCA 6 cases). (3)Compared with the IWSI group,the incidences of ipsilateral ICA stenosis and tandem stenoses of ICA in patients of the C-IWSI group were higher (54. 8%[n=17]vs. 12. 5%[n=3],41. 9%[n=13]vs. 8. 3%[n =2]),and there were significant differences(P =0. 001, 0.006]). The incidences of extracranial and intercranial ICA stenosis were higher than those of the IWSI group (35. 5%[n=11]vs. 0,45. 2%[n=14]vs. 12. 5%[n=3]),and there were significant differences (P=0.003,0.009).Conclusion Inthedifferenttypesofinternalwatershedinfarction,theincidenceof tandem stenoses of ICA is different. The IWSI patients with ipsilateral cortical watershed infarction often accompany by tandem stenoses of ICA.
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Objective To compare the clinical outcome among white blood cell, platelet and red blood cell hemapheresis. Methods Thirty-seven patients with high blood cell count received hemapheresis for forty times by CS-3000 plus. Results After white blood cell hemapheresis, the peripheral white blood cell counts decreased from (231 52?355 56)?10 9/L to(140 64?230 85)?10 9/L(P