To investigate the expression of hypoxia inducible factor 1-alpha (HIF-1α) and its correlation with P53 and vascular endothelial growth factor (VEGF), immunohistochemical technique was employed to detect the protein ...To investigate the expression of hypoxia inducible factor 1-alpha (HIF-1α) and its correlation with P53 and vascular endothelial growth factor (VEGF), immunohistochemical technique was employed to detect the protein expressions of HIF-1α, P53 and VEGF in specimens from 57 patients with lung cancer. The results indicated that the total positive proportion of HIF-1α expression was 63 % and the HIF-1α expression was more frequent in bronchiole-alveolar carcinoma (86 %) than in other lung cancer. There was a strong association of HIF-1α with VEGF and P53 protein expressions. It is concluded that HIF-1α overexpression is a common event in lung cancer, which may be related to the up-regulation of the angiogenic factor VEGF and oncogene mutant P53 protein.展开更多
Background: Myocardial infarction (MI) is a major disease burden. Wild-type p53-induced phosphatase 1 (Wipl) has been studied extensively in the context of cancer and the regulation of different types of stem cel...Background: Myocardial infarction (MI) is a major disease burden. Wild-type p53-induced phosphatase 1 (Wipl) has been studied extensively in the context of cancer and the regulation of different types of stem cells, but the role of Wipl in cardiac adaptation to M I is unknown. We investigated the significance of Wipl in a mouse model of MI. Methods: The study began in June 2014 and was completed in July 2016. We compared Wipl-knockout (Wipl-KO) mice and wild-type (WT) mice to deternline changes in cardiac function and survival in response to MI. The heart weight/body weight (HW/BW) ratio and cardiac function were measured before MI. Mouse MI was established by ligating the left anterior descending (LAD) coronary artery under 1.5% isoflurane anesthesia. After M1, survival of the mice was observed for 4 weeks. Cardiac function was examined by echocardiography. The HW/BW ratio was analyzed, and cardiac hypertrophy was measured by wheat germ agglutinin staining. Hematoxylin and eosin (H&E) staining was used to determine the infarct size. Gene expression of interleukin-6 (IL-6), turnor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) was assessed by quantitative real-time polymerase chain reaction (qPCR), and the levels of signal transducers and activators of transcription 3 (stat3) and phosphor-stat3 (p-stat3) were also analyzed by Western blotting. Kaplan-Meier survival analysis, log-rank test, unpaired l-test, and one-way analysis of variance (ANOVA) were used for statistical analyses. Results: Wipl-KO mice had a marginally increased HW/BW ratio and slightly impaired cardiac fiinction before LAD ligation. Alter MI, Wipl-deficient mice exhibited increased mortality (57.14% vs. 29.17%; n = 24 [WT], n - 35 [WipI-KO], P 〈 0.05), increased cardiac hypertrophy (HW/BW ratio: 7 days: 7.25±0.36 vs. 5.84 ± 0.18, n cross-sectional area: 7 days: 311.80 ± 8.29 vs. 268.90 ± 11.15, n P 〉 0.05), and reduced cardiac function (ejection fraction: 7 days 10, p〈 0.01, and 4 weeks: 6.05± 0.17 vs. 5.87 ±0.24, n= 10, P〉0.05; P 〈 0.05, and 4 weeks: 308.80 ± 11.26 vs. 317.00 ±13.55, n = 6 29.37± 1.38 vs. 34.72 ± 1.81, P 〈 0.05, and 4 weeks: 19.06 ± 2.07 vs 26.37 ± 2.95, P〈 0.05; fractional shortening: 7 days: 13.72 ± 0.71 vs. 16.50 ± 0.94, P〈 0.05, and 4 weeks: 8.79 ±1.00 vs. 12.48 ±1.48, P 〈 0.05; n = l0 [WT], n = 15 [Wipl-KO]). H&E staining revealed a larger infarct size in Wipl-KO mice than in WT mice (34.79% ± 2.44% vs. 19.55% ± 1.48%, n = 6, P 〈 0.01 ). The expression oflL-6 and p-stat3 was downregulated in Wipl-KO mice (IL-6:1.71 ± 0.27 vs. 4.46 ± 0.79, n = 6, P 〈 0.01 ; and p-stat3/stat3:1.15 ±0.15 vs. 1.97 ± 0.23, n = 6, P 〈 0.05). Conclusion: The results suggest that Wipl could protect the heart from MI-induced ischemic injury.展开更多
Differentiation of human fibroblasts into functional neurons depends on the introduction of viral-mediated transcription factors, which present risks of viral gene integration and tumorigenicity. In recent years, alth...Differentiation of human fibroblasts into functional neurons depends on the introduction of viral-mediated transcription factors, which present risks of viral gene integration and tumorigenicity. In recent years, although some studies have been successful in directly inducing neurons through sustained expression of small molecule compounds, they have only been shown to be effective on mouse-derived cells. Thus, herein we delivered vectors containing Epstein-Barr virus-derived oriP/Epstein-Barr nuclear antigen 1 encoding the neuronal transcription factor, Ascl1, the neuron-specific microRNA, miR124, and a small hairpin directed against p53, into human fibroblasts. Cells were incubated in a neuron-inducing culture medium. Immunofluorescence staining was used to detect Tuj-1, microtubule-associated protein 2, neuron-specific nucleoprotein NeuN and nerve cell adhesion molecules in the induced cells. The proportion of Tuj1-positive cells was up to 36.7% after induction for 11 days. From day 21, these induced neurons showed neuron-specific expression patterns of microtubule-associated protein 2, NeuN and neural cell adhesion molecule. Our approach is a simple, plasmid-based process that enables direct reprogramming of human fibroblasts into neurons, and provides alternative avenues for disease modeling and neurodegenerative medicine.展开更多
Neutrophil extracellular traps (NETs) participate in the rapid inhibition and clearance of pathogens during infection;however, the molecular regulation of NET formation remains poorly understood. In the current study,...Neutrophil extracellular traps (NETs) participate in the rapid inhibition and clearance of pathogens during infection;however, the molecular regulation of NET formation remains poorly understood. In the current study, we found that inhibition of the wild-type p53-induced phosphatase 1 (Wip1) significantly suppressed the activity of Staphylococcus aureus (S. aureus) and accelerated abscess healing in S. aureus-induced abscess model mice by enhancing NET formation. A Wip1 inhibitor significantly enhanced NET formation in mouse and human neutrophils in vitro. High-resolution mass spectrometry and biochemical assays demonstrated that Coro1a is a substrate of Wip1. Further experiments also revealed that Wip1 preferentially and directly interacts with phosphorylated Coro1a than compared to unphosphorylated inactivated Coro1a. The phosphorylated Ser426 site of Coro1a and the 28–90 aa domain of Wip1 are essential for the direct interaction of Coro1a and Wip1 and for Wip1 dephosphorylation of p-Coro1a Ser426. Wip1 deletion or inhibition in neutrophils significantly upregulated the phosphorylation of Coro1a-Ser426, which activated phospholipase C and subsequently the calcium pathway, the latter of which promoted NET formation after infection or lipopolysaccharide stimulation. This study revealed Coro1a to be a novel substrate of Wip1 and showed that Wip1 is a negative regulator of NET formation during infection. These results support the potential application of Wip1 inhibitors to treat bacterial infections.展开更多
文摘To investigate the expression of hypoxia inducible factor 1-alpha (HIF-1α) and its correlation with P53 and vascular endothelial growth factor (VEGF), immunohistochemical technique was employed to detect the protein expressions of HIF-1α, P53 and VEGF in specimens from 57 patients with lung cancer. The results indicated that the total positive proportion of HIF-1α expression was 63 % and the HIF-1α expression was more frequent in bronchiole-alveolar carcinoma (86 %) than in other lung cancer. There was a strong association of HIF-1α with VEGF and P53 protein expressions. It is concluded that HIF-1α overexpression is a common event in lung cancer, which may be related to the up-regulation of the angiogenic factor VEGF and oncogene mutant P53 protein.
文摘Background: Myocardial infarction (MI) is a major disease burden. Wild-type p53-induced phosphatase 1 (Wipl) has been studied extensively in the context of cancer and the regulation of different types of stem cells, but the role of Wipl in cardiac adaptation to M I is unknown. We investigated the significance of Wipl in a mouse model of MI. Methods: The study began in June 2014 and was completed in July 2016. We compared Wipl-knockout (Wipl-KO) mice and wild-type (WT) mice to deternline changes in cardiac function and survival in response to MI. The heart weight/body weight (HW/BW) ratio and cardiac function were measured before MI. Mouse MI was established by ligating the left anterior descending (LAD) coronary artery under 1.5% isoflurane anesthesia. After M1, survival of the mice was observed for 4 weeks. Cardiac function was examined by echocardiography. The HW/BW ratio was analyzed, and cardiac hypertrophy was measured by wheat germ agglutinin staining. Hematoxylin and eosin (H&E) staining was used to determine the infarct size. Gene expression of interleukin-6 (IL-6), turnor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) was assessed by quantitative real-time polymerase chain reaction (qPCR), and the levels of signal transducers and activators of transcription 3 (stat3) and phosphor-stat3 (p-stat3) were also analyzed by Western blotting. Kaplan-Meier survival analysis, log-rank test, unpaired l-test, and one-way analysis of variance (ANOVA) were used for statistical analyses. Results: Wipl-KO mice had a marginally increased HW/BW ratio and slightly impaired cardiac fiinction before LAD ligation. Alter MI, Wipl-deficient mice exhibited increased mortality (57.14% vs. 29.17%; n = 24 [WT], n - 35 [WipI-KO], P 〈 0.05), increased cardiac hypertrophy (HW/BW ratio: 7 days: 7.25±0.36 vs. 5.84 ± 0.18, n cross-sectional area: 7 days: 311.80 ± 8.29 vs. 268.90 ± 11.15, n P 〉 0.05), and reduced cardiac function (ejection fraction: 7 days 10, p〈 0.01, and 4 weeks: 6.05± 0.17 vs. 5.87 ±0.24, n= 10, P〉0.05; P 〈 0.05, and 4 weeks: 308.80 ± 11.26 vs. 317.00 ±13.55, n = 6 29.37± 1.38 vs. 34.72 ± 1.81, P 〈 0.05, and 4 weeks: 19.06 ± 2.07 vs 26.37 ± 2.95, P〈 0.05; fractional shortening: 7 days: 13.72 ± 0.71 vs. 16.50 ± 0.94, P〈 0.05, and 4 weeks: 8.79 ±1.00 vs. 12.48 ±1.48, P 〈 0.05; n = l0 [WT], n = 15 [Wipl-KO]). H&E staining revealed a larger infarct size in Wipl-KO mice than in WT mice (34.79% ± 2.44% vs. 19.55% ± 1.48%, n = 6, P 〈 0.01 ). The expression oflL-6 and p-stat3 was downregulated in Wipl-KO mice (IL-6:1.71 ± 0.27 vs. 4.46 ± 0.79, n = 6, P 〈 0.01 ; and p-stat3/stat3:1.15 ±0.15 vs. 1.97 ± 0.23, n = 6, P 〈 0.05). Conclusion: The results suggest that Wipl could protect the heart from MI-induced ischemic injury.
基金supported by the National Natural Science Foundation of China,No.81471126(to XZC)and 81771216(to XZC)the Natural Science Foundation of Zhejiang Province of China,No.LY17H090005(to JLP)a grant from the Medical Science and Technology Plan Project of Zhejiang Province of China,No.2016KYB119(to JLP)
文摘Differentiation of human fibroblasts into functional neurons depends on the introduction of viral-mediated transcription factors, which present risks of viral gene integration and tumorigenicity. In recent years, although some studies have been successful in directly inducing neurons through sustained expression of small molecule compounds, they have only been shown to be effective on mouse-derived cells. Thus, herein we delivered vectors containing Epstein-Barr virus-derived oriP/Epstein-Barr nuclear antigen 1 encoding the neuronal transcription factor, Ascl1, the neuron-specific microRNA, miR124, and a small hairpin directed against p53, into human fibroblasts. Cells were incubated in a neuron-inducing culture medium. Immunofluorescence staining was used to detect Tuj-1, microtubule-associated protein 2, neuron-specific nucleoprotein NeuN and nerve cell adhesion molecules in the induced cells. The proportion of Tuj1-positive cells was up to 36.7% after induction for 11 days. From day 21, these induced neurons showed neuron-specific expression patterns of microtubule-associated protein 2, NeuN and neural cell adhesion molecule. Our approach is a simple, plasmid-based process that enables direct reprogramming of human fibroblasts into neurons, and provides alternative avenues for disease modeling and neurodegenerative medicine.
基金supported by grants from the National Natural Science Foundation for General and Key Programs(31930041,YZ)the National Key Research and Development Program of China(2017YFA0105002,2017YFA0104401,2017YFA0104402,YZ)+1 种基金the Knowledge Innovation Program of the Chinese Academy of Sciences(XDA16030301,YZ)the Doctoral Research Foundation Project of Affiliated Hospital of Guizhou Medical University(gyfybsky-2022-1,WZ)。
文摘Neutrophil extracellular traps (NETs) participate in the rapid inhibition and clearance of pathogens during infection;however, the molecular regulation of NET formation remains poorly understood. In the current study, we found that inhibition of the wild-type p53-induced phosphatase 1 (Wip1) significantly suppressed the activity of Staphylococcus aureus (S. aureus) and accelerated abscess healing in S. aureus-induced abscess model mice by enhancing NET formation. A Wip1 inhibitor significantly enhanced NET formation in mouse and human neutrophils in vitro. High-resolution mass spectrometry and biochemical assays demonstrated that Coro1a is a substrate of Wip1. Further experiments also revealed that Wip1 preferentially and directly interacts with phosphorylated Coro1a than compared to unphosphorylated inactivated Coro1a. The phosphorylated Ser426 site of Coro1a and the 28–90 aa domain of Wip1 are essential for the direct interaction of Coro1a and Wip1 and for Wip1 dephosphorylation of p-Coro1a Ser426. Wip1 deletion or inhibition in neutrophils significantly upregulated the phosphorylation of Coro1a-Ser426, which activated phospholipase C and subsequently the calcium pathway, the latter of which promoted NET formation after infection or lipopolysaccharide stimulation. This study revealed Coro1a to be a novel substrate of Wip1 and showed that Wip1 is a negative regulator of NET formation during infection. These results support the potential application of Wip1 inhibitors to treat bacterial infections.