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• Research Paper Volume 13, Issue 9 pp 13023-13038

  A zinc finger protein gene signature enables bladder cancer treatment stratification

  Relevance score: 7.1138864

  Jiandong Zhang, Chen Zhang, Peng Cao, Xiang Zheng, Baozhong Yu, Haoyuan Cao, Zihao Gao, Feilong Zhang, Jiyuan Wu, Huawei Cao, Changzhen Hao, Zejia Sun, Wei Wang

  Keywords: bladder cancer, zinc finger proteins, prognosis, treatment

  Published in Aging on May 7, 2021

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  Bladder cancer (BC) is a commonly occurring malignant tumor affecting the urinary tract. Zinc finger proteins (ZNFs) constitute the largest transcription factor family in the human genome and are therefore attractive biomarker candidates for BC prognosis. In this study, we profiled the expression of ZNFs in The Cancer Genome Atlas (TCGA) BC cohort and developed a novel prognostic signature based on 7 ZNF-coding genes. After external validation of the model in the GSE48276 dataset, we integrated the 7-ZNF-gene signature with patient clinicopathological data to construct a nomogram that forecasted 1-, 2-, and 3-year OS with good predictive accuracy. We then accessed The Genomics of Drug Sensitivity in Cancer database to predict the therapeutic drug responses of signature-defined high- and low-risk BC patients in the TCGA cohort. Greater sensitivity to chemotherapy was revealed in the low-risk group. Finally, we conducted gene set enrichment analysis of the signature genes and established, by applying the ESTIMATE algorithm, distinct correlations between the two risk groups and the presence of stromal and immune cell types in the tumor microenvironment. By allowing effective risk stratification of BC patients, our novel ZNF gene signature may enable tailoring more intensive treatment for high-risk patients.

• Research Paper Volume 13, Issue 6 pp 8320-8334

  Celecoxib alleviates zinc deficiency-promoted colon tumorigenesis through suppressing inflammation

  Relevance score: 5.3814397

  Xiaolong Yin, Yuting Zhang, Yingling Wen, Yunyao Yang, Hongping Chen

  Keywords: celecoxib, zinc deficiency, colon tumors, Apc^min/+ mice, inflammatory mediators

  Published in Aging on March 3, 2021

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  Accumulating evidence has shown that dietary zinc deficiency (ZD) increases the risk of various cancers including esophageal and gastric cancer. However, the role of ZD in colon tumorigenesis is unknown and the related mechanisms need to be investigated. Apc^min/+ mice, widely used to mimic the spontaneous process of human intestinal tumor, were used to construct a ZD mice model in this study. Inflammatory mediators such as COX-2, TNF-α, CCL, CXCL, and IL chemokines families were evaluated using real-time PCR and Enzyme-linked immunosorbent assay (ELISA). Besides, the immunoreactivities of cyclin D1, PCNA, and COX-2 in the colon were detected by immunohistochemistry. We found that zinc deficiency could promote colon tumorigenesis in Apc^min/+ mice. The mechanisms are involved in the upregulation of inflammatory mediators: COX-2, TNF-α, CCL, CXCL, and IL chemokines families. Administration of celecoxib, a selective COX-2 inhibitor, decreased colon tumorigenesis in Apc^min/+ mice via inhibiting the inflammatory mediators. ZD plays an important role in the process of colon cancers of Apc^min/+ mice. Celecoxib attenuates ZD-induced colon tumorigenesis in Apc^min/+ mice by inhibiting the inflammatory mediators. Our novel finding would provide potential prevention of colorectal tumor-induced by ZD.

• Research Paper Volume 12, Issue 24 pp 25767-25777

  Zinc oxide nanoparticles (ZnO NPs) combined with cisplatin and gemcitabine inhibits tumor activity of NSCLC cells

  Relevance score: 6.1889143

  Chenping Hu, Wenxiu Du

  Keywords: nanoparticle, zinc oxide, cisplatin, gemcitabine, non-small cell lung cancer

  Published in Aging on November 20, 2020

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  Non-small cell lung cancer (NSCLC) is one of the most common malignancies worldwide. The use of a combination of chemotherapy drugs and zinc oxide nanoparticles (ZnO-NPs), which have proven to induce tumor-selective cell death, reduce the drug resistance and reduce the side effects in vitro. In the present study, we developed ZnO-NPs loaded with both cisplatin (Cp) and gemcitabine (Gem) (ZnO-NPs(Cp/Gem)), then the morphologies and the size distribution of ZnO-NPs(Cp/Gem) particles were observed by transmission electron microscopy (TEM) and dynamic light scattering (DLS). Also, MTT, western blot and Annexin V-PI were used to assess the anti-tumor role of ZnO-NPs(Cp/Gem) in A549 cells. The viability for A549 cells showed a significant decrease in the ZnO NPs(Cp/Gem) group, respectively relative to Cp, Gem, the combination of Cp and Gem (Cp+Gem), and ZnO-NPs loaded with Cp (ZnO-NPs(Cp)) or Gem (ZnO-NPs(Gem)). Furthermore, ZnO-NPs(Cp/Gem) remarkably enhanced the apoptosis-promoting effect of Cp and Gem in A549 cells. The xenograft model showed that Zno-NPS (Cp/Gem) significantly enhanced the inhibition of Cp and Gem on tumor formation. The above results suggested that therapy of NSCLC with ZnO-NPs(Cp/Gem) could enhance the cytotoxic action of chemotherapeutic agents synergistically, indicating a promising potential for ZnO-NPs in antitumor applications.

• Research Paper Volume 11, Issue 21 pp 9295-9309

  Zinc-induced protective effect for testicular ischemia-reperfusion injury by promoting antioxidation via microRNA-101-3p/Nrf2 pathway

  Relevance score: 6.177536

  Zhiqiang Qin, Kai Zhu, Jianxin Xue, Pu Cao, Luwei Xu, Zheng Xu, Kai Liang, Jiageng Zhu, Ruipeng Jia

  Keywords: testicular ischemia-reperfusion injury, zinc, microRNA-101-3p, antioxidation

  Published in Aging on November 5, 2019

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  The present study was performed to determine the protective effect of Zinc on the rat testicular ischemia-reperfusion (I/R) injury and its mechanism. In vivo, the pathological changes and the apoptosis index were significantly relieved in the rats with Low-dose Zinc pretreatment, compared to the I/R group. After Low-dose Zinc treatment, the levels of tissue Malondialdehyde (MDA) were significantly decreased, while tissue antioxidant indices were significantly increased. Meanwhile, the level of NF-κB was significantly lower compared to I/R group, while the levels of Nrf2-dependent antioxidant enzymes were significantly higher in Low-dose Zinc+I/R group. In vitro, Low-dose Zinc markedly increased Leydig cell (TM3) cell viability, and relieved testicular oxidative damage via down-regulating ROS. A total of 22 differently expressed microRNAs were screened out using microRNA microarray in rat testicular tissue caused by I/R injury, especially showing that miR-101-3p was selected as the target miRNA. Furthermore, the levels of Nrf2 and NF-κB were apparently increased/decreased in TM3 cells treated with Hypoxic/Reoxygenation (H/R) after miR-101-3p mimics/inhibitor. In addition, H/R-induced testicular oxidative damage was recovered in TM3 administrated with miR-101-3p inhibitor and si-Nrf2. Therefore, this study provided a novel insight for investigating protective effect of Zinc on testicular I/R injury by promoting antioxidation via miR-101-3p/Nrf2.

  

  Zinc prevented testicular ischemia-reperfusion (I/R) injury in rats. (A) H&E staining of testicular tissues in Control, I/R injury, and I/R injury treated with Zinc rats (×400). Among them, ① Control group (n=8), ② I/R group (n=8), ③ Low-dose Zinc+I/R group (n=8), ④ High-dose Zinc group+I/R (n=8). (B) Mean seminiferous tubular diameter (MSTD) in each group. (C) TUNEL assay of testicular tissues in each group. Apoptotic cells exhibit a brown nuclear stain under microscope (×400). (D) TUNEL positive cells per 10³ germ cells and Apoptotic index of testes in each group. Data are shown as mean ± SD. *significant difference vs. Control group (P< 0.05); ^#significant difference vs. I/R group (P< 0.05).

  
  
  

  

  Zinc alleviated I/R induced oxidative damage in testis tissues. (A) DHE staining of testicular tissues in Control, I/R injury, and I/R injury treated with Zinc group. ROS exhibited red fluorescence under fluorescent microscope. (B–G) Content of MDA, T-AOC, GSH, GSH/GSSG, GST and SOD of testicular tissues in each group. Data are expressed as mean±SD. *significant difference vs. Control group (P< 0.05); ^#significant difference vs. I/R group (P< 0.05).

  
  
  

  

  Zinc pre-treatment increased the expression levels of Nrf2 and its downstream target genes in testicular tissues. (A) Immunohistochemical Staining showed Nrf2 and NF-κB expression levels in Control, I/R injury and I/R injury treated with Zinc groups. (B) Statistical analyses of IHC results in Nrf2 and NF-κB expression levels in different groups. (C) Protein levels of Nrf2, NF-κB, HO-1, NQO-1 and GST in different groups. Histone H3 and β-actin were used as a protein control to normalize volume of protein expression. (D) Statistical analyses of Western Blotting results in Nrf2, NF-κB, HO-1, NQO-1 and GST protein levels in different groups. Data are expressed as mean± SD. *significant difference vs. Control group (P< 0.05); ^#significant difference vs. I/R group (P< 0.05).

  
  
  

  

  Differentially expressed miRNAs in testicular tissues of rats induced by I/R injury based on microarrays. (A) Hierarchical clustering analysis of the differentially expressed miRNAs between Control and I/R injury testis samples in rats. (B) A schematic diagram used to search the target miRNAs of Nrf2 in three databases. (C) Validation of the five differently expressed miRNAs in rats caused by I/R injury based on real-time PCR assay. (D) MiRNA-101-3p expression level of TM3 after transfecting miR-101-3p mimics and inhibitor. (E) Nrf2 expression level of TM3 after transfecting miR-101-3p mimics and inhibitor. All data are expressed as the mean ± SD. *significant difference vs. Control group (P< 0.05).

  
  
  

  

  Zinc up-regulated miR-101-3p via Nrf2/HO-1 signaling pathways in TM3 Hypoxia/Reoxygenation (H/R) model. (A) Cell viability of TM3 in Control, H/R injury, and H/R injury treated with Zinc groups. (B) MiRNA-101-3p expression level in H/R with or without Zinc pretreatment groups. (C) The intracellular ROS and Nrf2 levels in H/R with or without Zinc pretreatment groups. (D) Protein levels of Nrf2, NF-κB, HO-1, NQO-1 and GST of TM3 in different groups. Histone H3 and β-actin were used as a protein control to normalize volume of protein expression. (E) The construction diagram of the target genes (Nrf2) double-luciferase reporter genes. (F) The relative luciferase expression with Nrf2 3′-UTR after co-transfection with miR-101-3p mimics or NC mimics in TM3. Data are expressed as mean±SD. *significant difference vs. Control group (P< 0.05); ^#significant difference vs. H/R group (P< 0.05); **p < 0.01 compared with NC group; ns indicated no significance.

  
  
  

  

  Transfecting miR-101-3p mimics and inhibitor regulated H/R-induced oxidative damage in vitro. (A) MiRNA-101-3p expression level of TM3 in H/R group after transfecting miR-101-3p mimics and inhibitor. (B) The intracellular ROS and Nrf2 of TM3 in H/R group after transfecting miR-101-3p mimics and inhibitor. (C) Protein levels of Nrf2, NF-κB, HO-1, NQO-1 and GST of TM3 after transfecting miR-101-3p mimics and inhibitor. Histone H3 and β-actin were used as a protein control to normalize volume of protein expression. Data are expressed as mean± SD. *significant difference vs. Control group (P< 0.05).

  
  
  

  

  The interaction between miR-101-3p and Nrf2 in TM3. (A) Protein levels and statistical analyses of Western blotting results of Nrf2 in TM3 which administrated with si-Nrf2. (B) Cell viability of TM3 in different treated groups. (C) Protein levels of Nrf2, NF-κB, HO-1, NQO-1 and GST of TM3 in different groups. Histone H3 and β-actin were used as a protein control to normalize volume of protein expression. (D) Statistical analyses of Western blotting results in Nrf2, NF-κB, HO-1, NQO-1 and GST expression levels in different groups. Data are expressed as mean±SD. *significant difference vs. Control group (P< 0.05); ^#significant difference vs. H/R+NC inhibitor+si-Control group (P< 0.05); ^&significant difference vs. H/R+miR-101-3p inhibitor+si-Control group (P< 0.05).

  
  
  

• Research Paper Volume 10, Issue 8 pp 2170-2189

  Exposure to Zinc oxide nanoparticles during pregnancy induces oocyte DNA damage and affects ovarian reserve of mouse offspring

  Relevance score: 6.1104646

  Qiu-Yue Zhai, Wei Ge, Jun-Jie Wang, Xiao-Feng Sun, Jin-Mei Ma, Jing-Cai Liu, Yong Zhao, Yan-Zhong Feng, Paul W. Dyce, Massimo De Felici, Wei Shen

  Keywords: Zinc oxide nanoparticles, oocyte, meiosis, DNA damage, ovarian reserve

  Published in Aging on August 28, 2018

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  Zinc oxide nanoparticles (nZnO) have been shown to have higher toxic effects likely due to their ion-shedding ability and low solubility under neutral conditions. In order to investigate whether exposure to nZnO during embryonic development affects ovary development, 12.5 day post coitum (dpc) fetal mouse ovaries were cultured in the presence of nZnO for 6 days. We found that the nanoparticles (NPs) accumulated within the oocyte cytoplasm in a dose dependent manner, caused DNA damage and apoptosis, and result in a significant decrease in oocyte numbers. No such effects were observed when the ovaries were incubated in the presence of ZnSO₄ or bulk ZnO as controls. In addition, we injected intravenously 16 mg/kg body weight nZnO in 12.5 dpc pregnant mice on two consecutive days and analyzed the ovaries of fetuses or offspring at three critical periods of oogenesis: 17.5 dpc, 3 days post-partum (dpp) and 21 dpp. Evidence of increased DNA damage in pachytene oocytes in fetal ovaries and impaired primordial follicle assembly and folliculogenesis dynamics in the ovaries of the offspring were found. Our results indicate that certain types of NPs affect pre- and post-natal oogenesis in vitro and in vivo.

  

  Internalization of nZnO in fetal oocytes. (A) Up: confocal reflection imaging of tissue sections of ovaries cultured for 6 days stained for MVH (red) and Hoechst 33342 (blue); nZnO was reflected and visualized as white dots. Down: 3-D plotting of nZnO intensity is presented with the z-axis indicating the intensity of nZnO within the ovary section and the interface of the x- and y-axes indicating the whole ovary section. (B) Ovary sections observed at TEM; NPs are not detectable in the control, ZnSO₄ or bZnO whereas nZnO are recognizable as black particle in the oocyte cytoplasm (arrows). N: nucleus; C: cytoplasm. (C) Chemical characterization of nZnO nanoparticles with TEM equipped with energy dispersive spectrometer (EDX) within the oocyte cytoplasm.

  
  
  

  

  Apoptotic and DNA damage markers in nZnO treated fetal oocytes in vitro. (A-D) Representative q-RT-PCR and WB analyses of Bax, Bcl-2 and Mvh of ovarian tissues cultured for 6 days; Actin or Mvh was used as housekeeping gene and loading control, respectively. (E) TUNEL-staining of the ovarian tissues after 6 days of culture with nZnO. (F) Number of TUNEL-positive total cells, TUNEL-positive oocytes and TUNEL-positive granulosa cells per section. (G) Co-immunostaining of DNA damage marker γH2AX (green) and germ cell marker MVH (red) in ovary sections after 6 day nZnO exposure, Hoechst 33342 (blue) was used for nuclei staining. (H) Percentage of MVH positive oocytes also stained for γH2AX. (I) Number of MVH positive oocytes/ovary.

  
  
  

  

  nZnO induces DNA damage in fetal oocytes in vitro. (A) Representative double IF of pachytene and diplotene oocytes for SCP3 (red) and γH2AX (green) obtained from ovarian tissues cultured for 6 days. (B) Quantification of oocytes showing distinct γH2AX staining. (C) Representative WB for the indicated proteins from ovarian tissues cultured for 6 days; actin was used as loading control. (D) Representative double IF of pachytene and diplotene oocytes for SCP3 (red) and RAD51 (green). (E) Quantification of oocytes showing RAD51 foci.

  
  
  

  

  nZnO expose increased DNA damage and BAX/BCL-2 ratio in fetal oocytes in vivo. (A) Representative cytospreads of oocytes at the pachytene and the diplotene meiotic stage after nZnO intravenous injection of 12.5 dpc female mice. Chromosomes were stained for SCP3 (red) and DNA damage evidenced by γH2AX (green) staining. (B) Percentage of oocytes showing weak or strong γH2AX staining. (C) Representative images of western blotting analysis of BAX, BCL-2, and γH2AX. Actin was used as the loading control.

  
  
  

  

  nZnO expose decrease the oocyte number and affect oocyte specific gene expressionin 3 dpp ovaries. (A) Representative immunofluorescence pictures of MVH stained oocytes in sections of 3 dpp ovaries; Hoechst 33342 was used for nuclei staining; note oocytes within PF or in Cyst. (B) Number of oocytes per ovary. (C) Percentage of oocytes in PF or Cyst. (D) Representative WB of the indicated proteins in 3 dpp ovaries; (E) Quantitative RT‐PCR for Mvh and Lhx8 mRNA levels in 3 dpp ovaries, Actin or Mvh was used as housekeeping gene and loading control. (F) IF for NOBOX (red) and fluorescence intensity of NOBOX in oocytes of control and nZnO exposed ovaries in 3 dpp ovaries; Hoechst 3342 (blue) was used for nuclei staining.

  
  
  

  

  nZnO expose alters follicle dynamics in 21 dpp ovaries. (A) Identification of different type of follicles with immunohistochemistry of MVH positive oocytes in 21 dpp ovaries. (B) Percentage of different type of follicles in the same ovaries of (A). (C-D) Number of oocytes and PFs in the same ovaries of (A). (E) Representative images of GVBD and PBE. (F) Meiotic spindle morphologies in MI oocytes. (G) Representative morphologies of second filial generation.

  
  
  

  

  Exposure to nZnOs during pregnancy induces the DNA damage of fetal oocytes and affects ovarian reserve of mouse offspring. Maternal exposure to nZnO during embryo development affects the DNA damage of fetal oocytes and the establishment of the ovarian reserve in the female offspring using an in vitro ovary culture system or animal model.

  
  
  

• Editorial Volume 10, Issue 8 pp 1791-1792

  A promising connection between BDNF and Alzheimer’s disease

  Relevance score: 5.909533

  Maria Laura Giuffrida, Agata Copani, Enrico Rizzarelli

  Keywords: Aβ monomers, nerve growth factor, CREB, BDNF, copper and zinc

  Published in Aging on August 6, 2018

• Editorial Volume 8, Issue 6 pp 1161-1162

  Zinc intake, microRNA dysregulation, and esophageal cancer

  Relevance score: 7.98911

  Louise Y. Fong, John L. Farber, Carlo M. Croce

  Keywords: dietary zinc intake, microRNA

  Published in Aging on June 8, 2016

• Research Paper Volume 3, Issue 1 pp 33-43

  HIF-1α antagonizes p53-mediated apoptosis by triggering HIPK2 degradation

  Relevance score: 5.846458

  Lavinia Nardinocchi, Rosa Puca, Gabriella D'Orazi

  Keywords: HIF-1α, HIPK2, zinc, proteasomal degradation, p53 transcriptional activity, p53Ser46

  Published in Aging on January 18, 2011

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  Many human diseases are characterized by the development of tissue hypoxia. Hypoxia-inducible factor (HIF) is a transcription factor that regulates fundamental cellular processes in response to changes in oxygen concentration, such as angiogenesis, survival, and alterations in metabolism. The levels of HIF-1α subunit are increased in most solid tumors not only by low oxygen but also by growth factors and oncogenes and correlate with patient prognosis and treatment failure. The link between HIF-1α and apoptosis, a major determinant of cancer progression and treatment outcome, is poorly understood. Here we show that HIF-1α protects against drug-induced apoptosis by antagonizing the function of the tumor suppressor p53. HIF-1α upregulation induced proteasomal degradation of homeodomain-interacting protein kinase-2 (HIPK2), the p53 apoptotic activator. Inhibition of HIF-1α by siRNA, HIF-1α-dominant negative or by zinc re-established the HIPK2 levels and the p53-mediated chemosensitivity in tumor cells. Our findings identify a novel circuitry between HIF-1α and p53, and provide a paradigm for HIPK2 dictating cell response to antitumor therapies.

  

  (A) Luciferase assay in C38 and C27 prostate cancer cells showed significantly higher HIF-1α-luc promoter activity in C27 cells. *P=0.0159. (B) Luciferase assay of p53AIP1-luc reporter in C38 and C27 prostate cancer cells after bleomycin (Bleo) treatment showing impairment of p53 transcriptional activity in C27 cells. (C) Immunoblot of C38 and C27 cells after 40 Gy X-irradiation revealed PARP cleavage and Ser46 phosphorylation only in C38 cells. Blot image was cut and pasted. (D) RT-PCR analysis of p53 apoptotic target genes in C38 and C27 prostate cancer cells after bleomycin (Bleo) treatment. Gel image was cut and pasted. (E) Luciferase assay of p53 target Noxa-luc reporter in C38 cells after X-irradiation revealed impairment of luciferase activity after HIF-1α overexpression. (F) Immunoblot of RKO cells after adriamycin (ADR) treatment showed abolishment of (p)Ser46 after HIF-1α-Flag overexpression. (G) Luciferase assay of p53AIP1-luc reporter in C27 cells showed induction of luciferase activity after HIF-1α silencing with siRNA.

  
  
  

  

  (A) HIF-1α-Flag (4, 6, and 8 μg) and HIPK2-GFP (4 μg) expression vectors were co-transfected in 293 cells where immunoblot analyses showed that increased amounts of HIF-1α induced HIPK2 abolishment. (B) Immunoblot analysis of C38 cells transfected with HIF-1α expression and treated with proteasome inhibitor MG132 (10 μM for 4 h) or DMSO vehicle. The endogenous HIPK2 levels downregulated by HIF-1α were rescued by MG132. (C) RT-PCR analysis of HIPK2 in RKO colon cancer cells co-transfected with HIF-1α and HIPK2 expression vector. (D) Immunoblot of endogenous HIPK2 protein in C38 and C27 prostate cancer cells, showing lower HIPK2 levels in “constitutive hypoxic” C27 cells. (E) The HIPK2 mRNA levels were comparable between C38 and C27 cells. (F) Immunoblot in C27 cells showed rescue of endogenous HIPK2 protein levels after HIF-1α knock-down by siRNA.

  
  
  

  

  (A) Luciferase assay in 293 cells co-transfected with Noxa-luc reporter and HIPK2-GFP (4 μg) expression vector alone or in combination with HIF-1α-Flag (8 μg). Results represent mean ± s.d. from three experiments. The expression of the ectopic proteins was assayed by immunoblot. (B) Lysates from RKO cells co-transfected with HIF-1α and HIPK2 expression vectors were assayed for RT-PCR of p53 target gene Noxa. GAPDH is a loading control (C) Luciferase assay in H1299 cells co-transfected with Noxa-luc reporter and low amount of wtp53 expression vector or of p53S46D mutant, in combination with HIPK2, HIF-1α or HIF-1αDN mutant. Results represent mean ± s.d. from three experiments. (D) Tunel assay of RKO cells where HIF-1α overexpression significantly reduced the HIPK2-induced apoptotic cell death. *P=0.001. (E) Luciferase assay in RKO cells stable transfected with p53AIP1-luc reporter where the adryamicin (ADR)-induced luciferase activity was inhibited by HIF-1α overexpression but not by HIF-1α dominat negative (DN) mutant. Results represent mean ± s.d. from three experiments. (F) Lysates from RKO cells treated as indicated were assayed for RT-PCR analyses of p53 apoptotic target Noxa and for HIPK2 expression. GAPDH is a loading control.

  
  
  

  

  (A) Immunoblot of RKO cells in which the effect of HIPK2 overexpression on p53Ser46 phosphorylation was abolished by HIF-1α co-expression and restored by concomitant zinc (100 μm for 24 h) treatment. (B) Luciferase assay in RKO cells stable transfected with p53AIP1-luc reporter showing that the HIPK2-induced luciferase activity was inhibited by HIF-1α and rescued by zinc treatment (100 μm for 24 h); zinc did not rescued the HIPK2 inhibition triggered by the HIF-1αP/A mutant and the HIF-1αDNA mutant did not inhibit HIPK2-induced transcriptional activity. Results represent mean ± s.d. from three experiments. (C) Lysates from RKO cells treated as indicated were assayed for RT-PCR analyses of p53 apoptotic target Noxa. GAPDH is a loading control. (D) Tunel assay of RKO cells showing that the HIPK2-induced apoptotic cell death was significantly inhibited by HIF-1α and strongly rescued by zinc treatment. *P=0.001.

  
  
  

• Research Paper pp undefined-undefined

  Zbtb34 promotes embryonic stem cell proliferation by elongating telomere length

  Relevance score: 6.1380835

  Zheng Liu, Xinran Wei, Yue Gao, Xiaodie Gao, Xia Li, Yujuan Zhong, Xiujuan Wang, Chong Liu, Tianle Shi, Jiabin Lv, Tao Liu

  Keywords: Zbtb34, zinc finger, telomere, Pot1b, mouse embryonic stem cells

  Published in Aging on Invalid Date

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  Zbtb34 is a novel zinc finger protein, which is revealed by biological software analysis to have 3 zinc fingers, but its functions remain unknown. In this study, mouse Zbtb34 cDNA was amplified by PCR and inserted into the plasmid pEGFP-N1 to generate Zbtb34-EGFP fusion protein. The upregulation of Zbtb34 in mouse embryonic stem cells promoted telomere elongation and increased cell proliferation. In order to understand the above phenomena, the telomere co-immunoprecipitation technique was employed to investigate the relationship between Zbtb34 and telomeres. The results indicated that Zbtb34 could bind to the DNA sequences of the telomeres. Alanine substitution of the third zinc finger abolished such binding. Since Pot1 is the only protein binding to the single-stranded DNA at the end of the telomeres, we further investigated the relationship between Zbtb34 and Pot1. The results revealed that the upregulation of Zbtb34 decreased the binding of Pot1b to the telomeres. Through the upregulation of Pot1b, the binding of Zbtb34 to the telomeres was also reduced. In conclusion, we showed that the main biological function of Zbtb34 was to bind telomere DNA via its third ZnF, competing with Pot1b for the binding sites, resulting in telomere elongation and cell proliferationt.

• Research Paper pp undefined-undefined

  Development and validation of novel prognostic models for zinc finger proteins-related genes in soft tissue sarcoma

  Relevance score: 5.202393

  Junqing Li, Quan Zhou, Changsheng Zhang, Huimin Zhu, Jie Yao, Meng Zhang

  Keywords: soft tissue sarcomas, zinc finger proteins, molecular subtype, immune infiltration, differentially expressed genes

  Published in Aging on Invalid Date

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  As the most common transcriptional regulators, zinc finer proteins (ZNFs) play vital roles in occurrence and progression of malignant tumors. Whereas, information regarding the roles of ZNFs in soft tissue sarcomas (STS) remains scarce. In this study, a comprehensive bioinformatics analysis investigating roles of ZNFs in STS was performed. Initially, we extracted raw datasets of differentially expressed ZNFs from GSE2719. Using a sequence of bioinformatics methods, we then investigated the prognostic significance, function, and molecular subtype of these differentially expressed ZNFs. In addition, CCK8 and plate clone formation assays were used to explore the effect of ZNF141 on STS cells. A total of 110 differentially expressed ZNFs were identified. Nine ZNFs (HLTF, ZNF292, ZNF141, LDB3, PHF14, ZNF322, PDLIM1, NR3C2, and LIMS2) were selected to establish an overall survival (OS) prediction model, and seven ZNFs (ZIC1, ZNF141, ZHX2, ZNF281, ZNHIT2, NR3C2, and LIMS2) were used to develop a progression-free survival (PFS) prediction model. Compared with patients with low-risk in the TCGA training and testing cohorts, as well as the GEO validation cohorts, patients with high-risk had poorer OS and PFS. Using nomograms constructed with the identified ZNFs predicting OS and PFS, we established a clinically useful model. Four distinct molecular subtypes with different prognostic and immune infiltration characteristics were identified. In vitro experiments showed that ZNF141 promoted the proliferation and viability of STS cells. In conclusion, ZNF-related models are useful as prognostic biomarkers, suggesting their potentials as therapeutic targets in STS. These findings will enable us to develop novel strategies treating STS, which will potentially improve outcomes of patients with STS.

• Research Paper pp undefined-undefined

  3D printed porous zinc scaffold combined with bioactive serum exosomes promotes bone defect repair in rabbit radius

  Relevance score: 6.1380835

  Baoxin Zhang, Zhiwei Pei, Wanxiong He, Wei Feng, Ting Hao, Mingqi Sun, Xiaolong Yang, Xing Wang, Xiangyu Kong, Jiale Chang, Guanghui Liu, Rui Bai, Chang Wang, Feng Zheng

  Keywords: bone defect, zinc scaffold, 3D printing, exosome, bone repair

  Published in Aging on Invalid Date

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  Currently, the repair of large bone defects still faces numerous challenges, with the most crucial being the lack of large bone grafts with good osteogenic properties. In this study, a novel bone repair implant (degradable porous zinc scaffold/BF Exo composite implant) was developed by utilizing laser melting rapid prototyping 3D printing technology to fabricate a porous zinc scaffold, combining it under vacuum conditions with highly bioactive serum exosomes (BF EXO) and Poloxamer 407 thermosensitive hydrogel. The electron microscope revealed the presence of tea saucer-shaped exosomes with a double-layered membrane structure, ranging in diameter from 30–150 nm, with an average size of 86.3 nm and a concentration of 3.28E+09 particles/mL. In vitro experiments demonstrated that the zinc scaffold displayed no significant cytotoxicity, and loading exosomes enhanced the zinc scaffold’s ability to promote osteogenic cell activity while inhibiting osteoclast activity. In vivo experiments on rabbits indicated that the hepatic and renal toxicity of the zinc scaffold decreased over time, and the loading of exosomes alleviated the hepatic and renal toxic effects of the zinc scaffold. Throughout various stages of repairing radial bone defects in rabbits, loading exosomes reinforced the zinc scaffold’s capacity to enhance osteogenic cell activity, suppress osteoclast activity, and promote angiogenesis. This effect may be attributed to BF Exo’s regulation of p38/STAT1 signaling. This study signifies that the combined treatment of degradable porous zinc scaffolds and BF Exo is an effective and biocompatible strategy for bone defect repair therapy.