Search

Search Results

91 results found. Results per page: [ 20 ][ 40 ][ 60 ][ 80 ][ 100 ][ 200 ][ 300 ]

Sort by: [ Publication Date ][ Score ]

Year of publication: [ 2025 ][ 2024 ][ 2023 ][ 2022 ][ 2021 ][ 2020 ][ 2019 ][ 2018 ][ 2017 ][ 2016 ][ 2015 ][ 2014 ][ 2013 ][ 2012 ][ 2011 ][ 2010 ][ 2009 ][ Any ]

Direction: [ Desc ][ Asc ]

Page: 12345

• Research Paper Volume 14, Issue 4 pp 1627-1650

  The telomere-mitochondrial axis of aging in newborns

  Relevance score: 4.1488914

  Charlotte Van Der Stukken, Tim S. Nawrot, Rossella Alfano, Congrong Wang, Sabine A.S. Langie, Michelle Plusquin, Bram G. Janssen, Dries S. Martens

  Keywords: telomere length, mitochondrial DNA content, p53, PGC-1α, aging

  Published in Aging on February 15, 2022

  Show abstract
  Hide abstract

  Aging starts at the beginning of life as evidenced by high variability in telomere length (TL) and mitochondrial DNA content (mtDNAc) at birth. Whether p53 and PGC-1α are connected to these age-related markers in early life is unclear. In this study, we hypothesized that these hallmarks of aging are associated at birth.

  In 613 newborns from the ENVIRONAGE birth cohort, p53 and PGC-1α protein levels were measured in cord plasma, while TL and mtDNAc were measured in both cord blood and placental tissue. Cord blood methylation data of genes corresponding to the measured protein levels were available from the Human MethylationEPIC 850K BeadChip array. Pearson correlations and linear regression models were applied while accounting for selected covariates. In cord, a 10% increase in TL was associated with 5.22% (95% CI: 3.26 to 7.22; p < 0.0001) higher mtDNAc and −2.66% (95% CI: –5.04 to −0.23%; p = 0.032) lower p53 plasma level. In placenta, a 10% increase in TL was associated with 5.46% (95% CI: 3.82 to 7.13%; p < 0.0001) higher mtDNAc and −2.42% (95% CI: −4.29 to −0.52; p = 0.0098) lower p53 plasma level. Methylation level of TP53 was correlated with TL and mtDNAc in cord blood and with cord plasma p53 level.

  Our study suggests that p53 may be an important factor both at the protein and methylation level for the telomere-mitochondrial axis of aging at birth.

• Research Paper Volume 13, Issue 18 pp 22242-22255

  miR-21 regulates ischemic neuronal injury via the p53/Bcl-2/Bax signaling pathway

  Relevance score: 4.1488914

  Honglin Yan, Wenxian Huang, Jie Rao, Jingping Yuan

  Keywords: cerebral ischemia, neuronal injury, miR-21, p53, Bcl-2/Bax

  Published in Aging on September 22, 2021

  Show abstract
  Hide abstract

  Focal cerebral ischemia leads to a large number of neuronal apoptosis, and secondary neuronal death is the main cause of cerebral infarction. MicroRNA-21 (miR-21) has been shown to be a strong anti-apoptosis and pro-survival factor in ischemia. However, the precise mechanism of miR-21 in ischemic neuroprotection remains largely unknown. In this study, miR-21 was down-regulated while p53 was up-regulated following ischemia in vitro and in vivo. Overexpression of miR-21 in vitro and in vivo substantially inhibited the expression of p53 following ischemia, while inhibition of miR-21 in vitro and in vivo promoted p53 expression following ischemia. Moreover, the miR-21/p53 axis regulated the expression of Bcl-2/Bax and abolished OGD/R-induced neuronal injury in vitro. Furthermore, overexpression of miR-21 in vivo reduced neuronal death, protected against ischemic damage, and improved neurological functions by inhibiting p53/Bcl-2/Bax signaling, while inhibition of miR-21 enhanced the p53/Bcl-2/Bax signaling and aggravated the ischemic neuronal injury in vivo. Our data uncover a novel mechanism of miR-21 in regulating cerebral ischemic neuronal injury by inhibiting p53/Bcl-2/Bax signaling pathway, which suggests that miR-21/p53 may be attractive therapeutic molecules for treatment of ischemic stroke.

• Research Paper Volume 13, Issue 18 pp 22109-22119

  LHX9, a p53-binding protein, inhibits the progression of glioma by suppressing glycolysis

  Relevance score: 5.3065157

  Xiangying Luo, Jianwei Ge, Tao Chen, Jinfang Liu, Ziyuan Liu, Changlong Bi, Song Lan

  Keywords: LHX9, p53, glioma, glycolysis, PGK1

  Published in Aging on September 17, 2021

  Show abstract
  Hide abstract

  Purpose: LHX9 methylation has been reported in many tumors, but its functions and related mechanisms in glioma are still unknown and need to be verified.

  Methods: The protein level of LHX9 in glioma tissues was examined using western blotting and immunohistochemistry, and the functions of LHX9 in glioma cell lines were investigated using MTT and colony formation assays. In addition, the interaction between LHX9 and P53 was analyzed by immunoprecipitation, and the roles of LHX9 in cancer metabolism were explored by measuring metabolites.

  Results: In this study, we found that the LHX9 expression level was decreased in glioma specimens, and the upregulation of LHX9 expression inhibited the growth of glioma cells in liquid medium and on soft agar. Regarding the molecular mechanism, we found that LHX9 interacted with p53, and downregulation of LHX9 promoted the expression of the glycolysis-related enzyme PGK1 and increased the lactic acid content. By interfering with the expression of LHX9, the tumorigenicity of glioma cells was promoted, an outcome blocked by further interference with PGK1 expression.

  Conclusion: In summary, the decreased expression of LHX9 in gliomas activates the expression of the glycolysis-related enzyme PGK1, thereby promoting the development of gliomas, suggesting that the LHX9-PGK1 signaling axis can be used as a target for the treatment of glioma.

• Research Paper Volume 13, Issue 18 pp 21914-21940

  Metformin-induced chemosensitization to cisplatin depends on P53 status and is inhibited by Jarid1b overexpression in non-small cell lung cancer cells

  Relevance score: 5.649303

  Tharcisio Citrangulo Tortelli, Rodrigo Esaki Tamura, Mara de Souza Junqueira, Janio da Silva Mororó, Silvina Odete Bustos, Renato Jose Mendonça Natalino, Shonagh Russell, Laurent Désaubry, Bryan Eric Strauss, Roger Chammas

  Keywords: metformin, cisplatin, Jarid1b, p53, NSCLC

  Published in Aging on September 16, 2021

  Show abstract
  Hide abstract

  Metformin has been tested as an anti-cancer therapy with potential to improve conventional chemotherapy. However, in some cases, metformin fails to sensitize tumors to chemotherapy. Here we test if the presence of P53 could predict the activity of metformin as an adjuvant for cisplatin-based therapy in non-small cell lung cancer (NSCLC). A549, HCC 827 (TP53 WT), H1299, and H358 (TP53 null) cell lines were used in this study. A549 cells were pre-treated with a sub-lethal dose of cisplatin to induce chemoresistance. The effects of metformin were tested both in vitro and in vivo and related to the ability of cells to accumulate Jarid1b, a histone demethylase involved in cisplatin resistance in different cancers. Metformin sensitized A549 and HCC 827 cells (but not H1299 and H358 cells) to cisplatin in a P53-dependent manner, changing its subcellular localization to the mitochondria. Treatment with a sub-lethal dose of cisplatin increased Jarid1b expression, yet downregulated P53 levels, protecting A549Res cells from metformin-induced chemosensitization to cisplatin and favored a glycolytic phenotype. Treatment with FL3, a synthetic flavagline, sensitized A549Res cells to cisplatin. In conclusion, metformin could potentially be used as an adjuvant for cisplatin-based therapy in NSCLC cells if wild type P53 is present.

• Research Paper Volume 13, Issue 17 pp 21587-21598

  FOXN3 inhibits cell proliferation and invasion via modulating the AKT/MDM2/p53 axis in human glioma

  Relevance score: 4.423868

  Chaojia Wang, Hanjun Tu, Ling Yang, Chunming Ma, Juntao Hu, Jie Luo, Hui Wang

  Keywords: FOXN3, cell proliferation, cell migration, glioma, AKT/MDM2/p53 pathway

  Published in Aging on September 12, 2021

  Show abstract
  Hide abstract

  This study aimed to evaluate the biological role of forkhead box N3 (FOXN3) in human glioma and clarify the possible molecular mechanisms. FOXN3 expression patterns in clinical tissue specimens were characterized via qPCR and Western blotting. Kaplan-Meier survival curve was applied to assess the correlation between FOXN3 expression and overall survival. Effects of FOXN3 over-expression and depletion on glioma cell proliferation, apoptosis, migration and invasion were assessed by CCK8, colony formation assay, flow cytometry, scratch wound healing assay and Transwell invasion assay, respectively. Moreover, the involvement of AKT/murine double minute 2 (MDM2)/p53 pathway was evaluated. Additionally, tumor transplantation model assay was performed to determine the effects of FOXN3 over-expression on glioma cell growth in vivo. Results showed that FOXN3 was significantly down-regulated in glioma tissues compared with normal tissues. Patients with lower FOXN3 expression exhibited a shorter overall survival time. Gain- and loss-of-function analyses demonstrated that FOXN3 over-expression significantly suppressed proliferation, survival and motility of glioma cells, whereas FOXN3 knockdown remarkably promoted glioma cell proliferation, survival and motility. Furthermore, FOXN3 over-expression inhibited the activation of AKT/MDM2/p53 signaling pathway in glioma cells, while FOXN3 depletion facilitated its activation. Additionally, tumor xenograft assays revealed that FOXN3 over-expression retarded glioma cell growth in vivo. Collectively, these findings indicate that FOXN3 inhibits cell growth and invasion through inactivating the AKT/MDM2/p53 signaling pathway and that FOXN3-AKT/MDM2/p53 axis may represent a novel therapeutic target for glioma patients.

• Research Paper

  Local anesthetic levobupivacaine induces ferroptosis and inhibits progression by up-regulating p53 in non-small cell lung cancer

  Relevance score: 5.649303

  Minghua Meng, Meiling Huang, Cuicui Liu, Jiming Wang, Weihua Ren, Shaomin Cui, Jianhua Gu, Jinlan Xie, Bin Ma, Guangzhu Yang, Shuncheng He

  Keywords: NSCLC, progression, levobupivacaine, ferroptosis, p53

  Published in Aging on June 27, 2021

  Show abstract
  Hide abstract

  Non-small cell lung cancer (NSCLC) is a common malignancy with high mortality and poor prognosis. Levobupivacaine is a widely used local anesthetic and presents potential anti-tumor activity. Nevertheless, the function of levobupivacaine in the NSCLC development remains elusive. Here, we tried to investigate the impact of levobupivacaine on the NSCLC progression and the underlying mechanism. Significantly, we revealed that levobupivacaine could inhibit the proliferation and induce the apoptosis of NSCLC cells. Levobupivacaine was able to attenuate the invasion and migration in the cells. Meanwhile, the treatment of levobupivacaine enhanced the erastin-induced inhibition of cell growth of NSCLC cells. The treatment of levobupivacaine remarkably increased the levels of ROS, iron, and Fe2+ in NSCLC cells. Mechanically, levobupivacaine up-regulated the expression of p53 and induced ferroptosis by regulating p53 in NSCLC cells. Moreover, tumorigenicity analysis in nude mice showed that the treatment of levobupivacaine significantly repressed the tumor growth of NSCLC cells in vivo. In summary, we concluded that the local anesthetic levobupivacaine inhibits the progression and induces ferroptosis of NSCLC by up-regulating p53. Our finding provides new insights into the mechanism by which levobupivacaine attenuates the development of NSCLC. Levobupivacaine may serve as a potential anti-tumor candidate for the therapeutic strategy of NSCLC.

• Priority Research Paper Volume 13, Issue 10 pp 13380-13392

  Cdkn1a transcript variant 2 is a marker of aging and cellular senescence

  Relevance score: 4.8441844

  José Alberto López-Domínguez, Sandra Rodríguez-López, Ulises Ahumada-Castro, Pierre-Yves Desprez, Maria Konovalenko, Remi-Martin Laberge, César Cárdenas, José Manuel Villalba, Judith Campisi

  Keywords: p21, p53, mouse dermal fibroblast, ionizing radiation, doxorubicin

  Published in Aging on May 25, 2021

  Show abstract
  Hide abstract

  Cellular senescence is a cell fate response characterized by a permanent cell cycle arrest driven primarily the by cell cycle inhibitor and tumor suppressor proteins p16^Ink4a and p21^Cip1/Waf1. In mice, the p21^Cip1/Waf1 encoding locus, Cdkn1a, is known to generate two transcripts that produce identical proteins, but one of these transcript variants is poorly characterized. We show that the Cdkn1a transcript variant 2, but not the better-studied variant 1, is selectively elevated during natural aging across multiple mouse tissues. Importantly, mouse cells induced to senescence in culture by genotoxic stress (ionizing radiation or doxorubicin) upregulated both transcripts, but with different temporal dynamics: variant 1 responded nearly immediately to genotoxic stress, whereas variant 2 increased much more slowly as cells acquired senescent characteristics. Upon treating mice systemically with doxorubicin, which induces widespread cellular senescence in vivo, variant 2 increased to a larger extent than variant 1. Variant 2 levels were also more sensitive to the senolytic drug ABT-263 in naturally aged mice. Thus, variant 2 is a novel and more sensitive marker than variant 1 or total p21^Cip1/Waf1 protein for assessing the senescent cell burden and clearance in mice.

• Research Paper Volume 13, Issue 9 pp 12537-12551

  Silencing long noncoding RNA NEAT1 alleviates acute liver failure via the EZH2-mediated microRNA-139/PUMA axis

  Relevance score: 2.9862788

  Qiang Wang, Shu Liu, Huan Wang, Lian Liu, Sheng Zhang, Yingzi Ming, Yujun Zhao, Ke Cheng

  Keywords: acute liver failure, long noncoding RNA nuclear enriched abundant transcript 1, microRNA-139, p53-upregulated modulator of apoptosis, methylation

  Published in Aging on April 26, 2021

  Show abstract
  Hide abstract

  This study aimed to investigate the role of long noncoding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) in the development of ALF. We collected blood samples from patients with acute liver failure (ALF) and established an ALF mouse model induced by D-galactosamine/Lipopolysaccharide (D-GalN/LPS) for in vivo studies. Peripheral blood mononuclear cells (PMBCs) induced with LPS were isolated for in vitro experiments. Survival tests, histological analysis, and biochemical indicator assays were conducted. Luciferase assay was performed to determine the binding affinity between microRNA-139 (miR-139) and p53-upregulated modulator of apoptosis (PUMA). Expression of lncRNA NEAT1, enhancer of zeste homolog 2 (EZH2), and PUMA was upregulated, while the expression of miR-139 was downregulated in clinical samples and D-GalN/LPS induced ALF mouse model. LncRNA NEAT1 promoted the enrichment of H3K27me3 on the promoter region of miR-139 via EZH2, which led to suppression of miR-139. The inhibition of miR-139 resulted in the upregulation of its downstream target PUMA. The NEAT1/miR-139/PUMA pathway upregulated the production of pro-inflammatory cytokines, tumor necrosis factor alpha, interleukin (IL)-6, and IL-1β, thereby mediating the progression of ALF. In conclusion, silencing lncRNA NEAT1 upregulated the expression of miR-139 through EZH2, leading to the downregulation of PUMA, which alleviated the development of ALF.

• Research Paper Volume 13, Issue 8 pp 11774-11785

  Inhibition of sestrin 1 alleviates polycystic ovary syndrome by decreasing autophagy

  Relevance score: 4.742327

  Xiaoyuan Xu, Xinli Song, Xiaohua Xu, Yanluan Zheng, Lan Xu, Ling Shen

  Keywords: sestrin 1, polycystic ovary syndrome, p53, autophagy

  Published in Aging on April 22, 2021

  Show abstract
  Hide abstract

  Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, accounting for 50–70% of anovulatory infertility cases. However, the etiology of PCOS at the molecular level remains unclear. Here, bioinformatics analysis was performed to identify differentially expressed genes (DEGs) between adipose tissue of PCOS patients and matched tissues from non-hyperandrogenic women. RT-qPCR, western blot, cell counting kit-8 (CCK-8), EdU (5-Ethynyl-2'-deoxyuridine) staining, LC3 staining, ROS (reactive oxygen species) detection, and apoptosis assays were conducted to explore the effects of sestrin 1 on KGN human granulosa-like tumor cells. Bioinformatics analysis indicated that DEGs in adipose tissue from PCOS patients were enriched in the p53 signaling pathway. Moreover, sestrin 1 was identified as a major target of the p53 gene. Downregulation of sestrin 1 inhibited proliferation of KGN cells by inhibiting autophagy. Additionally, sestrin 1 downregulation increased ROS generation and promoted apoptosis in KGN cells. By contrast, overexpression of sestrin 1 increased cell viability by increasing autophagy in KGN cells. Together, these results suggest that downregulation of sestrin 1 may be a potential novel treatment strategy for PCOS.

• Research Paper Volume 13, Issue 5 pp 7180-7189

  Neuroprotective effect of hydrogen sulfide against glutamate-induced oxidative stress is mediated via the p53/glutaminase 2 pathway after traumatic brain injury

  Relevance score: 4.312628

  Jianping Sun, Xiaoyu Li, Xiaoyu Gu, Hailong Du, Gengshen Zhang, Jianliang Wu, Feng Wang

  Keywords: traumatic brain injury, hydrogen sulfide, glutamate, oxidative stress, p53

  Published in Aging on February 26, 2021

  Show abstract
  Hide abstract

  Several reports suggest that hydrogen sulfide (H₂S) exerts multiple biological and physiological effects on the pathogenesis of traumatic brain injury (TBI). However, the exact molecular mechanism involved in this effect is not yet fully known. In this study, we found that H₂S alleviated TBI-induced motor and spatial memory deficits, brain pathology, and brain edema. Moreover, sodium hydrosulfide (NaHS), an H₂S donor, treatment markedly increased the expression of Bcl-2, while inhibited the expression of Bax and Cleaved caspase-3 in TBI-challenged rats. Tunnel staining also demonstrated these results. Treatment with NaHS significantly reduced the glutamate and glutaminase 2 (GLS-2) protein levels, and glutamate-mediated oxidative stress in TBI-challenged rats. Furthermore, we demonstrated that H₂S treatment inhibited glutamate-mediated oxidative stress through the p53/GLS-2 pathway. Therefore, our results suggested that H₂S protects brain injury induced by TBI through modulation of the glutamate-mediated oxidative stress in the p53/GLS-2 pathway-dependent manner.

• Research Paper Volume 13, Issue 4 pp 5986-6009

  Overexpression of hsa_circ_0002874 promotes resistance of non-small cell lung cancer to paclitaxel by modulating miR-1273f/MDM2/p53 pathway

  Relevance score: 5.014036

  Jianhao Xu, Liwei Ni, Fenglun Zhao, Xiaoxiao Dai, Jialong Tao, Jia Pan, Aiming Shi, Zhu Shen, Cunjin Su, Yusong Zhang

  Keywords: hsa_circ_0002874, miR1273f, MDM2, P53, paclitaxel-resistance

  Published in Aging on February 17, 2021

  Show abstract
  Hide abstract

  Background: This study aimed to investigate the aberrant expression of hsa_circ_0002874 in non-small cell lung cancer (NSCLC) and elucidate associated molecular mechanisms that influence apoptosis and induce paclitaxel (PTX) resistance.

  Methods: Inhibitors were used to downregulate circRNA or miRNA expression. pCDNA plasmid transfection and mimics were used to upregulate circRNA or miRNA expression. Dual-luciferase reporter assays were conducted to evaluate interactions between miR1273f and MDM2. Xenograft tumor models were used to assess the effect of hsa_circ_0002874 and miR1273f on tumor growth. NSCLC tissues and matched non-cancerous tissues were also collected for correlation analysis.

  Results: hsa_circ_0002874 acts as a sponge for miR1273f which targets MDM2/P53. The stability of the hsa_circ_0002874/miR1273f/MDM2/P53 pathway was verified by upregulating and downregulating the expression of hsa_circ_0002874 and miR1273f. hsa_circ_0002874 downregulation or miR1273f upregulation reversed the resistance of the A549/Taxol cells in xenograft models. The expression of hsa_circ_0002874 was high, and the level of MDM2 was low in NSCLC tissues. P53 was only weakly expressed in NSCLC tissues with high expression of MDM2.

  Conclusions: hsa_circ_0002874 is strongly expressed in NSCLC tissues and maybe a potential marker for PTX resistance. hsa_circ_0002874 downregulation could regulate miR1273f/MDM2/P53 signaling pathway to reverse the PTX resistance of NSCLC and induce apoptosis in vitro and vivo.

• Research Paper Volume 13, Issue 4 pp 4831-4849

  An aging and p53 related marker: HOXA5 promoter methylation negatively correlates with mRNA and protein expression in old age

  Relevance score: 4.7651396

  Laura-Kim Feiner, Sascha Tierling, Sebastian Holländer, Matthias Glanemann, Claudia Rubie

  Keywords: ageing, DNA methylation, HOXA5, p53, gene expression

  Published in Aging on February 5, 2021

  Show abstract
  Hide abstract

  The process of aging has been associated with differential patterns of DNA methylation which relate to changes in gene expression. Hence, we aimed to identify genes with significant age-related methylation differences and to study their mRNA and protein expression profile. Genome-wide DNA methylation analysis was performed with the Illumina Infinium Methylation EPIC BeadChip Microarray on bisulfite-converted DNA prepared from monocytes derived from young (average age: 23.8 yrs) and old (average age: 81.5 yrs) volunteers that are separated by at least 50 years of age difference, n=4, respectively. Differentially methylated CpG sites were assigned to the associated genes and validated by deep sequencing analysis (n=20). Demonstrating an age-associated significant increase of methylation in the promoter region (p=1x10^-8), Homeobox A5 (HOXA5), also known to activate p53, emerged as an interesting candidate for further expression analyses by Realtime PCR, ELISA and Western Blot Analysis (n=30, respectively). Consistent with its hypermethylation we observed significant HOXA5 mRNA downregulation (p=0.0053) correlating with significant p53 downregulation (p=0.0431) in the old cohort. Moreover, we observed a significant change in HOXA5 protein expression (p=3x10^-5) negatively correlating with age and promoter methylation thus qualifying HOXA5 for an eligible p53-related aging marker.

• Research Paper Volume 12, Issue 23 pp 23647-23667

  Identification of the novel Np17 oncogene in human leukemia

  Relevance score: 5.2671304

  Bowen Wu, Yichao Gan, Ying Xu, Zhaoxing Wu, Ganyu Xu, Ping Wang, Chen Wang, Zhipeng Meng, Mengyuan Li, Jiawei Zhang, Haifeng Zhuang, Xuzhao Zhang, Linlin Yang, Jinfan Li, Xiaoxian Gan, Xiaofang Yu, Wendong Huang, Ying Gu, Rongzhen Xu

  Keywords: Np17, leukemia, oncogene, P53, Np9

  Published in Aging on November 21, 2020

  Show abstract
  Hide abstract

  We previously defined the HERV-K Np9 as a viral oncogene. Here we report the discovery of a novel oncogene, Np17, which is homologous to the viral Np9 gene and predominantly present in Hominoidea. Np17 is located on chromosome 8, consists of 7 exons, and encodes a 16.8kDa nuclear protein with149 amino-acid residue. Functionally, knockdown of Np17 induced growth inhibition of leukemia cells, whereas enforced expression of Np17 promoted growth of leukemia cells in vitro and in vivo. In human leukemia, Np17 was detected in 59.65% (34/57) of acute myeloid leukemia (AML) patients examined and associated with refractory/relapsed AML. Mechanistically, Np17 decreased p53 levels and its mechanism might be involved in recruiting nuclear MDM2 to p53 for ubiquitin-mediated degradation. These findings reveal that Np17 is a novel oncogene associated with refractory/relapsed leukemia.

• Research Paper Volume 12, Issue 21 pp 22112-22121

  Autophagy modulates mesenchymal-to-endothelial transition via p53

  Relevance score: 4.338167

  Jie Hu, Shuting Kong, Tiancheng Dong, Zhiwei Lin, Qihao Zhang, Xingxing Chen, Yongsheng Gong, Xiaofang Fan, Mingyu He, Hao Zhou

  Keywords: mesenchymal-to-endothelial transition, autophagy, p53, endothelial cells, fibrosis

  Published in Aging on November 13, 2020

  Show abstract
  Hide abstract

  Mesenchymal-to-endothelial transition (MEndT) is one of the mechanisms that influences cardiac fibrosis, which is a key process in cardiac remodeling. It has been reported that autophagy inhibits endothelial cell transition. However, whether autophagy could modulate MEndT in cardiac fibrosis has not yet been investigated. Here, we discussed the association between autophagy and MEndT and its possible mechanism. In this study, we induced endothelial-to-mesenchymal transition using transforming growth factor-β to generate mesenchymal cells and fibroblasts in wild-type human umbilical vein endothelial cells and cells with p53 knockout or overexpression. Then, autophagy was induced by Earle's balanced salt solution (EBSS) and was inhibited by bafilomycin A1 or lentivirus-ATG5-shRNA. The expression levels of MEndT and the autophagy markers CD31, VE-Cadherin, Vimentin, α-SMA, LC3, p62 and p53 were examined. We found that activation of autophagy could promote MEndT and increase cytoplasmic and total expression of p53, that but nuclear p53 expression was decreased, and that inhibition of autophagy activation could reverse the effect of EBSS. Moreover, after knockout of nuclear p53, autophagy promoted MEndT, while autophagy inhibited MEndT in p53 overexpressing cells. Our results demonstrate that autophagy modulate MEndT by nuclear p53 provide a new strategy for the treatment of fibrosis diseases.

• Research Paper Volume 12, Issue 20 pp 20702-20727

  Stress-induced p53 drives BAG5 cochaperone expression to control α-synuclein aggregation in Parkinson's disease

  Relevance score: 4.338167

  Huan-Yun Chen, Chin-Hsien Lin, Shu-Chun Teng

  Keywords: BAG5, cochaperone, p53, α-synuclein, Parkinson's disease

  Published in Aging on October 21, 2020

  Show abstract
  Hide abstract

  Parkinson’s disease (PD) is a common neurodegenerative disorder with the pathological hallmark of α-synuclein aggregation. Dysregulation of α-synuclein homeostasis caused by aging, genetic, and environmental factors underlies the pathogenesis of PD. While chaperones are essential for proteostasis, whether modulation of cochaperones may participate in PD formation has not been fully characterized. Here, we assessed the expression of several HSP70- and HSP90-related factors under various stresses and found that BAG5 expression is distinctively elevated in etoposide- or H₂O₂-treated SH-SY5Y cells. Stress-induced p53 binds to the BAG5 promoter directly to stimulate BAG5. Induced BAG5 binds α-synuclein and HSP70 in both cell cultures and brain lysates from PD patients. Overexpressed BAG5 may result in the loss of its ability to promote HSP70. Importantly, α-synuclein aggregation in SH-SY5Y cells requires BAG5. BAG5 expression is also detected in transgenic SNCA mutant mice and in PD patients. Together, our data reveal stress-induced p53-BAG5-HSP70 regulation that provides a potential therapeutic angle for PD.

• Priority Research Paper Volume 12, Issue 18 pp 17800-17814

  p21 can be a barrier to ferroptosis independent of p53

  Relevance score: 4.7651396

  Divya Venkatesh, Brent R. Stockwell, Carol Prives

  Keywords: p21, ferroptosis, cancer, p53-independent, organ damage

  Published in Aging on September 24, 2020

  Show abstract
  Hide abstract

  Traditionally, the p21 protein has been viewed as limiting cancer progression and promoting aging. In contrast, there are reports that p21 can enhance cancer survival and limit tissue damage, depending on the tissue of origin and type of stressor involved. Here, we provide evidence to support these latter two roles of p21 by exploring its ability to regulate ferroptosis. Ferroptosis is a form of cell death that is associated with certain degenerative diseases, some of which are aging-related. Our results reveal a correlation between p21 protein levels in cell lines that are resistant to ferroptosis (p21 high) versus cell lines that are sensitive and easily undergo ferroptosis (p21 low). We also show that p21 levels themselves are differentially regulated in response to ferroptosis in a p53-independent manner. Further, experimentally altering the abundance of p21 protein inverts the ferroptosis-sensitivity of both resistant and sensitive human cancer cell lines. Our data also indicate that the interaction of p21 with CDKs is crucial for its ability to restrict the progression of ferroptosis. While this study was performed in cancer cell lines, our results support the potential of p21 to aid in maintenance of healthy tissues by blocking the damage incurred due to ferroptosis.

  

  Regulation of ferroptosis by p53 is highly context specific. (A) The indicated cell lines were categorized based on the relative amount of cell death observed in response to 24 hours treatment with erastin in a 6-well format. After 24 hours of treatment, the sensitive cell lines had an EC50 of less than 2 μM of erastin, while the moderately sensitive cell lines had an EC50 that was greater than 2 μM, but lesser than 10 μM of erastin. In the resistant cell lines, erastin did not achieve 50% killing at this time point. (B, C) Viability of isogenic cell lines with wild-type (WT) p53 or no p53 (KO) in (B) HCT-116 and (C) RKO when treated with indicated doses of either doxorubicin (left panel) or IKE (right panel) for 24 hours. (D) Immunoblot showing p53 and p21 protein levels in HCT-116 and RKO cells. Multiple replicates of the wild-type and p53 KO cell lines cultured in separate dishes were used. Actin was used as a loading control. The data in (B, C) represent the mean ± SE for two of four independent experiments. The viability data have been normalized to that of the DMSO control.

  
  
  

  

  p21 protein is differentially regulated between cells that are sensitive and resistant in response to ferroptosis. (A–E) Impact of treatment with erastin/IKE on the protein levels of p21 and p53. (A) HT-1080 cells, (B) SK-HEP1 cells and (C) U2OS cells were treated for 16 hours whereas (D) H1299 cells and (E) HCT116 cells (+/+ and -/- isogenic lines with respect to p53 status) were treated for 48 hours.

  
  
  

  

  p21 mRNA is upregulated in both ferroptosis-sensitive and ferroptosis-resistant cells after treatment with IKE. (A–C) Left panels: Impact of IKE treatment on the mRNA levels of p21. (A) HT-1080 cells were treated for 16 hours while (B, C) H1299 and HCT-116 cells were treated for 48 hours. mRNA levels of ptgs2 and chac1 were measured in (A, B) as markers of ferroptosis. Right panels: the corresponding protein levels in the cells used in the left panels are shown. The data in left panels of (A–C) represent the mean ± SE for three biological replicates with two technical replicates each.

  
  
  

  

  Altering p21 protein levels changes the sensitivity of cells to ferroptosis. (A, B) HCT116 (A) or H1299 (B) cells were transfected with two different siRNAs (#1, #2) directed against p21 mRNA for 24 hours, and then treated with erastin or IKE as indicated for an additional 48 hours. As a control, cells were transfected with luciferase siRNA a (siCtrl/C). The right panels in A and B show the corresponding changes in p21 protein levels. (C) HCT-116 cells and HCT116 p21 (-/-) cells were treated with increasing doses of either erastin (left panel) or IKE (right panel) for 48 hours. (D) Left panel: Viability of HT-1080 cells that were transfected with the indicated plasmids expressing p21 variants or an empty vector and then treated with either DMSO or IKE for 48 hours. The panel on the right shows the corresponding immunoblot detecting p21 protein levels. The data in (A, B) represent the mean ± SE for two of three independent experiments, in (C) represent the mean ± SE for two out of four independent experiments, in (D) represent the mean ± SE for three independent experiments. The viability data have been normalized to the DMSO control in (A–C) and to their respective untreated control in (D).

  
  
  

• Research Paper Volume 12, Issue 18 pp 17990-18007

  SIRT1 activation by minocycline on regulation of microglial polarization homeostasis

  Relevance score: 4.742327

  Ling-Hsuan Wu, Bor-Ren Huang, Sheng-Wei Lai, Chingju Lin, Hsiao-Yun Lin, Liang-Yo Yang, Dah-Yuu Lu

  Keywords: microglia, SIRT1, minocycline, microglial polarization, acetyl-p53

  Published in Aging on September 23, 2020

  Show abstract
  Hide abstract

  Sirtuin 1 (SIRT1) has been reported to be involved in the mechanisms underlying longevity and has also been indicated as a valuable regulator of age-related neurological disorders. Some natural products increase SIRT1 activity and stimulate deacetylation of various proteins. In the present study, SIRT1 overexpression by genetic modification or treatment with SIRT1 activators significantly inhibited the secretion of nitric oxide and expression of inducible nitric oxide synthase, cyclooxygenase 2, and proinflammatory mediator—interleukin 1β—in microglia. SIRT1 activation also decreased the levels of K379 acetyl-p53 and the protein inhibitor of activated Stat 1 expression in microglial cells. In addition, it dramatically promoted M2 polarization of microglia, which enhanced cell motility and altered phagocytic ability. We also used minocycline, a well-known inhibitor of microglial activation, to study the mechanism of SIRT1 signaling. Minocycline treatment decreased neuroinflammatory responses and promoted M2 polarization of microglia. It also reduced the acetyl-p53 level in the brain tissues in an inflammatory mouse model. Our findings demonstrated that SIRT1 participates in the maintenance of microglial polarization homeostasis and that minocycline exerts regulatory effects on SIRT1 activation. Therefore, our results indicate that SIRT1 activation may be a useful therapeutic target for the treatment of neuroinflammation-associated disorders.

• Research Paper Volume 12, Issue 14 pp 14990-15001

  Lysine-specific histone demethylase 1B (LSD2/KDM1B) represses p53 expression to promote proliferation and inhibit apoptosis in colorectal cancer through LSD2-mediated H3K4me2 demethylation

  Relevance score: 5.3527546

  Shaoxin Cai, Jinsi Wang, Wei Zeng, Xuefei Cheng, Lihang Liu, Weihua Li

  Keywords: colorectal cancer, proliferation, apoptosis, LSD2, p53

  Published in Aging on July 29, 2020

  Show abstract
  Hide abstract

  Epigenetic alterations have been reported to play critical roles in the development of colorectal cancer (CRC). However, the biological function of the lysine-specific histone demethylase 1B (LSD2/KDM1B) in CRC is not well understood. Therefore, we investigated the characteristics of LSD2 in CRC. We observed significant upregulation of LSD2 in CRC tissue compared to that in normal colorectal tissue. LSD2 promotes CRC cell proliferation and inhibits cell apoptosis through cell cycle regulation, promoting CRC progression both in vitro and in vivo. We found that LSD2 performs these functions by inhibiting the p53-p21-Rb pathway. Finally, we found that LSD2 directly binds to p53 and represses p53 expression via H3K4me2 demethylation at the p53 promoter. Our results revealed that LSD2 acts as an oncogene by binding and inhibiting p53 activity in CRC. Thus, LSD2 may be a new molecular target for CRC treatment.

  

  LSD2 expression levels in human colorectal cancer (CRC) tissue and cells. (A) The ONCOMINE database was used to examine mRNA expression of LSD2 in CRC tissue. (B) Real-time Polymerase chain reaction (PCR) to evaluate mRNA expression of LSD2 in clinical CRC specimens relative to normal tissues (n=36). Data were expressed as means ± SEM. (C, D) Western Blot evaluation of LSD2 protein expression in CRC and normal tissue. (E) LSD2 protein expression in normal and CRC tissue was analysed by IHC. (F) Pearson’s χ2 tests to assess the association between colon tissue type and LSD2 expression by IHC(n=36). (G) Western blotting to assess LSD2 expression in CRC cell lines.

  
  
  

  

  LSD2 over-expression promotes CRC cell proliferation. (A) Western blot detection of LSD2 and GAPDH (loading control) protein expression in Caco2 and SW1116 cells with control or LSD2. (B, C) BrdU/PI assay to detect and quantify DNA synthesis in Caco2 and SW1116 cells with control or LSD2. **p < 0.01. (D) Cell Counting Kit-8 (CCK8) assay to measure the viability of Caco2 and SW1116 cells with control or LSD2. (E, F) Colony formation assays and quantification in approximately 500 Caco2 and SW1116 cells with control or LSD2. Data were expressed as means ± SEM, **p < 0.01.

  
  
  

  

  LSD2 down-regulation inhibits CRC cell proliferation. (A) Western blot showing protein expression of LSD2 and GAPDH (loading control) in HCT-116 and LoVo cells with control or sh-LSD2. (B, C) BrdU/PI assay to detect and quantification of DNA synthesis in HCT-116 and LoVo cells with control or sh-LSD2. **p < 0.01. (D) Cell Counting Kit-8 (CCK8) assay to detect the viability of HCT-116 and LoVo cells with control or sh-LSD2. (E, F) Colony formation assays and quantification in approximately 500 HCT-116 and LoVo cells with control or sh-LSD2. Data were expressed as means ± SEM, **p < 0.01.

  
  
  

  

  LSD2 promoted CRC cells proliferation in vivo. (A) Effects of LSD2 down-expression on tumor growth in a xenograft mouse model. Empty vector or sh-LSD2 was transfected into LoVo cells, which were injected in the nude mice (n = 6), and the tumors were obtained at day 35 and was determined by measuring their tumor volume (B) and tumor weight (C). Data were expressed as means ± SEM. (D) The tumor sections were under IHC staining using antibodies against LSD2, p53, p21,ki-67, *P < 0.05.

  
  
  

  

  LSD2 promotes proliferation by inducing G1-S arrest and reducing apoptosis in colorectal cancer (CRC) cells. (A) HCT-116 and LoVo cells stably expressing vector or sh-LSD2#1 or sh- LSD2#2. The percentage of cells in G0/G1, S. or G2/M phases was tested using a subG1 assay and flow cytometry. (B) Apoptotic rates of HCT-116 and LoVo cells stably expressing vector or sh-LSD2#1 or sh-LSD2#2 measured by flow cytometry in annexin V/PI assays. LR, early apoptotic cells; UR, terminal apoptotic cells. Values represent the means ± SD. (C) Quantitative analysis of DNA apoptosis. Data were expressed as means ± SEM. **p < 0.01. (D) Bcl-2, BAX, CL-caspase 3, and CL-caspase 9 protein expression measured by Western blot with GAPDH protein as the loading control.

  
  
  

  

  LSD2 inhibits p53 expression via demethylation of H3K4me2 through binding to the p53 promoter. (A, B) Real-time PCR assays to detect p53 mRNA expression for vector, LSD2, ShNC, and Sh-LSD2 in HCT-116 and LoVo cells. (C, D) p53 and H3K4me2 protein expression measured by Western blot for vector, LSD2, and ShNC in HCT-116 and LoVo cells. (E, F) P53 promoter activity in vector, LSD2, ShNC and Sh-LSD2 in HCT-116 and LoVo cells measured by luciferase assay. Data were expressed as means ± SEM. (G) ChIP assay in LoVo cells showing the interaction between LSD2 and H3K4me2 at the p53 promoter. **p < 0.01.

  
  
  

  

  LSD2 regulates colorectal cancer (CRC) cell proliferation and apoptosis through p53. ShRNA mediates p53 knockdown in HCT-116 LSD2-downregulated cell lines, while p53 over-expression in HCT-116 LSD2-upregulated cell lines was observed. (A) Protein expression of p53, p21, pRb and LSD2 measured by Western blot among the CRC cell lines mentioned above. (B) BrdU/PI assays were performed to measure DNA synthesis in the indicated CRC cell lines. (C) Quantitative analysis of DNA synthesis. (D) Western blot showing p53 and LSD2 protein expression in the p53 LSD2 double-downregulated HCT-116 and LoVo cell lines. (E) Flow cytometry detection of the apoptotic rates of the indicated CRC cell lines. (F) Quantitative analysis of DNA apoptosis. Data were expressed as means ± SEM. **p < 0.01.

  
  
  

• Research Paper Volume 12, Issue 16 pp 16270-16293

  CTCF promotes colorectal cancer cell proliferation and chemotherapy resistance to 5-FU via the P53-Hedgehog axis

  Relevance score: 4.7651396

  Qiuhua Lai, Qingyuan Li, Chengcheng He, Yuxin Fang, Simin Lin, Jianqun Cai, Jian Ding, Qian Zhong, Yue Zhang, Changjie Wu, Xinke Wang, Juan He, Yongfeng Liu, Qun Yan, Aimin Li, Side Liu

  Keywords: colorectal cancer, CTCF, Hedgehog, P53, chemotherapy resistance

  Published in Aging on July 20, 2020

  Show abstract
  Hide abstract

  CTCF is overexpressed in several cancers and plays crucial roles in regulating aggressiveness, but little is known about whether CTCF drives colorectal cancer progression. Here, we identified a tumor-promoting role for CTCF in colorectal cancer. Our study demonstrated that CTCF was upregulated in colorectal cancer specimens compared with adjacent noncancerous colorectal tissues. The overexpression of CTCF promoted colorectal cancer cell proliferation and tumor growth, while the opposite effects were observed in CTCF knockdown cells. Increased GLI1, Shh, PTCH1, and PTCH2 levels were observed in CTCF-overexpressing cells using western blot analyses. CCK-8 and apoptosis assays revealed that 5-fluorouracil chemosensitivity was negatively associated with CTCF expression. Furthermore, we identified that P53 is a direct transcriptional target gene of CTCF in colorectal cancer. Western blot and nuclear extract assays showed that inhibition of P53 can counteract Hedgehog signaling pathway repression induced by CTCF knockdown. In conclusion, we uncovered a crucial role for CTCF regulation that possibly involves the P53-Hedgehog axis and highlighted the clinical utility of colorectal cancer-specific potential therapeutic target as disease progression or clinical response biomarkers.

  

  CTCF is significantly upregulated in CRC tissues and acts as a potential oncogenic gene. (A) CTCF is upregulated in all gastrointestinal tumors (GEPIA, http://gepia.cancer-pku.cn/). (B) Kaplan-Meier relapse free survival analysis in CRC patients with high or low expression of CTCF in GSE31598 via online website PROGgeneV2 (http://genomics.jefferson.edu/proggene/). (C) GSEA indicated that high expression of CTCF was positively correlated with the cancer related gene set signatures (KEGG_PATHWAYS_IN_CANCER, KEGG_COLORECTAL_CANCER) in CRC patient gene expression profiles (GSE17538, n = 177, and TCGA, n = 465). (D) qRT-PCR analysis of CTCF expression in 77 pairs of CRC patient specimens. (E) Western blot analyses of CTCF in 12 pairs of tumor and match adjacent normal tissues collected from clinical CRC patients. N for Normal, T for Tumor. The above data are presented as mean ± SEM. * P<0.05, **P<0.01, and ***P<0.001.

  
  
  

  

  Upregulation of CTCF promotes human CRC cells proliferation. (A) GSEA plot indicated that high expression of CTCF is positively correlated with the cell cycle gene set signatures (KEGG_CELL_CYCLE) in published CRC patient gene expression profiles (GSE17538, n = 177, and TCGA, n = 465). (B, C) qRT-PCR and western blot analyses of CTCF expression level in constructed cell lines (HCT116 and RKO).(D, E) The relative growth rates were measured using CCK8 and colony formation assays and compared between CTCF overexpressed group and Vector group at indicated times in HCT116 and RKO cell lines. (F) Images of EdU staining in both indicated cell lines, and the relative percentage of EdU-positive cells in images of related groups are shown (G). (H, I) Tumor volume and weight were measured and analyzed. (J) The tumor sections were under IHC staining using antibody against Ki-67. The above data are presented as mean ± SEM. * P<0.05, **P<0.01, and ***P<0.001.

  
  
  

  

  Inhibition of CTCF represses human CRC cells proliferation. (A) GSEA results showed that “KEGG_DNA_REPLICATION” gene set enriches in the CTCF high expression group and “CYCLIN_D1_KE_V1_UP” gene set enriches in the CTCF low expression group (GSE17538, n = 177, and TCGA, n = 465). (B, C) qRT-PCR and western blot analyses of CTCF expression level in the constructed cell lines (SW480 and RKO). (D–G) Cell reproductive capacity was examined by CCK8, colony formation and EdU staining assays. (H, I) Tumor volume and weight of subcutaneous tumor were measured and analysed. (J) Immunohistochemistry was performed to determine Ki-67 expression. The above data are presented as mean ± SEM. * P<0.05, **P<0.01, and ***P<0.001.

  
  
  

  

  CTCF induces 5-FU-based chemoresistance in CRC. (A, B) Cell growth inhibition rate was measured via CCK8 analysis and compared between different groups with different treatment concentration at indicated time (48 hours). (C) The apoptosis rate of different transfected groups with 5-FU treatment were measured by flow cytometry. (D) Western blot analysis of CTCF in HCT116 and RKO cell lines after 5-FU (10 μM) treatment for 48 hours. (E, F) Western blot analyses of cleaved-PARP, cleaved Capase-3 and ABCG2 in HCT116 and SW480 cell lines. (G) Spearman correlation analyses between relative CTCF and ABCG2 mRNA expression in 13 fresh human CRC specimens. The above data are presented as mean ± SEM. * P<0.05, **P<0.01, and ***P<0.001.

  
  
  

  

  CTCF activates Hedgehog signaling pathway. (A) GSEA plots indicated that “GCNP_SHH_UP_EARLY.V1_UP” and “GCNP_SHH_UP_LATE.V1_UP” and “GCNP_GLI1_UP.V1_UP” gene signatures enrich in the CTCF high expression group and “GCNP_SHH_UP_LATE.V1_DN” gene set enriches in the CTCF low expression group (GSE17538, n = 177, and TCGA, n = 465). (B) Western blot analyses of Key molecules of Hedgehog signaling pathway in different transfected groups with or without the stimulation of Hedgehog signaling pathway inhibitor, GDC-0449 (2 μM). (C) Relative growth rate of different transfected groups with or without the administration of GDC-0449 (2 μM). (D–F) Images of EdU staining of both indicated cell lines with or without the administration of GDC-0449, and the relative percentage of EdU-positive cells in images of related groups is shown. The above data are presented as mean ± SEM. * P<0.05, **P<0.01, and ***P<0.001.

  
  
  

  

  CTCF enhances Hedgehog signaling pathway activation via targeting P53. (A) Venn diagram enrichment analysis of the 5-FU putative target genes. (B) Protein-protein interaction analysis via STRING (https://string-db.org/). (C) GSEA plots indicated that “P53_DN.V1_UP” gene set signature enriches in the CTCF high expression group and “P53_DN.V1_DN” gene set enriches in the CTCF low expression group (GSE17538, n = 177). (D) Schematic view of the P53 gene transcription start site (TSS) with a CTCF-binding site (CBS). (E) qRT-PCR analysis of P53 expression level in constructed cell lines. (F) ChIP-PCR results for CTCF on the CBS in HCT116 cells. (G) P53 luciferase reporter activity was analyzed in SW480 cells. (H) Western blot analysis of Key molecules of Hedgehog signaling pathway and P53 in different transfected groups with or without the stimulation of P53-specific siRNA. (I, J) Nuclear extract assays and western blot analyses of GLI1 in indicated cells. The above data are presented as mean ± SEM. * P<0.05, **P<0.01, and ***P<0.001.

  
  
  

  

  CTCF promotes chemoresistance by regulating P53-Hedgehog axis signaling. (A) Apoptosis assays showed the effect of GDC0449 on CTCF-mediated 5-FU stimulated apoptosis of CRC cells. (B) Western blot analysis of the effects of P53 on CTCF-mediated ABCG2 upregulation. (C) The representative images of subcutaneous tumors from different experimental groups are shown. (D, E) Tumor weight and volume analyses showed that JK184 recovered the stimulative cell proliferation caused by upregulated CTCF under stimulation of 5-FU. (F) A hypothetical model illustrating that CTCF transcriptionally represses P53 and activates the Hedgehog signaling pathway to promote proliferation and 5-FU chemotherapy resistance of CRC cells. The above data are presented as mean ± SEM. * P<0.05, **P<0.01, and ***P<0.001.

  
  
  

• Research Paper Volume 12, Issue 11 pp 10473-10487

  p53 plays a central role in the development of osteoporosis

  Relevance score: 5.0260425

  Tao Yu, Xiaomeng You, Haichao Zhou, Alex Kang, Wenbao He, Zihua Li, Bing Li, Jiang Xia, Hui Zhu, Youguang Zhao, Guangrong Yu, Yuan Xiong, Yunfeng Yang

  Keywords: osteoporosis, osteogenesis, bone mass density, p53

  Published in Aging on June 2, 2020

  Show abstract
  Hide abstract

  Osteoporosis is a metabolic disease affecting 40% of postmenopausal women. It is characterized by decreased bone mass per unit volume and increased risk of fracture. We investigated the molecular mechanism underlying osteoporosis by identifying the genes involved in its development. Osteoporosis-related genes were identified by analyzing RNA microarray data in the GEO database to detect genes differentially expressed in osteoporotic and healthy individuals. Enrichment and protein interaction analyses carried out to identify the hub genes among the deferentially expressed genes revealed TP53, MAPK1, CASP3, CTNNB1, CCND1, NOTCH1, CDK1, IGF1, ERBB2, CYCS to be the top 10 hub genes. In addition, p53 had the highest degree score in the protein-protein interaction network. In vivo and in vitro experiments showed that TP53 gene expression and serum p53 levels were upregulated in osteoporotic patients and a mouse osteoporosis model. The elevated p53 levels were associated with decreases in bone mass, which could be partially reversed by knocking down p53. These findings suggest p53 may play a central role in the development of osteoporosis.

  

  Heat map of the top 60 DEGs in GSE100609 (30 upregulated and 30 downregulated). The GSE100609 dataset, which included gene expression profiles from four healthy individuals and four osteoporotic patients, was obtained from the GEO database. In total, 228 upregulated and 281 downregulated DEGs were identified. Red, upregulation; blue, downregulation.

  
  
  

  

  (A) Enrichment analysis of upregulated genes: hsa05200, cancer pathway; hsa05222, small cell lung cancer pathway; hsa04115, p53 signaling pathway; hsa04310, wnt signaling pathway; hsa04015, rap1 signaling pathway. (B) Enrichment analysis of downregulated genes: hsa04360, axon guidance pathway; hsa05100, bacterial invasion of epithelial cells pathway; hsa05143, African trypanosomiasis pathway; hsa05010, Alzheimer's disease pathway; hsa04020, calcium signaling pathway.

  
  
  

  

  Protein-protein interactions. PPI network constructed using STRING and illustrating the interactions among DEGs.

  
  
  

  

  Degree, betweenness, closeness of hub genes. Within the PPI network, the top three hub genes with highest degree, betweenness and closeness scores are TP53, MAPK1, and CASP3.

  
  
  

  

  GO terms/KEGG pathways associated with top 10 enriched hub genes. Biological process module: GO:0070887, cellular response to chemical stimulus; GO:0031325, positive regulation of cellular metabolic process; GO:0010604, positive regulation of macromolecule metabolic process. Molecular functions module: GO:0019899, enzyme binding; GO:0005102, receptor binding; GO:0044877, macromolecular complex binding. KEGG pathway module: hsa05200, cancer pathway; hsa05205, proteoglycans in cancer pathway; hsa04115, p53 signaling pathway.

  
  
  

  

  Expression of top 50 genes based on degree score from the 6 modules and their positions on chromosome. The hub genes TP53, MAPK1, CASP3, CTNNB1, CCND1, NOTCH1, CDK1, IGF1, ERBB2, and CYCS are highlighted in blue. TP53, MAPK1, and CASP3 are located on chromosomes 17, 22, and 4, respectively.

  
  
  

  

  Downregulating p53 expression may protect against osteoporosis in vitro. (A, B) qRT-PCR and western blot analyses comparing p53 expression between healthy volunteers and osteoporosis patients. (C) Cellular morphology of hMSCs, scale bar, 50 μm. (D, E) hMSCs were treated with PBS, siRNA-NC, or siRNA-p53, after which p53 expression was assessed with qRT-PCR and western blotting. (F, G) qRT-PCR and western blot analysis of osteogenesis-related mRNAs in the three groups. Data are means±SD of triplicate experiments. *p < 0.05, **p < 0.01, ***p < 0.001.

  
  
  

  

  Downregulating p53 expression may protect against osteoporosis in vivo. (A) Cross sections of bone samples from osteoporosis model mice treated for 10 weeks with PBS, siRNA-NC, or siRNA-p53 (n=10 in each group). (B) BV, TV, BV/TV, and BMD values measured in osteoporosis model mice in each treatment group. Data are means±SD of triplicate experiments. *p < 0.05, **p < 0.01, ***p < 0.001.