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Temporomandibular joint aging and potential therapies
doi : 10.18632/aging.203332
Volume 13, Issue 14 pp 17955—17956
Mitochondria as extracellular vesicle cargo in aging
doi : 10.18632/aging.203358
Volume 13, Issue 14 pp 17957—17958
The need for geriatric scales in glioblastoma
doi : 10.18632/aging.203370
Volume 13, Issue 14 pp 17959—17960
Two novel nomograms based on inflammatory cytokines or lymphocyte subsets to differentially diagnose severe or critical and Non-Severe COVID-19
Zhijun Li, Nan Jiang, Xinwei Li, Bo Yang, Mengdi Jin, Yaoyao Sun, Yang He, Yang Liu, Yueying Wang, Daoyuan Si, Piyong Ma, Jinnan Zhang, Tianji Liu, Qiong Yu
doi : 10.18632/aging.203307
Volume 13, Issue 14 pp 17961—17977
We intend to evaluate the differences of the clinical characteristics, cytokine profiles and immunological features in patients with different severity of COVID-19, and to develop novel nomograms based on inflammatory cytokines or lymphocyte subsets for the differential diagnostics for severe or critical and non-severe COVID-19 patients. We retrospectively studied 254 COVID-19 patients, 90 of whom were severe or critical patients and 164 were non-severe patients. Severe or critical patients had significantly higher levels of inflammatory cytokines than non-severe patients as well as lower levels of lymphocyte subsets. Significantly positive correlations between cytokine profiles were observed, while they were all significantly negatively correlated with lymphocyte subsets. Two effective nomograms were developed according to two multivariable logistic regression cox models based on inflammatory cytokine profiles and lymphocyte subsets separately. The areas under the receiver operating characteristics of two nomograms were 0.834 (95% CI: 0.779–0.888) and 0.841 (95% CI: 0.756–0.925). The bootstrapped-concordance indexes of two nomograms were 0.834 and 0.841 in training set, and 0.860 and 0.852 in validation set. Calibration curves and decision curve analyses demonstrated that the nomograms were well calibrated and had significantly more clinical net benefits. Our novel nomograms can accurately predict disease severity of COVID-19, which may facilitate the identification of severe or critical patients and assist physicians in making optimized treatment suggestions.
Prognoses and genomic analyses of proteasome 26S subunit, ATPase (PSMC) family genes in clinical breast cancer
Tzu-Jen Kao, Chung-Che Wu, Nam Nhut Phan, Yen-Hsi Liu, Hoang Dang Khoa Ta, Gangga Anuraga, Yung-Fu Wu, Kuen-Haur Lee, Jian-Ying Chuang, Chih-Yang Wang
doi : 10.18632/aging.203345
Volume 13, Issue 14 pp 17970
Breast cancer is a complex disease, and several processes are involved in its development. Therefore, potential therapeutic targets need to be discovered for these patients. Proteasome 26S subunit, ATPase gene (PSMC) family members are well reported to be involved in protein degradation. However, their roles in breast cancer are still unknown and need to be comprehensively researched. Leveraging publicly available databases, such as cBioPortal and Oncomine, for high-throughput transcriptomic profiling to provide evidence-based targets for breast cancer is a rapid and robust approach. By integrating the aforementioned databases with the Kaplan–Meier plotter database, we investigated potential roles of six PSMC family members in breast cancer at the messenger RNA level and their correlations with patient survival. The present findings showed significantly higher expression profiles of PSMC2, PSMC3, PSMC4, PSMC5, and PSMC6 in breast cancer compared to normal breast tissues. Besides, positive correlations were also revealed between PSMC family genes and ubiquinone metabolism, cell cycle, and cytoskeletal remodeling. Meanwhile, we discovered that high levels of PSMC1, PSMC3, PSMC4, PSMC5, and PSMC6 transcripts were positively correlated with poor survival, which likely shows their importance in breast cancer development. Collectively, PSMC family members have the potential to be novel and essential prognostic biomarkers for breast cancer development.
HDAC2 and 7 down-regulation induces senescence in dermal fibroblasts
Céline Warnon, Karim Bouhjar, Noëlle Ninane, Mathilde Verhoyen, Antoine Fattaccioli, Maude Fransolet, Catherine Lambert de Rouvroit, Yves Poumay, Géraldine Piel, Denis Mottet, Florence Debacq-Chainiaux
doi : 10.18632/aging.203304
Volume 13, Issue 14 pp 17978—18005
Originally simply reported to be in a stable and irreversible growth arrest in vitro, senescent cells are now clearly associated with normal and pathological ageing in vivo. They are characterized by several biomarkers and changes in gene expression that may depend on epigenetic factors, such as histone acetylation, involving a balance between histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this study, we investigate the expression and the role of HDACs on the senescent phenotype of dermal fibroblasts. We report that during replicative senescence, most canonical HDACs are less expressed. Moreover, treatment with SAHA, a histone deacetylase inhibitor (HDACi) also known as Vorinostat, or the specific downregulation of HDAC2 or HDAC7 by siRNA, induces the appearance of senescence biomarkers of dermal fibroblasts. Conversely, the ectopic re-expression of HDAC7 by lentiviral transduction in pre-senescent dermal fibroblasts extends their proliferative lifespan. These results demonstrate that HDACs expression can modulate the senescent phenotype, highlighting their pharmaceutical interest in the context of healthy ageing.
Implication of integrin ?2?1 in senescence of SK-Mel-147 human melanoma cells
Nadezhda I. Kozlova, Galina E. Morozevich, Albert E. Berman
doi : 10.18632/aging.203309
Volume 13, Issue 14 pp 18006—18017
This investigation addressed the impact of integrin-initiated signaling pathways on senescence of tumor cells. In a model of human SK-Mel-147 melanoma cells, the silencing of integrin ?2?1 strongly reduced cell proliferation and enhanced the percentage of SA-?-Gal-positive cells, a phenotypic feature of cellular senescence. These changes were accompanied by a significant increase in the activity of Akt and mTOR protein kinases and also in the expression of p53 and p21 oncosuppressors. Pharmacological inhibition of Akt and mTORC1 and genetic inhibition of p53 and p21 reduced the senescence of ?2?1-depleted SK-Mel-147 cells to the level of control cells. Based on our earlier data on the non-canonical functions of Akt isomers in the invasion and anoikis of SK-Mel-147 cells, we investigated the role of Akt isomers in senescence induced by ?2?1 suppression. The inhibition of Akt1 strongly reduced the percentage of SA-?-Gal-positive cells in the ?2?1-depleted cell population, while the inhibition of Akt2 did not have a noticeable effect. Our data demonstrated for the first time that ?2?1 is involved in the protection of tumor cells against senescence and that senescence, which is induced by the downregulation of ?2?, is based on a signaling mechanism in which Akt1 performs a non-canonical function.
GAS6 ameliorates advanced age-associated meiotic defects in mouse oocytes by modulating mitochondrial function
Kyeoung-Hwa Kim, Eun-Young Kim, Kyung-Ah Lee
doi : 10.18632/aging.203328
Volume 13, Issue 14 pp 18018—18032
Previously, we reported that the silencing of growth arrest-specific gene 6 (Gas6) expression in oocytes impairs cytoplasmic maturation by suppressing mitophagy and inducing mitochondrial dysfunction, resulting in fertilization failure. Here, we show that oocyte aging is accompanied by an increase in meiotic defects associated with chromosome misalignment and abnormal spindle organization. Intriguingly, decreased Gas6 mRNA and protein expression were observed in aged oocytes from older females. We further explored the effect of GAS6 on the quality and fertility of aged mouse oocytes using a GAS6 rescue analysis. After treatment with the GAS6 protein, aged oocytes matured normally to the meiosis II (MII) stage. Additionally, maternal age-related meiotic defects were reduced by GAS6 protein microinjection. Restoring GAS6 ameliorated the mitochondrial dysfunction induced by maternal aging. Ultimately, GAS6-rescued MII oocytes exhibited increased ATP levels, reduced ROS levels and elevated glutathione (GSH) levels, collectively indicating improved mitochondrial function in aged oocytes. Thus, the age-associated decrease in oocyte quality was prevented by restoring GAS6. Importantly, GAS6 protein microinjection in aged oocytes also rescued fertility. We conclude that GAS6 improves mitochondrial function to achieve sufficient cytoplasmic maturation and attenuates maternal age-related meiotic errors, thereby efficiently safeguarding oocyte quality and fertility.
?-amyloid monomers drive up neuronal aerobic glycolysis in response to energy stressors
Rosa Santangelo, Maria Laura Giuffrida, Cristina Satriano, Marianna Flora Tomasello, Stefania Zimbone, Agata Copani
doi : 10.18632/aging.203330
Volume 13, Issue 14 pp 18033—18050
Research on cerebral glucose metabolism has shown that the aging brain experiences a fall of aerobic glycolysis, and that the age-related loss of aerobic glycolysis may accelerate Alzheimer’s disease pathology. In the healthy brain, aerobic glycolysis, namely the use of glucose outside oxidative phosphorylation, may cover energy demand and increase neuronal resilience to stressors at once. Currently, the drivers of aerobic glycolysis in neurons are unknown. We previously demonstrated that synthetic monomers of ?-amyloid protein (A?) enhance glucose uptake in neurons, and that endogenous A? is required for depolarization-induced glucose uptake in cultured neurons. In this work, we show that cultured cortical neurons increased aerobic glycolysis in response to the inhibition of oxidative phosphorylation by oligomycin or to a kainate pulse. Such an increase was prevented by blocking the endogenous A? tone and re-established by the exogenous addition of synthetic A? monomers. The activity of mitochondria-bound hexokinase-1 appeared to be necessary for monomers-stimulated aerobic glycolysis during oxidative phosphorylation blockade or kainate excitation. Our data suggest that, through A? release, neurons coordinate glucose uptake with aerobic glycolysis in response to metabolic stressors. The implications of this new finding are that the age-related drop in aerobic glycolysis and the susceptibility to Alzheimer’s disease could be linked to factors interfering with release and functions of A? monomers.
Beneficial effects of dietary supplementation with green tea catechins and cocoa flavanols on aging-related regressive changes in the mouse neuromuscular system
Sílvia Gras, Alba Blasco, Guillem Mòdol-Caballero, Olga Tarabal, Anna Casanovas, Lídia Piedrafita, Alejandro Barranco, Tapas Das, Ricardo Rueda, Suzette L. Pereira, Xavier Navarro, Josep E. Esquerda, Jordi Calderó
doi : 10.18632/aging.203336
Volume 13, Issue 14 pp 18051—18093
Besides skeletal muscle wasting, sarcopenia entails morphological and molecular changes in distinct components of the neuromuscular system, including spinal cord motoneurons (MNs) and neuromuscular junctions (NMJs); moreover, noticeable microgliosis has also been observed around aged MNs. Here we examined the impact of two flavonoid-enriched diets containing either green tea extract (GTE) catechins or cocoa flavanols on age-associated regressive changes in the neuromuscular system of C57BL/6J mice. Compared to control mice, GTE- and cocoa-supplementation significantly improved the survival rate of mice, reduced the proportion of fibers with lipofuscin aggregates and central nuclei, and increased the density of satellite cells in skeletal muscles. Additionally, both supplements significantly augmented the number of innervated NMJs and their degree of maturity compared to controls. GTE, but not cocoa, prominently increased the density of VAChT and VGluT2 afferent synapses on MNs, which were lost in control aged spinal cords; conversely, cocoa, but not GTE, significantly augmented the proportion of VGluT1 afferent synapses on aged MNs. Moreover, GTE, but not cocoa, reduced aging-associated microgliosis and increased the proportion of neuroprotective microglial phenotypes. Our data indicate that certain plant flavonoids may be beneficial in the nutritional management of age-related deterioration of the neuromuscular system.
Subclinical atherosclerosis and immune activation in young HIV-infected patients with telomere shortening
María José Alcaraz, Antonia Alcaraz, Raúl Teruel-Montoya, José A. Campillo, Alejandro de la Torre, Ángeles Muñoz, Cristina Tomás, Gabriel Puche, Carlos Báguena, Alfredo Cano, Alfredo Minguela, Enrique Bernal
doi : 10.18632/aging.203350
Volume 13, Issue 14 pp 18094—18105
Background: To date, available data on premature aging in young HIV-infected adults are scarce and no reports offer comprehensive assessment of telomere shortening (TS) in relation to subclinical atherosclerosis (SCA). In this study, we investigate if telomere shortening and immune activation markers are associated with SCA, which is one of the main degenerative diseases in young HIV-infected adults.
Autophagy inhibition reinforces stemness together with exit from dormancy of polydisperse glioblastoma stem cells
Aude Brunel, Sophie Hombourger, Elodie Barthout, Serge Battu, Donat Kögel, Patrick Antonietti, Elise Deluche, Sofiane Saada, Stéphanie Durand, Fabrice Lalloué, Marie-Odile Jauberteau, Gaëlle Begaud, Barbara Bessette, Mireille Verdier
doi : 10.18632/aging.203362
Volume 13, Issue 14 pp 18106—18130
Therapeutic resistance and infiltrative capacities justify the aggressiveness of glioblastoma. This is due to cellular heterogeneity, especially the presence of stemness-related cells, i.e. Cancer Stem Cells (CSC). Previous studies focused on autophagy and its role in CSCs maintenance; these studies gave conflicting results as they reported either sustaining or disruptive effects. In the present work, we silenced two autophagy related genes -either Beclin1 or ATG5- by shRNA and we explored the ensuing consequences on CSCs markers’ expression and functionalities. Our results showed that the down regulation of autophagy led to enhancement in expression of CSCs markers, while proliferation and clonogenicity were boosted. Temozolomide (TMZ) treatment failed to induce apoptotic death in shBeclin1-transfected cells, contrary to control. We optimized the cellular subset analysis with the use of Sedimentation Field Flow Fractionation, a biological event monitoring- and cell sorting-dedicated technique. Fractograms of both shBeclin1 and shATG5 cells exhibited a shift of elution peak as compared with control cells, showing cellular dispersion and intrinsic sub-fraction modifications. The classical stemness fraction (i.e. F3) highlighted data obtained with the overall cellular population, exhibiting enhancement of stemness markers and escape from dormancy. Our results contributed to illustrate CSCs polydispersity and to show how these cells develop capacity to bypass autophagy inhibition, thanks to their acute adaptability and plasticity.
Grape skin extract modulates neuronal stem cell proliferation and improves spatial learning in senescence-accelerated prone 8 mice
Kazunori Sasaki, Noelia Geribaldi-Doldan, Francis G. Szele, Hiroko Isoda
doi : 10.18632/aging.203373
Volume 13, Issue 14 pp 18131—18149
In recent years, the number of patients with neurodegenerative illness such as Alzheimer’s disease (AD) has increased with the aging of the population. In this study, we evaluated the effect of Grape skin extract (GSE) on neurotypic SH-SY5Y cells as an in vitro AD model, murine neurospheres as an ex vivo neurogenesis model and SAMP8 mice as an in vivo AD model. Our in vitro result showed that pre-treatment of SH-SY5Y cells with GSE ameliorated A?-induced cytotoxicity. Moreover, GSE treatment significantly decreased the number of neurospheres, but increased their size suggesting reduced stem cell self-renewal but increased proliferation. Our in vivo Morris water maze test indicated that GSE improves learning and memory in SAMP8 mice. To detect proliferation and newborn neurons, we measured BrdU+ cells in the dentate gyrus (DG). GSE treatment increased the number of BrdU+ cells in the DG of SAMP8 mice. Finally, we showed that GSE induced a decrease in inflammatory cytokines and an increase in neurotransmitters in the cerebral cortex of SAMP8 mice. These results suggested that GSE increased neurogenic zone proliferation and memory but decreased oxidative stress associated with pro-inflammatory cytokines in aging, thus protecting neurons.
Integration of segmented regression analysis with weighted gene correlation network analysis identifies genes whose expression is remodeled throughout physiological aging in mouse tissues
Margarida Ferreira, Stephany Francisco, Ana R. Soares, Ana Nobre, Miguel Pinheiro, Andreia Reis, Sonya Neto, Ana João Rodrigues, Nuno Sousa, Gabriela Moura, Manuel A. S. Santos
doi : 10.18632/aging.203379
Volume 13, Issue 14 pp 18150—18190
Gene expression alterations occurring with aging have been described for a multitude of species, organs, and cell types. However, most of the underlying studies rely on static comparisons of mean gene expression levels between age groups and do not account for the dynamics of gene expression throughout the lifespan. These studies also tend to disregard the pairwise relationships between gene expression profiles, which may underlie commonly altered pathways and regulatory mechanisms with age. To overcome these limitations, we have combined segmented regression analysis with weighted gene correlation network analysis (WGCNA) to identify high-confidence signatures of aging in the brain, heart, liver, skeletal muscle, and pancreas of C57BL/6 mice in a publicly available RNA-Seq dataset (GSE132040). Functional enrichment analysis of the overlap of genes identified in both approaches showed that immune- and inflammation-related responses are prominently altered in the brain and the liver, while in the heart and the muscle, aging affects amino and fatty acid metabolism, and tissue regeneration, respectively, which reflects an age-related global loss of tissue function. We also explored sexual dimorphism in the aging mouse transcriptome and found the liver and the muscle to have the most pronounced gender differences in gene expression throughout the lifespan, particularly in proteostasis-related pathways. While the data showed little overlap among the age-dysregulated genes between tissues, aging triggered common biological processes in distinct tissues, which we highlight as important features of murine tissue physiological aging.
Formononetin relieves the facilitating effect of lncRNA AFAP1-AS1-miR-195/miR-545 axis on progression and chemo-resistance of triple-negative breast cancer
Jingjing Wu, Wen Xu, Lina Ma, Jiayu Sheng, Meina Ye, Hao Chen, Yuzhu Zhang, Bing Wang, Mingjuan Liao, Tian Meng, Yue Zhou, Hongfeng Chen
doi : 10.18632/aging.203156
Volume 13, Issue 14 pp 18191—18222
This investigation attempted to discern whether formononetin restrained progression of triple-negative breast cancer (TNBC) by blocking lncRNA AFAP1-AS1-miR-195/miR-545 axis. We prepared TNBC cell lines (i.e. MDA-MB-231 and BT-549) and normal human mammary epithelial cell line (i.e. MCF-10A) in advance, and the TNBC cell lines were, respectively, transfected by pcDNA3.1-lncRNA AFAP1-AS1, si-lncRNA AFAP1-AS1, pcDNA6.2/GW/EmGFP-miR-545 or pcDNA6.2/GW/EmGFP-miR-195. Resistance of TNBC cells in response to 5-Fu, adriamycin, paclitaxel and cisplatin was evaluated through MTT assay, while potentials of TNBC cells in proliferation, migration and invasion were assessed via CCK8 assay and Transwell assay. Consequently, silencing of lncRNA AFAP1-AS1 impaired chemo-resistance, proliferation, migration and invasion of TNBC cells (P<0.05), and over-expression of miR-195 and miR-545, which were sponged and down-regulated by lncRNA AFAP1-AS1 (P<0.05), significantly reversed the promoting effect of pcDNA3.1-lncRNA AFAP1-AS1 on proliferation, migration, invasion and chemo-resistance of TNBC cells (P<0.05). Furthermore, CDK4 and Raf-1, essential biomarkers of TNBC progression, were, respectively, subjected to target and down-regulation of miR-545 and miR-195 (P<0.05), and they were promoted by pcDNA3.1-lncRNA AFAP1-AS1 at protein and mRNA levels (P<0.05). Additionally, formononetin significantly decreased expressions of lncRNA AFAP1-AS1, CDK4 and Raf-1, while raised miR-195 and miR-545 expressions in TNBC cells (P<0.05), and exposure to it dramatically contained malignant behaviors of TNBC cells (P<0.05). In conclusion, formononetin alleviated TNBC malignancy by suppressing lncRNA AFAP1-AS1-miR-195/miR-545 axis, suggesting that molecular targets combined with traditional Chinese medicine could yield significant clinical benefits in TNBC.
Combination of rapamycin and SAHA enhanced radiosensitization by inducing autophagy and acetylation in NSCLC
Yong Wang, Fen Liu, Chen Fang, Liyao Xu, Lin Chen, Zeyao Xu, Jiaquan Chen, Wei Peng, Biqi Fu, Yong Li
doi : 10.18632/aging.203226
Volume 13, Issue 14 pp 18223—18237
Radiotherapy plays an essential role in the treatment of non-small-cell lung cancer (NSCLC). However, cancer cells' resistance to ionizing radiation (IR) is the primary reason for radiotherapy failure leading to tumor relapse and metastasis. DNA double-strand breaks (DSB) repair after IR is the primary mechanism of radiotherapy resistance. In this study, we investigated the effects of autophagy-inducing agent, Rapamycin (RAPA), combined with the histone deacetylase inhibitor (HDACi), Suberoylanilide Hydroxamic Acid (SAHA), on the radiosensitivity of A549 and SK-MES-1 cells, and examined the combination effects on DNA damage repair, and determined the level of autophagy and acetylation in A549 cells. We also investigated the combination treatment effect on the growth of A549 xenografts after radiotherapy, and the level of DNA damage, autophagy, and acetylation. Our results showed that RAPA combined with SAHA significantly increased the inhibitory effect of radiotherapy compared with the single treatment group. The combined treatment increased the expression of DNA damage protein ?-H2AX and decreased DNA damage repair protein expression. RAPA combined with SAHA was induced mainly by regulating acetylation levels and autophagy. The effect of combined treatment to increase radiotherapy sensitivity will be weakened by inhibiting the level of autophagy. Besides, the combined treatment also showed a significantly inhibited tumor growth in the A549 xenograft model. In conclusion, these results identify a potential therapeutic strategy of RAPA combined with SAHA as a radiosensitizer to decreased DSB repair and enhanced DNA damage by inducing acetylation levels and autophagy for NSCLC.
Integrated analysis of m6A mRNA methylation in rats with monocrotaline-induced pulmonary arterial hypertension
Yunhong Zeng1,2, * , Ting Huang1,3, * , Wanyun Zuo4 , Dan Wang2 , Yonghui Xie1,2 , Xun Wang2 , Zhenghui Xiao5 , Zhi Chen2 , Qiming Liu4 , Na Liu4 , Yunbin Xiao2
doi : 10.18632/aging.203230
Volume 13, Issue 14 pp 18238—18256
N6-methyladenosine (m6A) modification is one of the most common chemical modifications of eukaryotic mRNAs, which play an important role in tumors and cardiovascular disease through regulating mRNA stability, splicing and translation. However, the changes of m6A mRNA and m6A-related enzymes in pulmonary arterial hypertension (PAH) remain largely unexplored.
The lncRNA H19/miR-541-3p/Wnt/?-catenin axis plays a vital role in melatonin-mediated osteogenic differentiation of bone marrow mesenchymal stem cells
Hui Han1 , Tingyu Tian1 , Guoqian Huang2 , Dalu Li2 , Shimao Yang2
doi : 10.18632/aging.203267
Volume 13, Issue 14 pp 18257—18273
Implant dentures become the first choice for denture restoration in patients with tooth loss. However, oral implants often fail in osteoporosis (OP) patients. Melatonin (MT) induces osteogenic differentiation of bone mesenchymal stem cells (BMSCs), suggesting its therapeutic potential in OP treatment. Long non-coding RNA H19 induces osteogenic differentiation of BMSCs, while its regulatory mechanism in MT-involved osteogenic and adipogenic differentiation of BMSCs remains elusive. Ovariectomized (OVX) rat was used to construct an OP model, and bone quality was assessed. Meanwhile, the expression of H19, miR-541-3p, MT and adiponectin (APN) was examined by quantitative reverse transcription-PCR (qRT-PCR) or ELISA. The adipogenic and osteogenic differentiation of BMSCs were determined by oil red O staining and alizarin red S staining, respectively. The targeting relationships between H19, miR-541-3p and APN mRNA were predicted by bioinformatics and confirmed by RNA immunoprecipitation and dual-luciferase reporter assay. The results showed that MT, H19 and APN were down-regulated, while miR-541-3p was up-regulated in the OVX rat model. At the cellular level, MT reduced adipogenic differentiation, heightened osteogenic differentiation of BMSCs, and activated Wnt/?-catenin pathway, which were reversed by the MT2 selective inhibitor 4-P-PDOT. Overexpressing H19 facilitated the osteogenic differentiation and inhibited the adipogenic differentiation of BMSCs mediated by MT, while H19 knockdown or overexpressing miR-541-3p had the opposite effect. Moreover, H19 functioned as a competitive endogenous RNA and sponged miR-541-3p, and miR-541-3p targeted APN. Overall, MT modulates the osteogenic and adipogenic differentiation of BMSCs by mediating H19/miR-541-3p/APN axis, providing a new reference for the targeted therapy of OP.
Predictive value of inflammation-based Glasgow prognostic score, platelet-lymphocyte ratio, and global registry of acute coronary events score for major cardiovascular and cerebrovascular events during hospitalization in patients with acute myocardial infarction
Xiaoqun Xu1, * , Long Cai1, * , Tielong Chen2, * , Shibiao Ding1 , Fengwei Zhang1 , Beibei Gao3 , Houyong Zhu2 , Jinyu Huang3
doi : 10.18632/aging.203273
Volume 13, Issue 14 pp 18274—18286
The goal of this study was to evaluate the predictive ability of the inflammation-based Glasgow Prognostic Score (GPS), platelet-lymphocyte ratio (PLR), Global Registry of Acute Coronary Events (GRACE) score and combined diagnostic models for the occurrence of major adverse cardiovascular and cerebrovascular events (MACEs) in patients with acute myocardial infarction (AMI).
Albiflorin alleviates cognitive dysfunction in STZ-induced rats
Xiaojun Ma1 , Min Song1 , Yushan Yan1 , Gaofei Ren1 , Jingwen Hou1 , Guijun Qin1 , Wang Wang2 , Zhizhen Li1
doi : 10.18632/aging.203274
Volume 13, Issue 14 pp 18287—18297
To explore the effect of albiflorin (AL) on streptozotocin (STZ)-induced Alzheimer's disease (AD) in rats.
NUDCD1 knockdown inhibits the proliferation, migration, and invasion of pancreatic cancer via the EMT process
Chunling Shi1 , Min Weng2 , Hengyue Zhu2 , Yangyang Guo2 , Dongdong Xu1 , Hairu Jin1 , Binshuang Wei1 , Zhensheng Cao1
doi : 10.18632/aging.203276
Volume 13, Issue 14 pp 18298—18309
NudC domain containing 1 (NUDCD1) is an oncoprotein frequently activated or upregulated in various human cancers, but its role in pancreatic cancer (PC) remains unknown. Thus, we aimed to determine the function and mechanism of NUDCD1 in PC. We employed Western blot and quantitative real-time polymerase chain reaction to assess NUDCD1 expression in cells and PC tissues. NUDCD1 was knocked down in Patu8988 and PANC-1 cells. We conducted real-time cell analysis, wound healing assay, transwell assay and colony formation assay to evaluate the metastatic and proliferative abilities of PC cells. Western blot was conducted to assess the expression of markers associated with apoptosis and epithelial–mesenchymal transition (EMT). Also, we established a tumor xenograft model to determine the role of NUDCD1 in vivo. NUDCD1 was overexpressed in PC tissues and cells. NUDCD1 knockdown suppressed the invasion, migration, and proliferative abilities of the cells and induced PC cell apoptosis. The specific mechanism of NUDCD1 was related to the modulation of the EMT process. Data obtained from in vivo experiments revealed that NUDCD1 knockdown inhibited the tumor growth, proliferation, and metastasis by modulating the EMT and inducing the apoptosis of PC cells.
BMI1 activates P-glycoprotein via transcription repression of miR-3682-3p and enhances chemoresistance of bladder cancer cell
Ming-Kun Chen1, * , Jun-Hao Zhou1, * , Peng Wang1, * , Yun-lin Ye2 , Yang Liu1 , Jia-Wei Zhou1 , Zi-Jian Chen1 , Jian-Kun Yang1 , De-Ying Liao1 , Zhi-Jian Liang1 , Xiao Xie1 , Qi-Zhao Zhou1 , Kang-Yi Xue1 , Wen-Bin Guo1 , Ming Xia1 , Ji-Ming Bao1 , Cheng Yang1 , Hai-Feng Duan1 , Hong-Yi Wang1 , Zhi-Peng Huang1 , Zi-Ke Qin2, & , Cun-Dong Liu1
doi : 10.18632/aging.203277
Volume 13, Issue 14 pp 18310—18330
Chemoresistance is the most significant reason for the failure of cancer treatment following radical cystectomy. The response rate to the first-line chemotherapy of cisplatin and gemcitabine does not exceed 50%. In our previous research, elevated BMI1 (B-cell specific Moloney murine leukemia virus integration region 1) expression in bladder cancer conferred poor survival and was associated with chemoresistance. Herein, via analysis of The Cancer Genome Atlas database and validation of clinical samples, BMI1 was elevated in patients with bladder cancer resistant to cisplatin and gemcitabine, which conferred tumor relapse and progression. Consistently, BMI1 was markedly increased in the established cisplatin- and gemcitabine-resistant T24 cells (T24/DDP&GEM). Functionally, BMI1 overexpression dramatically promoted drug efflux, enhanced viability and decreased apoptosis of bladder cancer cells upon treatment with cisplatin or gemcitabine, whereas BMI1 downregulation reversed this effect. Mechanically, upon interaction with p53, BMI1 was recruited on the promoter of miR-3682-3p gene concomitant with an increase in the mono-ubiquitination of histone H2A lysine 119, leading to transcription repression of miR-3682-3p gene followed by derepression of ABCB1 (ATP binding cassette subfamily B member 1) gene. Moreover, suppression of P-glycoprotein by miR-3682-3p mimics or its inhibitor XR-9576, could significantly reverse chemoresistance of T24/DDP&GEM cells. These results provided a novel insight into a portion of the mechanism underlying BMI1-mediated chemoresistance in bladder cancer.
Prediction of pregnancy outcome in fresh in vitro fertilization/intracytoplasmic sperm injection treatment in patients with poor ovarian reserve
Ying Chen1 , AiQin Niu1 , XingMei Feng1 , YaLi Zhang1 , Fei Li1, &
doi : 10.18632/aging.203282
Volume 13, Issue 14 pp 18331—18339
We retrospectively analyzed the clinical data from 39,185 cycles who undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) in the First People's Hospital of Shangqiu, these poor ovarian reserve patients were further categorized into the "unexpected" group (n=3337) and the "expected" group (n=2667) based on POSEIDON classification. In "expected" group, logistic regression analysis showed that female age (OR 0.920; 95% C.I 0.902~0.939; P < 0.001), treatment cycles (OR 0.693; 95% C.I 0.560~0.859; P = 0.001), duration of Gn administered (OR 1.077; 95% C.I 1.027~1.129; P = 0.002) and transferable embryos (OR 1.377; 95% C.I 1.319~1.437; P < 0.001) is independent predictive factors of live birth. In "expected" group, logistic regression analysis showed that female age (OR 0.874; 95% C.I 0.848~0.900; P < 0.001), AFC (OR 1.285; 95% C.I 1.131~1.461; P < 0.001), total dosage of Gn administered (OR 1.001; 95% C.I 1.000~1.002; P < 0.001), duration of Gn administered (OR 0.784; 95% C.I 0.639~0.961; P = 0.019), MII number (OR 0.841; 95% C.I 0.717~0.986; P = 0.032) and transferable embryos (OR 2.057; 95% C.I 1.762~2.400; P < 0.001) is independent predictive factors of live birth. We also established a smooth curve fit to predict the probability of live birth among the POSEIDON "unexpected" and "expected" group. These independent predictive factors on the pregnancy outcome of IVF/ICSI and the successful establishment of smooth curve fit can provide valuable reference for treats poor ovarian reserve patients in clinical work.
CircSPIDR acts as a tumour suppressor in cervical adenocarcinoma by sponging miR-431-5p and regulating SORCS1 and CUBN expression
Junfen Xu1 , Weiguo Lu1,2,3
doi : 10.18632/aging.203283
Volume 13, Issue 14 pp 18340—18359
To identify circular RNAs (circRNAs) with tumor suppressor activity against cervical adenocarcinoma, we compared the circRNA levels of cervical adenocarcinoma and normal cervical tissues. We found that circSPIDR was dramatically downregulated in cervical adenocarcinoma tissues. In cervical adenocarcinoma cells, overexpression of circSPIDR reduced cell viability, inhibited colony formation and promoted apoptosis, whereas knockdown of circSPIDR exerted the opposite effects. CircSPIDR overexpression also suppressed the tumorigenicity of cervical adenocarcinoma cells in a xenograft mouse model. CircSPIDR was found to sponge miR-431-5p, thereby de-repressing sortin-related VPS10 domain-containing receptor 1 (SORCS1) and cubilin (CUBN) and inhibiting the development of cervical adenocarcinoma. In clinical cervical samples, circSPIDR expression correlated negatively with miR-431-5p expression and positively with SORCS1 and CUBN expression. These results demonstrated that circSPIDR suppresses cervical adenocarcinoma by competitively binding to miR-431-5p, thus upregulating SORCS1 and CUBN. These findings suggest circSPIDR could serve as a novel therapeutic target for treatment of cervical adenocarcinoma patients.
Aberrant expression of WDR4 affects the clinical significance of cancer immunity in pan-cancer
Hanqian Zeng1,2 , Shiwen Xu2 , Erjie Xia2 , Suzita Hirachan3 , Adheesh Bhandari2 , Yanyan Shen1
doi : 10.18632/aging.203284
Volume 13, Issue 14 pp 18360—18375
Recent publications have presented research showing that WD repeat domain 4 (WDR4) plays a significant role in various kinds of malignant tumours. However, the expression profile of WDR4 is still unspecified, as is its significance in the analysis of human pan-cancer. We conducted an in-depth analysis of three aspects of WDR4 expression patterns from 33 types of cancer and determined the value of WDR4 for prognostic prediction and carcinoma drug resistance prediction. WDR4 was expressed in different cancer cell lines at inconsistent levels. Aberrant expression of WDR4 has been observed in various malignant cancers and is significantly implicated in overall survival outcomes. The expression level of WDR4 is also strongly associated with tumour immunity, such as immune scores and tumour-infiltrating immune cells. The level of WDR4 is related to microsatellite instability and tumour mutation burden in several types of malignancy, and validation studies implied that WDR4-associated terms and pathways are involved in malignancy. We explored the expression level of WDR4 across 33 types of cancer and showed that WDR4 plays a significant role during cancer development. More crucially, WDR4 is associated with immune infiltration, which suggests that WDR4 could be an immunotherapy target in cancers. In summary, our research showed that WDR4 plays a vital role in tumorigenesis and has the potential for to be targeted with treatments.
Association of a composite score of relative grip strength and timed up and go test with incident type 2 diabetes mellitus: Guangzhou Biobank Cohort Study
Xue Liang1 , Chao Qiang Jiang2 , Wei Sen Zhang2 , Feng Zhu2 , Ya Li Jin2 , Kar Keung Cheng4 , Tai Hing Lam2,3 , Lin Xu1,3
doi : 10.18632/aging.203285
Volume 13, Issue 14 pp 18376—18391
We investigated association of a score incorporating relative grip strength (RGS) and timed up and go (TUG) test with incident type 2 diabetes mellitus (T2DM) in older Chinese.
Curcumol may alleviate psoriasis-like inflammation by inhibiting keratinocyte proliferation and inflammatory gene expression via JAK1/STAT3 signaling
Mingfen Lv1 , Junyi Shao1 , Fan Jiang1 , Jingjing Liu1
doi : 10.18632/aging.203287
Volume 13, Issue 14 pp 18392—18403
Psoriasis is a chronic inflammatory skin disease characterized by abnormal proliferation and differentiation of keratinocytes. Since curcumol exhibits anti-inflammatory properties in various diseases, we investigated its anti-inflammatory potential in stimulated human keratinocytes. Our data show that curcumol significantly inhibits proliferation and induces cell cycle arrest in NHEK cells stimulated with proinflammatory cytokines (IL-1?, IL-17A, IL-22, oncostatin M, and TNF-?; mix M5). In addition, curcumol markedly ameliorates inflammatory response and promotes differentiation of M5-stimulated NHEK cells. Curcumol inhibits activity of JAK1, resulting in the inhibition of STAT3, downregulation of cyclin D2, and cell cycle arrest in stimulated NHEK cells. Together, our data show that curcumol reduces proliferation and inflammatory gene expression in stimulated keratinocytes by inhibiting the JAK1/STAT3 signaling, suggesting that it might serve as a potential therapeutic option for the treatment of psoriasis.
Expression mode and prognostic value of FXYD family members in colon cancer
Ming Jin1, * , Hui Zhang2, * , Jun Yang3 , Zhen Zheng2 , Kaitai Liu2
doi : 10.18632/aging.203290
Volume 13, Issue 14 pp 18404—18422
The FXYD gene family comprises seven members that encode a class of small-membrane proteins characterized by an FXYD motif and interact with Na+/K+-ATPase. Until now, the expression patterns and prognostic roles of the FXYD family in colon cancer (CC) have not been systematically reported. Gene expression, methylation, clinicopathological features and the prognoses of CC patients were obtained from The Cancer Genome Atlas (TCGA) database. The expression feature and prognostic values of FXYD members were identified. Gene set enrichment analysis (GSEA) was performed to explore the potential mechanism underlying the function of the FXYD family in CC. Tumor Immune Estimation Resource (TIMER) and CIBERSORT analysis were used to assess the correlations between FXYD family members and tumor immune infiltrating cells (TIICs). FXYD family members were differentially expressed in CC except for FXYD2. FXYD2, FXYD3 and FXYD4 were revealed as independent prognostic factors for recurrence, while FXYD3 and FXYD7 were identified as prognostic factors for survival according to univariate and multivariate analyses with Cox regression. GSEA revealed that FXYD family members were involved in complicated biological functions underlying cancer progression. TIMER and CIBERSORT analyses showed significant associations between FXYD family genes and TIICs. The present study comprehensively revealed the expression mode and prognostic value of FXYD members in CC, providing insights for further study of the FXYD family as potential clinical biomarkers in CC.
Yiqi Jiemin decoction alleviates allergic rhinitis in a guinea pig model by suppressing inflammation, restoring Th1/Th2 balance, and improving cellular metabolism
Zhanfeng Yan1, * , Lili Liu1, * , Jingjing Yuan1 , Lulu Jiao1 , Mo Zhou2 , Jinfeng Liu2 , Xiaohui Wen2 , Siming Liu1 , Pengpeng Hao1 , Jianhua Liu1 , Wei Wu1
doi : 10.18632/aging.203292
Volume 13, Issue 14 pp 18423—18441
We investigated the mechanisms underlying the therapeutic effects of Yiqi Jiemin decoction (YJD), a traditional Chinese medicine (TCM), in the ovalbumin (OVA)-induced allergic rhinitis (AR) model in guinea pigs. YJD significantly decreased infiltration of mast cells and eosinophils into the nasal mucosa of AR model guinea pigs. YJD also increased expression of TGF-? in the nasal mucosa, restored the balance of Th1/Th2 immune cell responses, and decreased serum levels of various pro-inflammatory mediators, including histamine (HA), neuropeptide Y (NPY), acetylcholine (ACH), norepinephrine and immunoglobulin E (IgE). Metabolic analyses using liquid chromatography coupled with high-resolution mass spectrometry revealed that YJD improved cellular metabolism in AR model guinea pigs and increased serum levels of glycocholic acid while decreasing levels 1-palmitoyl lysophosphatidic acid. RNA-sequencing analysis identified BPIFB2 as a potential diagnostic biomarker and therapeutic target for AR. Functional enrichment analyses showed that YJD significantly inhibited cytokine secretion pathways in AR model guinea pigs. These findings demonstrate that YJD protects against OVA-induced AR in guinea pigs by suppressing inflammation in the nasal mucosa, restoring Th1/Th2 balance, and improving cellular metabolism.
An interactive nomogram based on clinical and molecular signatures to predict prognosis in multiple myeloma patients
Linxin Liu1, * , Jian Qu2, * , Yuxin Dai3 , Tingting Qi2 , Xinqi Teng2 , Guohua Li2 , Qiang Qu4,5
doi : 10.18632/aging.203294
Volume 13, Issue 14 pp 18442—18463
Although novel drugs and treatments have been developed and improved, multiple myeloma (MM) is still recurrent and difficult to cure. In the present study, the magenta module containing 400 hub genes was determined from the training dataset of GSE24080 through weighted gene co-expression network analysis (WGCNA). Then, using the least absolute shrinkage and selection operator (Lasso) analysis, a fifteen-gene signature was firstly selected and the predictive performance for overall survival (OS) was favorable, which was identified by Receiver Operating Characteristic (ROC) curves. The risk score model was constructed based on survival-associated fifteen genes from the Lasso model, which classified MM patients into high-risk and low-risk groups. Areas under the curve (AUC) of ROC curve and log-rank test showed that the high-risk group was correlated to the dismal survival outcome of MM patients, which was also identified in testing dataset of GSE9782. The calibration plot, the AUC value of the ROC curve and Concordance-index showed that the interactive nomogram with risk score could favorably predict the probability of multi-year OS of MM patients. Therefore, it may help clinicians make a precise therapeutic decision based on the easy-to-use tool of the nomogram.
Fibroblastic galectin-1-fostered invasion and metastasis are mediated by TGF-?1-induced epithelial-mesenchymal transition in gastric cancer
Xiaolan You1 , Jian Wu1 , Xiaojun Zhao1 , Xingyu Jiang2 , Wenxuan Tao3 , Zhiyi Chen1 , Chuanjiang Huang1 , Tingrui Zheng1 , Xianhe Shen1
doi : 10.18632/aging.203295
Volume 13, Issue 14 pp 18464—18481
Background The gastric cancer (GC) microenvironment has important effects on biological behaviors, such as tumor cell invasion and metastasis. However, the mechanism by which the GC microenvironment promotes GC cell invasion and metastasis is unknown. The present study aimed to clarify the effects and mechanism of galectin-1 (GAL-1, encoded by LGALS1) on GC invasion and metastasis in the GC microenvironment.
ZC3HAV1 promotes the proliferation and metastasis via regulating KRAS in pancreatic cancer
Wei Huang1 , Hao Hua2 , Guoliang Xiao1 , Xianjin Yang1 , Qin Yang3 , Lu Jin4
doi : 10.18632/aging.203296
Volume 13, Issue 14 pp 18482—18497
Proliferation and metastasis are important malignant features of pancreatic cancer (PC), but the underlying molecular mechanism is unclear. ZC3HAV1, a PARP family member of proteins-enzymes, has been considered to play a significant part in a variety of biological processes. Nonetheless, the functions of ZC3HAV1 in developing PC are still unknown. This research aims to explore the biological function and the expression of ZC3HAV1 shown in PC. In our study, PCR analysis suggested that ZC3HAV1 was expressed at a high level in PC tissues and cell lines, and high ZC3HAV1 expression was remarkably related to poor prognosis. The functional assays indicated that upregulated ZC3HAV1 accelerated PC cell proliferation along with colony formation capacities in vitro. Subsequently, ZC3HAV1 could upregulate cyclin D1 and CDK2 and also promote G1/S transition in cells of PC. What’s more, we also discovered that ZC3HAV1 promotes the migration and the invasion of PC cells. It upregulates the expression of EMT (epithelial-mesenchymal transition) relevant markers. Conversely, the functional assays showed that ZC3HAV1 knockdown significantly reduced tumorigenesis. Using bioinformatics analysis and immunoprecipitation assays we found that ZC3HAV1 could directly bind to KRAS and positively regulate its expression. Furthermore, ZC3HAV1 overexpression activated MAPK signaling by increasing p-ERK levels. Conversely, knockdown of KRAS attenuated ZC3HAV1-mediated promotion of proliferation and invasion in cells of PC. The result indicated that ZC3HAV1 was in relation to poor prognosis and accelerated the proliferation and metastasis of PC cells by regulation of KRAS. Our research may offer brand-new evidence to diagnose and treat PC in clinic.
Exosomal miRNA-205 promotes breast cancer chemoresistance and tumorigenesis through E2F1
Yan Zhao1 , Li-Jun Jin2 , Xiao-Yu Zhang2
doi : 10.18632/aging.203298
Volume 13, Issue 14 pp 18498—18514
Breast cancer (BC) is a common malignant tumor in females. The challenge in treating BC is overcoming chemoresistance. Exosome-mediated transfer of miRNAs is a molecule-shuttle in intercellular communication. Thus, we aimed to investigate whether exosomal miRNA-205 could affect chemoresistance and tumorigenesis in recipient tumor cells and to elucidate the underlying mechanism in vivo and in vitro. Microarray and qRT-PCR assays demonstrated that miRNA-205 was upregulated in tamoxifen resistance MCF-7/TAMR-1 (M/T) cells and M/T cell-derived exosomes (M/T-Exo). The M/T-Exo was internalized by human BC cells (BCCs), causing increased expression of miRNA-205 in BCCs. Coculturing with M/T-Exo promoted tamoxifen resistance, proliferation, migration, and invasion while suppressed apoptosis in recipient BCCs, which were associated with activating the caspase pathway and phosphorylating Akt. Luciferase reporter assays showed that miRNA-205 directly targeted E2F Transcription Factor 1 (E2F1) in BCCs. Furthermore, knockdown of miRNA-205 or overexpression of E2F1 reversed the roles of M/T-Exo in BCCs. In vivo experiments showed that the intratumoral injection of M/T-Exo caused greater tamoxifen resistance and larger tumor size relative to mice treated with miRNA-205-knockdown or E2F1-overexpressing BCCs. Together, the results suggest that exosomal miRNA-205 may promote tamoxifen resistance and tumorigenesis in BC through targeting E2F1 in vivo and in vitro.
Agomelatine prevents angiotensin II-induced endothelial and mononuclear cell adhesion
Najiao Hong1 , Zhirong Ye1 , Yongjun Lin1 , Wensen Liu2 , Na Xu2 , Yan Wang3
doi : 10.18632/aging.203299
Volume 13, Issue 14 pp 18515—18526
Agomelatine is a non-selective melatonin receptor agonist and an atypical antidepressant with anti-inflammatory, neuroprotective, and cardioprotective effects. The renin-angiotensin system modulates blood pressure and vascular homeostasis. Angiotensin II (Ang II) and its receptor Ang II type I receptor (AT1R) are recognized as contributors to the pathogenesis of cardiovascular and cardiometabolic diseases, including diabetes, obesity, and atherosclerosis. The recruitment and attachment of monocytes to the vascular endothelium is a major event in the early stages of atherosclerosis and other cardiovascular diseases. In the present study, we demonstrate that agomelatine reduced Ang II-induced expression of AT1R while significantly inhibiting the attachment of monocytes to endothelial cells induced by Ang II and mediated by ICAM-1 and VCAM-1. Additionally, Ang II inhibited the expression of the chemokines CXCL1, MCP-1, and CCL5, which are critical in the process of immune cell recruitment and invasion. Agomelatine also suppressed the expression of TNF-?, IL-8, and IL-12, which are proinflammatory cytokines that promote endothelial dysfunction and atherogenesis. Importantly, we demonstrate that the inhibitory effect of agomelatine against the expression of adhesion molecules is mediated through the downregulation of Egr-1 signaling. Together, our findings provide evidence of a novel mechanism of agomelatine that may be practicable in the treatment and prevention of cardiovascular diseases.
LncRNA CCAT1 promotes prostate cancer cells proliferation, migration, and invasion through regulation of miR-490-3p/FRAT1 axis
Xiaowei Cai1, * , Yiheng Dai2, * , Peng Gao1, * , Guanyu Ren3 , Dingcai Cheng4 , Bo Wang2 , Yi Wang2 , Jiang Yu2 , Yiheng Du2 , Xizhi Wang2 , Boxin Xue1
doi : 10.18632/aging.203300
Volume 13, Issue 14 pp 18527—18544
Prostate cancer (PCa) is a prevalent cancer in males, with high incidence and mortality. Recent studies have shown the crucial role of long non-coding RNA (lncRNA) in PCa. Here, we aimed to explore the functional roles and inner mechanisms of lncRNA CCAT1 in PCa cells. qRT-PCR results showed that CCAT1 was upregulated in PCa tissues and cells. Functional assays demonstrated that CCAT1 knockdown suppressed cell proliferation, migration, invasion, yet promoted apoptosis, while CCAT1 promotion showed the opposite results. We also found that CCAT1 negatively regulated miR-490-3p expression and subsequently regulated FRAT1 expression. Inhibition of miR-490-3p or up-regulation of FRAT1 reversed the suppressive effects of CCAT1 knockdown on the PCa cells. In conclusion, CCAT1 regulated FRAT1 expression through miR-490-3p and then promote the PCa cells proliferation, migration, and invasion, which reveals the oncogenic function of CCAT1 in PCa progress.
The anti-dysenteric drug fraxetin enhances anti-tumor efficacy of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation
Yangyang Guo1, * , Yanyi Xiao1, * , Hangcheng Guo1, * , Hengyue Zhu1 , Dong Chen2 , Jilong Wang3 , Junjie Deng3 , Junjie Lan4 , Xiaodong Liu5,6 , Qiyu Zhang7 , Yongheng Bai1,5,7
doi : 10.18632/aging.203301
Volume 13, Issue 14 pp 18545—18563
Fraxetin, a natural product isolated and purified from the bark of Fraxinus bungeana A.DC., has anti-inflammatory, analgesic, and anti-dysenteric activities. This study aimed to investigate the anti-tumor effects of fraxetin in pancreatic ductal adenocarcinoma (PDA). The effects of fraxetin on the malignant biological behavior of PDA were evaluated. Besides, the effects of fraxetin on the sensitivity of PCCs to gemcitabine, angiogenesis, the epithelial-mesenchymal transition (EMT), glucose metabolism, reactive oxygen species (ROS), and STAT3 activity were analyzed. By reversing the EMT, fraxetin suppressed proliferation, invasion, and migration, and induced mitochondrial-dependent apoptosis in PCCs. Also, treatment with fraxetin inhibited PDA growth and metastasis in nude mouse models. Furthermore, fraxetin made PCCs more sensitive to the chemotherapy drug gemcitabine. Mechanically, fraxetin treatment suppressed oncogenic KRAS-triggered STAT3 activation in PCCs and PDA tissues. Fraxetin shows significant interactions with STAT3 Src Homology 2 (SH2) domain residues, thereby preventing its homo-dimer formation, which then blocks the activation of downstream signal pathways. The anti-tumor activity of fraxetin in PDA was functionally rescued by a STAT3 activator colivelin. As a result, fraxetin hindered hypoxia-induced angiogenesis by decreasing HIF-1? and VEGFA expression, controlled glucose metabolism by reducing GLUT1 expression, inhibited the EMT by blocking the Slug-E-cadherin axis, and drove ROS-mediated apoptosis by regulating the STAT3-Ref1 axis. In conclusion, fraxetin enhances the anti-tumor activity of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation.
Chocolate consumption and all-cause and cause-specific mortality in a US population: a post hoc analysis of the PLCO cancer screening trial
Guo-Chao Zhong1, * , Tian-Yang Hu2, * , Peng-Fei Yang3 , Yang Peng4 , Jing-Jing Wu5 , Wei-Ping Sun6 , Long Cheng7 , Chun-Rui Wang8
doi : 10.18632/aging.203302
Volume 13, Issue 14 pp 18564—18585
Few studies with mixed results have examined the association between chocolate consumption and mortality. We aimed to examine this association in a US population. A population-based cohort of 91891 participants aged 55 to 74 years was identified. Chocolate consumption was assessed via a food frequency questionnaire. Cox regression was used to estimate risk estimates. After an average follow-up of 13.5 years, 19586 all-cause deaths were documented. Compared with no regular chocolate consumption, the maximally adjusted hazard ratios of all-cause mortality were 0.89 [95% confidence interval (CI) 0.84–0.94], 0.84 (95% CI 0.79–0.90), 0.86 (95% CI 0.81–0.93), and 0.87 (95% CI 0.82–0.93) for >0–0.5 servings/week, >0.5–1 serving/week, >1–2 servings/week, and >2 servings/week, respectively (Ptrend = 0.009). A somewhat stronger inverse association was observed for mortality from cardiovascular disease and Alzheimer’s disease. A nonlinear dose–response pattern was found for all-cause and cardiovascular mortality (all Pnonlinearity < 0.01), with the lowest risk observed at chocolate consumption of 0.7 servings/week and 0.6 servings/week, respectively. The favorable associations with all-cause and cardiovascular mortality were found to be more pronounced in never smokers than in current or former smokers (all Pinteraction < 0.05). In conclusion, chocolate consumption confers reduced risks of mortality from all causes, cardiovascular disease, and Alzheimer’s disease in this US population.
Circular RNA circSP3 promotes hepatocellular carcinoma growth by sponging microRNA-198 and upregulating cyclin-dependent kinase 4
Molin Li1 , Hang Chen2 , Lulu Xia3 , Ping Huang1
doi : 10.18632/aging.203303
Volume 13, Issue 14 pp 18586—18605
As a new class of endogenous noncoding RNAs, circular RNAs (circRNAs), have been found to influence cell development and function by sponging microRNAs. MicroRNA (miR)-198 is downregulated in various cancers, including hepatocellular carcinoma (HCC). We therefore searched for dysregulated circRNAs that could sponge miR-198 in HCC. By analyzing relevant circRNA databases (circBase, TargetScan and CircInteractome), we found that the miR-198-binding circRNA hsa_circSP3 is upregulated in HCC. CircSP3 expression correlated negatively with miR-198 expression in HCC tissues. Dual luciferase reporter assays indicated that circSP3 bound to miR-198. CircSP3 overexpression in HCC cells induced expression of cyclin-dependent kinase 4, a target gene of miR-198. Silencing circSP3 inhibited HCC cell proliferation and migration by downregulating cyclin-dependent kinase 4, whereas inhibiting miR-198 reversed those effects. In vivo experiments confirmed that circSP3 promoted xenograft tumor growth. These data suggest that circSP3 may be a novel biomarker for HCC.
Obesity increases neuropathic pain via the AMPK-ERK-NOX4 pathway in rats
Chang-Ning Fu1,2, * , Hui Wei1, * , Wen-Shuang Gao1 , Sha-Sha Song1 , Shou-Wei Yue1 , Yu-Juan Qu1
doi : 10.18632/aging.203305
Volume 13, Issue 14 pp 18606—18619
This study focused on the relationship between extracellular-regulated kinase (ERK) and obesity-induced increases in neuropathic pain. We fed rats a high-fat diet to establish the obesity model, and rats were given surgery to establish the chronic compression of the dorsal root ganglia (CCD) model. U0126 was applied to inhibit ERK, and metformin or 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) was applied to cause AMP-activated protein kinase (AMPK) activation. Paw withdrawal mechanical threshold (PWMT) were calculated to indicate the level of neuropathic pain. The data indicated that compared with normal CCD rats, the PWMT of obese CCD rats were decreased, accompanied with an increase of ERK phosphorylation, NAD(P)H oxidase 4 (NOX4) protein expression, oxidative stress and inflammatory level in the L4 to L5 spinal cord and dorsal root ganglia (DRG). Administration of U0126 could partially elevate the PWMT and reduce the protein expression of NOX4 and the above pathological changes in obese CCD rats. In vitro, ERK phosphorylation, NOX4 protein expression increased significantly in DRG neurons under the stimulation of palmitic acid (PA), accompanied with increased secretion of inflammatory factors, oxidative stress and apoptosis level, while U0126 partially attenuated the PA-induced upregulation of NOX4 and other pathological changes. In the rescue experiment, overexpression of NOX4 abolished the above protective effect of U0126 on DRG neurons in high-fat environment. Next, we explore upstream mechanisms. Metformin gavage significantly reduced neuropathic pain in obese CCD rats. For the mechanisms, activating AMPK with metformin (obese CCD rats) or AICAR (DRG neurons in a high-fat environment) not only inhibited the ERK-NOX4 pathway, but also improved oxidative stress and inflammation caused by high-fat. In conclusion, the AMPK-ERK-NOX4 pathway may has a pivotal role in mediating obesity-induced increases in neuropathic pain.
Interleukin-2 inducible T-cell kinase: a potential prognostic biomarker and tumor microenvironment remodeling indicator for hepatocellular carcinoma
Binhua Pan1,3,4, * , Modan Yang1,3,4, * , Xuyong Wei1,4 , Wangyao Li1,3,4 , Kun Wang1,3,4 , Mengfan Yang1,3,4 , Di Lu1,4 , Rui Wang1,4 , Beini Cen1,4 , Xiao Xu1,2,3,4,5
doi : 10.18632/aging.203306
Volume 13, Issue 14 pp 18620—18644
The heterogeneous tumor microenvironment (TME) contributes to poor prognosis of hepatocellular carcinoma (HCC). However, determining the modulation of TME during HCC progression remains a challenge.
A nomogram for predicting late radiation-induced xerostomia among locoregionally advanced nasopharyngeal carcinoma in intensity modulated radiation therapy era
Kaixuan Yang1,2 , Wenji Xie1 , Xiangbin Zhang1 , Yu Wang3 , Arthur Shou4 , Qiang Wang1 , Jiangfang Tian1 , Jiangping Yang1 , Guangjun Li1
doi : 10.18632/aging.203308
Volume 13, Issue 14 pp 18645—18657
Dry mouth sensation cannot be improved completely even though parotids are spared correctly. Our purpose is to develop a nomogram to predict the moderate-to-severe late radiation xerostomia for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) in intensity modulated radiation therapy (IMRT) / volumetric modulated arc radiotherapy (VMAT) era.
LncRNA AC079630.4 expression associated with the progression and prognosis in lung cancer
Li-Fang Wang1 , Li-Ping Wu1 , Jian-Dong Wen1
doi : 10.18632/aging.203310
Volume 13, Issue 14 pp 18658—18668
Mounting evidence has demonstrated the important role of long non-coding RNAs (lncRNAs) in the development and progression of lung cancer. In this study, we combined the methods of bioinformatics analysis and experimental validation, and aim to investigate the clinical significance and underlying mechanism of the novel lncRNA AC079630.4 in lung cancer. Finally, we found that AC079630.4 was significantly down-regulated in lung cancer tissues, including in its subtypes. Samples with low AC079630.4 expression had a more advanced pathological stage and a worse prognosis than those with high expression. In functional prediction, the KEGG pathway of apoptosis and the TRAIL signaling pathway were enriched in the samples with high AC079630.4 expression. In experimental validation, AC079630.4 over-expression could significantly inhibit the proliferation and clonality, and up-regulated the receptors of TRAIL (TRAIL-R1 and TRAIL-R2) in lung cancer cells. In conclusion, we adopted the methods of bioinformatics analysis and experimental validation, and identified a novel lncRNA of AC079630.4 as a tumor suppressor in lung cancer.
Plasma metabolites changes in male heroin addicts during acute and protracted withdrawal
Yong Zhou1,2, * , Zhenrong Xie1,2, * , Zunyue Zhang1,2 , Jiqing Yang1,2 , Minghui Chen1,3 , Fengrong Chen1,2 , Yuru Ma1,2 , Cheng Chen1,2,4 , Qingyan Peng1,2 , Lei Zou1,2 , Jianyuan Gao1,2 , Yu Xu1,4 , Yiqun Kuang1,2 , Mei Zhu1 , Dingyun You5 , Juehua Yu1,2 , Kunhua Wang1,6, &
doi : 10.18632/aging.203311
Volume 13, Issue 14 pp 18669—18688
Heroin addiction and withdrawal have been associated with an increased risk for infectious diseases and psychological complications. However, the changes of metabolites in heroin addicts during withdrawal remain largely unknown.
Catalpol enhanced physical exercise-mediated brain functional improvement in post-traumatic stress disorder model via promoting adult hippocampal neurogenesis
Lina Sun1, *,& , Weiwei Zhang2, * , Ruiqi Ye1 , Lei Liu1 , Lili Jiang1 , Chao Xi3
doi : 10.18632/aging.203313
Volume 13, Issue 14 pp 18689—18700
Post-traumatic stress disorder (PTSD) is a serious psychiatric disorder characterized by hyper-response to environmental cues as well as the associated depressive and cognitive dysfunctions. According to the key roles of hippocampus for cognitive and emotional regulation, improving hippocampal functions, particularly hippocampal neural plasticity, is the necessary pathway to attenuate the core symptoms of PTSD. The effects of the alternative therapies such as exercise and natural compounds to reduce PTSD symptoms and promote adult hippocampal neurogenesis have been widely demonstrated. However, what is the effect of combining the exercise with traditional Chinese medical compounds remains unknown. In current study, we evaluated the effects of catalpol, which showed the pro-neurogenic effects in previous report, in regulating exercise-mediated PTSD therapeutic effects. With behavioral tests, we found that catalpol treatment promoted the effects of exercise to reduce the response of mice to dangerous cues, and simultaneously enhanced the antidepressant and cognitive protection effects. Moreover, by immunofluorescence we identified that catalpol promoted exercise-mediated hippocampal neurogenesis by enhancing the neural differentiation and mature neuronal survive. We further found that the promote effects of catalpol to exercise-induced environmental hyper-response, antidepressant effects and cognitive protective effects were all compromised by blocking neurogenesis with temozolomide (TMZ). This result indicates that hippocampal neurogenesis is prerequisite for catalpol to promote exercise-mediated brain functional improvement in PTSD model. In conclusion, our research identified the new function of natural compounds catalpol to promote the exercise-mediated brain functional changes in PTSD model, which depend on its effect promoting adult hippocampal neurogenesis.
Development and validation of a novel epigenetic-related prognostic signature and candidate drugs for patients with lung adenocarcinoma
Zhihao Wang1 , Kidane Siele Embaye1 , Qing Yang2 , Lingzhi Qin1 , Chao Zhang1 , Liwei Liu1 , Xiaoqian Zhan1 , Fengdi Zhang3 , Xi Wang1 , Shenghui Qin1
doi : 10.18632/aging.203315
Volume 13, Issue 14 pp 18701—18717
Epigenetic dysregulation has been increasingly proposed as a hallmark of cancer. Here, the aim of this study is to establish an epigenetic-related signature for predicting the prognosis of lung adenocarcinoma (LUAD) patients.
Endothelial microparticle-associated protein disulfide isomerase increases platelet activation in diabetic coronary heart disease
Xiao-Di Sun1,2 , Lu Han1,3 , Hong-Tao Lan1,4 , Ran-Ran Qin5 , Ming Song1 , Wei Zhang1 , Ming Zhong1 , Zhi-Hao Wang4
doi : 10.18632/aging.203316
Volume 13, Issue 14 pp 18718—18739
Endothelial microparticles (EMPs) carrying the protein disulfide isomerase (PDI) might play a key role in promoting platelet activation in diabetes. This study aimed to examine the activation of platelets, the amounts of MPs, PMPs, and EMPs, and the concentration and activity of PDI in patients with diabetic coronary heart disease (CHD) and non-diabetic CHD.
MicroRNA-106b-5p inhibits growth and progression of lung adenocarcinoma cells by downregulating IGSF10
Bo Ling1 , Xianjiu Liao1 , Qiang Tang2 , Guangbin Ye3,4 , Xiaoyun Bin3 , Jianchu Wang5 , Yaqin Pang6 , Guangzi Qi7
doi : 10.18632/aging.203318
Volume 13, Issue 14 pp 18740—18756
In this study, we investigated the mechanistic role and prognostic significance of IGSF10 in lung adenocarcinoma. Oncomine database analysis showed that IGSF10 expression was significantly reduced in most cancer types, including lung adenocarcinoma (LUAD). In the TCGA-LUAD dataset, IGSF10 expression correlated positively with proportions of tumor-infiltrated B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. Kaplan-Meier survival analysis showed that overall survival of patients with low IGSF10 expression was significantly shorter than those with high IGSF10 expression. MiRWalk2.0 database analysis and dual luciferase reporter assays confirmed that miR-106b-5p suppressed IGSF10 expression by binding to its 3’UTR. MiR-106b-5p levels inversely correlated with IGSF10 expression in the TCGA-LUAD dataset. Moreover, inhibition of miR-106b-5p significantly decreased in vitro proliferation, migration, and invasion by LUAD cells, whereas miR-106b-5p overexpression reversed those effects. These results demonstrate that IGSF10 is an independent prognostic factor for LUAD. Furthermore, miR-106b-5p suppressed IGSF10 expression in LUAD tissues by binding to its 3’UTR, which makes IGSF10 and miR-106b-5p potential prognostic biomarkers and therapeutic targets in LUAD patients.
Curcumin in combination with homoharringtonine suppresses lymphoma cell growth by inhibiting the TGF-?/Smad3 signaling pathway
Yu Zhang1 , Jingjing Xiang1 , Ni Zhu1 , Hangping Ge1 , Xianfu Sheng1 , Shu Deng1 , Junfa Chen1 , Lihong Yu2 , Yan Zhou2 , Jianping Shen1, &
doi : 10.18632/aging.203319
Volume 13, Issue 14 pp 18757—18768
Both homoharringtonine (HHT) and curcumin exhibit anti-proliferative effects on lymphoma cells, but the effects of combined HHT and curcumin treatment remain unclear. Here, we investigated the effects of HHT/curcumin combination on the proliferation, apoptosis, and invasion in lymphoma cells. CCK-8, flow cytometry, and transwell assays were used to assess proliferation, apoptosis, and invasion of U937 and Raji cells. p-Smad3, E-cadherin, and N-cadherin expression were also measured in Raji cells using Western blot assays. Combination of HHT and curcumin synergistically inhibited U937 and Raji cell proliferation and invasion. In addition, the combination treatment markedly increased apoptosis of Raji cells as evidenced by increased Bax, cleaved caspase 3, and cleaved caspase 9 expression. Meanwhile, the combination treatment promoted anti-tumor mechanisms in Raji cells as indicated by decreases in p-Smad3 and N-cadherin and increases in E-cadherin. In vivo experiments showed that the combination treatment suppressed tumor growth in a mouse Raji xenograft model. Our findings indicate that combination of HHT and curcumin inhibited lymphoma cell growth by downregulating the TGF-?/Smad3 pathway. These results suggest that HHT combined with curcumin might be a promising therapeutic approach for the treatment of lymphoma.
An association study in the Taiwan Biobank elicits three novel candidates for cognitive aging in old adults: NCAM1, TTC12 and ZBTB20
Eugene Lin1,2,3 , Po-Hsiu Kuo4,5 , Wan-Yu Lin4 , Yu-Li Liu6 , Albert C. Yang7,8 , Shih-Jen Tsai9,10
doi : 10.18632/aging.203321
Volume 13, Issue 14 pp 18769—18788
The dopamine receptor-related loci have been suggested to be associated with cognitive functions and neurodegenerative diseases. It is unknown whether genetic variants such as single nucleotide polymorphisms (SNPs) in the dopamine receptor-related loci could contribute to cognitive aging independently as well as by virtue of complicated interplays in the elder population. To assess whether SNPs in the dopamine receptor-related loci are associated with cognitive aging in the elder population, we evaluated SNPs in the DRD1, NCAM1-TTC12-ANKK1-DRD2, DRD3-LOC107986115-ZNF80-TIGIT-MIR568-ZBTB20, DRD4, and DRD5-SLC2A9 loci from 25,195 older Taiwanese individuals from the Taiwan Biobank. Mini-Mental State Examination (MMSE) was scrutinized for all participants, where MMSE scores were employed to evaluate cognitive functions. From our analysis, we identified three novel genes for cognitive aging that have not previously been reported: ZBTB20 on chromosome 3 and NCAM1 and TTC12 on chromosome 11. NCAM1 and ZBTB20 are strong candidates for having a role in cognitive aging with mutations in ZBTB20 resulting in intellectual disability, and NCAM1 previously found to be associated with associative memory in humans. Additionally, we found the effects of interplays between physical activity and these three novel genes. Our study suggests that genetic variants in the dopamine receptor-related loci may influence cognitive aging individually and by means of gene-physical activity interactions.
Identification of prognostic long non-coding RNA signature with potential drugs in hepatocellular carcinoma
Fengjie Hao1,2,3, * , Nan Wang1, * , Xiang Wang4 , Yongjun Chen1 , Junqing Wang1
doi : 10.18632/aging.203322
Volume 13, Issue 14 pp 18789—18805
Hepatocellular carcinoma (HCC) is the primary malignancy in the liver with high rate of death and recurrence. Novel prognostic model would be crucial for early diagnosis and improved clinical decision. The study aims to provide an effective lncRNA-based signature to predict survival time and tumor recurrence for HCC. Based on public database, lncRNA-based classifiers for overall survival and tumor recurrence were built with regression analysis and cross validation strategy. According to the risk-score of the classifiers, the whole cohorts were divided into groups with high and low risk. Afterwards, the efficiency of the lncRNA-based classifiers was evaluated and compared with other clinical factors. Finally, candidate small molecules for high risk groups were further screened using drug response databases to explore potential drugs for HCC treatment.
An immune-related lncRNA signature for the prognosis of pancreatic adenocarcinoma
Bing Qi1, * , Han Liu2, * , Qi Zhou3 , Li Ji4 , Xueying Shi3 , Yushan Wei5 , Yajun Gu6 , Akio Mizushima7 , Shilin Xia8
doi : 10.18632/aging.203323
Volume 13, Issue 14 pp 18806—18826
Recent evidence suggests that aberrant expression of long non-coding RNA (lncRNA) can drive the initiation and progression of malignancies. However, little is known about the prognostic potential of lncRNA. We aimed at constructing a lncRNA-based signature to improve the prognosis prediction of pancreatic adenocarcinoma (PAAD). The PAAD samples with clinical information were obtained from The Cancer Genome Atlas and International Cancer Genome Consortium. We established an eight-IRlncRNA signature in a training cohort. The prognostic value of eight-IRlncRNA signature was validated in two distinct cohorts when compared to other four prognostic models. We continued to analyze its independence in subgroups by univariate and multivariate Cox regression. We constructed a nomogram for clinicopathologic features and 1-, 3-, and 5-year overall survival performance. Moreover, Gene set enrichment analysis and Gene Set Variation Analysis distinguished the typical functions between high- and low-risk groups. In addition, we further observed the different correlations of immune cell between eight IRlncRNAs. Eight-IRlncRNA signature appears to be a good performer to predict the survival capability of PAAD patients, and the nomogram will enable PAAD patients to be more accurately managed in clinical practice.
Programmed cell death-ligand 1 expression predicts poor treatment response and prognostic value in esophageal squamous cell carcinoma patients without esophagectomy
Fang Zhang1 , Xiuyuan Zhu2 , Qi Zhang3 , Ping Zhou3 , Liang Hao1
doi : 10.18632/aging.203326
Volume 13, Issue 14 pp 18827—18838
Research on association between programmed cell death ligand 1 (PD-L1) expression in cancer cells and prognosis of esophageal squamous cell carcinoma (ESCC) has been controversial and has focused on patients with surgical resection. We aimed to investigate impact of PD-L1 on treatment response and prognostic value in ESCC and analyze which subset of patients may benefit from immunotherapy. The PD-L1 expression was evaluated by immunohistochemical analysis in all patients. Stratification analysis was performed according to whether surgery was performed. There were no significant correlations between PD-L1 expression with 3-year overall survival (OS) and progression-free survival (PFS) in 81 ESCC patients. Then stratification analysis was performed. Among these 44 patients without surgery, disease control rate (DCR) in negative PD-L1 expression group (78%) was significantly better than those (42%) in positive PD-L1 expression group (P = 0.032). There were no significant correlations between PD-L1 expression with 3-year OS and PFS in 37 ESCC patients receiving surgery. However, in 44 ESCC patients without surgery, the Kaplan-Meier method showed that 3-year OS and PFS in negative PD-L1 expression group were significantly better than those in positive PD-L1 expression group. In Cox univariate and multivariate model, PD-L1 was an independent prognosticator for inferior OS (p = 0.011; p = 0.017). Our research revealed prognostic role of PD-L1 expression in cancer cells may be variable in different treatment methods. Consequently, PD-L1 may serve as an independent prognostic factor and provide a theoretical basis for combining conventional therapy with immunotherapy targeting PD-L1 to achieve better treatment outcome in ESCC patients without esophagectomy.
Association between carotid artery perivascular fat density and cerebral small vessel disease
Dan-Hong Zhang1 , Jiao-Lei Jin1 , Cheng-Fei Zhu1 , Qiu-Yue Chen1 , Xin-Wei He1
doi : 10.18632/aging.203327
Volume 13, Issue 14 pp 18839—18851
Studies aiming to identify the significance of the carotid artery perivascular fat density are limited. The present study investigated the distribution pattern of pericarotid fat and its association with imaging markers of cerebral small vessel disease (CSVD). In total, 572 subjects who underwent both neck computed tomography angiography and cranial magnetic resonance imaging were analyzed. The pericarotid fat density near the origin of the internal carotid artery (ICA) and imaging markers of CSVD, such as lacunes, white matter hyperintensities (WMHs) and dilated perivascular spaces (PVSs), were assessed. We found that an increased pericarotid fat density was associated with the presence of lacunes and a higher WMH grade in all subjects, but in the patients with acute ischemic stroke, there was a difference only among the WMH grades. There was no significant difference in the pericarotid fat density in different grades of PVSs. The patients with acute ischemic stroke had a significantly higher mean pericarotid fat density than those without stroke. In conclusion, our study provides evidence suggesting that an increased pericarotid fat density is associated with the presence and degree of WMHs and lacunes. Our findings suggested that features that appear to extend beyond the vessel lumen of the ICA may be linked to CSVD.
Regulation of the IGF1 signaling pathway is involved in idiopathic pulmonary fibrosis induced by alveolar epithelial cell senescence and core fucosylation
Wei Sun1,2 , Xiaoyan Jing1 , Xiaoyu Yang1 , Hui Huang1 , Qun Luo3 , Shu Xia3 , Ping Wang1 , Na Wang1 , Qian Zhang1 , Jian Guo1 , Zuojun Xu1
doi : 10.18632/aging.203335
Volume 13, Issue 14 pp 18852—18869
Idiopathic pulmonary fibrosis (IPF) mainly occurs in elderly people over the age of sixty. IPF pathogenesis is associated with alveolar epithelial cells (AECs) senescence. Activation of PI3K/AKT signaling induced by insulin-like growth factor 1 (IGF1) participates in AEC senescence and IPF by releasing CTGF, TGF-?1, and MMP9. Our previous study demonstrated that core fucosylation (CF) modification, catalyzed by a specific core fucosyltransferase (FUT8) can regulate the activation of multiple signaling pathways, and inhibiting CF can alleviate pulmonary fibrosis in mice induced by bleomycin. However, whether CF is involved in IGF1-mediated AEC senescence in IPF remains unclear. In this study, we found that the IGF1/PI3K/AKT signaling pathway was activated in IPF lung tissue. Meanwhile, CF was present in senescent AECs. We also showed that IGF1 could induce AECs senescence with enhanced CF in vivo and in vitro. Inhibiting CF alleviated AECs senescence and pulmonary fibrosis induced by IGF1. In addition, activation of IGF1/PI3K/AKT signaling depends on CF. In conclusion, this study confirmed that CF is an important target regulating the IGF1 signaling pathway in AEC senescence and IPF, which might be a candidate target to treat IPF in the future.
Atorvastatin attenuates intermittent hypoxia-induced myocardial oxidative stress in a mouse obstructive sleep apnea model
Xiao-Bin Zhang1, * , Hui-Juan Cheng2, * , Ya-Ting Yuan1, * , Yan Chen1, * , Yi-Yuan Chen1, * , Kam Yu Chiu1 , Hui-Qing Zeng1
doi : 10.18632/aging.203339
Volume 13, Issue 14 pp 18870—18878
Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea (OSA), is associated with various cardiovascular diseases. In the present study, we assessed the effect of the lipid reducing agent atorvastatin on CIH-induced myocardial oxidative stress and apoptosis in a mouse OSA model. Forty-eight C57BL/6J mice were evenly divided among normoxia + vehicle, normoxia + atorvastatin, CIH + vehicle, and CIH + atorvastatin groups. CIH consisted of a hypoxia-reoxygenation cycle in which oxygen concentrations fluctuated from 21% to 6% and back over two minutes for 8 hours each day (30 events/hour). CIH exposure continued for 12 weeks. Atorvastatin (5 mg/kg) was administered from week 6 through the end of the experiment. CIH increased malondialdehyde levels and decreased superoxide dismutase activity, total antioxidant capacity, and nuclear factor erythroid 2-related factor 2 levels in cardiac tissue, indicating a reduction in antioxidant activity. Atorvastatin significantly reversed those effects (p < 0.05). CIH also increased B-cell lymphoma 2-associated protein X and cleaved caspased-3 levels as well as the myocardial apoptotic rate, as indicated by terminal deoxynucleotidyl transferase dUTP nick-end labeling. Atorvastatin had no effect on those changes (p > 0.05). Thus, atorvastatin administration exerts antioxidant but not anti-apoptotic effects after CIH and may therefore have therapeutic potential in OSA patients with cardiovascular comorbidities.
Myeloid DJ-1 deficiency protects acetaminophen-induced acute liver injury through decreasing inflammatory response
Bingrui Wang1,2, * , Jichang Li2, * , Junzhe Jiao2 , Min Xu2 , Yichun Luo2 , Fang Wang2 , Qiang Xia1 , Yueqiu Gao2 , Yu Feng3 , Xiaoni Kong2 , Xuehua Sun2
doi : 10.18632/aging.203340
Volume 13, Issue 14 pp 18879—18893
DJ-1 (also known as PARK7), a noted protein implicated in modulating ROS production and immune response, has been observed to play critical roles in the pathogenesis of many forms of liver disease through multiple mechanisms. However, its role and specific mechanism in acetaminophen (APAP) -induced liver injury have not been explored.
Prevalence of allergen-specific IgE in southern China: a multicenter research
Xue’an Wang1, * , Long Zhou2, * , Guixi Wei3, * , Hui Zhang4, * , Bin Yang1
doi : 10.18632/aging.203341
Volume 13, Issue 14 pp 18894—18911
Identifying allergen distribution is meaningful and significant for effective diagnosis and treatment of allergic diseases. This study compared the allergen sensitivity in four southern China cities. We enrolled 55,432 participants (27,408 male, 28,024 female) between 2007 and 2019. The allergen-specific IgE levels were compared by the ?2 test. The five prevalent sensitivities were for mite mix (10,985, 19.82%), cockroach (4,860, 8.77%), crab (4,450, 8.03%), fish mix (3,874, 6.99%), and house dust (3,486, 6.29%). Almost all allergen sensitivities decreased with age, particularly from infant to middle aged participants (p < 0.05). An exception was Shenzhen, where food allergen positive rates remained constant in all age groups studied. The proportion of male sensitive to at least one food allergen (OR 1.130; 95% CI 1.088–1.174, p < 0.0025) or aeroallergen (OR, 1.117; 95% CI, 1.078–1.158, p < 0.0025) was higher than female in all four cities. Except for dog dander and tree mix, all aeroallergens differed significantly between seasons (p < 0.05). Liuzhou had the highest rates of food allergen- and aeroallergen-positive participants. The allergen-specific IgE distribution differed among the studied cities, with significant seasonal differences. Young age, male sex, and aeroallergens were risk factors for allergic disease.
Normal-sized basal ganglia perivascular space related to motor phenotype in Parkinson freezers
Wen Lv1, * , Yumei Yue1, * , Ting Shen2,3 , Xingyue Hu1 , Lili Chen1 , Fei Xie1 , Wenying Zhang1 , Baorong Zhang3 , Yaxing Gui1 , Hsin-Yi Lai1,2,3,4 , Fang Ba5
doi : 10.18632/aging.203343
Volume 13, Issue 14 pp 18912—18923
Changes in basal ganglia (BG) perivascular spaces (PVSs) are related to motor and cognitive behaviors in Parkinson’s disease (PD). However, the correlation between the initial motor phenotype and PVSs distribution/burden in PD freezing of gait (FOG) remains unclear. In addition, the normal-sized PVSs (nPVSs) have not been well-studied. With high-resolution 7T-MRI, we studied nPVSs burden in BG, thalamus, midbrain and centrum semiovale. The numbers and volume of nPVSs were assessed in 10 healthy controls, 10 PD patients without FOG, 20 with FOG [10 tremor dominant (TD), 10 non-TD subtype]. Correlation analyses were further performed in relation to clinical parameters. In this proof of concept study, we found that the nPVS burden of bilateral and right BG were significantly higher in freezers. A negative correlation existed between the tremor score and BG-nPVSs count. A positive correlation existed between the levodopa equivalent daily dose and BG-nPVSs count. The nPVS burden correlated with the progression to FOG in PD, but the distribution and burden of nPVS differ in TD vs. non-TD subtypes. High resolution 7T-MRI is a sensitive and reliable tool to evaluate BG-nPVS, and may be a useful imaging marker for predicting gait impairment that may evolve into FOG in PD.
MicroRNA-1252-5p, regulated by Myb, inhibits invasion and epithelial-mesenchymal transition of pancreatic cancer cells by targeting NEDD9
Yuzheng Xue1, * , Tielong Wu1, * , Yingyue Sheng1 , Yao Zhong1 , Benshun Hu2 , Chuanqing Bao3
doi : 10.18632/aging.203344
Volume 13, Issue 14 pp 18924—18945
MicroRNAs (miRNAs) are known to be involved in the development and progression of pancreatic cancer (PAC). The expression levels and roles of miR-1252-5p in PAC remain unclear. Quantitative real-time PCR and in situ hybridization were used to detect miR-1252-5p expression in PAC cells and human tissues. We studied the gain and loss of function of miR-1252-5p in the PAC cell lines in vitro and in vivo. The direct targets of miR-1252-5p were analyzed using public databases and a dual-luciferase reporter assay. Expression levels of miR-1252-5p are downregulated in PAC cell lines and tissue samples, and its expression is negatively associated with adverse clinical features and poor prognosis. In vitro and in vivo experiments show that miR-1252-5p overexpression inhibits the proliferation, migration, invasion, and epithelial-mesenchymal transition of PAC cells, and miR-1252-5p knockdown enhances these biological behaviors. MiR-1252-5p negatively regulates neural precursor cell expressed, developmentally downregulated 9 (NEDD9) by directly binding its 3'- untranslated region. Further mechanism research revealed that the SRC/STAT3 pathway is involved in miR-1252-5p/NEDD9 mediation of PAC's biological behaviors. We also verified that Myb inhibited miR-1252-5p by directly binding at its promoter. MiR-1252-5p may act as a tumor-suppressing miRNA in PAC and may be a potential therapeutic target for PAC patients.
CircRNA circFOXK2 facilitates oncogenesis in breast cancer via IGF2BP3/miR-370 axis
Wei Zhang1 , Hui Liu1 , Junjie Jiang1 , Yunyun Yang2 , Wenjie Wang3 , Zhengyan Jia4
doi : 10.18632/aging.203347
Volume 13, Issue 14 pp 18978—18992
Metastasis is the leading cause of breast cancer (BC)-related deaths. Circular RNAs (circRNAs) have emerged as essential regulators for cancer progression and metastasis. Therefore, the objective of this study was to investigate the role of circRNAs in BC metastasis and related mechanism. In this study, we established the BC cell line with high or low potential of metastasis. RNA sequencing, migration and invasion assay, Fluorescence in situ hybridization, luciferase report assay, circRNA pulldown, and transmission electron microscopy were performed to elucidate the molecular mechanism. The results showed that circRNA circFOXK2 was significantly increased in BC cells with high metastatic ability, and the upregulation of circFOXK2 was correlated with poor clinicopathological characteristics. Functional experiments demonstrated that overexpression of circFOXK2 promoted migration and invasion of BC cells. Also. circFOXK2 could act with IGF2BP3, an RNA-binding protein, and miR-370 to synergistically promote BC metastasis. Moreover, miR-370 could be transferred through exosomes to enhance the metastatic ability of recipient cells. In conclusion, circFOXK2 functions as a key regulator in BC metastasis, and the role of circFOXK2 on BC metastasis is tightly associated with the involvement of IGF2BP3 and miR-370. CircFOXK2 might serve as a potential biomarker for the diagnosis and treatment of BC.
A network pharmacology approach to uncover the key ingredients in Ginkgo Folium and their anti-Alzheimer’s disease mechanisms
Peng Zeng1 , Meng Fang2 , Han Zhao2 , Jing Guo2
doi : 10.18632/aging.203348
Volume 13, Issue 14 pp 18993—19012
This study aimed to identify potential anti-Alzheimer’s disease (AD) targets and action mechanisms of Ginkgo Folium (GF) through a network pharmacology approach. Eighty-four potential targets of 10 active anti-AD ingredients of GF were identified, among which genkwanin (GK) had the greatest number of AD-related targets. KEGG pathway enrichment analysis showed that the most significantly enriched signaling pathway of GF against AD was Alzheimer disease (hsa05010). More importantly, 29 of the 84 targets were significantly correlated with tau, A? or both A? and tau pathology. In addition, GO analysis suggested that the main biological processes of GF in AD treatment were the regulation of chemical synaptic transmission (GO:0007268), neuron death (GO:0070997), amyloid-beta metabolic process (GO:0050435), etc. We further investigated the anti-AD effects of GK using N2A-APP cells (a classical cellular model of AD). Treatment N2A-APP cells with 100 ?M GK for 48 h affected core targets related to tau pathology (such as CDK5 and GSK3?). In conclusion, these findings indicate that GF exerts its therapeutic effects on AD by acting directly on multiple pathological processes of AD.
Glucagon-like peptide-1 attenuated carboxymethyl lysine induced neuronal apoptosis via peroxisome proliferation activated receptor-?
Haoqiang Zhang1,2 , Bing Song3 , Wenwen Zhu1,2 , Lili Liu3 , Xiqiao He3 , Zheng Wang1,2 , Ke An1,2 , Wuyou Cao1,2 , Jijing Shi1,2 , Shaohua Wang1,2
doi : 10.18632/aging.203351
Volume 13, Issue 14 pp 19013—19027
The role of peroxisome proliferator activated receptor-? (PPAR-?) in neuronal apoptosis remains unclear. We aim to investigate the role of PPAR-? in glucagon-like peptide-1 (GLP-1) alleviated neuronal apoptosis induced by carboxymethyl-lysine (CML).
Development and validation of prognostic model based on the analysis of autophagy-related genes in colon cancer
Yongfeng Wang1,2,5, * , Kaili Lin4, * , Tianchun Xu6 , Liuli Wang2,3 , Liangyin Fu1 , Guangming Zhang1 , Jing Ai1 , Yajun Jiao4 , Rongrong Zhu1 , Xiaoyong Han4 , Hui Cai1,2,5, &
doi : 10.18632/aging.203352
Volume 13, Issue 14 pp 19028—19047
Autophagy, a process of self-digestion, is closely related to multiple biological processes of colon cancer. This study aimed to construct and evaluate prognostic signature of autophagy-related genes (ARGs) to predict overall survival (OS) in colon cancer patients.
Combined treatment with C16 peptide and angiopoietin-1 confers neuroprotection and reduces inflammation in 3-nitropropionic acid-induced dystonia mice
Xiao-Xiao Fu1 , Hua-Ying Cai2, * , Hong Jiang3 , Shu Han1, *
doi : 10.18632/aging.203354
Volume 13, Issue 14 pp 19048—19063
Dystonia is a disorder associated with abnormalities in many brain regions including the basal ganglia and cerebellum. The toxin 3-Nitropropionic acid (3-NP) can induce neuropathologies in the mice striatum and nigra substance, including excitotoxicity, neuroinflammation, and extensive neuronal atrophy, characterized by progressive motor dysfunction, dystonia, and memory loss, mimicking those observed in humans. We established a mouse model of dystonia by administering 3-NP. Given the reported neuroprotective effects of the endothelial growth factor angiopoietin-1 (Ang-1) and the anti-inflammatory integrin ?v?3 binding peptide C16, we performed this study to evaluate their combined effects on 3-NP striatal toxicity and their therapeutic potential with multiple methods using an in vivo mouse model. Sixty mice were equally and randomly divided into three groups: control, 3-NP treatment, and 3-NP+C16+Ang-1 treatment. Behavioral and electrophysiological tests were conducted and the effect of the combined C16+Ang-1 treatment on neural function recovery was determined. We found that C16+Ang-1 treatment alleviated 3-NP-induced behavioral, biochemical, and cellular alterations in the central nervous system and promoted function recovery by restoring vascular permeability and reducing inflammation in the micro-environment. In conclusion, our results confirmed the neuroprotective effect of combined C16+Ang-1 treatment and suggest their potential as a complementary therapeutic against 3-NP-induced dystonia.
Type I collagen promotes tumor progression of integrin ?1 positive gastric cancer through a BCL9L/?-catenin signaling pathway
Yalei Lv1 , Yujie Shan1 , Lina Song2 , Yufei Zhao3 , Ruixue Lai3 , Junyan Su4 , Xiaoyun Zhang3
doi : 10.18632/aging.203355
Volume 13, Issue 14 pp 19064—19076
The mechanism of extracellular matrix induced tumor progression is poorly understood. Based on the TCGA database and clinical tumor tissues analysis, we observed abundant type I collagen expression in tumor tissues and poor overall survival in gastric patients with high integrin ?1 (ITGB1) expression. In vitro, our study found that 3D collagen culture promoted the capability of colony formation and growth in ITGB1 positive gastric cancer, whereas limited colony growth was observed in ITGB1 negative gastric cancer, suggesting the role of ITGB1 in type I collagen associated tumor progression. Mechanistically, we demonstrated that type I collagen was capable of promoting the activation of BCL9L/?-catenin signaling pathway through ITGB1, thereby contributing to the gastric cancer development. Subsequently, ?-catenin signals further up-regulated the expression anti-apoptosis protein BCL2, leading to the chemo-resistance in gastric cancer cells. Blockade of ?-catenin signals efficiently improved the anticancer effects of chemotherapy, providing an innovative sight for clinical gastric cancer therapy.
Correction for: Suppressing the KIF20A/NUAK1/Nrf2/GPX4 signaling pathway induces ferroptosis and enhances the sensitivity of colorectal cancer to oxaliplatin
Changshun Yang1, * , Yu Zhang2, * , Shengtao Lin1, * , Yi Liu3 , Weihua Li1
doi : 10.18632/aging.203382
Volume 13, Issue 14 pp 19077
Correction for: Silencing of long non-coding RNA H19 downregulates CTCF to protect against atherosclerosis by upregulating PKD1 expression in ApoE knockout mice
Yongyao Yang1, * , Feng Tang1, * , Fang Wei1 , Long Yang1 , Chunyan Kuang1 , Hongming Zhang2 , Jiusheng Deng3 , Qiang Wu1
doi : 10.18632/aging.203391
Volume 13, Issue 14 pp 19078—19079
