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Senescence-associated tumor growth is promoted by 12-Lipoxygenase
Shilpa Patil1 , Jessica L. Reedy1 , Bradley T. Scroggins1 , Ayla O. White1 , Seokjoo Kwon1 , Uma Shankavaram1 , Alfonso López-Coral1 , Eun Joo Chung1 , Deborah E. Citrin1
doi : 10.18632/aging.203890
Volume 14, Issue 3 pp 1068—1086
Radiation therapy is a commonly used treatment modality for cancer. Although effective in providing local tumor control, radiation causes oxidative stress, inflammation, immunomodulatory and mitogenic cytokine production, extracellular matrix production, and premature senescence in lung parenchyma. The senescence associated secretory phenotype (SASP) can promote inflammation and stimulate alterations in the surrounding tissue. Therefore, we hypothesized that radiation-induced senescent parenchymal cells in irradiated lung would enhance tumor growth. Using a murine syngeneic tumor model of melanoma and non-small cell lung cancer lung metastasis, we demonstrate that radiation causes a significant increase in markers of premature senescence in lung parenchyma within 4 to 8 weeks. Further, injection of B16F0 (melanoma) or Lewis Lung carcinoma (epidermoid lung cancer) cells at these time points after radiation results in an increase in the number and size of pulmonary tumor nodules relative to unirradiated mice. Treatment of irradiated mice with a senolytic agent (ABT-737) or agents that prevent senescence (rapamycin, INK-128) was sufficient to reduce radiation-induced lung parenchymal senescence and to mitigate radiation-enhanced tumor growth. These agents abrogated radiation-induced expression of 12-Lipoxygenase (12-LOX), a molecule implicated in several deleterious effects of senescence. Deficiency of 12-LOX prevented radiation-enhanced tumor growth. Together, these data demonstrate the pro-tumorigenic role of radiation-induced senescence, introduces the dual TORC inhibitor INK-128 as an effective agent for prevention of radiation-induced normal tissue senescence, and identifies senescence-associated 12-LOX activity as an important component of the pro-tumorigenic irradiated tissue microenvironment. These studies suggest that combining senotherapeutic agents with radiotherapy may decrease post-therapy tumor growth.
The effect of age on ventilation management and clinical outcomes in critically ill COVID–19 patients––insights from the PRoVENT–COVID study
Liselotte Hol1 , Paula Van Oosten2 , Sunny Nijbroek1 , Anissa Tsonas2 , Michela Botta2 , Ary Serpa Neto2,3,4 , Frederique Paulus2,5 , Marcus Schultz2,6,7 , PRoVENT–COVID * , Collaborative group #
doi : 10.18632/aging.203863
Volume 14, Issue 3 pp 1087—1109
Introduction: We analyzed the association of age with ventilation practice and outcomes in critically ill COVID–19 patients requiring invasive ventilation.
Dihydroartemisinin attenuates pulmonary inflammation and fibrosis in rats by suppressing JAK2/STAT3 signaling
Xiaolan You1 , Xingyu Jiang2 , Chuanmeng Zhang3 , Kejia Jiang4 , Xiaojun Zhao1 , Ting Guo3 , Xiaowei Zhu5 , Jingjing Bao5 , Hongmei Dou6
doi : 10.18632/aging.203874
Volume 14, Issue 3 pp 1110—1127
Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has induced a worldwide pandemic since early 2020. COVID-19 causes pulmonary inflammation, secondary pulmonary fibrosis (PF); however, there are still no effective treatments for PF. The present study aimed to explore the inhibitory effect of dihydroartemisinin (DHA) on pulmonary inflammation and PF, and its molecular mechanism. Morphological changes and collagen deposition were analyzed using hematoxylin-eosin staining, Masson staining, and the hydroxyproline content. DHA attenuated early alveolar inflammation and later PF in a bleomycin-induced rat PF model, and inhibited the expression of interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNFα), and chemokine (C-C Motif) Ligand 3 (CCL3) in model rat serum. Further molecular analysis revealed that both pulmonary inflammation and PF were associated with increased transforming growth factor-β1 (TGF-β1), Janus activated kinase 2 (JAK2), and signal transducer and activator 3(STAT3) expression in the lung tissues of model rats. DHA reduced the inflammatory response and PF in the lungs by suppressing TGF-β1, JAK2, phosphorylated (p)-JAK2, STAT3, and p-STAT3. Thus, DHA exerts therapeutic effects against bleomycin-induced pulmonary inflammation and PF by inhibiting JAK2-STAT3 activation. DHA inhibits alveolar inflammation, and attenuates lung injury and fibrosis, possibly representing a therapeutic candidate to treat PF associated with COVID-19.
Work-related stress and well-being in association with epigenetic age acceleration: A Northern Finland Birth Cohort 1966 Study
Anna Freni-Sterrantino1 , Giovanni Fiorito1,2 , Angelo D’Errico3 , Oliver Robinson1 , Marianna Virtanen4,5 , Leena Ala-Mursula6 , Marjo-Riitta Järvelin1,6 , Justiina Ronkainen6 , Paolo Vineis1,7,8
doi : 10.18632/aging.203872
Volume 14, Issue 3 pp 1128—1156
Recent evidence indicates consistent association of low socioeconomic status with epigenetic age acceleration, measured from DNA methylation. As work characteristics and job stressors are crucial components of socioeconomic status, we investigated their association with various measures of epigenetic age acceleration.
Improved impedance to maladaptation and enhanced VCAM-1 upregulation with resistance-type training in the long-lived Snell dwarf (Pit1dw/dw) mouse
Erik P. Rader1 , Marshall A. Naimo1,2 , James Ensey1 , Brent A. Baker1
doi : 10.18632/aging.203875
Volume 14, Issue 3 pp 1157—1185
Snell dwarf mice with the Pit1dw/dw mutation are deficient in growth hormone, prolactin, and thyroid stimulating hormone and exhibit >40% lifespan extension. This longevity is accompanied by compromised muscular performance. However, research regarding young (3-month-old) Snell dwarf mice demonstrate exceptional responsivity to resistance-type training especially in terms of a shifted fiber type distribution and increased protein levels of vascular cell adhesion molecule-1 (VCAM-1), a possible mediator of such remodeling. In the present study, we investigated whether this responsiveness persists at 12 months of age. Unlike 12-month-old control mice, age-matched Snell dwarf mice remained resistant to training-induced maladaptive decreases in performance and muscle mass. This was accompanied by retainment of the remodeling capacity in muscles of Snell dwarf mice to increase VCAM-1 protein levels and a shift in myosin heavy chain (MHC) isoform distribution with training. Even decreasing training frequency for control mice, an alteration which protected muscles from maladaptation at 12 months of age, did not result in the overt remodeling observed for Snell dwarf mice. The results demonstrate a distinct remodeling response to resistance-type exercise operative in the context of the Pit1dw/dw mutation of long-lived Snell dwarf mice.
Breast cancer mortality as a function of age
Azadeh Nasrazadani1, * , Juan Luis Gomez Marti2, * , Kevin E. Kip3 , Oscar C. Marroquin3 , Lara Lemon3,4 , Steve D. Shapiro5 , Adam M. Brufsky1
doi : 10.18632/aging.203881
Volume 14, Issue 3 pp 1186—1199
Background: Incidence of breast cancer (BC) in US women continues to increase with age as the strongest risk factor. We aimed to compare clinical, pathological and sociological variables associated to BC diagnosis, as well as the relative mortality rates of BC patients compared to the general US population.
Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells
Ingrid Espinoza1,8,9, * , Lin Yang1, * , Travis Vander Steen1 , Luciano Vellon2 , Elisabet Cuyà s3,4 , Sara Verdura3,4 , Lester Lau5 , Javier A. Menendez3,4 , Ruth Lupu1,6,7
doi : 10.18632/aging.203882
Volume 14, Issue 3 pp 1200—1213
CCN1/CYR61 promotes angiogenesis, tumor growth and chemoresistance by binding to its integrin receptor αvβ3 in endothelial and breast cancer (BC) cells. CCN1 controls also tissue regeneration by engaging its integrin receptor α6β1 to induce fibroblast senescence. Here, we explored if the ability of CCN1 to drive an endocrine resistance phenotype in estrogen receptor-positive BC cells relies on interactions with either αvβ3 or α6β1. First, we took advantage of site-specific mutagenesis abolishing the CCN1 receptor-binding sites to αvβ3 and α6β1 to determine the integrin partner responsible for CCN1-driven endocrine resistance. Second, we explored a putative nuclear role of CCN1 in regulating ERα-driven transcriptional responses. Retroviral forced expression of a CCN1 derivative with a single amino acid change (D125A) that abrogates binding to αvβ3 partially phenocopied the endocrine resistance phenotype induced upon overexpression of wild-type (WT) CCN1. Forced expression of the CCN1 mutant TM, which abrogates all the T1, H1, and H2 binding sites to α6β1, failed to bypass the estrogen requirement for anchorage-independent growth or to promote resistance to tamoxifen. Wild-type CCN1 promoted estradiol-independent transcriptional activity of ERα and enhanced ERα agonist response to tamoxifen. The α6β1-binding-defective TM-CCN1 mutant lost the ERα co-activator-like behavior of WT-CCN1. Co-immunoprecipitation assays revealed a direct interaction between endogenous CCN1 and ERα, and in vitro approaches confirmed the ability of recombinant CCN1 to bind ERα. CCN1 signaling via α6β1, but not via αvβ3, drives an endocrine resistance phenotype that involves a direct binding of CCN1 to ERα to regulate its transcriptional activity in ER+ BC cells.
Ribosomal DNA methylation in human and mouse oocytes increases with age
Ramya Potabattula1 , Tom Trapphoff2 , Marcus Dittrich1,3 , Kinga Fic4 , Grazyna E. Ptak4 , Stefan Dieterle2,5 , Thomas Haaf1
doi : 10.18632/aging.203891
Volume 14, Issue 3 pp 1214—1232
An age-dependent increase in ribosomal DNA (rDNA) methylation has been observed across a broad spectrum of somatic tissues and the male mammalian germline. Bisulfite pyrosequencing (BPS) was used to determine the methylation levels of the rDNA core promoter and the rDNA upstream control element (UCE) along with two oppositely genomically imprinted control genes (PEG3 and GTL2) in individual human germinal vesicle (GV) oocytes from 90 consenting women undergoing fertility treatment because of male infertility. Apart from a few (4%) oocytes with single imprinting defects (in either PEG3 or GTL2), the analyzed GV oocytes displayed correct imprinting patterns. In 95 GV oocytes from 42 younger women (26-32 years), the mean methylation levels of the rDNA core promoter and UCE were 7.4±4.0% and 9.3±6.1%, respectively. In 79 GV oocytes from 48 older women (33-39 years), methylation levels increased to 9.3±5.3% (P = 0.014) and 11.6±7.4% (P = 0.039), respectively. An age-related increase in oocyte rDNA methylation was also observed in 123 mouse GV oocytes from 29 4-16-months-old animals. Similar to the continuously mitotically dividing male germline, ovarian aging is associated with a gain of rDNA methylation in meiotically arrested oocytes. Oocytes from the same woman can exhibit varying rDNA methylation levels and, by extrapolation, different epigenetic ages.
PERK activation by SB202190 ameliorates amyloidogenesis via the TFEB-induced autophagy-lysosomal pathway
Mihyang Do1, * , Jeongmin Park1, * , Yubing Chen1 , So-Young Rah2 , Thu-Hang Thi Nghiem1 , Jeong Heon Gong1 , Seong-A Ju1 , Byung-Sam Kim1 , Rina Yu3 , Jeong Woo Park1 , Stefan W. Ryter4 , Young-Joon Surh5,6 , Uh-Hyun Kim2 , Yeonsoo Joe1 , Hun Taeg Chung1
doi : 10.18632/aging.203899
Volume 14, Issue 3 pp 1233—1252
The protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK), a key ER stress sensor of the unfolded protein response (UPR), can confer beneficial effects by facilitating the removal of cytosolic aggregates through the autophagy-lysosome pathway (ALP). In neurodegenerative diseases, the ALP ameliorates the accumulation of intracellular protein aggregates in the brain. Transcription factor-EB (TFEB), a master regulator of the ALP, positively regulates key genes involved in the cellular degradative pathway. However, in neurons, the role of PERK activation in mitigating amyloidogenesis by ALP remains unclear. In this study, we found that SB202190 selectively activates PERK independently of its inhibition of p38 mitogen-activated protein kinase, but not inositol-requiring transmembrane kinase/endoribonuclease-1α (IRE1α) or activating transcription factor 6 (ATF6), in human neuroblastoma cells. PERK activation by SB202190 was dependent on mitochondrial ROS production and promoted Ca2+-calcineurin activation. The activation of the PERK-Ca2+-calcineurin axis by SB202190 positively affects TFEB activity to increase ALP in neuroblastoma cells. Collectively, our study reveals a novel physiological mechanism underlying ALP activation, dependent on PERK activation, for ameliorating amyloidogenesis in neurodegenerative diseases.
Puerarin inhibits FUNDC1-mediated mitochondrial autophagy and CSE-induced apoptosis of human bronchial epithelial cells by activating the PI3K/AKT/mTOR signaling pathway
Li Wang1, * , Weizhou Jiang2, * , Jing Wang3 , Yuanyuan Xie4 , Weisi Wang5
doi : 10.18632/aging.203317
Volume 14, Issue 3 pp 1253—1264
Increasing evidence suggests that the pathogenesis of chronic obstructive pulmonary disease (COPD) is associated with FUN14 domain protein 1 (FUNDC1)-mediated mitophagy. Recently, studies have reported that puerarin has protective effects against excessive oxidative damage in cells. Therefore, we hypothesized that puerarin may be involved in COPD progression via regulating FUNDC1 mediated mitophagy. We found that the viability of cigarette smoke extract (CSE)-stimulated human bronchial epithelial cells (HBECs) was enhanced and apoptosis was reduced after treatment with different concentrations of puerarin. Puerarin reversed mitochondrial membrane potential (MMP) levels and ATP content, and decreased reactive oxygen species (ROS) content in CSE stimulated HBECs. Moreover, puerarin significantly inhibited apoptosis related proteins, as well as the expression of mitophagy related proteins. After inhibition of FUNDC1 phosphorylation by protein phosphatase inhibitor (PH0321), puerarin restored MMP level, decreased ROS content, promoted ATP synthesis, and downregulated autophagy related protein expression in HBECs. In addition, mitochondrial division inhibitor (Mdivi) inhibited the expression of autophagy related proteins and reduced apoptosis after blocking cell autophagy, which was the same as the inhibition of puerarin. Finally, puerarin activated the PI3K/Akt/mTOR signaling pathway to participate in COPD progression by up regulating the phosphorylation levels of PI3K, Akt and mTOR.
Hesperidin suppresses ERS-induced inflammation in the pathogenesis of non-alcoholic fatty liver disease
Qi Xie1,3 , Shuqing Gao1 , Min Lei2 , Zengning Li3,4
doi : 10.18632/aging.203817
Volume 14, Issue 3 pp 1265—1279
Objective: The current study aimed to establish a non-alcoholic fatty liver disease (NAFLD) model using HFD-fed SD rats and FFA-stimulated human THP-1 cells to examine whether hesperidin (HSP) plays a role in endoplasmic reticulum stress (ERS)-induced inflammation in the pathogenesis of NAFLD.
Predicting neuropsychiatric symptoms of persons with dementia in a day care center using a facial expression recognition system
Liang-Yu Chen1,2,3,4 , Tsung-Hsien Tsai5 , Andy Ho5 , Chun-Hsien Li5 , Li-Ju Ke4 , Li-Ning Peng1,3 , Ming-Hsien Lin1,3 , Fei-Yuan Hsiao6,7,8 , Liang-Kung Chen1,3,9
doi : 10.18632/aging.203869
Volume 14, Issue 3 pp 1280—1291
Background: Behavioral and psychological symptoms of dementia (BPSD) affect 90% of persons with dementia (PwD), resulting in various adverse outcomes and aggravating care burdens among their caretakers. This study aimed to explore the potential of artificial intelligence-based facial expression recognition systems (FERS) in predicting BPSDs among PwD.
Effect of visfatin on KATP channel upregulation in colonic smooth muscle cells in diabetic colon dysmotility
Ting Yu1, * , Lin Zhang1,2, * , Yan Wang1 , Xiaoxue Shen1 , Lin Lin1 , Yurong Tang1
doi : 10.18632/aging.203871
Volume 14, Issue 3 pp 1292—1306
The mechanisms of diabetes-related gastrointestinal dysmotility remains unclear. This study aimed to investigate the effect and mechanisms of proinflammatory adipokine visfatin (VF) in the contractile dysfunction of diabetic rat colonic smooth muscle. Twenty Sprague-Dawley rats were randomly divided into control and type 2 diabetes mellitus groups. VF levels in the serum and colonic muscle tissues were tested, the time of the bead ejection and contractility of colonic smooth muscle strips were measured, and the expression of ATP-sensitive potassium (KATP) channels in the colonic muscle tissues was analyzed. In vitro, we tested VF’s effects on intracellular reactive oxygen species (ROS) levels, NF-κB’s nuclear transcription, KATP channel expression, intracellular Ca2+ concentrations, and myosin light chain (MLC) phosphorylation in colonic smooth muscle cells (CSMCs). The effects of NAC (ROS inhibitor) and BAY 11-7082 (NF-κB inhibitor) on KATP expression were also tested. Diabetic rats showed elevated VF levels in serum and colonic muscle tissues, a delayed distal colon ejection response time, weakened contractility of colonic smooth muscle strips, and increased KATP channel expression in colonic muscle tissues. VF significantly inhibited the contractility of colonic smooth muscle strips from normal rats. In cultured CSMCs, VF caused ROS overload, increased NF-κB nuclear transcription activity and increased expression of Kir6.1, eventually reducing intracellular Ca2+ levels and MLC phosphorylation. NAC and BAY 11-7082 inhibited the VF–induced Kir6.1 upregulation. In conclusion, VF may cause contractile dysfunction of CSMCs by upregulating the expression of the Kir6.1 subunit of KATP channels via the ROS/NF-κB pathway and interfering with Ca2+ signaling.
Inhibiting effect of miR-29 on proliferation and migration of uterine leiomyoma via the STAT3 signaling pathway
Dai Huang1 , Hongyuan Xue2 , Weihua Shao3 , Xiaoxi Wang4 , Hongjuan Liao5 , Yuquan Ye6
doi : 10.18632/aging.203873
Volume 14, Issue 3 pp 1307—1320
Aim: Uterine leiomyoma is the most common benign tumor of female genitalia, and the incidence is rising gradually. This study explores the mechanism of miR-29 and STAT3 signaling pathways on uterine leiomyoma.
CTRP3 alleviates cardiac ischemia/reperfusion injury via LAMP1/JIP2/JNK signaling pathway
Yanbin Song1, * , Yunqing Zhang2, * , Zhaofei Wan3 , Junqiang Pan4 , Feng Gao1 , Fei Li1 , Jing Zhou1 , Junmin Chen1
doi : 10.18632/aging.203876
Volume 14, Issue 3 pp 1321—1335
Background: C1q/tumor necrosis factor-related protein 3 (CTRP3) has been reported to be a crucial regulator in myocardial infarction. Nevertheless, the potential molecular mechanism of CTRP3 in ischemia/reperfusion (I/R) injury remains largely unclear.
Hyperintensities of middle frontal gyrus in patients with diabetic optic neuropathy: a dynamic amplitude of low-frequency fluctuation study
Lin Yang1, * , Ang Xiao1, * , Qiu-Yu Li1, * , Hui-Feng Zhong2 , Ting Su3 , Wen-Qing Shi1 , Ping Ying1 , Rong-Bin Liang1 , San-Hua Xu1 , Yi Shao1 , Qiong Zhou1, &
doi : 10.18632/aging.203877
Volume 14, Issue 3 pp 1336—1350
Diabetic optic neuropathy (DON) is a diverse complication of diabetes and its pathogenesis has not been fully elucidated. The purpose of this study was to explore dynamic cerebral activity changes in DON patients using dynamic amplitude of low-frequency fluctuation (dALFF). In total, 22 DON patients and 22 healthy controls were enrolled. The dALFF approach was used in all participants to investigate dynamic intrinsic brain activity differences between the two groups. Compared with HCs, DON patients exhibited significantly increased dALFF variability in the right middle frontal gyrus (P < 0.01). Conversely, DON patients exhibited obviously decreased dALFF variability in the right precuneus (P < 0.01). We also found that there were significant negative correlations between HADS scores and dALFF values of the right middle frontal gyrus in the DON patients (r = -0.6404, P <0.01 for anxiety and r = -0.6346, P <0.01 for depression; HADS, Hospital Anxiety and Depression Scale). Abnormal variability of dALFF was observed in specific areas of the cerebrum in DON patients, which may contribute to distinguishing patients with DON from HCs and a better understanding of DON, hyperintensities of right middle frontal gyrus may be potential diagnostic marker for DON.
Identification and external validation of the hub genes associated with cardiorenal syndrome through time-series and network analyses
Jingjing Liang1,2 , Xiaohui Huang1 , Weiwen Li1,2 , Yunzhao Hu1,2
doi : 10.18632/aging.203878
Volume 14, Issue 3 pp 1351—1373
Cardiorenal syndrome (CRS), defined as acute or chronic damage to the heart or kidney triggering impairment of another organ, has a poor prognosis. However, the molecular mechanisms underlying CRS remain largely unknown. The RNA-sequencing data of the left ventricle tissue isolated from the sham-operated and CRS model rats at different time points were downloaded from the Gene Expression Omnibus (GEO) database. Genomic differences, protein–protein interaction networks, and short time-series analyses, revealed fibronectin 1 (FN1) and periostin (POSTN) as hub genes associated with CRS progression. The transcriptome sequencing data of humans obtained from the GEO revealed that FN1 and POSTN were both significantly associated with many different heart and kidney diseases. Peripheral blood samples from 20 control and 20 CRS patients were collected from the local hospital, and the gene expression levels of FN1 and POSTN were detected by real-time quantitative polymerase chain reaction. FN1 (area under the curve [AUC] = 0.807) and POSTN (AUC = 0.767) could distinguish CRS in the local cohort with high efficacy and were positively correlated with renal and heart damage markers, such as left ventricular ejection fraction. To improve the diagnostic ability, diagnosis models comprising FN1 and POSTN were constructed by logistic regression (F-Score = 0.718), classification tree (F-Score = 0.812), and random forest (F-Score = 1.000). Overall, the transcriptome data of CRS rat models were systematically analyzed, revealing that FN1 and POSTN were hub genes, which were validated in different public datasets and the local cohort.
Identification of immune-related cells and genes in the breast invasive carcinoma microenvironment
Xingfeng Chen1,2 , Yujing Wang3 , Yue Li1 , Geli Liu1 , Kui Liao4 , Fangzhou Song1
doi : 10.18632/aging.203879
Volume 14, Issue 3 pp 1374—1388
The clinical prognosis of breast cancer is closely related to its infiltrating immune status. The study sought to explore tumor-infiltrating immune cells (TILs) and immune-associated genes in the tumor microenvironment of breast invasive carcinoma (BRCA). The ESTIMATE algorithm was used to evaluate the microenvironment of breast cancer patients in TCGA database. The tumor's matrix score and immune score were obtained. The median was divided into two sub groups according to the median of the score, and the correlation between the score and prognosis was also discussed. Differentially expressed genes were screened from two subgroups with high and low score of breast cancer, and the differentially expressed genes were analyzed by GO and KEGG enrichment to explore their possible molecular functions, biological processes, cellular components and signal pathways involved in gene enrichment. It was found that there was a significant correlation between immune score and five-year survival rate, and the high score group had a better prognosis. Macrophage M1 and T cell CD8+ cells were positively related to 5-year overall survival in patients with breast invasive carcinoma. However, Macrophage M2 was negatively related to 5-year overall survival. We also observed that the low expression of four genes (CLEC3A, MCTS1, PDP1 and TCP1,) was related to favorable survival outcomes. High expression of FOXP3, CXCL9, CCR5, CXCR3, and CD37 was related to a high overall survival rate in BRCA. We identified a list of immune – related cells and genes that are useful for Prognostic evaluation and individualized treatment of BRCA.
Sublethal heat treatment promotes breast cancer metastasis and its molecular mechanism revealed by quantitative proteomic analysis
Shujun Xia1, * , Xiaoyu Li1, * , Shangyan Xu1 , Xiaofeng Ni1 , Weiwei Zhan1 , Wei Zhou1,2
doi : 10.18632/aging.203884
Volume 14, Issue 3 pp 1389—1406
Radiofrequency ablation (RFA) is a frequently used thermal ablation technique for breast tumors. The study aimed to identify the effect of sublethal heat treatment on biological function of breast cancer cells and reveal its potential molecular mechanism. The expression profile of dysregulated proteins in sublethal heat treated breast cancer cells was analyzed by quantitative proteomic analysis. The differentially expressed proteins in the sublethal heat treated breast cancer were identified. The potential biological functions of these proteins were evaluated. The proliferation and invasion ability of breast cancer cells were enhanced after sublethal heat treatment. The expression profile of proteins in sublethal heat treated breast cancer cells was abundant, and most of which were newly discovered. A total of 206 differentially expressed proteins were identified. Among them, 101 proteins were downregulated while 105 proteins were upregulated. GO and KEGG analysis indicated that various systems were involved in the process of sublethal heat treatment including cancer, immune system, et al. Immunohistochemistry staining showed that the expression of Heat shock protein 1B, NOB1 and CRIP1 was highly expressed while the expression of BCLAF1 was lower in sublethal heat treated group. The proliferation and invasion ability of breast cancer cells were enhanced after sublethal heat treatment. Sublethal heat treatment caused gene alterations in cancer and immune system. Heat shock protein 1B, NOB1 and CRIP1 were upregulated while BCLAF1 was downregulated in breast cancer after sublethal heat treatment.
A web-based calculator for predicting the prognosis of patients with sarcoma on the basis of antioxidant gene signatures
Kun Quan1, * , Zhiyou Cao1, * , Qiang Xu1 , Meisong Zhu1 , Xuqiang Liu1 , Min Dai1
doi : 10.18632/aging.203885
Volume 14, Issue 3 pp 1407—1428
Background: Oxidative stress plays a critical role in tumorigenesis, tumor development, and resistance to therapy. A systematic analysis of the interactions between antioxidant gene expression and the prognosis of patients with sarcoma is lacking but urgently needed.
Identification and validation of an immune-related gene pairs signature for three urologic cancers
Biao Xie1 , Kangjie Li1 , Hong Zhang1 , Guichuan Lai1 , Dapeng Li2, & , Xiaoni Zhong1
doi : 10.18632/aging.203886
Volume 14, Issue 3 pp 1429—1447
Reliable biomarkers are needed to recognize urologic cancer patients at high risk for recurrence. In this study, we built a novel immune-related gene pairs signature to simultaneously predict recurrence for three urologic cancers. We gathered 14 publicly available gene expression profiles including bladder, prostate and kidney cancer. A total of 2,700 samples were classified into the training set (n = 1,622) and validation set (n = 1,078). The 25 immune-related gene pairs signature consisting of 41 unique genes was developed by the least absolute shrinkage and selection operator regression analysis and Cox regression model. The signature stratified patients into high- and low-risk groups with significantly different relapse-free survival in the meta-training set and its subpopulations, and was an independent prognostic factor of urologic cancers. This signature showed a robust ability in the meta-validation and multiple independent validation cohorts. Immune and inflammatory response, chemotaxis and cytokine activity were enriched with genes relevant to the signature. A significantly higher infiltration level of M1 macrophages was found in the high-risk group versus the low-risk group. In conclusion, our signature is a promising prognostic biomarker for predicting relapse-free survival in patients with urologic cancer.
Screening of antibacterial compounds with novel structure from the FDA approved drugs using machine learning methods
Wen-Xing Li1,2 , Xin Tong3 , Peng-Peng Yang3 , Yang Zheng3 , Ji-Hao Liang3 , Gong-Hua Li4 , Dahai Liu5 , Dao-Gang Guan1,2 , Shao-Xing Dai3
doi : 10.18632/aging.203887
Volume 14, Issue 3 pp 1448—1472
Bacterial infection is one of the most important factors affecting the human life span. Elderly people are more harmed by bacterial infections due to their deficits in immunity. Because of the lack of new antibiotics in recent years, bacterial resistance has increasingly become a serious problem globally. In this study, an antibacterial compound predictor was constructed using the support vector machines and random forest methods and the data of the active and inactive antibacterial compounds from the ChEMBL database. The results showed that both models have excellent prediction performance (mean accuracy >0.9 and mean AUC >0.9 for the two models). We used the predictor to screen potential antibacterial compounds from FDA-approved drugs in the DrugBank database. The screening results showed that 1087 small-molecule drugs have potential antibacterial activity and 154 of them are FDA-approved antibacterial drugs, which accounts for 76.2% of the approved antibacterial drugs collected in this study. Through molecular fingerprint similarity analysis and common substructure analysis, we screened 8 predicted antibacterial small-molecule compounds with novel structures compared with known antibacterial drugs, and 5 of them are widely used in the treatment of various tumors. This study provides a new insight for predicting antibacterial compounds by using approved drugs, the predicted compounds might be used to treat bacterial infections and extend lifespan.
Identification of an EMT-related lncRNA signature and LINC01116 as an immune-related oncogene in hepatocellular carcinoma
Haisu Tao1,2, *,# , Yuxin Zhang1,2, *,# , Tong Yuan1,2, *,# , Jiang Li1,2, *,# , Junjie Liu1,2 , Yixiao Xiong1,2 , Jinghan Zhu1,2 , Zhiyong Huang1,2 , Ping Wang3, & , Huifang Liang1,2 , Erlei Zhang1,2, &
doi : 10.18632/aging.203888
Volume 14, Issue 3 pp 1473—1491
Background: Epithelial–mesenchymal transition (EMT) plays a critical role in the recurrence and metastasis of hepatocellular carcinoma (HCC). Some long noncoding (lnc)RNAs are involved in this process through the regulation of EMT-related transcription factors.
Identification and validation of a twelve immune infiltration-related lncRNA prognostic signature for bladder cancer
Chen-Qian Liu1, * , Qi-Dong Xia1, * , Jian-Xuan Sun1 , Jin-Zhou Xu1 , Jun-Lin Lu1 , Zheng Liu1 , Jia Hu1 , Shao-Gang Wang1
doi : 10.18632/aging.203889
Volume 14, Issue 3 pp 1492—1507
The prognosis of bladder cancer patients is strongly related to both the immune-infiltrating cells and the expression of lncRNAs. In this study, we analyzed the infiltration of immune cells in 403 bladder cancer samples obtained from TCGA by applying the ssGSEA to these samples, then dividing them into high/low immune cell infiltration groups. Based on these groupings, we found 404 differentially expressed immune infiltration-related lncRNAs, which were successively analyzed by univariate Cox regression, then Least Absolute Shrinkage and Selection Operator (LASSO), and finally stepwise multiple Cox regression. Then 12 differentially expressed immune infiltration-related lncRNAs were identified and used to construct a prognostic signature for bladder cancer. Subsequently, Kaplan-Meier analysis, univariate Cox regression, multivariate Cox regression, and multivariate time-dependent ROC analyses (for 1, 3, 5 years) all revealed that this signature performed well in predicting overall survival and served as an independent prognostic factor for patients with bladder cancer. Finally, both TIMER and CIBESORT showed that this 12-lncRNA prognostic signature for bladder cancer was associated with the infiltration of immune cell subtypes. Besides, nomogram considered risk score and clinical characteristics was assembled and showed great performance. More importantly, we found our signature could well distinguish the drug response of patients with bladder cancer. High risk patients showed a better response to cisplatin, doxorubicin, and anti- CTLA4 immunotherapy, low risk patients showed a better response to methotrexate and anti-PD1 immunotherapy compared with each other.
Comprehensive bioinformatics analysis identifies LAPTM5 as a potential blood biomarker for hypertensive patients with left ventricular hypertrophy
Tiegang Li1 , Weiqi Wang1 , Wenqiang Gan1 , Silin Lv1 , Zifan Zeng1 , Yufang Hou1 , Zheng Yan1 , Rixin Zhang1 , Min Yang1
doi : 10.18632/aging.203894
Volume 14, Issue 3 pp 1508—1528
Left ventricular hypertrophy (LVH) is a pivotal manifestation of hypertensive organ damage associated with an increased cardiovascular risk. However, early diagnostic biomarkers for assessing LVH in patients with hypertension (HT) remain indefinite. Here, multiple bioinformatics tools combined with an experimental verification strategy were used to identify blood biomarkers for hypertensive LVH. GSE74144 mRNA expression profiles were downloaded from the Gene Expression Omnibus (GEO) database to screen candidate biomarkers, which were used to perform weighted gene co-expression network analysis (WGCNA) and establish the least absolute shrinkage and selection operator (LASSO) regression model, combined with support vector machine-recursive feature elimination (SVM-RFE) algorithms. Finally, the potential blood biomarkers were verified in an animal model. A total of 142 hub genes in peripheral blood leukocytes were identified between HT with LVH and HT without LVH, which were mainly involved in the ATP metabolic process, oxidative phosphorylation, and mitochondrial structure and function. Notably, lysosomal associated transmembrane protein 5 (LAPTM5) was identified as the potential diagnostic marker of hypertensive LVH, which showed strong correlations with diverse marker sets of reactive oxygen species (ROS) and autophagy. RT-PCR validation of blood samples and cardiac magnetic resonance imaging (CMRI) showed that the expression of LAPTM5 was significantly higher in the HT with LVH model than in normal controls, LAPTM5 demonstrated a positive association with the left ventricle wall thickness as well as electrocardiogram (ECG) parameters widths of the QRS complex and QTc interval. In conclusion, LAPTM5 may be a potential biomarker for the diagnosis of LVH in patients with HT, and it can provide new insights for future studies on the occurrence and the molecular mechanisms of hypertensive LVH.
Construction and validation of a prognostic risk model of angiogenesis factors in skin cutaneous melanoma
Songyun Zou1, * , Yonggang Zhang2, * , Limei Zhang3, * , Dengchuan Wang4 , Shi Xu1
doi : 10.18632/aging.203895
Volume 14, Issue 3 pp 1529—1548
Melanoma can secrete tumor angiogenesis factors, which is the essential factor for tumor growth and metastasis. However, there are few reports on the relationship between angiogenesis factors and prognosis risk in melanoma. This study aimed to develop a prognostic risk model of angiogenesis for melanoma. Forty-nine differentially expressed angiogenesis were identified from the TCGA database, which were mainly involved in PI3K/Akt pathway, focal adhesion, and MAPK signaling pathway. We then establish an eleven-gene signature. The model indicated a strong prognostic capability in both the discovery cohort and the validation cohort. Patients of smaller height (<170 cm) and lower weight (<80 kg) and those with advanced-stage and ulcerated melanoma had higher risk scores. The risk score was positively correlated with mutation load, homologous recombination defect, neoantigen load and chromosome instability. In addition, the high-risk group had a higher degree of immune cell infiltration, better response to immunotherapy and lower immune score. Therefore, these results indicate that the risk model is an effective method to predict the prognosis of melanoma.
Cholesterol metabolism in aging simultaneously altered in liver and nervous system
Valéria Sutti Nunes1 , Guilherme da Silva Ferreira1 , Eder Carlos Rocha Quintão1
doi : 10.18632/aging.203880
Volume 14, Issue 3 pp 1549—1561
In humans, aging, triggers increased plasma concentrations of triglycerides, cholesterol, low-density lipoproteins and lower capacity of high-density lipoproteins to remove cellular cholesterol. Studies in rodents showed that aging led to cholesterol accumulation in the liver and decrease in the brain with reduced cholesterol synthesis and increased levels of cholesterol 24-hydroxylase, an enzyme responsible for removing cholesterol from the brain. Liver diseases are also related to brain aging, inducing changes in cholesterol metabolism in the brain and liver of rats. It has been suggested that late onset Alzheimer’s disease is associated with metabolic syndrome. Non-alcoholic fatty liver is associated with lower total brain volume in the Framingham Heart Study offspring cohort study. Furthermore, disorders of cholesterol homeostasis in the adult brain are associated with neurological diseases such as Niemann-Pick, Alzheimer, Parkinson, Huntington and epilepsy. Apolipoprotein E (apoE) is important in transporting cholesterol from astrocytes to neurons in the etiology of sporadic Alzheimer’s disease, an aging-related dementia. Desmosterol and 24S-hydroxycholesterol are reduced in ApoE KO hypercholesterolemic mice. ApoE KO mice have synaptic loss, cognitive dysfunction, and elevated plasma lipid levels that can affect brain function. In contrast to cholesterol itself, there is a continuous uptake of 27- hydroxycholesterol in the brain as it crosses the blood-brain barrier and this flow can be an important link between intra- and extracerebral cholesterol homeostasis. Not surprisingly, changes in cholesterol metabolism occur simultaneously in the liver and nervous tissues and may be considered possible biomarkers of the liver and nervous system aging.
The neuroprotective effects of icariin on ageing, various neurological, neuropsychiatric disorders, and brain injury induced by radiation exposure
Ling Rui Li1, * , Gautam Sethi2, * , Xing Zhang1 , Cui Liu Liu1 , Yan Huang1 , Qun Liu1 , Bo Xu Ren1 , Feng Ru Tang3
doi : 10.18632/aging.203893
Volume 14, Issue 3 pp 1562—1588
Epimedium brevicornum Maxim, a Traditional Chinese Medicine, has been used for the treatment of impotence, sinew and bone disorders, “painful impediment caused by wind-dampness,� numbness, spasms, hypertension, coronary heart disease, menopausal syndrome, bronchitis, and neurasthenia for many years in China. Recent animal experimental studies indicate that icariin, a major bioactive component of epimedium may effectively treat Alzheimer’s disease, cerebral ischemia, depression, Parkinson’s disease, multiple sclerosis, as well as delay ageing. Our recent study also suggested that epimedium extract could exhibit radio-neuro-protective effects and prevent ionizing radiation-induced impairment of neurogenesis. This paper reviewed the pharmacodynamics of icariin in treating different neurodegenerative and neuropsychiatric diseases, ageing, and radiation-induced brain damage. The relevant molecular mechanisms and its anti-neuroinflammatory, anti-apoptotic, anti-oxidant, as well as pro-neurogenesis roles were also discussed.
Correction for: microRNA-363-3p reduces endothelial cell inflammatory responses in coronary heart disease via inactivation of the NOX4-dependent p38 MAPK axis
Tao Zhou1 , Suining Li1 , Liehong Yang1 , Daokang Xiang1
doi : 10.18632/aging.203865
Volume 14, Issue 3 pp 1589
Correction for: Tomatidine suppresses inflammation in primary articular chondrocytes and attenuates cartilage degradation in osteoarthritic rats
Xiangyu Chu1, * , Tao Yu2, * , Xiaojian Huang1 , Yang Xi1 , Bowei Ni1 , Rui Zhang1 , Hongbo You1
doi : 10.18632/aging.203892
Volume 14, Issue 3 pp 1590—1591
