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Epigenetic regulation of drug metabolism in aging
doi : 10.18632/aging.203312
Volume 13, Issue 13 pp 16898—16899
Cognitive management in a digital world
doi : 10.18632/aging.203324
Volume 13, Issue 13 pp 16900—16901
Prognostic and immunological value of ATP6AP1 in breast cancer: implications for SARS-CoV-2
Jintian Wang1 , Yunjiang Liu1 , Shuo Zhang1
doi : 10.18632/aging.203229
Volume 13, Issue 13 pp 16904—16921
Abnormal ATPase H+ Transporting Accessory Protein 1 (ATP6AP1) expression may promote carcinogenesis. We investigated the association of ATP6AP1 with breast cancer (BC) and COVID-19. The Oncomine, Gene Expression Profiling Interactive Analysis, Human Protein Atlas and Kaplan-Meier plotter databases were used to evaluate the expression and prognostic value of ATP6AP1 in BC. ATP6AP1 was upregulated in BC tissues, and higher ATP6AP1 expression was associated with poorer outcomes. Data from the Tumor Immune Estimation Resource, Tumor-Immune System Interaction Database and Kaplan-Meier plotter indicated that ATP6AP1 expression correlated with immune infiltration, and that its prognostic effects in BC depended on tumor-infiltrating immune cell subtype levels. Multiple databases were used to evaluate the association of ATP6AP1 with clinicopathological factors, assess the mutation and methylation of ATP6AP1, and analyze gene co-expression and enrichment. The ATP6AP1 promoter was hypomethylated in BC tissues and differentially methylated between different disease stages and subtypes. Data from the Gene Expression Omnibus indicated that ATP6AP1 levels in certain cell types were reduced after SARS-CoV-2 infections. Ultimately, higher ATP6AP1 expression was associated with a poorer prognosis and with higher or lower infiltration of particular immune cells in BC. BC patients may be particularly susceptible to SARS-CoV-2 infections, which may alter their prognoses.
A model of the aged lung epithelium in idiopathic pulmonary fibrosis
Hoora Shaghaghi1, * , Karina Cuevas-Mora1, * , Rachel Para1 , Cara Tran1 , Willy Roque2 , Matthew J. Robertson3 , Ivan O. Rosas3 , Ross Summer1 , Freddy Romero3
doi : 10.18632/aging.203291
Volume 13, Issue 13 pp 16922—16937
Idiopathic pulmonary fibrosis (IPF) is an age-related disorder that carries a universally poor prognosis and is thought to arise from repetitive micro injuries to the alveolar epithelium. To date, a major factor limiting our understanding of IPF is a deficiency of disease models, particularly in vitro models that can recapitulate the full complement of molecular attributes in the human condition. In this study, we aimed to develop a model that more closely resembles the aberrant IPF lung epithelium. By exposing mouse alveolar epithelial cells to repeated, low doses of bleomycin, instead of usual one-time exposures, we uncovered changes strikingly similar to those in the IPF lung epithelium. This included the acquisition of multiple phenotypic and functional characteristics of senescent cells and the adoption of previously described changes in mitochondrial homeostasis, including alterations in redox balance, energy production and activity of the mitochondrial unfolded protein response. We also uncovered dramatic changes in cellular metabolism and detected a profound loss of proteostasis, as characterized by the accumulation of cytoplasmic protein aggregates, dysregulated expression of chaperone proteins and decreased activity of the ubiquitin proteasome system. In summary, we describe an in vitro model that closely resembles the aberrant lung epithelium in IPF. We propose that this simple yet powerful tool could help uncover new biological mechanisms and assist in developing new pharmacological tools to treat the disease.
Macrophage phenotype and function are dependent upon the composition and biomechanics of the local cardiac tissue microenvironment
Martin Haschak1,2 , Samuel LoPresti1,2 , Elizabeth Stahl1,3 , Siddhartha Dash1,4 , Branimir Popovich1 , Bryan N. Brown1,2,5,6
doi : 10.18632/aging.203054
Volume 13, Issue 13 pp 16938—16956
Macrophage accumulation and nitrosative stress are known mechanisms underlying age-related cardiovascular pathology and functional decline. The cardiac muscle microenvironment is known to change with age, yet the direct effects of these changes have yet to be studied in-depth. The present study sought to better elucidate the role that biochemical and biomechanical alterations in cardiac tissue have in the altered phenotype and functionality of cardiac resident macrophages observed with increasing age. To accomplish this, naïve bone marrow derived macrophages from young mice were seeded onto either functionalized poly-dimethyl-siloxane hydrogels ranging in stiffness from 2kPA to 64kPA or onto tissue culture plastic, both of which were coated with either young or aged solubilized mouse cardiac extracellular matrix (cECM). Both biomechanical and biochemical alterations were found to have a significant effect on macrophage polarization and function. Increased substrate stiffness was found to promote macrophage morphologies associated with pro-inflammatory macrophage activation, increased expression of pro-inflammatory inducible nitric oxide synthase protein with increased nitric oxide secretion, and attenuated arginase activity and protein expression. Additionally, exposure to aged cECM promoted attenuated responsivity to both canonical pro-inflammatory and anti-inflammatory cytokine signaling cues when compared to young cECM treated cells. These results suggest that both biomechanical and biochemical changes in the cardiovascular system play a role in promoting the age-related shift towards pro-inflammatory macrophage populations associated with cardiovascular disease development.
The dual distinct role of telomerase in repression of senescence and myofibroblast differentiation
Masanori Harada1,2 , Biao Hu1 , Jeffrey Lu1 , Jing Wang1,3 , Andrew E. Rinke1 , Zhe Wu1 , Tianju Liu1 , Sem H. Phan1
doi : 10.18632/aging.203246
Volume 13, Issue 13 pp 16957—16973
Many aging related diseases such as cancer implicate the myofibroblast in disease progression. Furthermore genesis of the myofibroblast is associated with manifestation of cellular senescence of unclear significance. In this study we investigated the role of a common regulator, namely telomerase reverse transcriptase (TERT), in order to evaluate the potential significance of this association between both processes. We analyzed the effects of TERT overexpression or deficiency on expression of CDKN2A and ACTA2 as indicators of senescence and differentiation, respectively. We assess binding of TERT or YB-1, a repressor of both genes, to their promoters. TERT repressed both CDKN2A and ACTA2 expression, and abolished stress-induced expression of both genes. Conversely, TERT deficiency enhanced their expression. Altering CDKN2A expression had no effect on ACTA2 expression. Both TERT and YB-1 were shown to bind the CDKN2A promoter but only YB-1 was shown to bind the ACTA2 promoter. TERT overexpression inhibited CDKN2A promoter activity while stimulating YB-1 expression and activation to repress ACTA2 gene. TERT repressed myofibroblast differentiation and senescence via distinct mechanisms. The latter was associated with TERT binding to the CDKN2A promoter, but not to the ACTA2 promoter, which may require interaction with co-factors such as YB-1.
The risk of Alzheimer’s disease according to dynamic changes in metabolic health and obesity: a nationwide population-based cohort study
Yun Kyung Cho1 , Jiwoo Lee2 , Hwi Seung Kim2 , Joong-Yeol Park2 , Woo Je Lee2 , Ye-Jee Kim3 , Chang Hee Jung2
doi : 10.18632/aging.203255
Volume 13, Issue 13 pp 16974—16989
We evaluated the association of metabolic health and obesity phenotypes with the risk of Alzheimer’s disease (AD).
Sex differences in genetic and environmental influences on frailty and its relation to body mass index and education
Jonathan K. L. Mak1 , Chandra A. Reynolds2 , Sara H?gg1 , Xia Li1 , Malin Ericsson1,3 , Nancy L. Pedersen1 , Juulia Jylh?v?1 , Ralf Kuja-Halkola1
doi : 10.18632/aging.203262
Volume 13, Issue 13 pp 16990—17023
Frailty is influenced by numerous genetic and environmental factors. However, sex differences in how these factors affect frailty, and the gene-environment interplay among frailty and two of its well-established risk factors, unhealthy body mass index (BMI) and low education, are less clear. In a large sample of 42,994 Swedish twins, we used structural equation models to estimate the genetic (heritability) and environmental sources of variance in frailty, defined as the frailty index (FI), separately in men and women. Genetic and individual-specific environmental factors contributed approximately equally to the FI variance. The heritability of FI was slightly, but significantly, higher in women (52%) than in men (45%), yet we found only weak-to-no indication of different sources of genetic variance influencing frailty across sexes. We observed a small-to-moderate genetic overlap between FI and BMI, and that the correlation between FI and education was largely explained by environmental factors common to twins in a pair. Additionally, genetic factors accounted for more of FI variation at both low and high BMI levels, with similar patterns in both sexes. In conclusion, the twin-based heritability of frailty is higher in women than in men, and different mechanisms may underlie the associations of frailty with BMI and education.
Prevalence and predictors of subclinical atrial fibrillation in hospitalized older adults
Francesco Spannella1,2 , Federico Giulietti1,2 , Lorenzo Pimpini3 , Francesca Elena Lombardi1,2 , Serena Re1,2 , Paola Schiavi1,2 , Gina Dragano1 , Roberto Antonicelli3 , Riccardo Sarzani1,2
doi : 10.18632/aging.203270
Volume 13, Issue 13 pp 17024—17037
Subclinical atrial fibrillation (SCAF) is associated with an increased risk of clinical AF, major cardiovascular events and death. Short-term evidence on SCAF in older populations is scarce, especially in the hospital setting. We performed a cross-sectional study on 60 multimorbid older consecutive patients (aged 80+) admitted to an Internal Medicine and Geriatrics Unit for acute medical diseases with no history of AF, in order to investigate prevalence and predictors of SCAF. Portable ECG monitoring was placed on admission and ECG recording lasted for 5 days. Mean age: 85.7±4.9 years. Female prevalence: 58.3%. High burden of comorbidities: 87.9%. All enrolled patients had CHA2DS2-VASc score ?3. SCAF was detected in 16 patients (26.7%) and 11 patients (18.4%) had at least a SCAF episode lasting 6 minutes or longer. No clinical, laboratory and echocardiographic parameters predicted SCAF. Patients with ?2004 supraventricular ectopic beats/24h (SVEBs/24h) had a 6-fold higher prevalence of SCAF than patients with <411 SVEBs/24h (p=0.038). Time to first SCAF episode was within 3 days of ECG recording in all enrolled patients. SCAF is highly prevalent in older adults hospitalized for acute diseases. This finding may affect clinical management and prognosis. Our study could foster larger multicenter studies in similar settings.
Lifetime depression and age-related changes in body composition, cardiovascular function, grip strength and lung function: sex-specific analyses in the UK Biobank
Julian Mutz1 , Cathryn M. Lewis1,2
doi : 10.18632/aging.203275
Volume 13, Issue 13 pp 17038—17079
Individuals with depression, on average, die prematurely, have high levels of physical comorbidities and may experience accelerated biological ageing. A greater understanding of age-related changes in physiology could provide novel biological insights that may help inform strategies to mitigate excess mortality in depression. We used generalised additive models to examine age-related changes in 15 cardiovascular, body composition, grip strength and lung function measures, comparing males and females with a lifetime history of depression to healthy controls. The main dataset included 342,393 adults (mean age = 55.87 years, SD = 8.09; 52.61% females). We found statistically significant case-control differences for most physiological measures. There was some evidence that age-related changes in body composition, cardiovascular function, lung function and heel bone mineral density followed different trajectories in depression. These differences did not uniformly narrow or widen with age and differed by sex. For example, BMI in female cases was 1.1 kg/m2 higher at age 40 and this difference narrowed to 0.4 kg/m2 at age 70. In males, systolic blood pressure was 1 mmHg lower in depression cases at age 45 and this difference widened to 2.5 mmHg at age 65. These findings suggest that targeted screening for physiological function in middle-aged and older adults with depression is warranted to potentially mitigate excess mortality.
Joint trajectories of episodic memory and odor identification in older adults: patterns and predictors
Christina S. Dintica1 , Miriam L. Haaksma2 , Jonas K. Olofsson3 , David A. Bennett4, * , Weili Xu1,5, *
doi : 10.18632/aging.203280
Volume 13, Issue 13 pp 17080—17096
Emerging evidence suggests that olfactory function is closely linked to memory function. The aims of this study were to assess whether olfactory and episodic memory functions follow similar age-related decline trajectories, to identify different patterns of decline, as well as predictors of the patterns.
Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43
Paul Dent1 , Laurence Booth1 , Jane L. Roberts2 , Andrew Poklepovic3 , Derek Cridebring4 , Eric M. Reiman4,5
doi : 10.18632/aging.203297
Volume 13, Issue 13 pp 17097—17117
Aberrant expression and denaturation of Tau, amyloid-beta and TDP-43 can lead to cell death and is a major component of pathologies such as Alzheimer’s Disease (AD). AD neurons exhibit a reduced ability to form autophagosomes and degrade proteins via autophagy. Using genetically manipulated colon cancer cells we determined whether drugs that directly inhibit the chaperone ATPase activity or cause chaperone degradation and endoplasmic reticulum stress signaling leading to macroautophagy could reduce the levels of these proteins. The antiviral chaperone ATPase inhibitor AR12 reduced the ATPase activities and total expression of GRP78, HSP90, and HSP70, and of Tau, Tau 301L, APP, APP692, APP715, SOD1 G93A and TDP-43. In parallel, it increased the phosphorylation of ATG13 S318 and eIF2A S51 and caused eIF2A-dependent autophagosome formation and autophagic flux. Knock down of Beclin1 or ATG5 prevented chaperone, APP and Tau degradation. Neratinib, used to treat HER2+ breast cancer, reduced chaperone levels and expression of Tau and APP via macroautophagy, and neratinib interacted with AR12 to cause further reductions in protein levels. The autophagy-regulatory protein ATG16L1 is expressed as two isoforms, T300 or A300: Africans trend to express T300 and Europeans A300. We observed higher basal expression of Tau in T300 cells when compared to isogenic A300 cells. ATG16L1 isoform expression did not alter basal levels of HSP90, HSP70 or HSP27, however, basal levels of GRP78 were reduced in A300 cells. The abilities of both AR12 and neratinib to stimulate ATG13 S318 and eIF2A S51 phosphorylation and autophagic flux was also reduced in A300 cells. Our data support further evaluation of AR12 and neratinib in neuronal cells as repurposed treatments for AD.
Human adipose-derived stem cells promote seawater-immersed wound healing via proangiogenic effects
Jiachao Xiong1, * , Hong Qiang2, * , Ting Li2, * , Jiayi Zhao3, * , Ziyu Wang3 , Fei Li4 , Jianwen Xu5
doi : 10.18632/aging.202773
Volume 13, Issue 13 pp 17118—17136
Seawater immersion can increase the damage to skin wounds and produce chronic wounds, and the application of human adipose-derived stem cells can significantly promote healing. However, the mechanism underlying angiogenesis is currently unclear. In this study, we investigated the vascularization effect of human adipose-derived stem cells on the repair of seawater-treated skin wounds and explored the underlying mechanisms using bioinformatics. The results showed that human adipose-derived stem cells differentiated into vascular endothelial cells and promoted seawater-immersed wound vascularization by promoting vascular endothelial cell proliferation and migration. The differentially expressed genes between human adipose-derived stem cells and fibroblasts were identified and analyzed (including via gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment, protein–protein interaction network, and correlation analyses). The genes may promote wound healing by regulating the mechanisms of extracellular matrix remodeling, programmed cell death, inflammation, and vascularization. In conclusion, this study provides novel insights into the use of human adipose-derived stem cells in the regeneration of seawater-immersed skin wounds and chronic wounds.
Machine-intelligence for developing a potent signature to predict ovarian response to tailor assisted reproduction technology
Sisi Yan1, * , Wenyi Jin2, * , Jinli Ding1, * , Tailang Yin1 , Yi Zhang1, * , Jing Yang1
doi : 10.18632/aging.203032
Volume 13, Issue 13 pp 17137—17154
The prediction of poor ovarian response (POR) for stratified interference is a critical clinical issue that has received an increasing amount of recent concern. Anthropogenic diagnostic modes remain too simple for the handling of actual clinical complexity. Therefore, this study conducted extensive selection using models that were derived from a variety of machine learning algorithms, including random forest (RF), decision trees, eXtreme Gradient Boosting (XGBoost), support vector machine (SVM), and artificial neural networks (ANN) for the development of two models called the COS pre-launch model (CPLM) and the hCG pre-trigger model (HPTM) to assess POR based on different requirements. The results demonstrated that CPLM constructed using ANN achieved the highest AUC result of all the algorithms in COS pre-launch (AUC=0.859, C-index=0.87, good calibration), and HPTL constructed using random forest was found to be the most effective in hCG pre-trigger (AUC=0.903, C-index=0.90, good calibration). It is notable that CPLM and HPTM exhibited better performance than common clinical characteristics (0.895 [CPLM], and 0.903 [HPTM] in comparison to 0.824 [anti-Müllerian hormone (AMH)], and 0.799 [antral follicle count (AFC)]). Furthermore, variable importance figure elucidated the values of AMH, AFC, and E2 level and follicle number on hCG day, which provides important theoretical guidance and experimental data for further application. Generally, the CPLM and HPTM can offer effective POR prediction for patients who are receiving assisted reproduction technology (ART), and has great potential for guiding the clinical treatment of infertility.
Hypoxia induces chemoresistance of esophageal cancer cells to cisplatin through regulating the lncRNA-EMS/miR-758-3p/WTAP axis
Zi-Jiang Zhu1, * , Yao Pang1, * , Gang Jin1 , Hong-Yi Zhang1 , Wen-Hao Wang1 , Jia-Wei Liu1 , Guang-Xin Tuo2 , Peng Wu2 , Yi Yang2 , Ze-Quan Wang3 , Kui Wang3
doi : 10.18632/aging.203062
Volume 13, Issue 13 pp 17155—17176
Hypoxia contributes significantly to the development of chemoresistance of many malignancies including esophageal cancer (EC). Accumulating studies have indicated that long non-coding RNAs play important roles in chemotherapy resistance. Here, we identified a novel lncRNA-EMS/miR-758-3p/WTAP axis that was involved in hypoxia-mediated chemoresistance to cisplatin in human EC. Hypoxia induced the expressions of lncRNA EMS and WTAP, and reduced the expression of miR-758-3p in EC cell line ECA-109. In addition, the expressions of EMS and WTAP were required for the hypoxia-induced drug resistance to cisplatin in EC cells, while overexpression of miR-758-3p reversed such chemoresistance. The targeting relationships between EMS and miR-758-3p, as well as miR-758-3p and WTAP, were verified by luciferase-based reporter assays and multiple quantitative assays after gene overexpression/knockdown. Moreover, we found significant correlations between tumor expressions of these molecules. Notably, higher levels of EMS/WTAP, or lower levels of miR-758-3p in tumors predicted worse survivals of EC patients. Furthermore, in a xenograft mouse model, targeted knockdown of EMS and WTAP in ECA-109 cells markedly attenuated the resistance of tumors to cisplatin treatments. Our study uncovers a critical lncRNA-EMS/miR-758-3p/WTAP axis in regulating hypoxia-mediated drug resistance to cisplatin in EC.
Carbon nanotubes (CNT)-loaded ginsenosides Rb3 suppresses the PD-1/PD-L1 pathway in triple-negative breast cancer
Xiao Luo1 , Hui Wang2 , Degang Ji3
doi : 10.18632/aging.203131
Volume 13, Issue 13 pp 17177—17189
Carbon nanotubes (CNTs), as advanced nanotechnology with specific properties and structures, have presented practical drug delivery properties. Ginsenoside Rg3 is a component of puffed ginseng and demonstrates anti-cancer activities. To explore the effect of CNTs-loaded Rg3 (Rg3-CNT) on the PD-1/PD-L1 signaling and the development of triple-negative breast cancer (TNBC). Our data revealed that Rg3 inhibited the cell viability of TNBC cells, in which Rg3-CNT further enhanced this effect in the system. Similarly, the colony formation of TNBC cells was decreased by Rg3, while Rg3-CNT could reinforce its effect in the cells. Besides, the treatment of Rg3 induced apoptosis of TNBC cells, in which Rg3-CNT treatment further increased the phenotype in the cells. Remarkably, Rg3-CNT, but not Rg3, attenuated PD-L1 expression in TNBC cells. Rg3-CNT decreased the PD-L1 upregulation induced by interferon-? (IFN-?) in breast cancer cells. Importantly, Rg3-CNT was able to reduce PD-1 expression in activated T cells. Specifically, Rg3-CNT reduced the PD-1/PD-L1 axis in a T cell/triple-negative TNBC cell co-culture system. Moreover, the levels of IFN-?, interleukins-2 (IL-2), interleukins-9 (IL-9), interleukins-10 (IL-10), interleukins-22 (IL-22), and interleukins-23 (IL-23) were significantly stimulated in the activated T cells, while the treatment of Rg3-CNT could reverse these phenotypes in the cells. Rg3-CNT attenuated the TNBC cell growth in vivo. The Rg3-CNT improved the anti-cancer effect of Rg3 toward TNBC by inhibiting the PD-1/PD-L1 axis. Our finding provides new insights into the mechanism by which Rg3-CNT attenuates the development of TNBC. Rg3-CNT may be applied as the potential therapeutic strategy for immunotherapy of TNBC.
miR-424-5p shuttled by bone marrow stem cells-derived exosomes attenuates osteogenesis via regulating WIF1-mediated Wnt/?-catenin axis
Yongkun Wei1, * , Huiling Ma2, * , Haiqing Zhou1 , Hanrong Yin1 , Jie Yang1 , Yongcai Song1 , Binhui Yang1, &
doi : 10.18632/aging.203169
Volume 13, Issue 13 pp 17190—17201
Emerging evidence proves that exosomes contain specific microRNAs(miRNAs) contribute to osteogenic differentiation of bone marrow stem cells (BMSCs). However, the role and mechanism of bone marrow stem cells (BMSCs)-derived exosomes overexpressing miR-424-5p in osteoblasts remains unclear. Firstly, the BMSCs-derived exosomes were isolated, and identified by Western blot with the exosome surface markers CD9, CD81 and CD63. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to detect the level of miR-424-5p in exosomes, and western blot was implemented to verify the WIF1/Wnt/?-catenin expression. The binding association between miR-424-5p and WIF1 was determined by the dual-luciferase reporter gene assay. Functional enhancement experiments were adopted to determine the role of exosome-carried miR-424-5p and WIF1/Wnt/?-catenin in osteogenic differentiation. ALP staining was adopted, and levels of RUNX2, OCN, and OPN were monitored using qRT-PCR to determine osteogenic differentiation. As a result, In vivo experiments showed that RUNX2, OCN and OPN levels decreased and the ALP activity was dampened after miR-424-5p overexpression in exosomes. Besides, exosomes overexpressing miR-424-5p attenuated osteogenic development via WIF1/Wnt/?-catenin. Our findings may bring evidence for miR-424-5p as a new biomarker for the treatment of osteoporosis.
Zhoushi Qiling decoction induces apoptosis of human prostate cancer cells via miR-143/Bcl-2 axis
Hongwen Cao1, * , Dan Wang1, * , Renjie Gao1, * , Lei Chen1 , Yigeng Feng1 , Dongwen Gao2
doi : 10.18632/aging.203171
Volume 13, Issue 13 pp 17202—17210
A number of traditional Chinese medicines (TCMs) are widely used in prostate cancer treatment in China. The aim of this study was to test the efficacy of a TCM, Zhoushi Qiling Decoction (ZQD), in combination with androgen deprivation therapy (ADT) and explore its underlying mechanism. A total of 151 patients were recruited to receive ADT treatment or ADT+ZQD treatment. The survival of patients who received ADT+ZQD treatment was significantly higher than those who received ADT therapy only. DU145 prostate cancer cells were treated with ZQD (50 mg/mL) for 24 h in vitro and expression levels of an array of miRNAs were examined. Our results suggested that miR-143 demonstrated prominent upregulation in DU145 cells after treatment with ZQD. In patient serum samples, miR-143 expression was also significantly upregulated after ADT+ZQE treatment, which was however absent in patients treated with ADT only. In DU145 cells, ZQD treatment led to a dose-dependent increase in apoptosis, which could be reduced by anti-miR-143 treatment. There was a binding site between miR-143 and B cell CLL/lymphoma-2 (Bcl-2) and ZQD treatment reduced Bcl-2 expression. ZQD treatment led to increased caspase-3 and Bax expression. ZQD treatment could promote apoptosis of prostate cancer cells by promoting miR-143 upregulation, which could be a possible mechanism underlying the inhibitory effect of ZQD in prostate cancer in patient.
Effects of long-term low dose saxitoxin exposure on nerve damage in mice
Qian Sun1,2, * , Xiao Chen1, * , Wei Liu1, * , Shenpan Li1,2, * , Yan Zhou1 , Xingfen Yang2 , Jianjun Liu1
doi : 10.18632/aging.203199
Volume 13, Issue 13 pp 17211—17226
Saxitoxin (STX), as a type of paralytic shellfish poisoning (PSP), is gaining widespread attention due to its long existence in edible shellfish. However, the mechanism underlying STX chronic exposure-induced effect is not well understood. Here, we evaluated the neurotoxicity effects of long-term low-dose STX exposure on C57/BL mice by behavioral tests, pathology analysis, and hippocampal proteomics analysis. Several behavioral tests showed that mice were in a cognitive deficiency after treated with 0, 0.5, 1.5, or 4.5 ?g STX equivalents/kg body weight in the drinking water for 3 months. Compared with control mice, STX-exposed mice exhibited brain neuronal damage characterized by decreasing neuronal cells and thinner pyramidal cell layers in the hippocampal CA1 region. A total of 29 proteins were significantly altered in different STX dose groups. Bioinformatics analysis showed that protein phosphatase 1 (Ppp1c) and arylsulfatase A (Arsa) were involved in the hippo signaling pathway and sphingolipid metabolism pathway. The decreased expression of Arsa indicates that long-term low doses of STX exposure can cause neuronal inhibition, which is a process related to spatial memory impairment. Taken together, our study provides a new understanding of the molecular mechanisms of STX neurotoxicity.
miR-let-7c-5p and miR-149-5p inhibit proinflammatory cytokine production in osteoarthritis and rheumatoid arthritis synovial fibroblasts
Yat-Yin Law1,2 , Wei-Fang Lee3 , Chin-Jung Hsu4,5 , Yen-You Lin6 , Chun-Hao Tsai5,7 , Chien-Chung Huang6,8 , Min-Huan Wu9,10 , Chih-Hsin Tang6,11,12 , Ju-Fang Liu13
doi : 10.18632/aging.203201
Volume 13, Issue 13 pp 17227—17236
Osteoarthritis (OA) and rheumatoid arthritis (RA) are two of the most common types of arthritis. Both are characterized by the infiltration of a number of proinflammatory cytokines into the joint microenvironment. miRNAs play critical roles in the disease processes of arthritic disorders. However, little is known about the effects of miRNAs on critical inflammatory cytokine production with OA and RA progression. Here, we found higher levels of proinflammatory cytokines including interleukin 1 beta (IL-1?), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-?) in human OA and RA synovial fibroblasts (SFs) compared with normal SFs. Searches of open-source microRNA (miRNA) software determined that miR-let-7c-5p and miR-149-5p interfere with IL-1?, IL-6 and TNF-? transcription; levels of all three proinflammatory cytokines were lower in human OA and RA patients compared with normal controls. Anti-inflammatory agents dexamethasone, celecoxib and indomethacin reduced proinflammatory cytokine production by promoting the expression of miR-let-7c-5p and miR-149-5p. Similarly, ibuprofen and methotrexate also enhanced miR-let-7c-5p and miR-149-5p expression in human SFs. The evidence suggests that increasing miR-let-7c-5p and miR-149-5p expression is a novel strategy for OA and RA.
Association between Alzheimer’s disease genes and trajectories of cognitive function decline in Han Chinese in Taiwan
Tsung-Jen Hsieh1,2, * , Wei-Ju Lee3,4,5,6,7, * , Yi-Chu Liao4,7,8 , Chih-Cheng Hsu1 , Yao-Hwei Fang1 , Tzu-Yu Chen1 , Yung-Shuan Lin4,8 , I-Shou Chang9 , Shuu-Jiun Wang4,7,8 , Chao A. Hsiung1 , Jong-Ling Fuh4,7,8 , Alzheimer’s Disease Neuroimaging Initiative #
doi : 10.18632/aging.203204
Volume 13, Issue 13 pp 17237—17252
Genetic background has been considered one of the important contributors to the rate of cognitive decline among patients with Alzheimer’s disease (AD). We conducted a 4-year longitudinal follow-up study, recruited 255 AD and 44 mild cognitive impairment (MCI) patients, and used a data-driven trajectory analysis to examine the influence of selected AD risk genes on the age for and the rate of cognitive decline in Han Chinese population. Genotyping of selected single-nucleotide polymorphisms in the APOE, ABCA7, SORL1, BIN1, GAB2, and CD33 genes was conducted, and a Bayesian hierarchical model was fitted to analyze the trajectories of cognitive decline among different genotypes. After adjusting for sex and education years, the APOE ?4 allele was associated with an earlier mean change of ?2.39 years in the age at midpoint of cognitive decline, the G allele in ABCA7 rs3764650 was associated with an earlier mean change of ?1.75 years, and the T allele in SORL1 rs3737529 was associated with a later mean change of 2.6 years. Additionally, the rate of cognitive decline was associated with the APOE ?4 allele and SORL1 rs3737529. In summary, APOE and SORL1 might be the most important genetic factors related to cognitive decline in Han Chinese population.
Association between mean platelet volume and pulmonary embolism: a systematic review and meta-analysis
Wenyi Lin1, * , Yu Wu2, * , Xuan Lu1 , Yu Hu1
doi : 10.18632/aging.203205
Volume 13, Issue 13 pp 17253—17273
Platelet activation plays an important role in the progression of pulmonary embolism (PE). Mean platelet volume (MPV) can serve as a marker of platelet activity in patients with PE. Many studies have reported different results regarding the relationship. Therefore, we aimed to perform a systematic review and meta-analysis to evaluate the relationship between MPV and PE. Two reviewers independently searched relevant articles in databases from inception to April 21, 2021 and identified all studies on MPV and PE as the outcomes of interest. Further, we selected studies meeting the criteria and extracted the data. Of the 2505 publications identified, we included 18 studies after screening. Results showed MPV was significantly higher in patients with PE (0.83 fL, 95% CI: 0.38-1.28, P<0.001) than in controls. The mean difference in MPV between those who died and survivors of PE was 1.23 fL (95% CI: 0.96-1.51, P<0.001). Hence, an increased MPV is associated with PE. MPV could be a useful tool to predict the occurrence and death risk of PE together with other risk factors.
Circ_0081001 down-regulates miR-494-3p to enhance BACH1 expression and promotes osteosarcoma progression
Shizhang Liu1 , Keke Duan1 , Xiaoxia Zhang1 , Xiane Cao2 , Xixia Wang3 , Fanbin Meng2 , Huitong Liu1 , Bingqiang Xu1 , Xi Wang1
doi : 10.18632/aging.203207
Volume 13, Issue 13 pp 17274—17284
The study was aimed at deciphering the function and mechanism of circ_0081001 in osteosarcoma (OS). In this study, quantitative real-time polymerase chain reaction (qRT-PCR) was utilized for quantifying circ_0081001, miR-494-3p, and BTB domain and CNC homolog 1 (BACH1) mRNA expressions in OS tissues and cells. Cell counting kit-8 (CCK-8) assay, together with 5-Ethynyl-2'-deoxyuridine (EdU) assay, was performed for evaluating cell proliferation; the alterations in apoptosis were analyzed utilizing flow cytometry; Transwell assay was conducted for examining cell migration and invasion; moreover, Western blot was utilized for the quantification of BACH1 protein expression; bioinformatics, dual-luciferase reporter gene, and RNA-binding protein immunoprecipitation assays were executed for validating the binding relationships between circ_0081001 and miR-494-3p, and between miR-494-3p and BACH1. As shown, circ_0081001, whose expression was elevated in OS tissues, had a negative association with miR-494-3p expression and a positive correlation with BACH1 expression. After circ_0081001 was overexpressed, the proliferation, migration, and invasion of OS cells were boosted but the apoptosis was reduced, whereas miR-494-3p exhibited opposite effects. The binding sites between circ_0081001 and miR-494-3p, and between miR-494-3p and the 3’UTR of BACH1 were experimentally verified. In conclusion, circ_0081001/miR-494-3p/BACH1 axis promoted the malignant biological behaviors of OS cells.
Knockdown of lncRNA ZNRD1-AS1 suppresses gastric cancer cell proliferation and metastasis by targeting the miR-9-5p/HSP90AA1 axis
Ming-Chen Ba1, * , Zheng Ba2, * , Yuan-Feng Gong1 , Kun-Peng Lin1 , Yin-Bing Wu1 , Yi-Nuo Tu1
doi : 10.18632/aging.203209
Volume 13, Issue 13 pp 17285—17301
LncRNAs play an important role in a variety of biological processes, such as cancer pathogenesis. The lncRNA zinc ribbon domain containing 1 antisense RNA 1 (ZNRD1-AS1) is a natural antisense transcript of ZNRD1. In this study, we found that ZNRD1-AS1 levels were significantly upregulated in gastric cancer tissues compared to those in adjacent healthy gastric tissues. ZNRD1-AS1 levels were correlated with lymph node metastasis, distal metastasis, and TNM stage, but were not correlated with age and sex. ZNRD1-AS1 knockdown suppressed cell proliferation, migration, and invasion, and promoted apoptosis. ZNRD1-AS1 overexpression had the opposite effect. ZNRD1-AS1 knockdown suppressed tumor growth and pulmonary metastasis in a nude mouse model ZNRD1-AS1 can bind to miR-9-5p and ZNRD1-AS1 knockdown can decrease the protein level of heat shock protein 90 alpha family class A member 1 (HSP90AA1), which is the target of miR-9-5p. The miR-9-5p inhibitor rescued the effect of ZNRD1-AS1 knockdown, and the mutant of miR-9-5p binding site on ZNRD1-AS1 sequence blocked the effect of ZNRD1-AS1 overexpression. In conclusion, ZNRD1-AS1 levels were upregulated in gastric cancer tissues, and knockdown of ZNRD1-AS1 suppressed gastric cancer cell proliferation and metastasis by targeting the miR-9-5p/HSP90AA1 axis. Our findings provide novel insights into the mechanism underlying the role of ZNRD1-AS1 in gastric cancer.
Bioinformatics analysis for the identification of key genes and long non-coding RNAs related to bone metastasis in breast cancer
Xu Teng1 , Tianshu Yang1 , Wei Huang1 , Weishi Li2 , Lin Zhou3 , Zihang Wang3 , Yajuan Feng3 , Jingyao Zhang4 , Xin Yin1 , Pei Wang1 , Gen Li1 , Hefeng Yu1 , Zhongqiang Chen2 , Dongwei Fan2
doi : 10.18632/aging.203211
Volume 13, Issue 13 pp 17302—17315
The molecular mechanism of bone metastasis in breast cancer is largely unknown. Herein, we aimed to identify the key genes and long non-coding RNAs (lncRNAs) related to the bone metastasis of breast cancer using a bioinformatics approach. We screened differentially expressed genes and lncRNAs between normal breast and breast cancer bone metastasis samples using the GSE66206 dataset from the Gene Expression Omnibus. We also constructed a differentially expressed lncRNA-mRNA interaction network and analyzed the node degrees to identify the driving genes. After finding potential pathogenic modules of breast cancer bone metastasis, we identified breast cancer bone metastasis-related modules and functional enrichment analysis of the genes and lncRNAs in the modules. Based on the above analysis, we constructed a differentially expressed lncRNA-mRNA network related to bone metastasis in breast cancer and identified core driver genes, including BNIP3 and the lncRNA RP11-317-J19.1. The role of core driver genes and lncRNAs in the network implies their biological functions in regulating bone development and remodeling. Thus, targeting the core driver genes and lncRNAs in the network may be a promising therapeutic strategy to manage bone metastasis.
Anoctamin 5 promotes osteosarcoma development by increasing degradation of Nel-like proteins 1 and 2
Runsang Pan1 , Qiaoying Lu1 , Chong Ren1 , Hao Li1 , Fanqiang Zeng1 , Xiaobin Tian2 , Houping Chen1
doi : 10.18632/aging.203212
Volume 13, Issue 13 pp 17316—17327
Anoctamin 5 (ANO5) is a member of the Anoctamin (ANO) family of calcium-activated chloride channels. Although ANO5 expression is upregulated in various cancers, its role in osteosarcoma remains largely unknown. In this study, bioinformatics analysis, western blot, and immunohistochemical staining revealed that ANO5 was upregulated in osteosarcoma cell lines and osteosarcoma tissues, and ANO5 expression was positively associated with tumor size, tumor grade, and metastasis. Functional experiments demonstrated that inhibition of ANO5 decreased, while ANO5 overexpression increased, osteosarcoma cell proliferation and mobility in vitro. Immunoprecipitation, western blot, and confocal microscopy experiments showed that ANO5 bound to and promoted the degradation of Nel-like proteins 1 (NELL1) and 2 (NELL2). Moreover, a subcutaneous tumor transplantation model revealed that ANO5 knockdown reduced osteosarcoma cell proliferation and increased NELL1 and NELL2 expression in vivo. Finally, rescue experiments showed that knockdown of NELL1 or NELL2 reversed the inhibitory effects of ANO5 knockdown on osteosarcoma cell proliferation and migration. These results demonstrated that upregulation of ANO5 promoted osteosarcoma development by decreasing the stability of the NELL1 and NELL2 proteins and that ANO5 may be an effective target for the treatment of osteosarcoma.
Plasma cell-free circRNAs panel act as fingerprint predicts the occurrence of laryngeal squamous cell carcinoma
Jiahui Han1 , Qiuhong Lin1 , Chunguang Dong1
doi : 10.18632/aging.203215
Volume 13, Issue 13 pp 17328—17336
Circular RNAs (circRNAs) have recently emerged as a new class of RNAs, highly enriched in the human tissues and very stable within cells, exosomes and body fluids. In this study, we aimed to screen the plasma cell-free derived circRNAs in laryngeal squamous cell carcinoma (LSCC) and investigate whether these circRNAs could predicted LSCC as potential biomarkers.
Age as a modifier of the effects of chemoradiotherapy with infusional 5-fluorouracil after D2 dissection in gastric cancer
Hung-Chang Wu1 , Wen-Li Lin2 , Chien-Liang Lin2 , Cheng-Yao Lin2,3,4 , Shang-Wen Chen2 , Yan-Xun Chen2 , Chao-Hsun Chen2 , Sung-Wei Lee5 , Shang-Hung Chen6,7 , Chao-Jung Tsao2 , Wen-Tsung Huang2, * , How-Ran Guo3,8, *
doi : 10.18632/aging.203223
Volume 13, Issue 13 pp 17337—17348
Adjuvant concurrent chemoradiotherapy (CCRT) is the standard care for patients with resected advanced gastric cancer, but its survival benefits remain undetermined in patients undergoing D2 lymph node dissection (D2 dissection). We evaluated safety and efficacy of adjuvant CCRT with 5-fluorouracil (5-FU) versus chemotherapy alone in 110 gastric cancer patients with D2 dissection treated in Taiwan between January 2009 and January 2013. All the 71 patients receiving adjuvant CCRT were treated with daily infusional 5-FU and radiotherapy. Adjuvant CCRT was associated with higher risks of major hematologic (56.3% vs. 23.8%, p = 0.002) and gastrointestinal (46.9% vs. 14.3%, p = 0.027) toxicities and death (12.5% vs. 0.0%, p = 0.041) in patients above 70 years old, but this was not the case in those ?70 years of age. Univariate Cox proportional regressions identified adjuvant CCRT as a factor for better overall survival (OS) (hazard ratio [HR]=0.52; 95% confidence interval [CI]: 0.27–0.99) and disease-free survival (DFS) (HR=0.46, 95% CI: 0.24–0.88), but it was not a significant factor for OS or DFS after adjusting for other factors in the multivariate analysis. However, in stratified analyses by age, we found adjuvant CCRT was an independent prognostic factor for better OS (HR=0.07; 95% CI: 0.01–0.38) in patients ?70 years old, but not in those above 70 years of age. Therefore, it was concluded that age may to be a modifier of the effects of adjuvant CCRT.
miR-144-3p inhibited the growth, metastasis and epithelial-mesenchymal transition of colorectal adenocarcinoma by targeting ZEB1/2
Taiyuan Li1,2, * , Cheng Tang1, * , Zhixiang Huang1, * , Lingling Yang3, * , Hua Dai4 , Bo Tang1 , Benping Xiao5 , Jianfeng Li1 , Xiong Lei1,2, &
doi : 10.18632/aging.203225
Volume 13, Issue 13 pp 17349—17369
miR-144-3p is aberrantly expressed in several types of human cancer and functions as a tumor suppressor by inhibiting metastasis. However, the clinical significance and biological function of miR-144-3p in colorectal adenocarcinoma (CRA) have yet to be elucidated. Here we reported that miR-144-3p expression level was significantly down-regulated in CRA tissues compared with matched noncancerous colorectal mucosae tissues. Low miR-144-3p expression was correlated with adverse clinicopathologic characteristics and poor prognosis of CRA patients. Cox regression analysis showed that low miR-144-3p expression was an independent risk factor for DFS and OS in CRA. In vitro and in vivo assays showed that miR-144-3p significantly inhibited proliferation, migration and invasion of CRA cells. In particular, miR-144-3p could suppress EMT process of CRA cells by regulating the cytoskeleton and EMT markers. Bioinformatics analysis indicated that EMT associated transcription factors ZEB1 and ZEB2 were potential targets of miR-144-3p, and miR-144-3p inhibited ZEB1 and ZEB2 expression and was negatively correlated with their expression in CRA. Finally, we confirmed that ZEB1 and ZEB2 down-regulation collaboratively mediated the inhibitory effect of miR-144-3p on proliferation, invasion and EMT of CRA cells. In conclusion, our study provided evidence that miR-144-3p could inhibit CRA cell proliferation, invasion and EMT by targeting ZEB1/2.
Baicalein ameliorates osteoporosis via AKT/FOXO1 signaling
Pan Cai1, * , Yan Lu2, * , Zhifeng Yin3 , Xiuhui Wang1 , Xiaoxiao Zhou1 , Zhuokai Li1
doi : 10.18632/aging.203227
Volume 13, Issue 13 pp 17370—17379
In this study, we used bioinformatics and an in vitro cellular model of glucocorticoid-induced osteoporosis to investigate mechanisms underlying the beneficial effects of baicalein (BN) against osteoporosis. STITCH database analysis revealed 30 BN-targeted genes, including AKT1, CCND1, MTOR, and PTEN. Functional enrichment analysis demonstrated that BN-targeted genes were enriched in 49 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. MIRWALK2.0 database analysis identified 110 enriched KEGG pathways related to osteoporosis. A Venn diagram demonstrated that 26 KEGG pathways were common between osteoporosis and BN-targeted genes. The top 5 common KEGG pathways were prostate cancer, bladder cancer, glioma, pathways in cancer, and melanoma. BN-targeted genes in the top 5 shared KEGG pathways were involved in PI3K-AKT, MAPK, p53, ErbB, and mTOR signaling pathways. In addition, glucocorticoid-induced osteoporosis in MC3T3-E1 cells was partially reversed by BN through inhibition of AKT, which, by upregulating FOXO1, enhanced expression of bone turnover markers (ALP, OCN, Runx2, and Col 1) and extracellular matrix mineralization. These findings demonstrate that BN suppresses osteoporosis via an AKT/FOXO1 signaling pathway.
Trajectory patterns of blood pressure change up to six years and the risk of dementia: a nationwide cohort study
Gang Cheng1 , Simin He1 , Qiong He1 , Xiaowei Xie1 , Cai Tang1 , Qunhui Xie1 , Xihong Wu1 , Ni Jiang1 , Chao Li1 , Xianying Min1 , Yan Yan1
doi : 10.18632/aging.203228
Volume 13, Issue 13 pp 17380—17406
The present study aimed to investigate the associations between the trajectory of blood pressure (BP) change and the risk of subsequent dementia and to explore the differences in age, gender, and hypertension subgroups. We included 10,660 participants aged ? 60 years from 1998 to 2018 waves of the Chinese Longitudinal Healthy Longevity Survey. Latent growth mixture models were used to estimate BP trajectories. Cox-proportional hazard models were used to analyze the effects of BP trajectories on the risk of dementia. According to the results, stabilized systolic BP (SBP) was found to be associated with a higher risk of dementia compared with normal SBP [adjusted hazard ratio (aHR): 1.62; 95% confidence interval (CI): 1.27-2.07] and elevated SBP (aHR: 2.22; 95% CI: 1.51-3.28) in and only in the subgroups of the oldest-old, women, and subjects without hypertension at baseline. Similarly, stabilized pulse pressure (PP) was associated with a higher risk of dementia compared with normal PP (aHR: 1.52; 95% CI: 1.24-1.88) and elevated PP (aHR: 2.12; 95% CI: 1.48-3.04) in and only in the subgroups of the oldest-old, women, and subjects with hypertension at baseline. These findings suggest that stabilized SBP and PP have predictive significance for the occurrence of dementia in late life, and the factors of age, gender, and late-life hypertension should be considered when estimating the risk of BP decline on dementia.
Antiparasitic mebendazole (MBZ) effectively overcomes cisplatin resistance in human ovarian cancer cells by inhibiting multiple cancer-associated signaling pathways
Linjuan Huang1,2 , Ling Zhao1,2 , Jing Zhang1,2 , Fang He2,3 , Hao Wang2,4 , Qing Liu2,5 , Deyao Shi2,6 , Na Ni2,4 , William Wagstaff2 , Connie Chen2 , Russell R. Reid2,7 , Rex C. Haydon2 , Hue H. Luu2 , Le Shen2,8 , Tong-Chuan He2,8 , Liangdan Tang1
doi : 10.18632/aging.203232
Volume 13, Issue 13 pp 17407—17427
Ovarian cancer is the third most common cancer and the second most common cause of gynecologic cancer death in women. Its routine clinical management includes surgical resection and systemic therapy with chemotherapeutics. While the first-line systemic therapy requires the combined use of platinum-based agents and paclitaxel, many ovarian cancer patients have recurrence and eventually succumb to chemoresistance. Thus, it is imperative to develop new strategies to overcome recurrence and chemoresistance of ovarian cancer. Repurposing previously-approved drugs is a cost-effective strategy for cancer drug discovery. The antiparasitic drug mebendazole (MBZ) is one of the most promising drugs with repurposing potential. Here, we investigate whether MBZ can overcome cisplatin resistance and sensitize chemoresistant ovarian cancer cells to cisplatin. We first established and characterized two stable and robust cisplatin-resistant (CR) human ovarian cancer lines and demonstrated that MBZ markedly inhibited cell proliferation, suppressed cell wounding healing/migration, and induced apoptosis in both parental and CR cells at low micromole range. Mechanistically, MBZ was revealed to inhibit multiple cancer-related signal pathways including ELK/SRF, NFKB, MYC/MAX, and E2F/DP1 in cisplatin-resistant ovarian cancer cells. We further showed that MBZ synergized with cisplatin to suppress cell proliferation, induce cell apoptosis, and blunt tumor growth in xenograft tumor model of human cisplatin-resistant ovarian cancer cells. Collectively, our findings suggest that MBZ may be repurposed as a synergistic sensitizer of cisplatin in treating chemoresistant human ovarian cancer, which warrants further clinical studies.
CircRNA FUT10 regulates the regenerative potential of aged skeletal muscle stem cells by targeting HOXA9
Menghai Zhu1 , Chong Lian2 , Gang Chen2 , Peng Zou2 , Beng Gang Qin2
doi : 10.18632/aging.203233
Volume 13, Issue 13 pp 17428—17441
Skeletal muscle is capable of repairing itself after injury to maintain the stability of its own tissue, but this ability declines with aging. Circular RNAs (circRNAs) are involved in cell aging. However, there is little research into their role and underlying mechanisms, especially in skeletal muscle stem cells (SkMSCs). In this study, we assessed circRNA FUT10 expression in aged and adult SkMSCs. We observed that circRNA FUT10 was upregulated in aged SkMSCs compared with that in adult SkMSCs. Furthermore, we identified putative miR-365-3p binding sites on circRNA FUT10, suggesting that this circRNA sponges miR-365a-3p. We also found that HOXA9 is a downstream target of miR-365a-3p and confirmed that miR-365a-3p can bind to circRNA FUT10 and the 3?-untranslated region of HOXA9 mRNA. This finding indicated that miR-365a-3p might serve as a “bridge” between circRNA FUT10 and HOXA9. Finally, we found that the circRNA FUT10/miR365a-3p/HOXA9 axis is involved in SkMSC aging. Collectively, our results show that the circRNA FUT10/miR365a-3p/HOXA9 axis is a promising therapeutic target and are expected to facilitate the development of therapeutic strategies to improve the prognosis of degenerative muscle disease.
Prognostic signatures associated with high infiltration of Tregs in bone metastatic prostate cancer
Fanjing Meng1, * , Xu Han1, * , Zhixue Min2 , Xuehui He1 , Sha Zhu1
doi : 10.18632/aging.203234
Volume 13, Issue 13 pp 17442—17461
Metastatic cancer especially bone metastasis (BM) is the lethal end-stage of castration-resistant prostate cancer (CRPC). To understand the possible molecular mechanisms underlying the development of the distant metastasis is of potential clinical value. We sought to identify differentially expressed genes between patient-matched primary and bone metastatic CRPC tumors. Functional enrichment, protein-protein interaction networks, and survival analysis of DEGs were performed. DEGs with a prognostic value considered as candidate genes were evaluated, followed by genetic analysis of tumor infiltrating immune cells based on Wilcoxon test and immunofluorescence identification. Expression profiles analysis showed that 381 overlapping genes were screened as differentially expressed genes (DEGs), of which 16 DEGs were randomly selected to be validated and revealed that most of these genes showed a transcriptional profile similar to that seen in the datasets (Pearson’s r = 0.76). Six core genes were found to be involved in regulation of extracellular matrix receptor interaction and chemotactic activity, and four of them were significantly correlated with the survival of PCa patients with bone metastases. Immune infiltration analysis showed that the expressions levels of COL3A1, RAC1, FN1, and SDC2 in CD4+T cells were significantly higher than those in tumor cells, especially regulatory T cell infiltration was significantly increased in BM tumors. We analyzed gene expression signatures specifically associated with the development of bone metastases of CRPC patients. Characterization of genes associated with BM of mCRPC is critical for identification of predictive biomarkers and potential therapeutic targets.
miR-30a-5p suppresses lung squamous cell carcinoma via ATG5 - mediated autophagy
Jichen Yang1 , Sunyin Rao1 , Run Cao1 , Shouyong Xiao1 , Xin Cui1 , Lianhua Ye1
doi : 10.18632/aging.203235
Volume 13, Issue 13 pp 17462—17472
Autophagy plays a complicated role in cancer progression. This study aims at assessing the function of ATG5-induced autophagy in progression of lung squamous cell carcinoma and its upstream mechanism.
Activin receptor-like kinase 4 haplodeficiency alleviates the cardiac inflammation and pacing-induced ventricular arrhythmias after myocardial infarction
Yuli Yang1, * , Qian Wang1, * , Xingxing Cai1, * , Zhixing Wei1 , Jianwen Hou2 , Yudong Fei1 , Wei Li1 , Yigang Li1
doi : 10.18632/aging.203236
Volume 13, Issue 13 pp 17473—17488
Inflammation process is an important determinant for subsequent changes in cardiac function and remodeling after acute myocardial infarction (MI). Recent studies have implicated that ALK4 haplodeficiency improves cardiac function after MI. However, it remains unknown if the beneficial effects are partly attributed to ALK4 haplodeficiency-induced modulation on inflammatory response in the inflammatory phase of MI. In this research, we aimed to explore the mechanism of ALK4 haplodeficiency in the inflammatory stage of MI.
HDAC inhibitor Trichostatin A suppresses adipogenesis in 3T3-L1 preadipocytes
Xin Lv1,2, * , Jun Qiu3, * , Tao Hao3 , Haoran Zhang3 , Haiping Jiang1,3 , Yang Tan4
doi : 10.18632/aging.203238
Volume 13, Issue 13 pp 17489—17498
Background and purpose: Obesity is becoming a major global health issue and is mainly induced by the accumulation of adipose tissues mediated by adipogenesis, which is reported to be regulated by peroxisome proliferator-activated receptor ? (PPAR?) and CCAAT enhancer-binding protein ? (C/EBP?). Trichostatin A (TSA) is a novel histone deacetylase inhibitor (HDACI) that was recently reported to exert multiple pharmacological functions. The present study will investigate the inhibitory effect of TSA on adipogenesis, as well as the underlying mechanism.
Downregulation of LINC00665 suppresses the progression of lung adenocarcinoma via regulating miR-181c-5p/ZIC2 axis
Wei Wei1 , Xiaoliang Zhao1 , Jiang Liu2 , Zhenfa Zhang1
doi : 10.18632/aging.203240
Volume 13, Issue 13 pp 17499—17515
Long non-coding RNA (lncRNA) LINC00665 was demonstrated to be upregulated in lung adenocarcinoma (LUAD) and target miR-181c-5p. ZIC2, which is upregulated in LUAD, serves as a putative target of miR-181c-5p. In this study, we aimed to reveal whether LINC00665 regulates miR-181c-5p/ZIC2 axis to promote LUAD progression. The results showed that LINC00665, HOXA1, ZIC2, and HOXA11 levels were increased in LUAD tissues, while miR-181c-5p level was decreased when compared to the adjacent normal tissues. High expression levels of LINC00665, ZIC2, HOXA1 and HOXA11, and low expression of miR-181c-5p were closely linked to poor prognosis of LUAD patients. Knockdown of LINC00665 induced obvious inhibitions in cell viability, clone formation, invasion and tumorigenesis in LUAD cells, whereas miR-181c-5p downregulation significantly neutralized these effects. In addition, downregulation of ZIC2 obviously reversed the enhancements of cell viability, clone formation, invasion and tumorigenesis induced by miR-181c-5p knockdown. In summary, the present study reveals that silencing of LINC00665 suppresses LUAD progression through targeting miR-181c-5p/ZIC2 axis.
Glycolysis- and immune-related novel prognostic biomarkers of Ewing's sarcoma: glucuronic acid epimerase and triosephosphate isomerase 1
Jie Jiang1 , Xinli Zhan1 , Guoyong Xu1 , Tuo Liang1 , Chaojie Yu1 , Shian Liao1 , Liyi Chen1 , Shengsheng Huang1 , Xuhua Sun1 , Ming Yi1 , Zide Zhang1 , Yuanlin Yao1 , Chong Liu1
doi : 10.18632/aging.203242
Volume 13, Issue 13 pp 17516—17535
Materials and Methods: A combination of the weighted correlation network analysis and differentially expression analysis was used for initial screening; glycolysis-related genes were extracted and subjected to univariate Cox, LASSO regression, and multivariate Cox analyses to construct prognostic models. The immune cell composition of each sample was analysed using CIBERSORT software. Immunohistochemical analysis was performed for assessing the differential expression of modelled genes in Ewing's sarcoma and paraneoplastic tissues.
IGF IIR?-triggered pathological manifestations in the heart aggravate renal inflammation in STZ-induced type-I diabetes rats
Henry Cherng-Han Lin1 , Catherine Reena Paul2 , Chia-Hua Kuo3 , Yung-Hsien Chang4 , William Shao-Tsu Chen5,6 , Tsung-Jung Ho7,8,9 , Cecilia Hsuan Day10 , Vijaya Padma Viswanadha11 , Yuhsin Tsai12, * , Chih-Yang Huang2,13,14,15,16, *
doi : 10.18632/aging.203244
Volume 13, Issue 13 pp 17536—17547
Pathological manifestations in either heart or kidney impact the function of the other and form the basis for the development of cardiorenal syndrome. However, the mechanism or factors involved in such scenario are not completely elucidated. In our study, to find the correlation between late fetal gene expression in diabetic hearts and their influence on diabetic nephropathy, we created a rat model with cardiac specific overexpression of IGF-IIR?, which is an alternative splicing variant of IGFIIR, expressed in pathological hearts. In this study, transgenic rats over expressing cardiac specific IGF-IIR? and non-transgenic animal models established in SD rats were administered with single dose of streptozotocin (STZ, 55 mg/Kg) to induce Type I diabetes. The correlation between IGF-IIR? and kidney damages were further determined based on their intensity of damage in the kidneys. The results show that cardiac specific overexpression of IGF-IIR? elevates the diabetes associated inflammation and morphological changes in the kidneys. The diabetic transgenic rats showed advancement in the pathological features such a renal tubular damage, collagen accumulation and enhancement in STAT3 associated mechanism of renal fibrosis. The results therefore show that that IGF-IIR? expression in the heart during pathological condition may worsen symptoms of diabetic nephropathy in rats.
Comprehensive analysis of the prognosis and immune infiltration for CXC chemokines in colorectal cancer
Xi Yang1, * , Yuanfeng Wei1, * , Feng Sheng2 , Yirong Xu3 , Jiao Liu3 , Ling Gao1 , Ju Yang4 , Xinchen Sun5 , Junxing Huang3, & , Qing Guo3
doi : 10.18632/aging.203245
Volume 13, Issue 13 pp 17548—17567
The C-X-C motif (CXC) chemokines are a family of chemotactic molecules that have been identified as potential prognostic markers and prospective therapeutic targets for many kinds of cancer types. Increasing evidence shows that CXC chemokines are associated with the progression of colorectal cancer (CRC); however, the correlations of CXC chemokines with prognostic and immune infiltrates in CRC remain to be clarified. In this study, we analyzed the mRNA expression level, prognostic data and immune infiltrates of CXC chemokines in CRC patients from the Gene Expression Profiling Interactive Analysis, Oncomine, cBioPortal and databases using GeneMANIA, STRING, DAVID 6.8, and TIMER. Our results showed that CXCL1/2/3/4/5/8/9/10/11/13/14/16 were significantly overexpressed in CRC tissues. Furthermore, expression of CXCL1/2/3/9/10/11 was associated with tumor stage in CRC. A significant association was also identified between the co-expression of CXCL16 with EGFR, KRAS and NRAS. In addition, the survival analysis suggested that high CXCL2/3/8/9/10/11/14 expression is correlated with clinical outcomes of CRC patients. Moreover, a significant association was observed between the CXCL8/9/10/11 expression and immune infiltration in colonic and rectal adenocarcinoma. Overall, CXC chemokines are not only implicated as prognostic biomarkers for CRC patients, but may also influence the immune status of CRC tissues.
Aging-dependent loss of GAP junction proteins Cx46 and Cx50 in the fiber cells of human and mouse lenses accounts for the diminished coupling conductance
Xiao-Dong Gong1, * , Yan Wang1, * , Xue-Bin Hu1, * , Shu-Yu Zheng1, * , Jia-Ling Fu1, * , Qian Nie1 , Ling Wang1 , Min Hou1 , Jia-Wen Xiang1 , Yuan Xiao1 , Qian Gao1 , Yue-Yue Bai1 , Yi-Zhi Liu1 , David Wan-Cheng Li1
doi : 10.18632/aging.203247
Volume 13, Issue 13 pp 17568—17591
The homeostasis of the ocular lens is maintained by a microcirculation system propagated through gap junction channels. It is well established that the intercellular communications of the lens become deteriorative during aging. However, the molecular basis for this change in human lenses has not been well defined. Here, we present evidence to show that over 90% of Cx46 and Cx50 are lost in the fiber cells of normal human lenses aged 50 and above. From transparent to cataractous lenses, while Cx43 was upregulated, both Cx46 and Cx50 were significantly down-regulated in the lens epithelia. During aging of mouse lenses, Cx43 remained unchanged, but both Cx46 and Cx50 were significantly downregulated. Under oxidative stress treatment, mouse lenses develop in vitro cataractogenesis. Associated with this process, Cx43 was significantly upregulated, in contrast, Cx46 and Cx50 were sharply downregulated. Together, our results for the first time reveal that downregulation in Cx46 and Cx50 levels appears to be the major reason for the diminished coupling conductance, and the aging-dependent loss of Cx46 and Cx50 promotes senile cataractogenesis.
DNA methylation biomarkers for diagnosis of primary liver cancer and distinguishing hepatocellular carcinoma from intrahepatic cholangiocarcinoma
Yi Bai1 , Wen Tong2 , Fucun Xie3 , Liuyang Zhu2 , Hao Wu2 , Rui Shi1 , Lianjiang Wang1 , Long Yang1 , Zhisong Liu4 , Fei Miao4 , Qiang Zhao5 , Yaming Zhang1, &
doi : 10.18632/aging.203249
Volume 13, Issue 13 pp 17592—17606
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two most common pathology subtypes of primary liver cancer (PLC). Identifying DNA methylation biomarkers for diagnosis of PLC and further distinguishing HCC from ICC plays a vital role in subsequent treatment options selection. To obtain potential diagnostic DNA methylation sites for PLC, differentially methylated CpG (DMC) sites were first screened by comparing the methylation data between normal liver samples and PLC samples (ICC samples and HCC samples). A random forest algorithm was then used to select specific DMC sites with top Gini value. To avoid overfitting, another cohort was taken as an external validation for evaluating the area under curves (AUCs) of different DMC sites combination. A similar model construction strategy was applied to distinguish HCC from ICC. In addition, we identified DNA Methylation-Driven Genes in HCC and ICC via MethylMix method and performed pathway analysis by utilizing MetaCore. Finally, we not only performed methylator phenotype based on independent prognostic sites but also analyzed the correlations between methylator phenotype and clinical factors in HCC and ICC, respectively. To diagnose PLC, we developed a model based on three PLC-specific methylation sites (cg24035245, cg21072795, and cg00261162), whose sensitivity and specificity achieved 98.8%,94.8% in training set and 97.3%,81% in validation set. Then, to further divide the PLC samples into HCC and ICC, we established another mode through three methylation sites (cg17769836, cg17591574, and cg07823562), HCC accuracy and ICC accuracy achieved 95.8%, 89.8% in the training set and 96.8%,85.4% in the validation set. In HCC, the enrichment pathways were mainly related to protein folding, oxidative stress, and glutathione metabolism. While in ICC, immune response, embryonic hepatocyte maturation were the top pathways. Both in HCC and ICC, methylator phenotype correlated well with overall survival time and clinical factors involved in tumor progression. In summary, our study provides the biomarkers based on methylation sites not only for the diagnosis of PLC but also for distinguishing HCC from ICC.
Comprehensive analysis of an immune-related ceRNA network in identifying a novel lncRNA signature as a prognostic biomarker for hepatocellular carcinoma
Rui Chen1,2, * , Yunlong Chen1,2, * , Wenjie Huang3 , Yingnan Zhao1,2 , Wang Luo1,2 , Jinyu Lin1,2 , Zhuangxiong Wang1,2 , Jian Yang1,2
doi : 10.18632/aging.203250
Volume 13, Issue 13 pp 17607—17628
The function of competitive endogenous RNA (ceRNA) network in the immune regulation of hepatocellular carcinoma (HCC) is unclear. Our study aimed to construct an immune-related ceRNA network and develop an immune-related long noncoding RNA (lncRNA) signature to assess the prognosis of HCC patients and to optimize the treatment methods. We firstly constructed a ceRNA regulatory network for HCC using differentially expressed lncRNAs, mRNAs and microRNAs (miRNAs) from the Cancer Genome Atlas. A signature was constructed by 11 immune-related prognostic lncRNAs from the ceRNA network. The survival analysis and receiver operating characteristic analysis validated the reliability of the signature. Multivariate Cox regression analysis revealed that the signature could act an independent prognostic indicator. This signature also showed high association with immune cell infiltration and immune check blockades. LINC00491 was identified as the hub lncRNA in the signature. In vitro and in vivo evidence demonstrated that silencing of LINC00491 significantly inhibited HCC growth. Finally, 59 lncRNAs, 21 miRNAs, and 26 mRNAs were obtained to build the immune-related ceRNA network for HCC. In conclusion, our novel immune-related lncRNA prognostic signature and the immune-related ceRNA network might provide in-depth insights into tumor-immune interaction of HCC and promote better individual treatment strategies in HCC patients.
Association of dietary tomato intake with bladder cancer risk in a prospective cohort of 101,683 individuals with 12.5 years of follow-up
Xin Xu1 , Bo Xie1 , Shiqi Li1 , Shuo Wang1 , Dan Xia1 , Hongzhou Meng1
doi : 10.18632/aging.203252
Volume 13, Issue 13 pp 17629—17637
Previous studies have provided limited evidence for the effect of tomato intake on bladder cancer incidence. This study aimed to evaluate the association between dietary tomato or lycopene consumption and bladder cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression model adjusting for confounders. After a median of 12.5 years of follow-up, 774 incident bladder cancer cases were identified. We found no statistically significant association between dietary intake of raw tomatoes and bladder cancer risk (Adjusted model: HRQ5 VS Q1 = 1.20, 95% CI: 0.95-1.52; P for trend = 0.243). Dietary intakes of tomato catsup, tomato salsa and tomato juice were also not associated with the risk of bladder cancer (all P for trend > 0.05). There was no statistically significant association between dietary consumption of lycopene and bladder cancer risk (Adjusted model: HRQ5 vs. Q1 = 1.04, 95% CI 0.82-1.33; P for trend = 0.590). In summary, analysis of the PLCO study suggested that dietary consumption of tomato or lycopene was not associated with the risk of bladder cancer.
Pretreatment neutrophil-to-lymphocyte ratio predicts the benefit of gastric cancer patients with systemic therapy
Songtao Du1,2,3,4, * , Zhenhao Fang1,2, * , Lin Ye2,4 , Huiyan Sun2,4 , Guangtong Deng2,4 , Wei Wu1,2 , Furong Zeng1,2,4
doi : 10.18632/aging.203256
Volume 13, Issue 13 pp 17638—17654
Pretreatment neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with the prognosis of inoperable gastric cancer patients with systemic therapy. However, no consensus on the association has been reached. In this study, we mainly evaluated whether pretreatment NLR predicted the benefit of inoperable gastric cancer patients with systemic therapy, including chemotherapy, targeted therapy and immunotherapy. PubMed, Embase and Cochrane Library databases were systematically searched from inception up to September 16th, 2020. A total of 36 studies including 8614 patients were involved in the meta-analysis. Pooled data revealed that high pretreatment NLR was significantly associated with poor outcomes of OS (HR = 1.78, 95% CI = [1.59, 1.99]) and PFS (HR = 1.63, 95% CI = [1.39, 1.91]) in gastric cancer. Subgroup analyses stratified by country, study type, case load, analysis of HR, cutoff of pretreatment NLR, or treatment types arrived at the same conclusion. Pooled data based on different effect models and sensitivity analyses did not change the conclusion. Overall, high pretreatment NLR predicts the poor prognosis of inoperable gastric cancer patients with systemic therapy. Measurement of pretreatment NLR will assist clinicians with patient counseling and clinical treatment guiding accordingly.
Characterization of ferroptosis signature to evaluate the predict prognosis and immunotherapy in glioblastoma
Xiaopeng Zhu1 , Yuxiang Zhou1 , Yangqian Ou1 , Zebo Cheng1 , Deqing Han1 , Zhou Chu2 , Sian Pan3
doi : 10.18632/aging.203257
Volume 13, Issue 13 pp 17655—17672
Glioblastoma (GBM) is the most common type of brain cancer with poor survival outcomes and unsatisfactory response to current therapeutic strategies. Recent studies have demonstrated that ferroptosis-related genes (FRGs) are linked with the occurrence and development of GBM and may become promising biological indicators in GBM therapy.
Circular RNA circCCDC66 promotes glioma proliferation by acting as a ceRNA for miR-320a to regulate FOXM1 expression
Ling Qi1,2 , Weiyao Wang1,2 , Guifang Zhao1,3 , Hong Jiang4 , Yu Zhang5 , Donghai Zhao3 , Hong Jin3 , Haiyang Xu6 , Hongquan Yu6
doi : 10.18632/aging.203258
Volume 13, Issue 13 pp 17673—17689
In this study, we determine the potential roles and uncover the regulatory mechanisms of circCCDC66 in regulating cell growth and cell metastasis of glioma.
?-Cyperone (CYP) down-regulates NF-?B and MAPKs signaling, attenuating inflammation and extracellular matrix degradation in chondrocytes, to ameliorate osteoarthritis in mice
Huawei Zhang1,2, * , Sunlong Li1,2, * , Jiajie Lu1,2 , Jie Jin1,2 , Gaosheng Zhu1,2 , Libo Wang1,2 , Yingzhao Yan3 , Linjie He1,2 , Ben Wang4 , Xiangyang Wang1,2 , Huachen Yu1,2
doi : 10.18632/aging.203259
Volume 13, Issue 13 pp 17690—17706
Inflammation and extracellular matrix (ECM) degradation have been implicated in the pathological process of osteoarthritis (OA). ?-Cyperone is the main active component of the traditional Chinese medicine Cyperus rotundus L. In this study, we found that ?-Cyperone abolished the IL-1?-induced production of inflammatory cytokines in isolated rat chondrocytes, such as cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-?), interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS), in a dose-dependent manner (0.75, 1.5 or 3 ?M). Also, the results showed that ?-Cyperone downregulated the expression of metalloproteinases (MMPs) and thrombospondin motifs 5 (ADAMTS5), and upregulated the expression of type-2 collagen. Mechanistically, molecular docking tests revealed that ?-Cyperone stably and effectively binds to p65, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). ?-Cyperone inhibited NF-?B activation by blocking its nuclear transfer, and decreasing the phosphorylation of mitogen-activated protein kinase (MAPKs). In addition, in vivo studies based on a mouse model of arthritis showed that ?-Cyperone prevented the development of osteoarthritis. Therefore, ?-Cyperone may be a potential anti-OA drug.
Screening and identification of angiogenesis-related genes as potential novel prognostic biomarkers of hepatocellular carcinoma through bioinformatics analysis
Zili Zhen1,2,3 , Zhemin Shen2,3 , Yanmei Hu4 , Peilong Sun1,2
doi : 10.18632/aging.203260
Volume 13, Issue 13 pp 17707—17733
Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality, which makes the prognostic prediction challenging. Angiogenesis appears to be of critical importance in the progression and metastasis of HCC. Some of the angiogenesis-related genes promote this process, while other anti-angiogenesis genes suppress tumor growth and metastasis. Therefore, the comprehensive prognostic value of multiple angiogenesis-related genes in HCC needs to be further clarified. In this study, the mRNA expression profile of HCC patients and the corresponding clinical data were acquired from multiple public databases. Univariate Cox regression analysis was utilized to screen out differentially expressed angiogenesis-related genes with prognostic value. A multigene signature was established with the least absolute shrinkage and selection operator Cox regression in the Cancer Genome Atlas cohort, and validated through an independent cohort. The results suggested that a total of 16 differentially expressed genes (DEGs) were associated with overall survival (OS) and a 7-gene signature was constructed. The risk score of each patient was calculated using this signature, the median value of which was used to divide these patients into a high-risk group and a low-risk group. Compared with the low-risk group, the patients in the high-risk group had a poor prognosis. The risk score was an independent predictor for OS through multivariate Cox regression analysis. Then, unsupervised learning was used to verify the validity of this 7-gene signature. A nomogram by further integrating clinical information and the prognostic signature was utilized to predict prognostic risk and individual OS. Functional enrichment analyses demonstrated that these DEGs were enriched in the pathways of cell proliferation and mitosis, and the immune cell infiltration was significantly different between the two risk groups. In summary, a novel angiogenesis-related genes signature could be used to predict the prognosis of HCC and for targeted therapy.
Clinical significance and prognostic role of an immune-related gene signature in gastric adenocarcinoma
Rui Mao1,3, * , Kehao Liu1, * , Nana Zhao2, * , Pengsen Guo1 , Yingxin Wu1 , Zheng Wang4 , Yanjun Liu1,3 , Tongtong Zhang1,3,5
doi : 10.18632/aging.203266
Volume 13, Issue 13 pp 17734—17767
Limited progress has been made in the treatment of gastric adenocarcinoma (GAC) in recent years, but the potential of immunotherapy in GAC is worthy of consideration. The purpose of this study was to develop a reliable, personalized signature based on immune genes to predict the prognosis of GAC. Here, we identified two groups of patients with significantly different prognoses by performing unsupervised clustering analysis of The Cancer Genome Atlas (TCGA) database based on 881 immune genes. The immune signature was constructed with a training set composed of 350 GAC samples from the TCGA and subsequently validated with 431 samples from GSE84437, 432 samples from GSE26253, and 145 GAC samples from real-time quantitative reverse transcription polymerase chain reaction data. This classification system can also be used to predict prognosis in different clinical subgroups. Further analysis suggested that high-risk patients were characterized by low immune scores, distinctive immune cell proportions, different immune checkpoint profiles, and a low tumor mutational burden. Ultimately, the signature was identified as an independent prognostic factor. In general, the signature can accurately predict recurrence and overall survival in patients with GAC and may serve as a powerful prognostic tool to further optimize cancer immunotherapy.
Methylation silencing CDH23 is a poor prognostic marker in diffuse large B-cell lymphoma
Baoping Cao1 , Xiaochuan Guo1 , Lefu Huang1 , Bin Wang1 , Weixia Wang1 , Dong Han1 , Weijing Zhang1 , Kaili Zhong1
doi : 10.18632/aging.203268
Volume 13, Issue 13 pp 17768—17788
Cadherin-23(CDH23) mediates homotypic and heterotypic cell-cell adhesions in cancer cells. However, the epigenetic regulation, the biological functions, the mechanisms and the prognostic value of CDH23 in diffuse large B-cell lymphoma (DLBCL) are still unclear. The Gene Expression Profiling Interactive Analysis (GEPIA) and the Gene Expression Omnibus (GEO) database were employed to analyze the CDH23 expression level in DLBCL. The correlation of CDH23 expression and methylation was analyzed by LinkedOmics database. The prognostic value was analyzed via GEPIA. Correlated genes, target kinase, target miRNA, target transcription factor and biological functions were identified by LinkedOmics and GeneMANIA database. The relationship between CDH23 and the immune cell infiltration was explored by the Tumor Immune Estimation Resource (TIMER). The expression of CDH23 was reduced by DNA methylation significantly in DLBCL tissue. Reduction of CDH23 represented poor outcome of DLBCL patients. Functional enrichment analysis showed that CDH23 mainly enriched in cancer cell growth, cell metastasis, cell adhesion, cell cycle, drug catabolic process, leukocyte mediated immunity and DNA repair by some cancer related kinases, miRNAs and transcription factors. These results indicated that methylated reduction of CDH23 represented poor outcome of DLBCL. CDH23 is associated with essential biological functions and key molecules in DLBCL. CDH23 may play crucial roles in DLBCL tumorigenesis. Our results lay a foundation for further investigation of the role of CDH23 in DLBCL tumorigenesis.
Bioinformatics analysis of the role of CXC ligands in the microenvironment of head and neck tumor
Fengyang Jing1, * , Jianxiong Wang2, * , Liming Zhou1 , Yujie Ning1 , Shengqian Xu2 , Youming Zhu1
doi : 10.18632/aging.203269
Volume 13, Issue 13 pp 17789—17817
Chemokines play a significant role in cancer. CXC-motif chemokine ligands (CXCLs) are associated with the tumorigenesis and progression of head and neck squamous cell carcinoma (HNSC); however, their specific functions in the tumor microenvironment remain unclear. Here, we analyzed the molecular networks and transcriptional data of HNSC patients from the Oncomine, GEPIA, String, cBioPortal, Metascape, TISCH, and TIMER databases. To verify immune functions of CXCLs, their expression was analyzed in different immune cell types. To our knowledge, this is the first report on the correlation between CXCL9–12 and 14 expression and advanced tumor stage. CXCL2, 3, 8, 10, 13, and 16 were remarkably related to tumor immunity. Kaplan–Meier and TIMER survival analyses revealed that high expression of CXCL1, 2, 4, and 6–8 is correlated with low survival in HNSC patients, whereas high expression of CXCL9, 10, 13, 14, and 17 predicts high survival. Only CXCL13 and 14 were associated with overall survival in human papilloma virus (HPV)-negative patients. Single-cell datasets confirmed that CXCLs are associated with HNSC-related immune cells. Thus, CXCL1–6, 8–10, 12–14, and 17 could be prognostic targets for HNSC, and CXCL13 and 14 could be novel biomarkers of HPV-negative HNSC.
Particulate matter exposure is highly correlated to pediatric asthma exacerbation
Xin Yang1, * , Yuanyuan Zhang1, * , Xueqin Zhan1 , Xuchen Xu1 , Shuxian Li1 , Xuefeng Xu2 , Songmin Ying3,4 , Zhimin Chen1
doi : 10.18632/aging.203281
Volume 13, Issue 13 pp 17818—17829
Asthma is a heterogeneous disease in which environmental factors play an important role, and the effect of particulate matter (PM) on the occurrence and severity of asthma is drawing more attention. This study aims to identify the correlation between PM and pediatric asthma exacerbation and explore the potential mechanisms. The asthma visits data (N = 16,779,739) in a university-based tertiary children’s hospital from January 2013 to December 2017 were collected, and the relationship between asthma visits and local PM concentration was analyzed. For further study, we established a house dust mite (HDM)-induced allergic airway inflammation model with PM intervention. We detected a correlation between PM concentration and pediatric asthma visits, especially in children under 6 years old. The in vivo data showed that PM aggravated HDM-induced airway inflammation, and IL-33 neutralizing antibody exerted a protective role. Our study suggests that PM is a risk factor in promoting pediatric asthma exacerbation, in which IL-33 might be a promising target.
Linc00941 regulates esophageal squamous cell carcinoma via functioning as a competing endogenous RNA for miR-877-3p to modulate PMEPA1 expression
Yan Zhang1, * , Huayun Zhu1, * , Ning Sun1 , Xiaomei Zhang1 , Geyu Liang2 , Jiali Zhu1, * , Lei Xia1 , Yingying Kou1 , Jianwei Lu1
doi : 10.18632/aging.203286
Volume 13, Issue 13 pp 17830—17846
Esophageal squamous cell carcinoma (ESCC) represents one of the most common malignancies and is the fifth leading cause of cancer-related deaths. Long intergenic non-coding RNAs (lincRNAs) have been suggested to be dysregulated in various types of cancers, and a growing number of lincRNAs have been implicated to be functional in the ESCC progression. In this study, we examined the role of linc00941 in the ESCC progression and explored the underlying molecular mechanisms. The bioinformatics analysis identified the up-regulation of linc00941 in the ESCC tissues. Further in vitro studies showed that linc00941 was up-regulated in ESCC cell lines. The loss-of-function studies demonstrated that linc00941 knockdown suppressed ESCC cell proliferation, invasion and migration, and also suppressed the in vivo tumor growth. Furthermore, bioinformatics prediction along with luciferase reporter assay and RNA immunoprecipitation assay implied that linc00941 acted as a competing endogenous RNA for miR-877-3p, and linc00941 regulated ESCC cell progression via at least targeting miR-877-3p. Subsequently, miR-877-3p targeted prostate transmembrane protein, androgen induced 1 (PMEPA1) 3’ untranslated region and repressed PMEPA1 expression in ESCC cells; overexpression of PMEPA1 attenuated the inhibitory effects of linc00941 knockdown on the ESCC cell progression. Linc00941 knockdown suppressed epithelial-mesenchymal transition (EMT) via targeting miR-877-3p/PMEPA1 axis in ESCC cells. In conclusion, our results indicated the oncogenic role of linc00941 in ESCC, and knockdown of linc00941 suppressed ESCC cell proliferation, invasion, migration and EMT via interacting with miR-877-3p/PMEPA1 axis.
Prognostic value of fatty acid metabolism-related genes in patients with hepatocellular carcinoma
Dongsheng He1 , Lifang Cai1 , Weiming Huang1 , Qingqing Weng1 , Xi Lin1 , Mengxing You1, * , Shengyin Liao1, *
doi : 10.18632/aging.203288
Volume 13, Issue 13 pp 17847—17863
The deregulation of fatty acid metabolism plays a crucial role in cancer. However, the prognostic value of genes involved in the metabolism in hepatocellular carcinoma (HCC) remains largely unknown. We first constructed a multi-fatty acid metabolic gene prognostic model of HCC based on The Cancer Genome Atlas (TCGA) and further validated it using the International Cancer Genome Consortium (ICGC) database. The model was integrated with the clinical parameters, and a nomogram was built and weighted. Moreover, immune cell infiltration of the tumor microenvironment was investigated. A prognostic model was constructed using 6 selected fatty acid metabolism-related genes, and HCC patients were divided into high- and low-risk groups. Receiver operating characteristic curve (ROC) analysis, principal component analysis (PCA), and t-distributed stochastic neighbor embedding (t-SNE) analysis showed the optimal performance of the model. The concordance index (C-index), ROC curve, calibration plot and decision curve analysis (DCA) all confirmed the satisfactory predictive capacity of the nomogram. The analysis of immune cell infiltration in HCC patients revealed a correlation with different risk levels. Our findings indicate that a prognostic model based on fatty acid metabolism-related genes has superior predictive capacities, which provides the possibility for further improving the individualized treatment of patients with HCC.
A innovative prognostic symbol based on neutrophil extracellular traps (NETs)-related lncRNA signature in non-small-cell lung cancer
Chen Fang1 , Fen Liu2 , Yong Wang1 , Shangkun Yuan1 , Renfang Chen1 , Xiaotong Qiu1 , Xiaoying Qian1 , Xinwei Zhang1 , Zhehao Xiao1 , Qian Wang1 , Biqi Fu3 , Yong Li1
doi : 10.18632/aging.203289
Volume 13, Issue 13 pp 17864—17879
Neutrophil extracellular traps (NETs) are closely related to cancer progression. NETs-related lncRNAs play crucial roles in non-small-cell lung cancer (NSCLC) but there have been no systematic studies regarding NETs-related long noncoding RNA (lncRNA) signatures to forecast the prognosis of NSCLC patients. It’s essential to build commensurate NETs-related lncRNA signatures. The expression profiles of prognostic mRNAs and lncRNAs and relevant clinical data of NSCLC patients were downloaded from The Cancer Genome Atlas (TCGA) database. The NETs-related genes came from the results of our transcriptome RNA microarray data. The co-expression network of lncRNAs and NETs-related genes was structured to confirm NETs-related lncRNAs. The 19 lncRNAs correlated with overall survival (OS) were selected by exploiting univariate Cox regression (P < 0.05). Lasso regression and multivariate Cox regression (P < 0.05) were utilized to develop a 12-NETs-related lncRNA signature. We established a risk score based on the signature, which suggested that patients in the high-risk group displayed significantly shorter OS than patients in the low-risk group (P < 0.0001, P = 0.0023 respectively in the two cohorts). The risk score worked as an independent predictive factor for OS in both univariate and multivariate Cox regression analyses (HR> 1, P< 0.001). Additionally, by RT-qPCR, we confirmed that NSCLC cell lines have higher levels of the three adverse prognostic NETs-related lncRNAs than normal lung cells. The expression of lncRNAs significantly increases after NETs stimulation. In short, the 12 NETs-related lncRNAs and their model could play effective roles as molecular markers in predicting survival for NSCLC patients.
Anti-aging effects of a functional food via the action of gut microbiota and metabolites in aging mice
Jie Zhang1, * , Zhewen Chen2, * , Huaixi Yu3, * , Yanwen Lu1 , Weinan Yu1 , Mingyong Miao4,5 , Hanping Shi6
doi : 10.18632/aging.202873
Volume 13, Issue 13 pp 17880—17900
Wushen (WS) is a mixed food containing 55 natural products that is beneficial to human health. This study aimed to reveal the preventive effect of WS on aging via a combined analysis of gut microbiome and metabolome. Senescence-accelerated mouse prone 8 (SAMP8) mice were used as aging model and senescence-accelerated mouse resistant 1 (SAMR1) mice as control. The mice were fed four diet types; control diet (for SAMR1 mice), standard diet (for SAMP8 mice, as SD group), WS diet, and fecal microbiota transplantation (FMT; transplanted from aging-WS mice). Our results showed that the weight, food intake, neurological function, and general physical conditions significantly improved in WS-fed mice compared to those fed with SD. The CA1 hippocampal region in WS-fed aged mice showed fewer shriveled neurons and increased neuronal layers compared to that of the SD group. WS-fed mice showed a decrease in malondialdehyde and an increase in superoxide dismutase levels in the brain; additionally, IL-6 and TNF-? levels significantly decreased, whereas IL-2 levels and the proportion of lymphocytes, CD3+CD8+ T, and CD4+IFN?+T cells increased in WS-fed mice. After fed with WS, the abundance of Ruminococcus and Butyrivibrio markedly increased, whereas Lachnoclostridium and Ruminiclostridium significantly decreased in the aging mice. In addition, 887 differentially expressed metabolites were identified in fecal samples, among these, Butyrivibrio was positively correlated with D-glucuronic acid and Ruminococcus was positively associated with 5-acetamidovalerate. These findings provide mechanistic insight into the impact of WS on aging, and WS may be a valuable diet for preventing aging.
Chloroquine suppresses proliferation and invasion and induces apoptosis of osteosarcoma cells associated with inhibition of phosphorylation of STAT3
Chenglong Chen1,2, * , Hongliang Zhang1,2, * , Yiyang Yu1,2 , Qingshan Huang1,2 , Wei Wang1,2 , Jianfang Niu1,2 , Jingbing Lou1,2 , Tingting Ren1,2 , Yi Huang1,2 , Wei Guo1,2
doi : 10.18632/aging.203196
Volume 13, Issue 13 pp 17901—17913
Osteosarcoma (OS) is characterized by a high rate of metastasis. It has been found that tumor cells can bypass apoptosis which leads to an uncontrolled proliferation, but chloroquine (CQ) can have an effect on the tumors by inducing apoptosis. We aimed to explore the effects and the hypothetical mechanism of CQ effects on OS.
Roxadustat for the treatment of anemia in patients with chronic kidney diseases: a meta-analysis
Li Zhang1 , Jie Hou1 , Jia Li1 , Sen-Sen Su1 , Shuai Xue2
doi : 10.18632/aging.203143
Volume 13, Issue 13 pp 17914—17929
Anemia is a common complication of chronic kidney disease (CKD). Treating renal anemia with erythropoiesis-stimulating agents (ESAs) or erythropoietin analogs is effective but has side effects. Therefore, we performed a meta-analysis to assess the efficacy and safety of roxadustat in treating CKD-induced anemia.
Research progress of melatonin (MT) in improving ovarian function: a review of the current status
Yi Ming Guo1,2, * , Tie Cheng Sun3, * , Hui Ping Wang1,2 , Xi Chen4
doi : 10.18632/aging.203231
Volume 13, Issue 13 pp 17930—17947
Melatonin (MT) is an endogenous hormone mainly synthesized by pineal cells, which has strong endogenous effects of eliminating free radicals and resisting oxidative damages. Melatonin (MT) can not only regulate the body’s seasonal and circadian rhythms; but also delay ovarian senescence, regulate ovarian biological rhythm, promote follicles formation, and improve oocyte quality and fertilization rate. This review aimd to provide evidence concerning the synthesis and distribution, ovarian function, and role of MT in development of follicles and oocytes. Moreover, the role of MT as antioxidative, participating in biological rhythm regulation, was also reviewed. Furthermore, the effects of MT on various ovarian related diseases were analyzed, particularly for the ovarian aging and polycystic ovary syndrome (PCOS).
Correction for: Prediction of cognitive performance in old age from spatial probability maps of white matter lesions
Cui Zhao1,2 , Ying Liang1,2 , Ting Chen1,2 , Yihua Zhong1,2 , Xianglong Li1,2 , Jing Wei1,2 , Chunlin Li1,2 , Xu Zhang1,2
doi : 10.18632/aging.203325
Volume 13, Issue 13 pp 17948
Correction for: Aucubin exerts anti-osteoporotic effects by promoting osteoblast differentiation
Yutong Li1,3 , Yongfeng Zhang2 , Xinrui Zhang2 , Wenqian Lu2 , Xin Liu2 , Min Hu1,3 , Di Wang2
doi : 10.18632/aging.203365
Volume 13, Issue 13 pp 17949—17952
Correction for: STAT5A induced LINC01198 promotes proliferation of glioma cells through stabilizing DGCR8
Cheng Tan1, * , Yimeng Dai2, * , Xiaoyang Liu1 , Guifang Zhao3,4 , Weiyao Wang3,4 , Jia Li1 , Ling Qi3,4
doi : 10.18632/aging.203346
Volume 13, Issue 13 pp 17953—17954
