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Adipokines, cell polarity disruption and breast cancer
Danila Coradini
doi : 10.18632/aging.203621
Volume 13, Issue 19 pp 22625—22626
Preventing metastatic emergence of breast cancer
Alan Wells, Colin Beckwitt, Juan Luis Gomez Marti
doi : 10.18632/aging.203631
Volume 13, Issue 19 pp 22627—22628
Green tea catechins EGCG and ECG enhance the fitness and lifespan of Caenorhabditis elegans by complex I inhibition
Jing Tian1,2 , Caroline Geiss1 , Kim Zarse1,3 , Corina T. Madreiter-Sokolowski3,4 , Michael Ristow1,3
doi : 10.18632/aging.203597
Volume 13, Issue 19 pp 22629—22648
Green tea catechins are associated with a delay in aging. We have designed the current study to investigate the impact and to unveil the target of the most abundant green tea catechins, epigallocatechin gallate (EGCG) and epicatechin gallate (ECG).
Effects of periostin deficiency on kidney aging and lipid metabolism
Jung Nam An1, * , Hyoseon Kim2,3, * , Eun Nim Kim4 , Ara Cho5 , Yeongeun Cho2 , Young Wook Choi6 , Jin Hyuk Kim5 , Seung Hee Yang7,8 , Bum Soon Choi4 , Chun Soo Lim5,9 , Yon Su Kim9,10 , Kwang Pyo Kim2,3 , Jung Pyo Lee5,9
doi : 10.18632/aging.203580
Volume 13, Issue 19 pp 22649—22665
Periostin plays a crucial role in fibrosis, which is involved in kidney aging. A few studies have shown that lipid metabolism is involved in kidney aging. We investigated the role of periostin in lipid metabolism during kidney aging. Renal function, fibrosis, and inflammatory markers were studied using urine, blood, and tissue samples from wild-type (WT) C57BL/6 mice and Postn-null mice of 2 and 24 months of age. Lipids were quantitatively profiled using liquid chromatography-tandem mass spectrometry in the multiple reaction monitoring mode. Renal function was worse and tubular atrophy/interstitial fibrosis, periostin expression, and inflammatory and fibrotic markers were more severe in aged WT mice than in young WT mice. In aged Postn-null mice, these changes were mitigated. Thirty-five differentially regulated lipids were identified. Phosphatidylcholines, cholesteryl ester, cholesterol, ceramide-1-phosphate, and CCL5 expression were significantly higher in aged WT mice than in aged Postn-null mice. Particularly, linoleic acid, linolenic acid, arachidonic acid, and docosahexaenoic acid differed strongly between the two groups. Lysophosphatidylcholine acyltransferase 2, which converts lysophosphatidylcholine to phosphatidylcholine, was significantly higher in aged WT mice than in aged Postn-null mice. Periostin expression in the kidneys increased with age, and periostin ablation delayed aging. Changes in lipids and their metabolism were found in Postn-null mice. Further research on the precise mechanisms of and relationships between lipid expression and metabolism, kidney aging, and periostin expression is warranted.
Increased plasma brain-derived neurotrophic factor (BDNF) as a potential biomarker for and compensatory mechanism in mild cognitive impairment: a case-control study
Ted Kheng Siang Ng1,2,3,4 , Christina Coughlan5 , Patricia C. Heyn2,6 , Alex Tagawa2,6 , James J. Carollo2,6 , Ee Heok Kua1,7 , Rathi Mahendran1,7
doi : 10.18632/aging.203598
Volume 13, Issue 19 pp 22666—22689
Previous meta-analyses examining the continuum of Alzheimer’s disease (AD) concluded significantly decreased peripheral brain-derived neurotrophic factor (BDNF) in AD. However, across different meta-analyses, there remain inconsistent findings on peripheral BDNF levels in individuals with mild cognitive impairment (MCI). This issue has been attributed to the highly heterogenous clinical and laboratory factors. Thus, BDNF’s level, discriminative accuracy for identifying all-cause MCI and its subtypes, and its associations with other biomarkers and neurocognitive domains, remain largely unknown.
Circulating CD5L is associated with cardiovascular events and all-cause mortality in individuals with chronic kidney disease
Esmeralda Castelblanco1,2,7 , Maria R. Sarrias3 , Àngels Betriu4 , Berta Soldevila5,15 , Maria Barranco-Altirriba1,6 , Josep Franch-Nadal7,8,9,15 , Jose M. Valdivielso4 , Marcelino Bermudez-Lopez4 , Per-Henrik Groop10,11,12,13 , Elvira Fernández4 , Núria Alonso5,8,15 , Didac Mauricio1,7,14,15
doi : 10.18632/aging.203615
Volume 13, Issue 19 pp 22690—22709
This study assessed the association of CD5L and soluble CD36 (sCD36) with the risk of a cardiovascular event (CVE), including CV death and all-cause mortality in CKD. We evaluated the association of CD5L and sCD36 with a predefined composite CV endpoint (unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, congestive heart failure, arrhythmia, peripheral arterial disease [PAD] or amputation by PAD, aortic aneurysm, or death from CV causes) and all-cause mortality using Cox proportional hazards regression, adjusted for CV risk factors. The analysis included 1,516 participants free from pre-existing CV disease followed up for 4 years. The median age was 62 years, 38.8% were female, and 26.8% had diabetes. There were 98 (6.5%) CVEs and 72 (4.8%) deaths, of which 26 (36.1%) were of CV origin. Higher baseline CD5L concentration was associated with increased risk of CVE (HR, 95% CI, 1.17, 1.0–1.36), and all-cause mortality (1.22, 1.01–1.48) after adjusting for age, sex, diabetes, systolic blood pressure, dyslipidemia, waist circumference, smoking, and CKD stage. sCD36 showed no association with adverse CV outcomes or mortality. Our study showed for the first time that higher concentrations of CD5L are associated with future CVE and all-cause mortality in individuals with CKD.
Neurovascular dysfunction and neuroinflammation in a Cockayne syndrome mouse model
Gustavo Satoru Kajitani1,2 , Lear Brace1 , Jose Humberto Trevino-Villarreal1 , Kaspar Trocha1 , Michael Robert MacArthur1,3 , Sarah Vose1 , Dorathy Vargas4 , Roderick Bronson4 , Sarah Jayne Mitchell1,3 , Carlos Frederico Martins Menck2 , James Robert Mitchell1,3, *
doi : 10.18632/aging.203617
Volume 13, Issue 19 pp 22710—22731
Cockayne syndrome (CS) is a rare, autosomal genetic disorder characterized by premature aging-like features, such as cachectic dwarfism, retinal atrophy, and progressive neurodegeneration. The molecular defect in CS lies in genes associated with the transcription-coupled branch of the nucleotide excision DNA repair (NER) pathway, though it is not yet clear how DNA repair deficiency leads to the multiorgan dysfunction symptoms of CS. In this work, we used a mouse model of severe CS with complete loss of NER (Csa?/?/Xpa?/?), which recapitulates several CS-related phenotypes, resulting in premature death of these mice at approximately 20 weeks of age. Although this CS model exhibits a severe progeroid phenotype, we found no evidence of in vitro endothelial cell dysfunction, as assessed by measuring population doubling time, migration capacity, and ICAM-1 expression. Furthermore, aortas from CX mice did not exhibit early senescence nor reduced angiogenesis capacity. Despite these observations, CX mice presented blood brain barrier disruption and increased senescence of brain endothelial cells. This was accompanied by an upregulation of inflammatory markers in the brains of CX mice, such as ICAM-1, TNF?, p-p65, and glial cell activation. Inhibition of neovascularization did not exacerbate neither astro- nor microgliosis, suggesting that the pro-inflammatory phenotype is independent of the neurovascular dysfunction present in CX mice. These findings have implications for the etiology of this disease and could contribute to the study of novel therapeutic targets for treating Cockayne syndrome patients.
The central role of the glutamate metabolism in long-term antiretroviral treated HIV-infected individuals with metabolic syndrome
Marco Gelpi1, * , Flora Mikaeloff2, * , Andreas D. Knudsen1 , Rui Benfeitas3 , Shuba Krishnan2 , Sara Svenssson Akusjärvi2 , Julie Høgh1 , Daniel D. Murray4 , Henrik Ullum5 , Ujjwal Neogi2,6, * , Susanne D. Nielsen1, *
doi : 10.18632/aging.203622
Volume 13, Issue 19 pp 22732—22751
Metabolic syndrome (MetS) is a significant factor for cardiometabolic comorbidities in people living with HIV (PLWH) and a barrier to healthy aging. The long-term consequences of HIV-infection and combination antiretroviral therapy (cART) in metabolic reprogramming are unknown. In this study, we investigated metabolic alterations in well-treated PLWH with MetS to identify potential mechanisms behind the MetS phenotype using advanced statistical and machine learning algorithms.
Exposure to ionizing radiation disrupts normal epigenetic aging in Japanese medaka
Emily M. Bertucci1,2 , Marilyn W. Mason2 , Olin E. Rhodes1,2 , Benjamin B. Parrott1,2
doi : 10.18632/aging.203624
Volume 13, Issue 19 pp 22752—22771
Alterations to the epigenome are a hallmark of biological aging and age-dependent patterning of the DNA methylome (“epigenetic aging”) can be modeled to produce epigenetic age predictors. Rates of epigenetic aging vary amongst individuals and correlate to the onset of age-related disease and all-cause mortality. Yet, the origins of epigenetic-to-chronological age discordance are not empirically resolved. Here, we investigate the relationship between aging, DNA methylation, and environmental exposures in Japanese medaka (Oryzias latipes). We find age-associated DNA methylation patterning enriched in genomic regions of low CpG density and that, similar to mammals, most age-related changes occur during early life. We construct an epigenetic clock capable of predicting chronological age with a mean error of 61.1 days (~8.4% of average lifespan). To test the role of environmental factors in driving epigenetic age variation, we exposed medaka to chronic, environmentally relevant doses of ionizing radiation. Because most organisms share an evolutionary history with ionizing radiation, we hypothesized that exposure would reveal fundamental insights into environment-by-epigenetic aging interactions. Radiation exposure disrupted epigenetic aging by accelerating and decelerating normal age-associated patterning and was most pronounced in cytosines that were moderately associated with age. These findings empirically demonstrate the role of DNA methylation in integrating environmental factors into aging trajectories.
Immunological age prediction in HIV-infected, ART-treated individuals
Lesley R. de Armas1 , Suresh Pallikkuth1 , Li Pan1 , Stefano Rinaldi1 , Rajendra Pahwa1 , Savita Pahwa1
doi : 10.18632/aging.203625
Volume 13, Issue 19 pp 22772—22791
Anti-retroviral therapy (ART) improves life expectancy in people living with HIV (PWH), but it remains unclear how chronic HIV infection affects normal aging of the immune system. Plasma cell-free protein expression and immune phenotypes were assessed in blood from ART treated PWH (19-77yrs, n = 106) and age-matched, HIV-negative controls (HC, n = 103). Using univariate spearman correlation, we identified 277 and 491 age-associated parameters out of a total 1,357 in HC and PWH, respectively. PWH exhibited shared and distinct age-associated immune profiles compared to HC highlighting the effect of HIV infection on immunological aging. Our analysis resulted in an 8-parameter, plasma-detectable inflammatory index that correlated with chronological age of all study participants but was higher overall in PWH. Additionally, predictive modeling for age in HC participants and age-associated parameters generated a 25-parameter signature, IMAP-25, with 70% and 53% accuracy in HC and PWH, respectively. Applying the IMAP-25 signature to immunological data from PWH revealed accelerated aging in PWH by 5.6 yrs. Overall, our results demonstrate that immune signatures, easily monitored in human blood samples, can be used as an indicator of one’s ‘immunological age’ during ART-treated HIV infection and can be applied to other disease states that affect the immune system.
Identification of hub genes and key pathways of paraquat-induced human embryonic pulmonary fibrosis by bioinformatics analysis and in vitro studies
Xiangxia Zeng1 , Jinlun Hu2,3 , Mei Yan2,3 , Chunming Xie3,4 , Weigan Xu3,4 , Qiaohua Hu3,4 , Jinxia Feng3,4 , Zi Cong Gu2,3 , Yue Fu2,3,4
doi : 10.18632/aging.203570
Volume 13, Issue 19 pp 22792—22801
Paraquat (N,N0-dimethyl-4,40-bipyridinium dichloride;PQ) is a highly toxic pesticide, which usually leads to acute lung injury and subsequent development of pulmonary fibrosis. The exact mechanism underlying PQ-induced lung fibrosis remain largely unclear and as yet, no specific treatment drugs have been approved. Our study aimed to identify its potential mechanisms of PQ-induced fibrosis through a modeling study in vitro studies and bioinformatics analysis.
Highly expressed centromere protein L indicates adverse survival and associates with immune infiltration in hepatocellular carcinoma
Zhili Zeng1, * , Xiao Jiang1, * , Zhibin Pan6, * , Ruisheng Zhou1, * , Zhuangteng Lin3, * , Ying Tang2,4 , Ying Cui7 , Enxin Zhang4,5 , Zebiao Cao1
doi : 10.18632/aging.203574
Volume 13, Issue 19 pp 22802—22829
Hepatocellular carcinoma (HCC) is characterized by rapid progression, high recurrence rate and poor prognosis. Early prediction for the prognosis and immunotherapy efficacy is of great significance to improve the survival of HCC patients. However, there is still no reliable predictor at present. This study is aimed to explore the role of centromere protein L (CENPL) in predicting prognosis and its association with immune infiltration in HCC.
Inhibition of JAK2/STAT3 signaling pathway by panaxadiol limits the progression of pancreatic cancer
Xuhui Fan1,2, * , Haotian Fu1, * , Ni Xie3 , Hangcheng Guo1 , Tiantian Fu1 , Yunfeng Shan1
doi : 10.18632/aging.203575
Volume 13, Issue 19 pp 22830—22842
Pancreatic cancer is the fourth leading cause of cancer-related death with the characteristics of chemoresistance and early metastasis. Panaxadiol, a triterpenoid saponin extracted from the roots of American ginseng, has been proved to display anti-tumor activity in colon cancer. In this study, we found panaxadiol significantly inhibited proliferation, and induced apoptosis in human pancreatic cancer cell lines PANC-1 and Patu8988 in a dose-dependent manner. Furthermore, the expression of apoptosis-related proteins (Bax, Bcl2, Cleaved-caspase3) was detected via western blot and immunofluorescence staining. In addition, panaxadiol was also found to inhibit the migration of pancreatic cancer cells by wound healing and transwell assays. In vivo, the growth of xenograft pancreatic cancer models was also notably suppressed by panaxadiol compared to the control group. Moreover, the down-regulation of JAK2-STAT3 signaling pathway was responsible for the underlying pro-apoptosis mechanism of panaxadiol, and this result was in good agreement with molecular docking analysis between panaxadiol and STAT3. In conclusion, our work comprehensively explored the anti-tumor ability in PANC-1 and Patu8988 cells of panaxadiol and provided a potential choice for the clinical treatment of pancreatic cancer patients.
Allicin protects against myocardial I/R by accelerating angiogenesis via the miR-19a-3p/PI3K/AKT axis
Mengru Liu1,2 , Peng Yang2 , Dongliang Fu2 , Tong Gao1,2 , Xinyi Deng2,3 , Mingjing Shao2 , Jiangquan Liao2 , Hong Jiang2 , Xianlun Li1,2,3
doi : 10.18632/aging.203578
Volume 13, Issue 19 pp 22843—22855
Allicin is an allyl 2-propenethiosulfinate or diallyl thiosulfinate acid with cardioprotective effects in myocardial ischemia/reperfusion (MI/R) injury. This study aims to examine the underlying mechanism by which Allicin protects against MI/R.
Retrospective analysis of renal prognosis in elderly coronary artery disease patients complicated with renal insufficiency
Jun Li1, & , Fa-Hu Liu2 , Jing Guo3 , Ya-Fen Yu1 , Chun-Qing Li1
doi : 10.18632/aging.203579
Volume 13, Issue 19 pp 22856—22866
The aim of this study was to retrospectively analyze the renal prognosis of elderly coronary artery disease (CAD) patients complicated with renal insufficiency.
Computational study of effective matrix metalloproteinase 9 (MMP9) targeting natural inhibitors
Naimeng Liu2 , Xinhui Wang3 , Hao Wu1 , Xiaye Lv5 , Haoqun Xie4 , Zhen Guo4 , Jing Wang4 , Gaojing Dou2,4 , Chenxi Zhang1 , Mindan Sun1
doi : 10.18632/aging.203581
Volume 13, Issue 19 pp 22867—22882
The present study screened ideal lead natural compounds that could target and inhibit matrix metalloproteinase 9 (MMP9) protein from the ZINC database to develop drugs for clear cell renal cell carcinoma (CCRCC)-targeted treatment.
Transcriptome study of oleanolic acid in the inhibition of breast tumor growth based on high-throughput sequencing
Zhuoran Liang1,2, * , Ruolan Pan3, * , Xia Meng3 , Jinxing Su3 , Yong Guo1 , Gang Wei1 , Zhi Zhang1 , Kan He3
doi : 10.18632/aging.203582
Volume 13, Issue 19 pp 22883—22897
The function of oleanolic acid (OA) in various types of cancer has been reported frequently, especially for breast cancer. However, the regulation of breast tumor growth in response to OA treatment has not been studied in depth. Here, we first explored the effect of OA treatment on breast tumors in vitro and in vivo and then used RNA-seq technology to study the effect and molecular mechanism of OA treatment of MCF-7 cells, particularly at the level of functional genomics. The results showed that 40 ?M OA treatment could significantly inhibit the proliferation and induce the apoptosis of MCF-7 cells. Through analysis of RNA sequencing data quality and differentially expressed genes (DEGs), 67 significantly downregulated genes and 260 significantly upregulated genes were identified to be involved in OA treatment of MCF-7 cells. Among these genes, 43 unique DEGs were enriched in several signaling pathways and Gene Ontology terms, such as p53 signaling pathway, TNF signaling pathway and mTOR signaling pathway. Six downregulated genes, including THBS1, EDN1, CACNG4, CCN2, AXIN2 and BMP4, as well as six upregulated genes, including ATF4, SERPINE1, SESN2, PPARGC1A, EGR1 and JAG1, were selected as target genes in response to OA treatment. The inhibitory effect of OA on breast cancer was also found in the following mouse experiments. Our study provides evidence and molecular support for the treatment of breast cancer with OA.
Downregulation of KIF2C and TEKT2 is associated with male infertility and testicular carcinoma
Haiming Cao1, * , Zi Wan2, * , Fei Wang4 , Ziyin Liu5 , Xiaofeng Li3 , Jianquan Hou1
doi : 10.18632/aging.203583
Volume 13, Issue 19 pp 22898—22911
Genetic factors are important in spermatogenesis and fertility maintenance, and are potentially significant biomarkers for the early detection of infertility. However, further understanding of these biological processes is required.
Significance of CD8+ T cell infiltration-related biomarkers and the corresponding prediction model for the prognosis of kidney renal clear cell carcinoma
Yuan Tian1 , Yumei Wei2 , Hongmei Liu3 , Heli Shang3 , Yuedong Xu4 , Tong Wu1 , Wei Liu1 , Alan Huang5 , Qi Dang6 , Yuping Sun7
doi : 10.18632/aging.203584
Volume 13, Issue 19 pp 22912—22933
Cytotoxic T cells expressing cell surface CD8 played a key role in anti-cancer immunotherapy, including kidney renal clear cell carcinoma (KIRC). Here we set out to comprehensively analyze and evaluate the significance of CD8+ T cell-related markers for patients with KIRC. We checked immune cell response in KIRC and identified cell type-specific markers and related pathways in the tumor-infiltrating CD8+ T (TIL-CD8T) cells. We used these markers to explore their prognostic signatures in TIL-CD8+ T by evaluating their prognostic efficacy and group differences at various levels. Through pan-cancer analysis, 12 of 63 up-regulated and 162 of 396 down-regulated genes in CD8+ T cells were found to be significantly correlated with the survival prognosis. Based on our highly integrated multi-platform analyses across multiple datasets, we constructed a 6-gene risk scoring model specific to TIL-CD8T. In this model, high TIL-CD8 sig score was corresponding to a higher incidence frequency of copy number variation and drug sensitivity to sorafenib. Moreover, the prognosis of patients with the same or similar immune checkpoint gene levels could be distinguished from each other by TIL-CD8 sig score.
Agomelatine might be more appropriate for elderly, depressed, type 2 diabetes mellitus patients than paroxetine/fluoxetine
Zihong Liang1 , Yanbo Jia2 , Lizhen Zhao1 , Runxiu Zhu3 , Xuemei He1 , Bagen Tong1 , Fan Yang1 , Lixia Hao1 , Pengfei Cui4 , Jun Yuan3
doi : 10.18632/aging.203586
Volume 13, Issue 19 pp 22934—22946
Agomelatine was a novel and melatonergic antidepressant. The present study was conducted to find out whether age was an important factor for agomelatine in treating depressed type 2 diabetes mellitus (T2DM) patients. In total, 193 depressed T2DM patients were included. There were 84 patients ranged from 27 years old to 49 years old (age phase I) (n = 44 receiving agomelatine, n = 40 receiving paroxetine or fluoxetine), and 109 patients ranged from 50 years old to 70 years old (age phase II) (n = 56 receiving agomelatine, n = 53 receiving paroxetine or fluoxetine). The Hamilton Depression Rating Scale (HDRS) score, Hamilton Anxiety Rating Scale (HARS) score, fasting plasma glucose (FPG), hemoglobin A1c (HbA1c) level and body mass index (BMI) were assessed after 12 weeks treatment. After treatment, we found that among patients in age phase I, there were no significant differences in final average HDRS score, HARS score, FPG, HbA1c level, BMI, response rate and remission rate between the two groups. However, among patients in age phase II, compared to patients receiving paroxetine or fluoxetine, patients receiving agomelatine had the significantly lower average HDRS score, HARS score, HbA1c level and BMI, and significantly higher response rate and remission rate. The incidence of treatment-related adverse events was similar between the two groups in both age phases. These results suggested that age was an important factor for agomelatine in treating depressed T2DM patients. Compared to paroxetine/fluoxetine, agomelatine might be more appropriate for elderly depressed T2DM patients.
A novel prognostic signature based on immune-related genes of diffuse large B-cell lymphoma
Zizheng Wu1, * , Qingpei Guan1, * , Xue Han1, * , Xianming Liu1 , Lanfang Li1 , Lihua Qiu1 , Zhengzi Qian1 , Shiyong Zhou1 , Xianhuo Wang1 , Huilai Zhang1
doi : 10.18632/aging.203587
Volume 13, Issue 19 pp 22947—22962
Diffuse large B-cell lymphoma (DLBCL) presents a great clinical challenge and has a poor prognosis, with immune-related genes playing a crucial role. We aimed to develop an immune-related prognostic signature for improving prognosis prediction in DLBCL.
RUNX2 and LAMC2: promising pancreatic cancer biomarkers identified by an integrative data mining of pancreatic adenocarcinoma tissues
Guihua Jin1 , Qingqing Ruan1 , Fugen Shangguan1 , Linhua Lan1
doi : 10.18632/aging.203589
Volume 13, Issue 19 pp 22963—22984
Pancreatic carcinoma (PC) is a severe disease associated with high mortality. Although strategies for cancer therapy have made great progress, outcomes of pancreatic carcinoma patients remain extremely poor. Therefore, it is urgent to find novel biomarkers and therapeutic targets. To identify biomarkers for early diagnosis and therapy, three mRNA microarray datasets and two miRNA datasets were selected, and combinative analysis was performed by GEO2R. Functional and pathway enrichment analysis were performed using DAVID database. MiRTarBase, miRWalk and Diana Tools were used to get key genes. TCGA, HPA and western blotting were used to verify diagnostic and prognostic value of key genes. By integrating mRNA and miRNA expression profiles, we identified 114 differentially expressed genes and 114 differentially expressed miRNAs, respectively. Then, three overlapping key genes, RUNX2, LAMC2 and FBXO32, were found. Their protein levels in pancreatic tissue from PC patients and normal people were analyzed by immunohistochemical staining and western blotting. RUNX2 showed a potential property to identify PC. Aberrant over-expression of LAMC2 was associated with poor prognosis of PC patients, tumor status and subtypes. In summary, our current study identified that RUNX2 and LAMC2 may be promising targets for early diagnosis and therapy of PC patients.
Vitellogenin 2 promotes muscle development and stimulates the browning of white fat
Yilei Li1, * , Xiaoli Sun2, * , Yun Bai1 , Yunyan Ji1 , Huawei Ren1 , Xiuju Yu1 , Yi Yan1 , Xiaoyan He1 , Yanjun Dong3 , Liping Zhang1,4 , Xiaomao Luo1 , Haidong Wang1
doi : 10.18632/aging.203590
Volume 13, Issue 19 pp 22985—23003
Eggs are rich in nutrients and contain a lot of protein. Although eggs have proved to accelerate the growth of C2C12 cells, the regulatory and mechanism of fertilized egg yolk extract (FEYE) on skeletal muscle development and fat metabolism remains unclearly. The mice were treated with FEYE by gavage for 24 d, we found that FEYE can inhibit the expression of skeletal muscle atrophy genes such as MSTN and Murf-1, and up-regulate the expression levels of MYOD, MYOG and Irisin. In addition, the treatment of FEYE induced UCP1 and PGC1? high expression in WAT, thereby causing WAT browning reaction. In order to confirm the composition of FEYE, we performed protein full spectrum identification (LC MS/MS) analysis and found the most enriched component is vitellogenin 2 (VTG2). Therefore, we added the recombinant protein VTG2 to C2C12 cells and found that VTG2 promoted the proliferation and differentiation of C2C12 cells. After that, we further proved that VTG2 inhibited the expression of MSTN and improved the expression of MYOD and Irisin. Finally, the dual luciferase test proved that VTG2 directly inhibited the transcriptional activity of MSTN. Our results conclude that FEYE inhibits the expression of MSTN in muscle tissues by delivering VTG2, thereby promoting skeletal muscle development, and can also promote the expression level of FNDC5 in serum. Then, FNDC5 acts on the fat through the serum, stimulating the browning reaction of white adipocytes. Therefore, VTG2 can be used to stop muscle consumption, improve skeletal muscle aging, and prevent obesity.
lncRNA MEG3 aggravated neuropathic pain and astrocyte overaction through mediating miR-130a-5p/CXCL12/CXCR4 axis
Jiacai Dong1 , Rui Xia2 , Zhonggui Zhang3 , Cheng Xu3
doi : 10.18632/aging.203592
Volume 13, Issue 19 pp 23004—23019
Long non-coding RNAs (lncRNAs) exert a critical function in mediating neuropathic pain (NP). MEG3, a novel lncRNA, contributes to astrocyte activation and inflammation. However, its role in NP remains unclear.
DCP1A is an unfavorable prognostic-related enhancer RNA in hepatocellular carcinoma
Hao Wu1, * , Jinrui Zhang1, * , Yi Bai2 , Sai Zhang3 , Zhixin Zhang1 , Wen Tong1 , Pinsheng Han1 , Bing Fu1 , Yamin Zhang2 , Zhongyang Shen3
doi : 10.18632/aging.203593
Volume 13, Issue 19 pp 23020—23035
Long non-coding RNAs (lncRNAs) are associated with occurrence and development of tumors. Enhancer RNA (eRNA) is a special type of lncRNAs produced from transcription of enhancer elements. The function of eRNAs in tumors have elicited significant attention recently. However, the clinical significance and role of eRNAs in hepatocellular carcinoma (HCC) has not been fully explored. The current study sought to explore the expression level and prognostic value of key eRNAs in HCC. Bioinformatics analyses were used to explore expression levels of key prognostic eRNAs in HCC and their correlation with target genes. A total of 1580 enhancer RNAs (eRNAs) and 1791 target genes were initially retrieved from TCGA-LIHC gene expression database. Further analysis through survival and correlation analysis led to identification of 12 eRNAs and 13 target genes. The findings showed that DCP1A was the most prognosis-related eRNA. This eRNA showed the highest correlation with the target gene, PRKCD. Analysis showed that poor overall survival (OS) in HCC patients was correlated with high expression level of DCP1A (eRNA) and PRKCD (target gene). The up-regulation of DCP1A was associated with advanced tumor stage, larger tumor size and higher histological grade. The results of pan-cancer analysis showed that the expression of DCP1A was differentially expressed in 13 other types of tumor tissues and their corresponding normal tissues. This eRNA was highly expressed in digestive system tumors. Functional analysis showed that high expression level of DCP1A was implicated in multiple tumor-related signaling pathways. The findings of the current study indicated DCP1A is a novel biomarker that can be used as a potential therapeutic target for HCC patients.
Low expression of endoplasmic reticulum stress-related gene SERP1 is associated with poor prognosis and immune infiltration in skin cutaneous melanoma
Yuchao Fan1, *,# , Xiao Liang2, *,# , Deshui Yu3
doi : 10.18632/aging.203594
Volume 13, Issue 19 pp 23036—23071
Stress-associated endoplasmic reticulum protein 1 (SERP1) is a gene induced by endoplasmic reticulum (ER) stress and a major contributor to multiple tumor types. Skin cutaneous melanoma (SKCM) is a highly aggressive and fatal cancer with poor treatment outcomes after progression. In this study, we evaluated SERP1’s role in tumorigenesis, prognosis, and immune infiltration in SKCM. Patients with SKCM had low SERP1 expression. We identified differentially expressed genes between high- and low-SERP1 expression groups and conducted functional, pathway, and gene enrichment analyses. Protein–protein (PPI) and gene–gene interaction (GGI) networks were constructed via STRING and GeneMANIA, respectively. SERP1 mutation information was obtained through cBioPortal; location in the skin was identified through the Human Protein Atlas. Kaplan–Meier analysis revealed an association between low SERP1 expression and overall survival (OS), disease-specific survival (DSS), progress-free interval (PFI) rates, and worse prognosis in patients with multiple clinicopathological features. Cox regression analysis and nomograms further presented SERP1 level as an independent prognostic factor for patients with SKCM. Furthermore, there were significant correlations between SERP1 expression and immune infiltrates; thus, low SERP1 expression is associated with immune cell infiltration and can be considered a poor prognostic biomarker in patients with SKCM.
Establishment of a novel ferroptosis-related lncRNA pair prognostic model in colon adenocarcinoma
Hong Li1, * , Lili Liu2, * , Tianyi Huang3, * , Ming Jin3 , Zhen Zheng3 , Hui Zhang3 , Meng Ye4 , Kaitai Liu3
doi : 10.18632/aging.203599
Volume 13, Issue 19 pp 23072—23095
Long non-coding RNAs (lncRNAs) have been reported to be prognostic factors for cancer. Ferroptosis is an iron-dependent process of programmed cell death. Here, we established a ferroptosis-related lncRNA (frlncRNA) pair signature and revealed its prognostic value in colon adenocarcinoma (COAD) by analyzing the data from The Cancer Genome Atlas (TCGA). FrlncRNAs were identified based on co-expression analysis using the Pearson correlation. Differentially expressed frlncRNAs (DEfrlncRNAs) were recognized and paired, followed by prognostic assessment using univariate Cox regression analysis. The least absolute shrinkage and selection operator (LASSO) penalized Cox analysis was used to determine and construct a risk score prognostic model, by which the receiver operating characteristic (ROC) curves for predicting the overall survival (OS) were conducted. Following the evaluation of whether it was an independent prognostic factor, correlations between the risk score model and clinicopathological characteristics, hypoxia- and immune-related factors, and somatic variants were investigated. In total, 148 DEfrlncRNA pairs were identified, 25 of which were involved in a risk score prognostic signature. The area under ROC curves (AUCs) representing the predictive effect for 1-, 3-, and 5-year survival rates were 0.860, 0.885, and 0.934, respectively. The risk score model was confirmed as an independent prognostic factor and was significantly superior to the clinicopathological characteristics. Correlation analyses showed disparities in clinicopathological characteristics, hypoxia- and immune-related factors, and somatic variants, as well as specific signaling pathways between high- and low-risk groups. The novel risk score prognostic model constructed by pairing DEfrlncRNAs showed promising clinical prediction value in COAD.
Zhoushi Qi Ling decoction represses docetaxel resistance and glycolysis of castration-resistant prostate cancer via regulation of SNHG10/miR-1271-5p/TRIM66 axis
Hongwen Cao1, * , Dan Wang1, * , Peng Sun1, * , Lei Chen1 , Yigeng Feng1 , Renjie Gao1
doi : 10.18632/aging.203602
Volume 13, Issue 19 pp 23096—23107
Docetaxel resistance developed in half of castration-resistant prostate cancer (CRPC) patients hinders its long-term clinical application. The current study was designed to investigate the effects of Chinese medicine Zhoushi Qi Ling decoction on the docetaxel resistance of prostate cancer as well as elucidate the underlying molecular mechanism. In our study, Qi Ling significantly decreased viability and colony formation as well as increased apoptosis of docetaxel-resistant (DR) CRPC cells. Qi Ling-treated DR cells exhibited decreased glucose consumption, lactate release and pyruvate production. Moreover, lncRNA SNHG10 was upregulated in DR tissues of CRPC patients and was negatively correlated with the progression-free survival. Bioinformatics analysis indicated miR-1271-5p as the associated miRNA possibly binding with SNHG10. miR-1271-5p up-regulation dramatically decreased the luciferase activity of SNHG10 in DR cells. SNHG10 knockdown sharply increased the expression of miR1271-5p in DR cells. Targetscan predicted TRIM66 as one of the downstream targets of miR-1271-5p. miR-1271-5p up-regulation drastically reduced luciferase activity as well as TRIM66 expression in DR cells. Also, the knockdown of SNHG10 remarkably suppressed the expression of TRIM66 in DR cells. Additionally, Qi Ling treatment reduced SNHG10 and TRIM66, while increased miR1271-5p, in DR cells. In summary, Qi Ling inhibited docetaxel resistance and glycolysis of CRPC possibly via SNHG10/miR-1271-5p/TRIM66 pathway.
METTL3 regulates hippocampal gene transcription via N6-methyladenosine methylation in sevoflurane-induced postoperative cognitive dysfunction mouse
Baiqing He1 , Jian Wang2
doi : 10.18632/aging.203604
Volume 13, Issue 19 pp 23108—23118
Elderly patients are prone to cognitive impairment and memory loss after surgical operations. This perioperative cerebral damage, named postoperative cognitive dysfunction (POCD), is profoundly affected by anesthesia. N6-methyladenosine (m6A) RNA methylation is a widely-studied epigenetic modification to regulate gene expression; however, is has never been studied in POCD. In the present study, elderly POCD mouse models were constructed using sevoflurane, and we observed a compromised global m6A RNA methylation in the mice’s hippocampuses compared with the control. Our RIP-Seq data suggested that 1244 genes (SOX2, SYN1, and BDNF) showed m6A RNA methylation in their 5?UTRs, which was significantly lower than that in the control; while only 56 genes (BACE1 and IL17A) showed m6A RNA methylation in their 5?UTRs, which was significantly higher than that in the control. Unexpectedly, m6A RNA methylation with significant differences in exons, introns, or 3?UTRs was observed in only few genes. Although we failed to find any differences in the expression of m6A-associated proteins, such as m6A “writers”, “erasers”, and “readers”, between the sevoflurane treatment and control groups, RIP-qPCR assays indicated that the binding affinity of METTL3 on mRNA 5?UTRs was particularly weakened in target genes by sevoflurane. Finally, we found that phosphorylation of METTL3 could be reduced by sevoflurane because of the inactivation of the MAPK/ERK pathway. Overall, our study determined that the inactivation of METTL3 in the mouse hippocampus, induced by sevoflurane-mediated MAPK/ERK suppression in vivo, resulted in a perturbation in m6A RNA methylation signals in the pathogenesis of POCD.
Ribosome profiling reveals translatome remodeling in cancer cells in response to zinc oxide nanoparticles
Saisai Wei1,2, * , Wenhao Guo1,3, * , Yu Qian1 , Jie Xiang1 , Kangli Liu1 , Xiang-Jing Gao4 , Xiangwei Gao1 , Yicheng Chen1,5
doi : 10.18632/aging.203606
Volume 13, Issue 19 pp 23119—23132
The anticancer effect of zinc oxide nanoparticles (ZnO NPs) largely relies on cellular responses such as alteration of gene expression. Although ZnO NPs have been reported to induce transcriptional changes, the potential of ZnO NPs to affect cellular translatome remains largely unknown. Using ribosome profiling, we demonstrated that the transcription of 78 genes and the translation of 1,448 genes are affected during one hour of ZnO NPs exposure in A549 human lung cancer cells. The mitogen-activated protein kinase (MAPK) pathway is up-regulated upon ZnO NP treatment. The upstream open reading frame (uORF) plays a pervasive role in the induction of up-regulated genes, including TLNRD1 and CCNB1IP1. Knockdown of TLNRD1 or CCNB1IP1 reduces ZnO NP-induced cytotoxicity. Together, our study characterizes the landscape of translational alteration under ZnO NPs treatment and provides potential targets to augment the anticancer effect of ZnO NPs.
Short-term high-fat diet favors the appearances of apoptosis and gliosis by activation of ERK1/2/p38MAPK pathways in brain
Chao-Jin Xu1, * , Mei-Qi Li2, * , Li-Zhao2 , Wei-Guang Chen1 , Jun-Ling Wang3
doi : 10.18632/aging.203607
Volume 13, Issue 19 pp 23133—23148
High-fat diet (HFD) has been associated with neuroinflammation and apoptosis in distinct brain regions. To explore the effect of short-term (7, 14 and 21 days) high-fat overfeeding on apoptosis, inflammatory signaling proteins, APP changes and glial cell activities in cerebral cortex and cerebellum. Mice were fed with HFD for different lengths (up to 21 days) and after each time body weights of mice was tested, then the apoptotic proteins, IL-1?, APP, BACE1and MAPKs, Akt and NF-?B signaling activity were evaluated by western blots. Results demonstrate that short period of high-fat overnutrition significantly promotes apoptosis, APP expression at day 21 of cerebral cortex and at day 7 of cerebellum compared to chow diet. In addition, increased GFAP+astrocytes, Iba-1+microglia and IL-1? 30 were observed in cerebral cortex after 21 days HFD, but no changes for 7 days overfeeding of cerebellum. Serendipitously, ERK1/2 pathway was activated both in cerebral cortex and cerebellum for different time course of HFD. Furthermore, increased phospho-p38 MAPK level was observed in cerebellum only. In consistent with in vivo results, SH-SY5Y cells treatment with cholesterol (50 ?M, 100 ?M) for 48 h culture in vitro demonstrated that pro-apoptotic proteins were enhanced as well. In brief, short-term HFD consumption increases sensitivity to apoptosis, APP and IL-1? production as well as gliosis in cerebral cortex and cerebellum, which may be related to enhancement of ERK1/2 and p38 MAPK activation.
Comprehensive analysis of aberrant alternative splicing related to carcinogenesis and prognosis of papillary thyroid cancer
Xiaobo Zheng1 , Li Feng2 , Yunfan Yin3 , Chune Yu4 , Xiujing He4 , Jiao Zhu5 , Ming Zhang1,6 , Jing Yu4 , Mingqing Xu1,7
doi : 10.18632/aging.203608
Volume 13, Issue 19 pp 23149—23168
As a key mechanism, alternative splicing (AS) plays a role in the cancer initiation and development. However, in papillary thyroid cancer (PTC), data for the comprehensive AS event profile and its clinical implications are lacking. Herein, a genome-wide AS event profiling using RNA-Seq data and its correlation with matched clinical information was performed using a 389 PTC patient cohort from the project of The Cancer Genome Atlas (TCGA). We identified 1,925 cancer-associated AS events (CASEs) by comparing paired tumors and neighboring healthy tissues. Parent genes with CASEs remarkably enriched in the pathways were linked with carcinogenesis, such as P53, KRAS, IL6-JAK-STAT3, apoptosis, and MYC signaling. The regulatory networks of AS implied an obvious correlation between the expression of splicing factor and CASE. We identified eight CASEs as predictors for overall survival (OS) and disease-free survival (DFS). The established risk score model based on DFS-associated CASEs successfully predicted the prognosis of PTC patients. From the unsupervised clustering analysis results, it is found that different clusters based on AS correlated with prognosis, molecular features, and immune characteristics. Taken together, the comprehensive genome-wide AS landscape analysis in PTC showed new AS events linked with tumorigenesis and prognosis, which provide new insights for clinical monitoring and therapy for PTC.
LncRNA-SNHG1 promotes macrophage M2-like polarization and contributes to breast cancer growth and metastasis
Shoukai Zong1 , Wei Dai2 , Xiangting Guo3 , Kai Wang4
doi : 10.18632/aging.203609
Volume 13, Issue 19 pp 23169—23181
Breast cancer is one of the most common malignant cancers among women. Cancer cells and adjacent cells determine the development of the disease. Tumor associated macrophages (TAMs) are involved in the regulation of different stages of cancer progression. LncRNAs play an important role in tumor growth and metastasis. However, the function of lncRNA in macrophage and tumor cell interaction is poorly described. Here we reported that lncRNA SNHG1 functioned as a modulator of M2 macrophage polarization and regulated tumor growth and angiogenesis. We indicated that knockdown of SNHG1 inhibited M2 macrophage polarization by suppression of STAT6 phosphorylation. SNHG1 silencing significantly alleviated migration of MCF-7 cells and tube formation of Human Umbilical Vein Endothelial Cells (HUVEC). Furthermore, we found that implantation of cell mixture of MCF-7 cells and macrophages promoted tumor growth and angiogenesis. However, knockdown of SNHG1 in macrophages reversed that effect. Collectively, we demonstrated the important role of lncRNA SNHG1 in macrophages and breast cancer cells interaction. We highlight the essential effect of lncRNA in tumor progression and provide a new method for the prevention and treatment of breast tumor metastasis.
Decreased gray matter volume and increased white matter volume in patients with neovascular age-related macular degeneration: a voxel-based morphometry study
Yan-Kun Shen1, * , Qian-Min Ge1, * , Yi-Cong Pan1, * , Hui-Ye Shu1 , Li-Juan Zhang1 , Qiu-Yu Li1 , Rong-Bin Liang1 , Yi Shao1 , Yao Yu1, &
doi : 10.18632/aging.203610
Volume 13, Issue 19 pp 23182—23192
To measure white and gray matter volume (WMV, GMV) in patients with neovascular age-related macular degeneration (nAMD) using voxel-based morphometry (VBM).
Network pharmacology for systematic understanding of Schisandrin B reduces the epithelial cells injury of colitis through regulating pyroptosis by AMPK/Nrf2/NLRP3 inflammasome
Weiwei Zhang1, * , Wusan Wang2, * , Chaozhuang Shen3, * , Xiaohu Wang3, * , Zhichen Pu3, & , Qin Yin1,4, &
doi : 10.18632/aging.203611
Volume 13, Issue 19 pp 23193—23209
Ulcerative colitis (UC) is a chronic inflammatory disease with increasing incidence and prevalence in many countries. The purpose of this study is to explore the function of Schisandrin B and its underlying molecular mechanisms in colitis.
Integrated analysis of tumor-associated macrophage infiltration and prognosis in ovarian cancer
Qianxia Tan1 , Huining Liu1 , Jie Xu2 , Yanqun Mo1 , Furong Dai1
doi : 10.18632/aging.203613
Volume 13, Issue 19 pp 23210—23232
Ovarian cancer (OC) is a frequently lethal gynecologic malignancy, characterized by a poor prognosis and high recurrence rate. The immune microenvironment has been implicated in the progression of OC. We characterized the immune landscape in primary and malignant OC ascites using single-cell and bulk transcriptome raw OC data acquired from the Gene Expression Omnibus and The Cancer Genome Atlas databases. We then used the CIBERSORT deconvolution algorithm, weighted gene co-expression network analysis, univariate and multivariate Cox analyses, and the LASSO algorithm to develop a tumor-associated macrophage-related gene (TAMRG) prognostic signature, which enabled us to stratify and predict overall survival (OS) of OC patients. In addition, inter- and intra-patient heterogeneity of infiltrating immune cells was characterized at single-cell resolution. Tumor-infiltrating macrophages with an M2 phenotype exhibited immunosuppressive activity. M1 macrophages positively correlated with OS, whereas activated mast cells, neutrophils, M2 macrophages, and activated memory CD4+ T cells were all negatively correlated with OS. A total of 219 TAMRGs were identified, and a novel 6-gene signature (TAP1, CD163, VSIG4, IGKV4-1, CD3E, and MS4A7) with independent prognostic value was established. These results show that a TAMRG-based signature may be a promising prognostic and therapeutic target in OC.
Long non-coding RNA CRNDE as potential biomarkers facilitate inflammation and apoptosis in alcoholic liver disease
Yifeng Yan1,2 , Liang Ren1 , Yan Liu1 , Liang Liu1
doi : 10.18632/aging.203614
Volume 13, Issue 19 pp 23233—23244
Due to persistent inconsistencies in the expression data of alcoholic liver disease (ALD), it is necessary to turn to “pre-laboratory” comprehensive analysis in order to accelerate effective precision medicine and transformation research. We screened pseudogene-derived lncRNA associated with ALD by comparative analysis of 2 independent data sets from GEO. Three lncRNAs (CRNDE, RBMS3-AS3, and LINC01088) were demonstrated to be potentially useful diagnostic markers in ALD. Among them, the expression of CRNDE is up-regulated. Therefore, we focus on CRNDE. Kyoto Encyclopedia of Genes and Genomes pathways analysis revealed higher CRNDE can activate MAPK signaling pathway, apoptosis, wnt signaling pathway, and hematopoietic cell lineage. Next, we established ALD animal model and verified the success of the modeling. The result showed ALD tissues in mice had significantly higher CRNDE levels than normal tissues. Moreover, the increase of IL-6 in the serum of mice in the low-dose group is related to the activation of inflammatory factors after alcohol-induced liver injury. In addition, alcohol can induce apoptosis, and knockdown of CRNDE can reduce apoptosis. Our integrated expression profiling identified CRNDE independently associated with ALD. CRNDE can facilitate inflammation and apoptosis in ALD.
Identification of potential target genes of non-small cell lung cancer in response to resveratrol treatment by bioinformatics analysis
Peng Gao1, * , Guanghui Ren2, *
doi : 10.18632/aging.203616
Volume 13, Issue 19 pp 23245—23261
Non-small cell lung cancer (NSCLC) is the most common type in lung cancer in the world, and it severely threatens the life of patients. Resveratrol has been reported to inhibit cancer. However, mechanisms of resveratrol inhibiting NSCLC were unclear. The aim of this study was to identify differentially expressed genes (DEGs) of NSCLC treated with resveratrol and reveal the potential targets of resveratrol in NSCLC. We obtained mRNA expression profiles of two datasets from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI-GEO) and 271 DEGs were selected for further analysis. Data from STRING shown that 177 nodes and 342 edges were in the protein-protein interaction (PPI) network, and 10 hub genes (ANPEP, CD69, ITGAL, PECAM1, PTPRC, CD34, ITGA1, CCL2, SOX2, and EGFR) were identified by Cytoscape plus-in cytoHubba. Survival analysis revealed that NSCLC patients showing low expression of PECAM1, ANPEP, CD69, ITGAL, and PTPRC were associated with worse overall survival (OS) (P < 0.05), and high expression of SOX2 and EGFR was associated with worse OS for NSCLC patients (P < 0.05). Overall, we identified ANPEP, CD69, ITGAL, and PTPRC as potential candidate genes which were main effects of resveratrol on the treatment of NSCLC. ANPEP, ITGAL, CD69, and PTPRC are all clusters of differentiation (CD) antigens, might be the targets of resveratrol. The bioinformatic results suggested that the inhibitory effect of resveratrol on lung cancer may be related to the immune signaling pathway. Further studies are needed to validate these findings and to explore their functional mechanisms.
Whole-exome sequencing of rectal cancer identifies locally recurrent mutations in the Wnt pathway
Yi Yang1, * , Xiaodong Gu1, * , Zhenyang Li1, * , Chuang Zheng1 , Zihao Wang1 , Minwei Zhou1 , Zongyou Chen1 , Mengzhen Li2 , Dongbing Li2 , Jianbin Xiang1
doi : 10.18632/aging.203618
Volume 13, Issue 19 pp 23262—23283
Locally recurrent rectal cancer (LRRC) leads to a poor prognosis and appears as a clinically predominant pattern of failure. In this research, whole-exome sequencing (WES) was performed on 21 samples from 8 patients to search for the molecular mechanisms of LRRC. The data was analyzed by bioinformatics. Gene Expression Profiling Interactive Analysis (GEPIA) and Human Protein Atlas (HPA) were performed to validate the candidate genes. Immunohistochemistry was used to detect the protein expression of LEF1 and CyclinD1 in LRRC, primary rectal cancer (PRC), and non-recurrent rectal cancer (NRRC) specimens. The results showed that LRRC, PRC, and NRRC had 668, 794, and 190 specific genes, respectively.
Transcriptome research identifies four hub genes related to primary myelofibrosis: a holistic research by weighted gene co-expression network analysis
Weihang Li1, * , Yingjing Zhao2, * , Dong Wang1 , Ziyi Ding1 , Chengfei Li3 , Bo Wang5 , Xiong Xue5 , Jun Ma5 , Yajun Deng5 , Quancheng Liu5 , Guohua Zhang5 , Ying Zhang5 , Kai Wang4 , Bin Yuan5
doi : 10.18632/aging.203619
Volume 13, Issue 19 pp 23284—23307
This study aimed to identify specific diagnostic as well as predictive targets of primary myelofibrosis (PMF).
Transcriptome and proteome analysis of the antitumor activity of maslinic acid against pancreatic cancer cells
Hewei Zhang1 , Lijun Kong1 , Yan Zhang1 , Cheng Wang1, * , Linxiao Sun1, *
doi : 10.18632/aging.203623
Volume 13, Issue 19 pp 23308—23327
Maslinic acid (MA) is a triterpenoid compound of natural abundance in olive plants possessing numerous biological activities. The effect and molecular mechanism of MA on pancreatic cancer cells remain elusive. Here, we explored the anti-tumor activity of MA on human pancreatic cancer cells and the potential underlying molecular mechanism. The anti-cancer effects of MA on whole-cell processes, including proliferation, migration, and invasion in pancreatic cancer cells, were systematically assessed by colony formation, transwell, and migration assays. The search for potential therapeutic targets was achieved via transcriptomics and proteomics analyses. MA was demonstrated to inhibit the proliferation, migration, and invasion of PANC-1 and Patu-8988 cells, but induced apoptosis of these cells. Several key candidate genes and proteins of functional relevance for the anti-tumor activity of MA were identified through the association analysis of transcriptomics and proteomics. To our knowledge, this is the first transcription and proteomics-based comprehensive analysis of the mechanism of MA against pancreatic cancer. The findings demonstrate that MA holds promise as a therapeutic drug for managing pancreatic cancer.
Effects of Yu Linzhu on ovarian function and oocyte mitochondria in natural aging mice
Zhen Yang1 , Mao-Lin Wei1 , Xiao-Ying Dong1
doi : 10.18632/aging.203626
Volume 13, Issue 19 pp 23328—23337
To study the effect of Yu Linzhu on ovarian function and mitochondria in natural aging mice.
A novel mutation in PCK2 gene causes primary angle-closure glaucoma
Menghan Xu1,2, * , Jin Yang1,3, * , Jiayue Sun1 , Xuemei Xing1 , Zheng Liu4 , Tao Liu1,5
doi : 10.18632/aging.203627
Volume 13, Issue 19 pp 23338—23347
Primary angle-closure glaucoma (PACG) is an ophthalmic genetic disease characterized by direct contact between the iris and trabecular meshwork, resulting in an obstructed outflow of aqueous humor from the eye. However, it is unclear as to what role genetics plays in the development of PACG. The present study investigated the disease-causing mutation in a five-generation Chinese PACG family using whole-genome sequencing. A novel heterozygous missense mutation c.977C>T in PCK2 gene was identified in five affected family members, but not in any unaffected and 86 unrelated healthy individuals. This nucleotide substitute is predicted to result in a proline to leucine substitution p.Pro326Leu. Furthermore, the function of this mutation was analyzed through various in vitro assays using the RGC-5 cell line. Our results demonstrate that the p.Pro326Leu mutation induces RGC-5 cell cycle arrest and apoptosis with a decreased BcL-XL. The increasing P53, P27, P21, AKT, and P-GSK3? were also detected in the cells transfected with c.977C>T mutation, suggesting that this mutation within PCK2 gene cause PACG through impairment of AKT/GSK3? signaling pathway.
Differential moderation effects of ApoE and 5-HTTLPR genotypes on social vulnerability in predicting mortality among community-dwelling middle-aged and older adults: a nationwide population-based study
Hsin-Yu Liu1,2,3,10 , Li-Ning Peng1,3 , Wei-Ju Lee1,5 , Ming-Yueh Chou1,4 , Chih-Kuang Liang1,4 , Fei-Yuan Hsiao6,7,8 , Ming-Hsien Lin1,3 , Liang-Kung Chen1,3,9
doi : 10.18632/aging.203629
Volume 13, Issue 19 pp 23348—23360
Aging is a dynamic complex process involving social vulnerability over time. The social vulnerability index (SVI) was developed that predicted adverse health outcomes. This study examined effects between SVI status and two genotypes, apolipoprotein E (ApoE) and Serotonin transporter genotyping (5-HTTLPR), on all-cause mortality. Data from the Social Environment and Biomarkers of Aging Study (SEBAS) were obtained, and SVI was constructed using 32 self-reported items of social determinants. Data from 985 participants (age: 65.73 ± 9.47 years, 54.62% males) were obtained for analysis, and the median SVI was 0.35 (IQR 0.29–0.42) with a near normal distribution. Participants with a higher SVI were more likely to be women and have poor cognitive function, more depressive symptoms and poor physical function. Adjusted for age and sex, each incremental deficit in SVI was associated with a 12% increase in mortality risk (HR: 1.12, 95% CI: 1.04–1.20, p = 0.002). An interaction was found between ApoE and SVI but not 5-HTTLPR. The strata-specific hazard ratio confirmed that associations between SVI and mortality was only in non-?4 carriers (HR: 1.15, 95% CI: 1.07–1.24, p < 0.001), and SVI did not significantly predict mortality among ?4 carriers (HR: 0.84, 95% CI: 0.65–1.10). Differential SVI effects on mortality among middle-age and older adults were identified. In conclusion, a higher SVI was associated with all-cause mortality among middle-aged and older adults, and the association was moderated by ApoE genotypes but not 5-HTTLPR. Further study is needed to evaluate the clinical efficacy of healthy aging intervention programs considering gene-environment interactions and social vulnerability.
piRNA-36741 regulates BMP2-mediated osteoblast differentiation via METTL3 controlled m6A modification
Jianmin Liu1 , Ming Chen2 , Longyang Ma1 , Xingbo Dang1 , Gongliang Du1
doi : 10.18632/aging.203630
Volume 13, Issue 19 pp 23361—23375
The osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is essential for bone formation, and its imbalance can lead to bone diseases such as osteoporosis. It is reported that PIWI-interacting RNA-36741 (piR-36741) is up-regulated during the osteogenic differentiation, but its role in regulating osteogenic differentiation remains unclear. Here, the primary human BMSCs were used to induce osteogenic differentiation, and the expression of piR-36741 and METTL3 (methyltransferase like 3) was up-regulated during the osteogenic differentiation of BMSCs. Moreover, interference with piR-36741 or METTL3 markedly hindered the osteogenic differentiation of BMSCs, which was manifested by a reduction in osteoblast marker expression (including RUNX2, COL1A1, OPN and OCN), osteogenic phenotype and matrix mineralization. Mechanistically, the piR-36741-PIWIL4 complex directly interacted with METTL3 and prevented METTL3-mediated m6A modification of BMP2 mRNA transcripts, thereby promoting BMP2 expression. And overexpression of BMP2 reversed the inhibitory effect of piR-36741 silence on osteogenic differentiation and the Smad pathway activity. In addition, administration with piR-36741 mimic alleviated ovariectomy-induced osteoporosis in mice. In conclusion, piRNA-36741 overexpression promoted osteogenic differentiation of BMSCs and mitigated ovariectomy-induced osteoporosis through METTL3-mediated m6A methylation of BMP2 transcripts.
Potentiated lung adenocarcinoma (LUAD) cell growth, migration and invasion by lncRNA DARS-AS1 via miR-188-5p/ KLF12 axis
Yangyang Liu1,2, * , Lu Liang2, * , Liang Ji2, * , Fuquan Zhang1 , Donglai Chen3 , Shanzhou Duan1 , Hao Shen2 , Yao Liang2 , Yongbing Chen1
doi : 10.18632/aging.203632
Volume 13, Issue 19 pp 23376—23392
Lung adenocarcinoma (LUAD) is the most common histological type of non-small cell lung cancer (NSCLC). Due to the nonspecific early symptoms, the majority of the diagnosed LUAD patients are in the middle and late stages, with multiple metastases, and have missed the optimal period for treatment. Current studies have reported lncRNA DARS-AS1 as a cancer-promoting gene that expedites tumorigenesis. This is the first study demonstrating that DARS-AS1 is involved in the mediating process of LUAD. Cell functional experiments revealed that lncRNA DARS-AS1 participated in enhancing LUAD proliferation, invasion, and migration by inhibiting miR-188-5p. The investigation on DARS-AS1/miR-188-5p led to the discovery of KLF12 as a downstream target of miR-188-5p, and the regulatory pathway was established as DARS-AS1/miR-188-5p/KLF12. According to western blot results, DARS-AS1 promoted LUAD cell growth, migration, and invasion via stimulation of the PI3K/AKT pathway, activating the EMT process, and up-regulating the CyclinD1 and Bcl-2 proteins. This was the first report on the DARS-AS1/miR-188-5p/KLF12 axis and offered a novel strategy for early diagnosis, a new therapeutic method, and an improved prognosis for LUAD.
Cosmc transfection decreases malignant behavior of Tn+ cells and enhances sensitivity to apoptosis when induced by Apo2L/TRAIL via alteration of O-glycan structure
Ruisong Ding1, * , Xingyou Hu2, * , Wen Hu1, * , Zhenzhen Du1 , Panpan Huang1 , Mengyang Wang1 , Jiaoyue Sheng4 , Yanchao Ma1 , Ailing Wang3 , Xiying Luan1 , Menghua Dong1 , Qizhi Cao1 , Yanfen Zou5 , Tao Hu1
doi : 10.18632/aging.203633
Volume 13, Issue 19 pp 23393—23406
Cosmc mutations may cause abnormal O-glycosylation and result in Tn antigen expression. In the current study, it was discovered that proliferation and migration of Tn+ cells (Jurkat T and LS174T-Tn+ cells) with mutant Cosmc decreased after transfected Cosmc, and their sensitivity to apoptosis induced by Apo2L/TRAIL increased. Core 1-, 2-, and 3-derived O-glycans were absent in Tn+ cells. After Cosmc transfection, normal extended core 1-derived O-glycans appeared and were accompanied by increased T-synthase activity. Core 2-derived O-glycans appeared in transfected LS174T-Tn+ cells, and their structural types and levels were lower than those in LS174T-Tn? cells. Core 3-derived O-glycans were present only in LS174T-Tn? cells. The activity of C3GnT in LS174T-Tn+ cells was lower than that in LS174T-Tn? cells, and it was absent in Jurkat T cells. Cosmc transfection did not alter C3GnT activity or core 3-derived O-glycans in Jurkat T and LS174T-Tn+ cells. The results demonstrated that the composition and structure of O-glycans were different among various Tn+ cells, which not only affected cell malignant behavior but also modulated sensitivity to apoptotic stimuli. Thus, Cosmc transfection may effectively decrease the malignant behavior of Tn+ tumor cells and enhance their sensitivity to apoptosis when induced by Apo2L/TRAIL through modification of O-glycans.
Iron: an underrated factor in aging
Dennis Mangan1, &
doi : 10.18632/aging.203612
Volume 13, Issue 19 pp 23407—23415
Iron is an essential element for virtually all living organisms, but its reactivity also makes it potentially harmful. Iron accumulates with aging, and is associated with many age-related diseases; it also shortens the lifespans of several model organisms. Blocking iron absorption through drugs or natural products extends lifespan. Many life-extending interventions, such as rapamycin, calorie restriction, and old plasma dilution can be explained by the effects they have on iron absorption, excretion, and metabolism. Control of body iron stores so that they remain in a low normal range may be an important, lifespan- and healthspan-extending intervention.
Impact of aging on primary liver cancer: epidemiology, pathogenesis and therapeutics
Rocio I.R. Macias1,5 , Maria J. Monte1,5 , Maria A. Serrano1,5 , Jesús M. González-Santiago2 , Isabel Martín-Arribas2 , André L. Simão3 , Rui E. Castro3 , Javier González-Gallego4,5 , José L. Mauriz4,5 , Jose J.G. Marin1,5
doi : 10.18632/aging.203620
Volume 13, Issue 19 pp 23416—23434
Aging involves progressive physiological and metabolic reprogramming to adapt to gradual deterioration of organs and functions. This includes mechanisms of defense against pre-malignant transformations. Thus, certain tumors are more prone to appear in elderly patients. This is the case of the two most frequent types of primary liver cancer, i.e., hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Accordingly, aging hallmarks, such as genomic instability, telomere attrition, epigenetic alterations, altered proteostasis, mitochondrial dysfunction, cellular senescence, exhaustion of stem cell niches, impaired intracellular communication, and deregulated nutrient sensing can play an important role in liver carcinogenesis in the elders. In addition, increased liver fragility determines a worse response to risk factors, which more frequently affect the aged population. This, together with the difficulty to carry out an early detection of HCC and iCCA, accounts for the late diagnosis of these tumors, which usually occurs in patients with approximately 60 and 70 years, respectively. Furthermore, there has been a considerable controversy on what treatment should be used in the management of HCC and iCCA in elderly patients. The consensus reached by numerous studies that have investigated the feasibility and safety of different curative and palliative therapeutic approaches in elders with liver tumors is that advanced age itself is not a contraindication for specific treatments, although the frequent presence of comorbidities in these individuals should be taken into consideration for their management.
