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Aging, stem cells and cancer updated
Osama A. Elkashty, Arvind Hariharan, Simon D. Tran
doi : 10.18632/aging.203535
Volume 13, Issue 17 pp 20854—20855
CX3CR1 and malignant progression of glioma
Sungho Lee, Benjamin Deneen, Ganesh Rao
doi : 10.18632/aging.203536
Volume 13, Issue 17 pp 20856—20857
Regulation of p73 by Pirh2-AIP4 loop
H. Helena Wu, Rami Abou Zeinab, Roger P. Leng
doi : 10.18632/aging.203537
Volume 13, Issue 17 pp 20858—20859
Circulating acetylated polyamines correlate with Covid-19 severity in cancer patients
Mélanie Bourgin1,2,3, * , Lisa Derosa1,7,8, * , Carolina Alves Costa Silva1,7,8,9, * , Anne-Gaëlle Goubet1,7,8,9, * , Agathe Dubuisson1,7, * , François-Xavier Danlos1,9, * , Claudia Grajeda-Iglesias1,2,3 , Luigi Cerbone12,13 , Arthur Geraud11,12 , Ariane Laparra11 , Fanny Aprahamian1,2,3 , Nitharsshini Nirmalathasan1,2,3 , Frank Madeo4,5,6 , Laurence Zitvogel1,7,8,9 , Guido Kroemer1,2,3,10 , Sylvère Durand1,2,3
doi : 10.18632/aging.203525
Volume 13, Issue 17 pp 20860—20885
Cancer patients are particularly susceptible to the development of severe Covid-19, prompting us to investigate the serum metabolome of 204 cancer patients enrolled in the ONCOVID trial. We previously described that the immunosuppressive tryptophan/kynurenine metabolite anthranilic acid correlates with poor prognosis in non-cancer patients. In cancer patients, we observed an elevation of anthranilic acid at baseline (without Covid-19 diagnosis) and no further increase with mild or severe Covid-19. We found that, in cancer patients, Covid-19 severity was associated with the depletion of two bacterial metabolites, indole-3-proprionate and 3-phenylproprionate, that both positively correlated with the levels of several inflammatory cytokines. Most importantly, we observed that the levels of acetylated polyamines (in particular N1-acetylspermidine, N1,N8-diacetylspermidine and N1,N12-diacetylspermine), alone or in aggregate, were elevated in severe Covid-19 cancer patients requiring hospitalization as compared to uninfected cancer patients or cancer patients with mild Covid-19. N1-acetylspermidine and N1,N8-diacetylspermidine were also increased in patients exhibiting prolonged viral shedding (>40 days). An abundant literature indicates that such acetylated polyamines increase in the serum from patients with cancer, cardiovascular disease or neurodegeneration, associated with poor prognosis. Our present work supports the contention that acetylated polyamines are associated with severe Covid-19, both in the general population and in patients with malignant disease. Severe Covid-19 is characterized by a specific metabolomic signature suggestive of the overactivation of spermine/spermidine N1-acetyl transferase-1 (SAT1), which catalyzes the first step of polyamine catabolism.
The potential role of abnormal angiotensin-converting enzyme 2 expression correlated with immune infiltration after SARS-CoV-2 infection in the prognosis of breast cancer
Yufeng Jiang1, * , Ling Chen2, *,& , Jinsheng Shen1, & , Xiaofei Mei1 , Jialu Yao1 , Tan Chen1 , Yafeng Zhou1
doi : 10.18632/aging.203418
Volume 13, Issue 17 pp 20886—20895
The potential role of abnormal ACE2 expression after SARS-CoV-2 infection in the prognosis of breast cancer is still ambiguous. In this study, we analyzed ACE2 changes in breast cancer and studied the correlation between ACE2 and the prognosis and further analyzed the relationship between immune infiltration and the prognosis of different breast cancer subtypes. Finally, we inferred the prognosis of breast cancer patients after SARS-CoV-2 infection. We found that ACE2 expression decreased significantly in breast cancer, except for basal-like subtype. Decreased ACE2 expression level was correlated with abnormal immune infiltration and poorer prognosis of luminal B breast cancer (RFS: HR 0.76, 95%CI=0.63-0.92, p=0.005; DMFS: HR 0.70, 95%CI=0.49-1.00, p=0.046). The expression of ACE2 was strongly positively correlated with the immune infiltration level of CD8+ T cell (r=0.184, p<0.001), CD4+ T cell (r=0.104, p=0.02) and neutrophils (r=0.101, p=0.02). ACE2 expression level in the luminal subtype was positively correlated with CD8A and CD8B markers in CD8+ T cells, and CEACAM3, S100A12 in neutrophils. In conclusion, breast tumor tissues might undergo a further decrease in the expression level of ACE2 after SARS-CoV-2 infection, which could contribute to further deterioration of immune infiltration and worsen the prognosis of luminal B breast cancer after SARS-CoV-2 infection.
Prognostic value of neutrophil-to-lymphocyte ratio, lactate dehydrogenase, D-dimer, and computed tomography score in patients with coronavirus disease 2019
Yu-Qing Cai1,2, * , Xiao-Bin Zhang2, * , Hui-Qing Zeng1,2 , Xiao-Jie Wei3 , Lan Hu4 , Zhen-Yu Zhang5 , Quan Ming6 , Qiu-Ping Peng6 , Li-Da Chen7
doi : 10.18632/aging.203501
Volume 13, Issue 17 pp 20896—20905
This study aimed to explore the significance of neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), D-dimer, and CT score in evaluating the severity and prognosis of coronavirus disease 2019 (COVID-19).
High-dose vitamin C ameliorates cardiac injury in COVID-19 pandemic: a retrospective cohort study
Guozhi Xia1 , Bowen Qin2 , Chaoran Ma3 , Yaowu Zhu4 , Qiangsun Zheng1
doi : 10.18632/aging.203503
Volume 13, Issue 17 pp 20906—20914
Cardiac injury is common and associated with poor clinical outcomes in COVID-19. Data are lacking whether high-dose intravenous vitamin C (HIVC) could help to ameliorate myocardial injury in the pandemic.
Reduced uremic metabolites are prominent feature of sarcopenia, distinct from antioxidative markers for frailty
Masahiro Kameda1 , Takayuki Teruya2 , Mitsuhiro Yanagida2 , Hiroshi Kondoh1
doi : 10.18632/aging.203498
Volume 13, Issue 17 pp 20915—20934
Due to global aging, frailty and sarcopenia are increasing. Sarcopenia is defined as loss of volume and strength of skeletal muscle in elderlies, while frailty involves multiple domains of aging-related dysfunction, impaired cognition, hypomobility, and decreased social activity. However, little is known about the metabolic basis of sarcopenia, either shared with or discrete from frailty. Here we analyzed comprehensive metabolomic data of human blood in relation to sarcopenia, previously collected from 19 elderly participants in our frailty study. Among 131 metabolites, we identified 22 sarcopenia markers, distinct from 15 frailty markers, mainly including antioxidants, although sarcopenia overlaps clinically with physical frailty. Notably, 21 metabolites that decline in sarcopenia or low SMI are uremic compounds that increase in kidney dysfunction. These comprise TCA cycle, urea cycle, nitrogen, and methylated metabolites. Sarcopenia markers imply a close link between muscle and kidney function, while frailty markers define a state vulnerable to oxidative stress.
Hyperbaric oxygen therapy alleviates vascular dysfunction and amyloid burden in an Alzheimer’s disease mouse model and in elderly patients
Ronit Shapira1 , Amos Gdalyahu1 , Irit Gottfried1 , Efrat Sasson4 , Amir Hadanny4 , Shai Efrati2,3,4 , Pablo Blinder1,2 , Uri Ashery1,2
doi : 10.18632/aging.203485
Volume 13, Issue 17 pp 20935—20961
Vascular dysfunction is entwined with aging and in the pathogenesis of Alzheimer’s disease (AD) and contributes to reduced cerebral blood flow (CBF) and consequently, hypoxia. Hyperbaric oxygen therapy (HBOT) is in clinical use for a wide range of medical conditions. In the current study, we exposed 5XFAD mice, a well-studied AD model that presents impaired cognitive abilities, to HBOT and then investigated the therapeutical effects using two-photon live animal imaging, behavioral tasks, and biochemical and histological analysis. HBOT increased arteriolar luminal diameter and elevated CBF, thus contributing to reduced hypoxia. Furthermore, HBOT reduced amyloid burden by reducing the volume of pre-existing plaques and attenuating the formation of new ones. This was associated with changes in amyloid precursor protein processing, elevated degradation and clearance of Aß protein and improved behavior of 5XFAD mice. Hence, our findings are consistent with the effects of HBOT being mediated partially through a persistent structural change in blood vessels that reduces brain hypoxia. Motivated by these findings, we exposed elderly patients with significant memory loss at baseline to HBOT and observed an increase in CBF and improvement in cognitive performances. This study demonstrates HBOT efficacy in hypoxia-related neurological conditions, particularly in AD and aging.
Glutamine promotes escape from therapy-induced senescence in tumor cells
Francesco Pacifico1 , Nadia Badolati2 , Stefano Mellone1 , Mariano Stornaiuolo2 , Antonio Leonardi3 , Elvira Crescenzi1
doi : 10.18632/aging.203495
Volume 13, Issue 17 pp 20962—20991
Therapy-induced senescence (TIS) is a major cellular response to anticancer therapies. While induction of a persistent growth arrest would be a desirable outcome in cancer therapy, it has been shown that, unlike normal cells, cancer cells are able to evade the senescence cell cycle arrest and to resume proliferation, likely contributing to tumor relapse. Notably, cells that escape from TIS acquire a plastic, stem cell-like phenotype. The metabolic dependencies of cells that evade senescence have not been thoroughly studied. In this study, we show that glutamine depletion inhibits escape from TIS in all cell lines studied, and reduces the stem cell subpopulation. In line with a metabolic reliance on glutamine, escaped clones overexpress the glutamine transporter SLC1A5. We also demonstrate a central role of glutamine synthetase that mediates resistance to glutamine deprivation, conferring independence from exogenous glutamine. Finally, rescue experiments demonstrate that glutamine provides nitrogen for nucleotides biosynthesis in cells that escape from TIS, but also suggest a critical involvement of glutamine in other metabolic and non-metabolic pathways. On the whole, these results reveal a metabolic vulnerability of cancer stem cells that recover proliferation after exposure to anticancer therapies, which could be exploited to prevent tumor recurrence.
Transcriptomic analysis of elderly women with low muscle mass: association with immune system pathway
Levi H. Jales Neto1, * , Bidossessi W. Hounkpe1, * , Georgea H. Fernandes1 , Liliam Takayama1 , Valéria F. Caparbo1 , Neuza H.M. Lopes2 , Alexandre C. Pereira3 , Rosa M.R. Pereira1
doi : 10.18632/aging.203505
Volume 13, Issue 17 pp 20992—21008
Despite the well-established association of gene expression deregulation with low muscle mass (LMM), the associated biological mechanisms remain unclear. Transcriptomic studies are capable to identify key mediators in complex diseases. We aimed to identify relevant mediators and biological mechanisms associated with age-related LMM. LMM-associated genes were detected by logistic regression using microarray data of 20 elderly women with LMM and 20 age and race-matched controls extracted from our SPAH Study (GSE152073). We performed weighted gene co-expression analysis (WGCNA) that correlated the identified gene modules with laboratorial characteristics. Gene enrichment analysis was performed and an LMM predictive model was constructed using Support Vector Machine (SVM). Overall, 821 discriminating transcripts clusters were identified (|beta coefficient| >1; p-value <0.01). From this list, 45 predictors of LMM were detected by SVM and validated with 0.7 of accuracy. Our results revealed that the well-described association of inflammation, immunity and metabolic alterations is also relevant at transcriptomic level. WGCNA highlighted a correlation of genes modules involved in immunity pathways with vitamin D level (R = 0.63, p = 0.004) and the Agatston score (R = 0.51, p = 0.02). Our study generated a predicted regulatory network and revealed significant metabolic pathways related to aging processes, showing key mediators that warrant further investigation.
Glutathione is an aging-related metabolic signature in the mouse kidney
Eunyong Ahn1 , Jueun Lee1 , Jisu Han1 , Seung-Min Lee2 , Ki-Sun Kwon2,3 , Geum-Sook Hwang1,4
doi : 10.18632/aging.203509
Volume 13, Issue 17 pp 21009—21028
The ability to maintain systemic metabolic homeostasis through various mechanisms represents a crucial strength of kidneys in the study of metabolic syndrome or aging. Moreover, age-associated kidney failure has been widely accepted. However, efforts to demonstrate aging-dependent renal metabolic rewiring have been limited.
Familial longevity is associated with lower baseline bone turnover but not differences in bone turnover in response to rhTSH
Ana Zutinic1 , Ferdinand Roelfsema2 , Hanno Pijl2 , Bart E. Ballieux3 , Rudi G.J. Westendorp4 , Gerard J. Blauw1 , Diana van Heemst1
doi : 10.18632/aging.203511
Volume 13, Issue 17 pp 21029—21039
Offspring from long-lived families have a different thyroid status than controls, characterised by higher circulating levels of thyroid stimulating hormone (TSH) and similar levels of thyroid hormone. Expression of the TSH receptor has previously been observed on various extrathyroidal tissues, including bone. However, potential physiological consequences of differences in circulating TSH as observed in familial longevity on bone tissue remain unclear.
Knock-down of odr-3 and ife-2 additively extends lifespan and healthspan in C. elegans
Ioan Valentin Matei1, * , Vimbai Netsai Charity Samukange1, * , Gabriela Bunu1 , Dmitri Toren1,2 , Simona Ghenea1, * , Robi Tacutu1, *
doi : 10.18632/aging.203518
Volume 13, Issue 17 pp 21040—21065
Genetic manipulations can ameliorate the aging process and extend the lifespan of model organisms. The aim of this research was to identify novel genetic interventions that promote both lifespan and healthspan, by combining the effects of multiple longevity-associated gene inactivations in C. elegans. For this, the individual and combined effects of the odr-3 mutation and of ife-2 and cku-70 knock-downs were studied, both in the wild type and daf-16 mutant backgrounds. We found that besides increasing the lifespan of wild type animals, the knock-down of ife-2 (starting at L4) also extends the lifespan and healthspan of long-lived odr-3 mutants. In the daf-16 background, ife-2 and odr-3 impairment exert opposing effects individually, while the daf-16; odr-3; ife-2 deficient animals show a similar lifespan and healthspan as daf-16, suggesting that the odr-3 and ife-2 effector outcomes converge downstream of DAF-16. By contrast, cku-70 knock-down did not extend the lifespan of single or double odr-3; ife-2 inactivated animals, and was slightly deleterious to healthspan. In conclusion, we report that impairment of odr-3 and ife-2 increases lifespan and healthspan in an additive and synergistic manner, respectively, and that this result is not improved by further knocking-down cku-70.
Sex-specific differences in DNA double-strand break repair of cycling human lymphocytes during aging
Melanie Rall-Scharpf1 , Thomas W.P. Friedl1 , Shahar Biechonski2 , Michael Denkinger3 , Michael Milyavsky2 , Lisa Wiesmüller1
doi : 10.18632/aging.203519
Volume 13, Issue 17 pp 21066—21089
The gender gap in life expectancy and cancer incidence suggests differences in the aging process between the sexes. Genomic instability has been recognized as a key factor in aging, but little is known about sex-specific differences. Therefore, we analyzed DNA double-strand break (DSB) repair in cycling human peripheral blood lymphocytes (PBL) from male and female donors of different age. Reporter-based DSB repair analyses revealed differential regulation of pathway usage in PBL from male and female donors with age: Non-homologous end joining (NHEJ) was inversely regulated in men and women; the activity of pathways requiring end processing and strand annealing steps such as microhomology-mediated end joining (MMEJ) declined with age in women but not in men. Screening candidate proteins identified the NHEJ protein KU70 as well as the end resection regulatory factors ATM and BLM showing reduced expression during aging in women. Consistently, the regulatory factor BLM contributed to the MMEJ proficiency in young but not in old women as demonstrated by knockdown analysis. In conclusion, we show that DSB repair is subject to changes upon aging and age-related changes in DSB repair are distinct in men and women.
Effect of the Notch1-mediated PI3K-Akt-mTOR pathway in human osteosarcoma
Kexiang Zhang1 , Song Wu1 , Hongwei Wu2 , Li Liu1 , Jiahui Zhou1
doi : 10.18632/aging.203261
Volume 13, Issue 17 pp 21090—21101
Osteosarcoma is one of the most common malignant bone tumours in early adolescence. The incidence rate of osteosarcoma has stagnated over the past 30 years, highlighting the need to develop novel therapies. In osteosarcoma cells, Notch1 expression is absent, and the Notch1 pathway is related to cancer cell proliferation, apoptosis and autophagy. Our study aimed to investigate the role of Notch1 in osteosarcoma development.
Bortezomib enhances the anti-cancer effect of the novel Bruton’s tyrosine kinase inhibitor (BGB-3111) in mantle cell lymphoma expressing BTK
Xianhuo Wang1, * , Yue Fei1, * , Xia Liu1, * , Tingting Zhang1, * , Wei Li1, * , Xiaohui Jia1 , Xianming Liu1 , Lihua Qiu1 , Zhengzi Qian1 , Shiyong Zhou1 , Xiubao Ren2 , Qiongli Zhai3 , Bin Meng3 , Lanfang Li1, & , Huilai Zhang1, &
doi : 10.18632/aging.203314
Volume 13, Issue 17 pp 21102—21121
BGB-3111, a novel Bruton’s tyrosine kinase (BTK) inhibitor, shows promising anti-cancer effects in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), and Waldenstrom macroglobulinemia (WM). This study aimed to investigate the anti-cancer effects of BGB-3111 combined with bortezomib (BTZ) against the BTK-expressing MCL. We found that BTK, which was overexpressed in 59.4% of patients with MCL, was mainly characterized by high Ki67 and elevated MIPI scores. BGB-3111 strongly inhibited cell proliferation, induced cell cycle arrest in the G1/G0-phase, and promoted cell apoptosis in the MCL cells expressing BTK. BGB-3111 provides better safety than another BTK inhibitor, ibrutinib as ibrutinib inhibits the inducible T-cell kinase (ITK) as an off-target effect but BGB-3111 does not inhibit ITK. Low doses of BTZ enhanced the anti-cancer effect induced by the low dose of BGB-3111 by downregulating the expression levels of PARP and Bcl-2 and increasing the expression levels of cleaved PARP and cleaved caspase-9. In addition, low doses of BGB-3111, but not of BTZ, inhibited BTK phosphorylation. However, low-doses of BTZ strengthened the anti-cancer effect induced by the low-doses of BGB-3111 via synergistically suppressing the I?B? and P65 phosphorylation. Taken together, our findings validate that BGB-3111 is a novel and effective BTK inhibitor for MCL-expressing BTK. Hence, it can be harnessed as a potential therapeutic strategy through a combinatorial treatment comprising low-dose BGB-3111 and low-dose BTZ to gain strong anti-cancer effects and better safety for MCL patients.
Circular RNA ZNF609 enhances proliferation and glycolysis during glioma progression by miR-378b/SLC2A1 axis
Zhihuang Zhao1 , Gang Li1 , Yonggang Han1 , Yabin Li1 , Zhisheng Ji1 , Rui Guo2 , Xiaohong Yu3
doi : 10.18632/aging.203331
Volume 13, Issue 17 pp 21122—21133
Glioma is a prevalent brain malignancy with aggressive progression and with grave prognosis in adults. Circular RNAs have been reported to regulate glioma development and function as the diagnostic, prognostic, and therapeutic biomarkers. In this study, we were interested the function of circular RNA ZNF609 in modulating glioma. Remarkably, knockdown of ZNF609 by siRNA in glioma cells reduced cell viabilities and Edu-positive. The silencing of ZNF609 stimulated the apoptosis of glioma cells. Meanwhile, the ZNF609 depletion inhibited the invasion and migration of glioma cells. In glioma cells, the mRNA and protein expression of E-cadherin was enhanced, while Vimentin was reduced by the inhibition of ZNF609. The glucose uptake, lactate product, and ATP production in glioma cells were suppressed by ZNF609 knockdown. Mechanically, miR-378b was sponged by ZNF609 and targeted SLC2A1 in glioma cells. ZNF609 enhanced SLC2A1 expression by inhibiting miR-378b. The inhibition of miR-378b or the enhancement of SLC2A1 reversed ZNF609 depletion-regulated glioma cell proliferation in vitro. The depletion of ZNF609 suppressed glioma cell growth in the nude mice. Therefore, we concluded that ZNF609 contributed to cell survival and glycolysis of glioma by targeting miR-378b/SLC2A1 axis. ZNF609 and miR-378b may function as potential treatment targets in glioma.
RNA N6-methyladenosine demethylase FTO promotes osteoporosis through demethylating Runx2 mRNA and inhibiting osteogenic differentiation
Jing Wang1,2, *,# , Qiang Fu3, *,# , Jian Yang2, *,# , Jin-Long Liu4, *,# , Shu-Ming Hou2 , Xing Huang2 , Jia-Shi Cao2 , Tie-Long Liu2 , Kun-Zheng Wang1
doi : 10.18632/aging.203377
Volume 13, Issue 17 pp 21134—21141
As a systemic disease, osteoporosis (OP) results in bone density loss and fracture risk, particularly in the hip and vertebrae. However, the underlying molecular mechanisms of OP development have not been fully illustrated. N6-Methyladenosine (m6A) is the most abundant modification of mRNAs, which is involved in many of pathological processes in aging disease. However, its role and regulatory mechanism in OP remains unknown. Here, we aimed to investigate the roles of m6A and its demethylase FTO in OP development. The results showed that m6A methylated RNA level was up-regulated in the bone marrow mesenchymal stem cells (BMSCs) from patients with OP. The level of N6-methyladenosine demethylase FTO was consistently decreased in the BMSCs from patients with OP. Functionally, lentivirus-mediated FTO overexpression in normal BMSCs to compromised osteogenic potential. Mechanism analysis further suggested that FTO overexpression decreased the m6A methylated and total level of runt related transcription factor 2 (Runx2) mRNA, subsequently inhibited osteogenic differentiation. We found that FTO inhibition could effectively improve the bone formation in ovariectomized osteoporotic mice in vivo. Together, these results reveal that RNA N6-methyladenosine demethylase FTO promotes osteoporosis through demethylating runx2 mRNA and inhibiting osteogenic differentiation.
Serglycin promotes proliferation, migration, and invasion via the JAK/STAT signaling pathway in osteosarcoma
Bin Lv1,2,3,4, * , Guangyu Gao5, * , Yuhong Guo1,2,3,4, * , Zhiping Zhang1,2,3 , Renfeng Liu1,2,3,4 , Zhengzai Dai1,2,3,4 , Cheng Ju6 , Yiping Liang1 , Xiaofeng Tang1 , Min Tang7 , Xiao-Bin Lv1
doi : 10.18632/aging.203392
Volume 13, Issue 17 pp 21142—21154
Osteosarcoma (OS) is a common disease in the world, and its pathogenesis is still unclear. This study aims to identify the key genes that promote the proliferation, invasion, and metastasis of osteosarcoma cells.
Liver-specific over-expression of Cripto-1 in transgenic mice promotes hepatocyte proliferation and deregulated expression of hepatocarcinogenesis-related genes and signaling pathways
Yu Liu1,2, * , Yan-Qing Li3, * , Shi-Hao Huang1, * , Yong-Long Li1,2, * , Jia-Wei Xia4, * , Jun-Shuang Jia1, * , Fang Wei1 , Jia-Hong Wang1 , Guan-Qi Dai1 , Yu-Cai Wang1 , Xiao-Yan Li1,2 , Liu-Xin Han4 , Xiao-Ling Zhang5 , Xu-Dong Xiang6 , Wen-Tao Zhao7 , Dong Xiao1,2 , Xiao-Lin Lin1
doi : 10.18632/aging.203402
Volume 13, Issue 17 pp 21155—21190
In this study, we investigated the role of embryonic gene Cripto-1 (CR-1) in hepatocellular carcinoma (HCC) using hepatocyte-specific CR-1-overexpressing transgenic mice. The expression of truncated 1.7-kb CR-1 transcript (SF-CR-1) was significantly higher than the full-length 2.0-kb CR-1 transcript (FL-CR-1) in a majority of HCC tissues and cell lines. Moreover, CR-1 mRNA and protein levels were significantly higher in HCC tissues than adjacent normal liver tissues. Hepatocyte-specific over-expression of CR-1 in transgenic mice enhanced hepatocyte proliferation after 2/3 partial hepatectomy (2/3 PHx). CR-1 over-expression significantly increased in vivo xenograft tumor growth of HCC cells in nude mice and in vitro HCC cell proliferation, migration, and invasion. CR-1 over-expression in the transgenic mouse livers deregulated HCC-related signaling pathways such as AKT, Wnt/?-catenin, Stat3, MAPK/ERK, JNK, TGF-? and Notch, as well as expression of HCC-related genes such as CD5L, S100A8, S100A9, Timd4, Orm2, Orm3, PDK4, DMBT1, G0S2, Plk2, Plk3, Gsta1 and Gsta2. However, histological signs of precancerous lesions, hepatocyte dysplasia or HCC formation were not observed in the livers of 3-, 6- or 8-month-old hepatocyte-specific CR-1-overexpressing transgenic mice. These findings demonstrate that liver-specific CR-1 overexpression in transgenic mice deregulates signaling pathways and genes associated with HCC.
LncRNA PITPNA-AS1 promotes gastric cancer by increasing SOX4 expression via inhibition of miR-92a-3p
Licheng Liu1 , Anna Dai2 , Zao Zhang3 , Meiying Ning3 , Dong Han3 , Li Li3 , Zhuangzhuang Li3
doi : 10.18632/aging.203403
Volume 13, Issue 17 pp 21191—21201
Gastric cancer (GC) is a malignant tumor of digestive tract with high mortality. Elucidating the molecular mechanisms of GC and obtaining new molecular targets are particularly important for the prevention and treatment of GC. The discovery of long non-coding RNAs (lncRNAs) provides the possibility for further elucidating the molecular mechanisms of GC and discovering new molecular markers.
UPF1 impacts on mTOR signaling pathway and autophagy in endometrioid endometrial carcinoma
Minfen Zhang1,3, * , Hui Chen1, * , Ping Qin1 , Tonghui Cai1 , Lingjun Li1 , Ruichao Chen1 , Shaoyan Liu1 , Hui Chen3 , Wanrun Lin4 , Hao Chen4 , Amanda L. Strickland5 , Hanzhen Xiong1, & , Qingping Jiang1,2
doi : 10.18632/aging.203421
Volume 13, Issue 17 pp 21202—21215
Most EEC cases are associated with activities of the mTOR pathway, which regulates protein synthesis, cell growth and autophagy. While Up-Frameshift 1(UPF1) is a key protein factor in the nonsense-mediated mRNA degradation pathway (NMD), its role in carcinogenesis of EEC remains unclear. In this study, we first evaluated the expression level of UPF1 in EEC tissues and cell lines. Then, we investigated the effect of UPF1 on cellular function and mTOR signaling pathway; these effects were further validated in vivo. Finally, its effect on autophagy was evaluated by western blot and GFP-mRFP-LC3 staining. UPF1 expression in the EEC tissue samples was significantly higher than that of matched normal tissue samples. Overexpression of UPF1 promoted migration and invasion of EEC cells. Conversely, depletion of UPF1 suppressed migration and invasion of EEC cells. In addition, overexpression of UPF1 increased the in vivo growth of our EEC xenograft tumors. Finally, UPF1 increased the activity of the mTOR/P70S6K/4EBP1 signaling pathway and inhibited autophagy in EEC cells. These findings suggest that UPF1 functions as an oncogene to promote EEC carcinogenesis. Our findings propose UPF1 as a new potential therapeutic target for EEC.
Dual roles of WISP2 in the progression of hepatocellular carcinoma: implications of the fibroblast infiltration into the tumor microenvironment
Qingan Jia1 , Yaoyao Zhang1 , Binghui Xu1 , Xia Liao2 , Yang Bu3 , Zihan Xu4 , Xianglong Duan5 , Qiangbo Zhang6,7
doi : 10.18632/aging.203424
Volume 13, Issue 17 pp 21216—21231
The dismal outcome of hepatocellular carcinoma (HCC) patients is attributable to high frequency of metastasis and. Identification of effective biomarkers is a key strategy to inform prognosis and improve survival. Previous studies reported inconsistent roles of WISP2 in carcinogenesis, while the role of WISP2 in HCC progression also remains unclear. In this study, we confirmed that WISP2 was downregulated in HCC tissues, and WISP2 was acting as a protective factor, especially in patients without alcohol intake using multiple online datasets. In addition, we reported that upregulation of WISP2 in HCC was related to inhibition of the malignant phenotype in vitro, but these alterations were not observed in vivo. WISP2 also negatively correlated with tumour purity, and increased infiltration of fibroblasts promoted malignant progression in HCC tissues. The enhanced infiltration ability of fibroblasts was related to upregulated HMGB1 after overexpression of WISP2 in HCC. The findings shed light on the anticancer role of WISP2, and HMGB1 is one of the key factors involved in the inhibition of the efficiency of WISP2 through reducing the tumour purity with fibroblast infiltration.
LncRNA SNHG17 promotes tumor progression and predicts poor survival in human renal cell carcinoma via sponging miR-328-3p
Jie Wu1 , Gang Dong1 , Tingting Liu1 , Shaojin Zhang2 , Lulu Sun1 , Weijie Liang3
doi : 10.18632/aging.203440
Volume 13, Issue 17 pp 21232—21250
Accumulating data shows that dysregulation of long non-coding RNAs (lncRNAs) are involved in human tumors' occurrence and progression. Small nucleolar RNA host genes (SNHGs) are recently revealed to play a carcinogenic role in various human neoplasms. However, the functions and underlying mechanisms of lncRNA SNHG17 in renal cell carcinoma (RCC) are still elusive. We analyzed the relationship between SNHG17 expression levels and clinicopathologic characteristics and prognosis in patients with RCC according to TCGA RNA-sequencing data and our cohort data. Loss-of-function and gain-of-function experiments were conducted to examine the biological behaviors of SNHG17 on RCC cell proliferation, migration, invasion, apoptosis, and tumor growth in vivo. The interaction between SNHG17, miR-328-3p, and Histone’sH2Avariant (H2AX) was verified by bioinformatics, dual-luciferase reporter gene, and RNA immunoprecipitation (RIP). Highly expressed SNHG17 was evident in RCC tissue samples and cell lines, and SNHG17 overexpression was related to advanced TNM stage and reduced relapse-free and overall survival of patients with RCC. Knockdown of SNHG17 prohibited malignant phenotypes, whereas ectopic SNHG17 expression showed the opposite effects. More importantly, SNHG17 could upregulate the expression of H2AX by acting as a miR-328-3p sponge. In vivo experiments confirmed that SNHG17 promoted the growth of RCC tumors. SNHG17/miR-328-3p/H2AXaxis might be involved in RCC progression, which provided a potential therapeutic target for RCC.
Betulinic acid induces autophagy-dependent apoptosis via Bmi-1/ROS/AMPK-mTOR-ULK1 axis in human bladder cancer cells
Yan Zhang1, * , Ning He1, * , Xuejian Zhou1 , Feifan Wang1 , Hairong Cai1 , Shih Han Huang1 , Xianwu Chen1 , Zhenghui Hu1 , Xiaodong Jin1
doi : 10.18632/aging.203441
Volume 13, Issue 17 pp 21251—21267
Betulinic acid (BA), a pentacyclic triterpenoid isolated from tree bark, exhibits antitumor effects against solid malignancies and triggers autophagy and/or apoptosis in human cancer cells. Nonetheless, the relationship between autophagy and apoptosis and the potential modulatory actions of BA on autophagy-dependent bladder cancer cell death remain unclear. The present study showed that BA exposure significantly suppressed viability, proliferation, and migration of EJ and T24 human bladder cancer cells. These effects reflected caspase 3-mediated apoptosis and could be attenuated or abolished by inhibiting ROS production with N-acetyl-L-cysteine, inhibiting autophagy with chloroquine, or silencing ATG7 with targeted siRNA. BA-induced autophagy was evidenced by epifluorescence imaging of lentivirus-induced expression of mCherry-GFP-LC3B and increased expression of two autophagy-related proteins, LC3B-II and TEM. Moreover, enhanced AMPK phosphorylation and decreased mTOR and ULK-1 phosphorylation suggested BA activates autophagy via the AMPK/mTOR/ULK1 pathway. Accordingly, exposure to dorsomorphin (Compound C), an AMPK inhibitor, and AICAR, an AMPK activator, respectively inhibited and stimulated BA-induced autophagy in EJ and T24 cells. The effects of Bmi-1 overexpression in vitro and decreased Bmi-1 expression in BA-treated T24 cell xenografts in nude mice suggested that downregulation of Bmi-1 is the underlying mechanism in BA-mediated, autophagy-dependent apoptosis.
Celecoxib reverses the glioblastoma chemo-resistance to temozolomide through mitochondrial metabolism
Delong Yin1, * , Guoqing Jin2, * , Hong He3 , Wei Zhou1 , Zhenbo Fan1 , Chen Gong4 , Jing Zhao4 , Huihua Xiong4
doi : 10.18632/aging.203443
Volume 13, Issue 17 pp 21268—21282
Temozolomide (TMZ) is used for the treatment of high-grade gliomas. Acquired chemoresistance is a serious limitation to the therapy with more than 90% of recurrent gliomas showing little response to a second line of chemotherapy. Therefore, it is necessary to explore an alternative strategy to enhance the sensitivity of glioblastoma (GBM) to TMZ in neuro-oncology. Celecoxib is well known and widely used in anti-inflammatory and analgesic. Cyclooxygenase-2 (COX-2) expression has been linked to the prognosis, angiogenesis, and radiation sensitivity of many malignancies such as primitive neuroectodermal tumor and advanced melanoma. The objective of this study was to explore the chemotherapy-sensitizing effect of celecoxib on TMZ in GBM cells and its potential mechanisms. From the study, we found that the combination therapy (TMZ 250uM+celecoxib 30uM) showed excellent inhibitory effect to the GBM, the LN229 and LN18, which were the TMZ resistant GBM cell lines. Our data suggest that the combination therapy may inhibits cell proliferation, increases apoptosis, and increases the autophagy on LN229 and LN18. The potential molecular mechanisms were related to mitochondrial metabolism and respiratory chain inhibition.
RUFY3 promotes the progression of hepatocellular carcinoma through activating NF-?B-mediated epithelial-mesenchymal transition
Yang Zhang1,2 , Weixing Ni2 , Lei Qin1
doi : 10.18632/aging.203444
Volume 13, Issue 17 pp 21283—21293
RUFY3 (RUN and FYVE domain-containing protein 3) has been demonstrated to exhibit carcinogenic effect in multiple malignancies. However, the exact role of RUFY3 in hepatocellular carcinoma (HCC) progression remains elusive. Herein, we aimed to identify the role and the underlying mechanism of RUFY3 in HCC progression. The RUFY3 levels in HCC specimens were detected by qRT-PCR, western blot, and immunohistochemistry, and its clinical significance in HCC patients was assessed. The effect of RUFY3 on HCC cell growth, migration, and invasion was explored by CCK-8 assay, wound healing assay, and transwell migration and invasion assays in vitro. The effect of RUFY3 on HCC cell growth and metastasis was also conducted in vivo through establishing xenograft tumor and lung metastatic mice model. The underlying mechanism responsible for RUFY3-induced HCC cell behavior was also investigated. Our results indicated that high levels of RUFY3 significantly correlated with tumor size, microvascular invasion, clinical stage, and poor prognosis for HCC patients. In addition, RUFY3 facilitated HCC cell growth, invasion, and metastasis both in vitro and in vivo through activating nuclear factor-?-gene binding (NF-?B)-mediated epithelial-mesenchymal transition (EMT). Taken together, our results revealed that RUFY3 accelerated HCC progression via driving NF-?B-mediated EMT, suggesting a novel target for HCC treatment.
PPM1D is a potential prognostic biomarker and correlates with immune cell infiltration in hepatocellular carcinoma
Zhangtao Yu1,2,3, * , Yinghui Song1,2,3,4, * , Mengting Cai5 , Bo Jiang1,2,3 , Zhihua Zhang1,2,3 , Le Wang1,2,3 , Yu Jiang1,2,3 , Lianhong Zou6 , Xiehong Liu6 , Nanhui Yu6 , Xianhai Mao1,2,3 , Chuang Peng1,2,3 , Sulai Liu1,2,3,4
doi : 10.18632/aging.203459
Volume 13, Issue 17 pp 21294—21308
Protein phosphatase magnesium-dependent 1 delta (PPM1D), also referred to as wild-type p53-induced phosphatase 1 (Wip1) or protein phosphatase 2C delta (PP2C?), is an oncogenic nuclear serine/threonine phosphatase belonging to the PP2C family. However, the knowledge regarding PPM1D mRNA expression, tumor immunity, and the prognosis in hepatocellular carcinoma (HCC) is scanty.
Activation of the gut microbiota-kynurenine-liver axis contributes to the development of nonalcoholic hepatic steatosis in nondiabetic adults
Guoyuan Sui1, *,# , Lianqun Jia1, *,# , Dongmei Quan2 , Na Zhao1 , Guanlin Yang1
doi : 10.18632/aging.203460
Volume 13, Issue 17 pp 21309—21324
The contribution of gut-liver signaling to the development of non-alcoholic hepatic steatosis (NHS) in non-diabetic adults remains unclear. We therefore performed comprehensive 16S ribosomal RNA sequencing and fecal metabolomics analyses in 32 controls and 59 non-diabetic adults with NHS and performed fecal microbiota transplantation into germ-free mice using controls and NHS patients as donors. Compared to controls, the abundance of the genera Collinsella and Acinetobacter were higher, while that of Lachnospira was lower, in NHS subjects. Fecal metabolomics analysis showed decreased L-tryptophan levels and increased abundance of the tryptophan metabolite kynurenine in individuals with NHS. Correlation analysis showed that kynurenine levels positively associated with the abundance of Collinsella and Acinetobacter. ROC analysis demonstrated that the combination of tryptophan and kynurenine could discriminate NHS patients from controls with good statistical power [P < 0.05; AUC = 0.833 (95% CI, 0.747 to 0.918)]. Supporting a key role of dysbiotic gut microbiota in NHS development, incipient hepatic steatosis and increased kynurenine levels were observed in GF mice colonized with samples from NHS patients. These results indicate that enhanced kynurenine production resulting from altered gut microbiota composition contributes to NHS in nondiabetic adults and suggest the relevance of tryptophan metabolites as diagnostic biomarkers.
Knockdown of PSMC2 contributes to suppression of cholangiocarcinoma development by regulating CDK1
Xiaohui Duan1,2,3 , Jianhui Yang1,2,3 , Bo Jiang1,2,3 , Wenbin Duan1,2,3 , Rongguang Wei1,2,3 , Hui Zhang1,2,3 , Xianhai Mao1,2,3,4
doi : 10.18632/aging.203463
Volume 13, Issue 17 pp 21325—21344
Cholangiocarcinoma (CCA) has been well known as the second most common primary tumor of hepatobiliary system. PSMC2 (proteasome 26S subunit ATPase 2) is a key member of the 19S regulatory subunit of 26S proteasome, responsible for catalyzing the unfolding and translocation of substrates into the 20S proteasome, whose role in CCA is totally unknown. In this study, the results of immunohistochemistry analysis showed the upregulation of PSMC2 in CCA tissues compared with normal tissues, which was statistically analyzed to be associated with CCA tumor grade. Subsequently, the loss-of-function study suggested that knockdown of PSMC2 significantly suppressed cell proliferation, cell migration, promoted cell apoptosis and arrested cell cycle distribution in vitro. The decreased tumorigenicity of CCA cells with PSMC2 knockdown was confirmed in vivo by using mice xenograft model. In PSMC2 knockdown cells, pro-apoptotic protein Caspase3 was upregulated; anti-apoptotic proteins such as Bcl-2 and IGF-II were downregulated; among EMT markers, E-cadherin was upregulated while N-cadherin and Vimentin were downregulated, by which may PSMC2 regulates cell apoptosis and migration. Furthermore, through RNA-seq and verification by qPCR, western blotting and co-IP assays, CDK1 was identified as the potential downstream of PSMC2 mediated regulation of CCA. PSMC2 and CDK1 showed mutual regulation effects on expression level of each other. Knockdown of PSMC2 could aggregate the influence of CDK1 knockdown on cellular functions of CCA cells. In summary, our findings suggested that PSMC2 possesses oncogene-like functions in the development and progression of CCA through regulating CDK1, which may be used as an effective therapeutic target in CCA treatment.
Up-regulation of circARF3 reduces blood-brain barrier damage in rat subarachnoid hemorrhage model via miR-31-5p/MyD88/NF-?B axis
Li Cai1 , Beihai Ge2 , Shengbo Xu1 , Xiangwen Chen1 , Hong Yang1
doi : 10.18632/aging.203468
Volume 13, Issue 17 pp 21345—21363
Inflammation events have been found to aggravate brain injury and blood-brain barrier (BBB) damage following subarachnoid hemorrhage (SAH). This study probed the role and mechanism of a novel circRNA, circARF3, in regulating the BBB injury in SAH rats and hypoxia-induced vascular endothelial cell (VEC) injury in vitro. Levels of circARF3 and miR-31-5p were monitored by RT-PCR. The expression of inflammatory factors IL-1? and TNF-? was verified by ELISA. In vivo SAH model was constructed in Sprague Dawley (SD) rats. The BBB integrity and cerebral edema, as well as the neurological functions of the rats were evaluated. The apoptotic neurons and microglia in brain lesions were examined by immunohistochemistry (IHC). The MyD88/NF-?B pathway was tested by Western blot. Furthermore, gain-of functional assay were constructed to explore the effects of circARF3 and miR-31-5p in primary cultured brain microvascular endothelial cell (BMEC) injury and microglial inflammation induced by oxygen and glucose deprivation (OGD). circARF3 was significantly down-regulated in plasma and CSF in SAH patients with higher Fisher stages. In the SAH rat model, overexpressing circARF3 improved BBB integrity and neurological score, decreased neuronal apoptosis and microglial activation in ipsilateral basal cortex, with declined miR-31-5p expression and MyD88-NF-?B activation. In vitro, overexpressing circARF3 attenuated OGD-mediated integrity destruction of BMECs and microglial induced neuroinflammation, while overexpressing miR-31-5p had opposite effects. Mechanistically, circARF3 sponged miR-31-5p as an endogenous competitive RNA and dampens its expression, thus inactivating MyD88-NF-?B pathway. CircARF3 attenuates BBB destruction in SAH rats by regulating the miR-31-5p-activated MyD88-NF-?B pathway.
Deferoxamine accelerates endothelial progenitor cell senescence and compromises angiogenesis
Yi-Nan Lee1,2 , Hsueh-Hsiao Wang3 , Cheng-Huang Su1,2,3 , Hsin-I Lee3 , Yen-Hung Chou3,4 , Chin-Ling Hsieh1,2 , Wen-Ting Liu1,2 , Kuo-Tung Shu1,2 , Kai-Ting Chang1,2 , Hung-I Yeh1,2,3 , Yih-Jer Wu1,2,3,4
doi : 10.18632/aging.203469
Volume 13, Issue 17 pp 21364—21384
Senescence reduces the circulating number and angiogenic activity of endothelial progenitor cells (EPCs), and is associated with aging-related vascular diseases. However, it is very time-consuming to obtain aged cells (~1 month of repeated replication) or animals (~2 years) for senescence studies. Here, we established an accelerated senescence model by treating EPCs with deferoxamine (DFO), an FDA-approved iron chelator. Four days of low-dose (3 ?M) DFO induced senescent phenotypes in EPCs, including a senescent pattern of protein expression, impaired mitochondrial bioenergetics, altered mitochondrial protein levels and compromised angiogenic activity. DFO-treated early EPCs from young and old donors (< 35 vs. > 70 years old) displayed similar senescent phenotypes, including elevated senescence-associated ?-galactosidase activity and reduced relative telomere lengths, colony-forming units and adenosine triphosphate levels. To validate this accelerated senescence model in vivo, we intraperitoneally injected Sprague-Dawley rats with DFO for 4 weeks. Early EPCs from DFO-treated rats displayed profoundly senescent phenotypes compared to those from control rats. Additionally, in hind-limb ischemic mice, DFO pretreatment compromised EPC angiogenesis by reducing both blood perfusion and capillary density. DFO thus accelerates EPC senescence and appears to hasten model development for cellular senescence studies.
Identification and validation of a ferroptosis-related gene signature predictive of prognosis in breast cancer
Qin Liu1, * , Jian-Ying Ma2, * , Gaosong Wu1
doi : 10.18632/aging.203472
Volume 13, Issue 17 pp 21385—21399
Ferroptosis, a novel form of regulated cell death, is closely associated with the occurrence and development of malignant tumors. Here, we utilized a bioinformatics approach to identify ferroptosis-related genes to establish a robust and reliable prognostic signature in breast cancer (BC). Univariate Cox regression and LASSO regression analyses of patient’s survival and gene expression data identified a prognostic signature consisting of 10 ferroptosis-related genes (FRGs). The signature demonstrated a favorable prediction performance, and was validated in two independent datasets, GSE21653 and GSE25066. Analyses of immune infiltrates, tumor microenvironment, immune checkpoints, mutations, drug sensitivity, and clinicopathological features revealed significant differences between low- and high-risk BC patients. A multivariate analysis revealed that the signature was an independent prognostic predictor in BC, and a nomogram combining the risk score and tumor stage intuitively displayed high accuracy and reliability with respect to predicting the survival outcomes of BC patients. These findings indicate that the identified prognostic signature is a potential indicator predictive of prognosis and immunotherapeutic responses in BC patients.
Baseline beliefs about medication are associated with outcomes of antidepressants in inpatients with first-diagnosed depression under supervised therapeutic compliance
Fan-Zhen Kong1, * , Cai-Fang Ji1, * , Xiang-Dong Du1, * , Robert Logan2, * , Hui-Ying Zhao1 , Guan-Hui Wu3 , Yan-Song Liu1 , Zhen Tang1 , Mei-E Niu4
doi : 10.18632/aging.203477
Volume 13, Issue 17 pp 21400—21407
The aim of the present study was to explore the effect of baseline beliefs about medication on therapeutic outcomes of antidepressants in inpatients with first-diagnosed depression under supervised therapeutic compliance. Ninety-seven inpatients with first-diagnosed depression were included to collect their baseline demographic data to evaluate the Hamilton depression rating scale (HAMD) scores and the beliefs about medicine questionnaire-specific (BMQ-S) scores at baseline and the end of the eight-week treatment. Additionally, we explored the relationship between inpatients’ medication beliefs and therapeutic effect of antidepressants. The inpatients were divided into remitted depression and unremitted depression groups according to outcomes at the end of the eight-week treatment. There was no significant difference in the baseline HAMD between the two groups (P > 0.050). The scores on the BMQ-S of the unremitted group were significantly lower than those of the remitted group (P < 0.001). The HAMD scores were significantly reduced in both groups after the eight-week treatment (P < 0.001). There was no significant difference in the BMQ-S scores before and after the treatment (P > 0.050). The medication beliefs of the unremitted inpatients after the treatment were still lower than those of the remitted inpatients (P < 0.001). Logistic-regression analysis showed that low BMQ-S scores at the baseline were an independent risk factor for antidepressant efficacy. Beliefs about medication at baseline may be correlated with the therapeutic efficacy in inpatients with first-diagnosed depression under supervised therapeutic compliance.
Blood transfusion practices affect CD4+ CD25+ FOXP3+ regulatory T cells/T helper-17 cells and the clinical outcome of geriatric patients with hip fracture
Ling Wang1,2, * , Wei Chen3, * , Fu-Biao Kang4, * , Ya-Hui Zhang3 , Li-Li Qi5 , Ying-Ze Zhang2,3
doi : 10.18632/aging.203479
Volume 13, Issue 17 pp 21408—21420
Hip fracture (HF) is common among older individuals and associated with high mortality, poor vitality and functional impairment. HF patients suffer whole body immunological changes and that lead to severe consequences, including immobilization, physical impairment and a high risk of complications. The objective of this study was to decipher the pattern of dynamic immunological changes, especially in two major T cell subsets, CD4+ CD25+ FOXP3+ regulatory T (Treg) cells and T helper-17 (Th17) cells, and their balance, during the hospital stay and to observe whether blood transfusion could influence these cells and clinical patietns’ prognosis. In this study, ninety-eight consecutive HF patients were initially enrolled, and finally fifty-one patients qualified for the study, and correlation analysis of their clinical parameters was carried out to predict the meaning of their distribution in clinical practice. Our results showed that the frequency of Tregs gradually decreased, while the frequency of Th17 cells slowly increased in HF patients who received blood transfusion. The Treg frequency was inversely correlated with the level of hemoglobin (Hb), and Th17 cell frequency was positively related to fluctuations in Hb levels in HF patients after trauma. HF patients with a better prognosis and survival time showed decreased a Treg frequency and a decreased Treg/Th17 ratio. Transfusion helped reverse the imbalance in the frequencies of Tregs and Th17 cells and the Treg/Th17 ratio and especially contributed to a better outcome in HF patients with moderate-to-severe anemia. In conclusion, a higher frequency of peripheral blood Tregs and a higher Treg/Th17 ratio may be associated with unfavorable outcomes in HF patients, and blood transfusion may benefit moderate-to-severe HF patients rebalance their immune response.
Low lean mass is associated with lower urinary tract symptoms in US men from the 2005–2006 national health and nutrition examination survey dataset
Zheng Qin1,2,3 , Junjie Zhao4 , Jiameng Li1,2,3 , Qinbo Yang1,2,3 , Jiwen Geng1,2,3 , Ruoxi Liao1,2,3 , Baihai Su1,2,3
doi : 10.18632/aging.203480
Volume 13, Issue 17 pp 21421—21434
We investigated the relationship between low lean mass (LLM) and lower urinary tract symptoms (LUTS) using the 2005–2006 National Health and Nutrition Examination Survey (NHANES) dataset. We enrolled 959 men with an average age of 52.08 ± 7.91 years and performed weighted multiple regression analysis to determine the independent relationship between exposure variables (LLM, alternate LLM) and outcomes variables (urinary hesitancy, incomplete emptying, urinary frequency, nocturia, daytime LUTS, clinical LUTS) after adjusting for confounding factors. The prevalence of urinary hesitancy (OR = 7.76, P < 0.0001), incomplete emptying (OR = 2.49, P = 0.0070), urinary frequency (OR = 3.28, P < 0.0001), daytime LUTS (OR = 3.88, P < 0.0001) and clinical LUTS (OR = 8.11, P < 0.0001) was significantly higher among men with LLM compared to men without LLM. Moreover, alternate LLM (ALLM) was positively associated with urinary hesitancy (OR = 17.97, P < 0.0001), incomplete emptying (OR = 4.68, P = 0.0003), daytime LUTS (OR = 2.47, P = 0.0136) and clinical LUTS (OR = 12.18, P < 0.0001). These findings demonstrate that both LLM and ALLM were associated with a higher risk of LUTS in men aged ? 40 years, which suggested that early management and treatment of lean mass loss may improve or alleviate LUTS.
MiR-185-5p targets RAB35 gene to regulate tumor cell-derived exosomes-mediated proliferation, migration and invasion of non-small cell lung cancer cells
Hongqing Wen1, * , Zhiyan Liu1, * , Jingjing Tang1 , Lina Bu1
doi : 10.18632/aging.203483
Volume 13, Issue 17 pp 21435—21450
Non-small cell lung cancer (NSCLC) is the most common malignant tumor, and its recurrence and metastasis are the main causes of death. Recently, there is evidence that tumor derived exosomes play an important role in the occurrence and development of NSCLC.
Identification and epidemiological evaluation of gastric cancer risk factors: based on a field synopsis and meta-analysis in Chinese population
Fujiao Duan1,2,4 , Chunhua Song1,2 , Jiachen Shi3 , Peng Wang1,2 , Hua Ye1,2 , Liping Dai1,2 , Jianying Zhang1,2 , Kaijuan Wang1,2
doi : 10.18632/aging.203484
Volume 13, Issue 17 pp 21451—21469
To summarize and assess the credibility and strength of non-genetic factors and genetic variation on gastric cancer risk, we performed a field synopsis and meta-analysis to identify the risk of gastric cancer in Chinese population. Cumulative evidence was graded according to the Venice criteria, and attributable risk percentage (ARP) and population attributable risk percentage (PARP) were used to evaluate the epidemiological effect. A total of 956 studies included non-genetic (404 studies) and genetic factors (552 studies) were quantified, and data on 1161 single nucleotide polymorphisms (SNPs) were available. We identified 14 non-genetic factors were significantly associated with gastric cancer risk. For the analysis of time trends, H. pylori infection rate in gastric cancer and population showed a downward trend. Meanwhile 22 variants were identified significantly associated with gastric cancer: 3 (PLCE1 rs2274223, PSCA rs2976392, MUC1 rs4072037) were high and 19 SNPs were intermediate level of summary evidence, respectively. For non-genetic factors, the top three for ARP were 54.75% (pickled food), 65.87% (stomach disease), and 49.75% (smoked and frying). For PARP were 34.22% (pickled food), 34.24% (edible hot food) and 23.66%(H. pylori infection). On the basis of ARP and PARP associated with SNPs of gastric cancer, the top three for ARP were 53.91% (NAT2, rs1799929),53.05% (NAT2 phenotype), and 42.85% (IL-10, rs1800896). For PARP (Chinese Han in Beijing) were 36.96% (VDR, rs731236), 25.58% (TGFBR2, rs3773651) and 20.56% (MUC1, rs4072037). Our study identified non-genetic risk factors and high-quality biomarkers of gastric cancer susceptibility and their contribution to gastric cancer.
SCFAs promote intestinal double-negative T cells to regulate the inflammatory response mediated by NLRP3 inflammasome
Shuiliang Ruan1 , Liping Zhai2 , Shasha Wu3 , Caiqun Zhang3 , Qiaobing Guan2
doi : 10.18632/aging.203487
Volume 13, Issue 17 pp 21470—21482
Short-chain fatty acids (SCFAs) are a product of intestinal bacteria metabolism. Our previous study has found that intestinal bacteria in patients with Alzheimer’s disease (AD) can promote the activation of NLRP3 inflammasome and mediate neuroinflammation. In this study, we mainly explored the regulation of intestinal microenvironmental immunity by intestinal bacterial metabolite SCFAs and the mechanism of NLRP3 activation. First, wild-type (WT) and APP/PS1 mice were intervened with SCFAs. As a result, the proportion of double-negative T cells (CD3+CD4?CD8?, DNTs) in the intestine was increased, SCFAs could promote the expression of intestinal NLRP3 and inflammatory factors (IL-18, IL-6 and TNF-?). Moreover, SCAFs could also promote the level of inflammatory factors in the cerebrospinal fluid (CSF) of mice and aggravate the cognitive impairment in AD mice. CD3+ T cells isolated from the spleen were pre-treated with SCFAs, followed by detection of the proportion of DNTs. Consequently, SCFAs could promote the formation of DNTs, activate OX40 signal and simultaneously up-regulate the protein expression of Bcl-2, Bcl-xl and Survivin. Knockdown of OX40 could inhibit SCFAs-induced differentiation of DNTs. The co-culture of DNTs and intestinal macrophages showed that DNTs could activate Fas/FasL-TNF-? signal and induce the activation of NLRP3 inflammasome. In AD mouse models, treatment with Fas and TNFR1 inhibitors could significantly inhibit SCFAs-induced NLRP3 activation and inflammatory factors, while attenuate the inflammatory response in the brain tissue of mice and improve the cognitive ability of mice, however, without significant effect on the level of DNTs.
2,5-dimethyl celecoxib induces apoptosis and autophagy via activation of ROS/JNK axis in nasopharyngeal carcinoma cells
Tan Tan1,2, * , Xiangjie Fu3, * , Jiaquan Qu4 , Miao Zhang1 , He Chen1 , Yaochun Wang1 , Bo Wang1 , Juan Li1 , Jie Liu1 , Peijun Liu1
doi : 10.18632/aging.203488
Volume 13, Issue 17 pp 21483—21496
2,5-dimethyl celecoxib (DMC), a close derivative of celecoxib, has also been reported to have anticancer effects. However, the effects and underlying molecular mechanisms of DMC with respect to nasopharyngeal carcinoma are still largely unknown. In this study, we present that DMC has displayed anticancer potency in nasopharyngeal carcinoma in vitro and in vivo. Mechanistically, we found DMC induced apoptosis and autophagy for anticancer therapy against nasopharyngeal carcinoma. Furthermore, DMC-induced autophagy could remarkably attenuate after the treatment of reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) and c-Jun N-terminal kinase (JNK) inhibitor SP600125 (SP). Taken together, these results suggested DMC induced apoptosis and autophagic death via activation of ROS/JNK axis in NPC cells, which providing us new insights into developing potential therapeutic agents for nasopharyngeal carcinoma patients.
m6A demethylase ALKBH5 suppression contributes to esophageal squamous cell carcinoma progression
Dong Xiao1,2,3,5, * , Ting-Xiao Fang4, * , Ye Lei1,2,3, * , Sheng-Jun Xiao6, * , Jia-Wei Xia7, * , Tao-Yan Lin3,8 , Yong-Long Li1,2,3 , Jian-Xue Zhai4 , Xiao-Yan Li1,2 , Shi-Hao Huang3 , Jun-Shuang Jia3 , Yu-Guang Tian1,2 , Xiao-Lin Lin3 , Kai-Can Cai4, & , Yan Sun9
doi : 10.18632/aging.203490
Volume 13, Issue 17 pp 21497—21512
Esophageal squamous cell carcinoma (ESCC) is a highly malignant gastrointestinal cancer with a high recurrence rate and poor prognosis. Although N6-methyladenosine (m6A), the most abundant epitranscriptomic modification of mRNAs, has been implicated in several cancers, little is known about its participation in ESCC progression. We found reduced expression of ALKBH5, an m6A demethylase, in ESCC tissue specimens with a more pronounced effect in T3-T4, N1-N3, clinical stages III–IV, and histological grade III tumors, suggesting its involvement in advanced stages of ESCC. Exogenous expression of ALKBH5 inhibited the in vitro proliferation of ESCC cells, whereas depletion of endogenous ALKBH5 markedly enhanced ESCC cell proliferation in vitro. This suggests ALKBH5 exerts anti-proliferative effects on ESCC growth. Furthermore, ALKBH5 overexpression suppressed tumor growth of Eca-109 cells in nude mice; conversely, depletion of endogenous ALKBH5 accelerated tumor growth of TE-13 cells in vivo. The growth-inhibitory effects of ALKBH5 overexpression are partly attributed to a G1-phase arrest. In addition, ALKBH5 overexpression reduced the in vitro migration and invasion of ESCC cells. Altogether, our findings demonstrate that the loss of ALKBH5 expression contributes to ESCC malignancy.
Converting health risks into loss of life years - a paradigm shift in clinical risk communication
Shan Pou Tsai1 , Chi Pang Wen2,3 , Min Kuang Tsai2 , Po Jung Lu2 , Jackson Pui Man Wai4 , Christopher Wen5 , Wayne Gao6 , Xifeng Wu7,8
doi : 10.18632/aging.203491
Volume 13, Issue 17 pp 21513—21525
For facilitating risk communication in clinical management, such a ratio-based measure becomes easier to understand if expressed as a loss of life expectancy. The cohort, consisting of 543,410 adults in Taiwan, was recruited between 1994 and 2008. Health risks included lifestyle, biomarkers, and chronic diseases. A total of 18,747 deaths were identified. The Chiang’s life table method was used to estimate a loss of life expectancy. We used Cox regression to calculate hazard ratios (HRs) for health risks. The increased mortality from cardio-metabolic risks such as high cholesterol (HR=1.10), hypertension (HR=1.48) or diabetes (HR=2.02) can be converted into a loss of 1.0, 4.4, and 8.9 years in life expectancy, respectively. The top 20 of the 30 risks were associated with a loss of 4 to 10 years of life expectancy, with 70% of the cohort having at least two such risk factors. Smoking, drinking, and physical inactivity each had 5-7 years loss. Individuals with diabetes or an elevated white count had a loss of 7-10 years, while prolonged sitting, the most prevalent risk factor, had a loss of 2-4 years. Those with diabetes (8.9 years) and proteinuria (9.1 years) present at the same time showed a loss of 16.2 years, a number close to the sum of each risk. Health risks, expressed as life expectancy loss, could facilitate risk communication. The paradigm shift in expressing risk intensity can help set public health priorities scientifically to promote a focus on the most important ones in primary care.
Calorie intake rather than food quantity consumed is the key factor for the anti-aging effect of calorie restriction
Yaru Liang1 , Yuqi Gao1 , Rui Hua1 , Maoyang Lu1 , Huiling Chen1 , Zhuoran Wang2 , Liyuan Li1 , Kaiqiang Hu1 , Yuemiao Yin1 , Kang Xu1 , Hongqi Gao3 , Qingfei Liu1 , Ying Qiu3 , Zhao Wang1
doi : 10.18632/aging.203493
Volume 13, Issue 17 pp 21526—21546
Although calorie restriction has been reported to extend lifespan in several organisms, animals subjected to calorie restriction consume not only fewer calories but also smaller quantities of food. Whether it is the overall restriction of calories or the coincidental reduction in the quantity of food consumed that mediates the anti-aging effects is unclear. Here, we subjected mice to five dietary interventions. We showed that both calorie and quantity restriction could improve early survival, but no maximum lifespan extension was observed in the mice fed isocaloric diet in which food quantity was reduced. Mice fed isoquant diet with fewer calories showed maximum lifespan extension and improved health among all the groups, suggesting that calorie intake rather than food quantity consumed is the key factor for the anti-aging effect of calorie restriction. Midlife liver gene expression correlations with lifespan revealed that calorie restriction raised fatty acid biosynthesis and metabolism and biosynthesis of amino acids but inhibited carbon metabolism, indicating different effects on fatty acid metabolism and carbohydrate metabolism. Our data illustrate the effects of calories and food quantity on the lifespan extension by calorie restriction and their potential mechanisms, which will provide guidance on the application of calorie restriction to humans.
HSP90 acts as a senomorphic target in senescent retinal pigmental epithelial cells
Dan-Dan Chen1 , Xuyan Peng1 , Yuxuan Wang1 , Mingjun Jiang1 , Mengjiao Xue1 , Guohui Shang4 , Xuhui Liu1 , Xiaolin Jia1 , Baixue Liu1 , Yingwei Lu1 , Hongmei Mu3 , Fengyan Zhang1 , Yanzhong Hu1,2,3
doi : 10.18632/aging.203496
Volume 13, Issue 17 pp 21547—21570
The senescence of retinal pigment epithelial (RPE) cells is associated with age-related macular degeneration (AMD), a leading cause of blindness in the world. HSP90 is a predominant chaperone that regulates cellular homeostasis under divergent physio-pathological conditions including senescence. However, the role of HSP90 in senescent RPE cells still remains unclear. Here, we reported that HSP90 acts as a senomorphic target of senescent RPE cells in vitro. Using H2O2-induced senescent ARPE-19 cells and replicative senescent primary RPE cells from rhesus monkey, we found that HSP90 upregulates the expression of IKK?, and HIF1? in senescent ARPE-19 cells and subsequently controls the induction of distinct senescence-associated inflammatory factors. Senescent ARPE-19 cells are more resistant to the cytotoxic HSP90 inhibitor IPI504 (IC50 = 36.78 ?M) when compared to normal ARPE-19 cells (IC50 = 6.16 ?M). Administration of IPI504 at 0.5–5 ?M can significantly inhibit the induction of IL-1?, IL-6, IL-8, MCP-1 and VEGFA in senescent ARPE-19 and the senescence-mediated migration of retinal capillary endothelial cells in vitro. In addition, we found that inhibition of HSP90 by IPI504 reduces SA-?-Gal’s protein expression and enzyme activity in a dose-dependent manner. HSP90 interacts with and regulates SA-?-Gal protein stabilization in senescent ARPE-19 cells. Taken together, these results suggest that HSP90 regulates the SASP and SA-?-Gal activity in senescent RPE cells through associating with distinctive mechanism including NF-?B, HIF1? and lysosomal SA-?-Gal. HSP90 inhibitors (e.g. IPI504) could be a promising senomorphic drug candidate for AMD intervention.
TNFSF9 promotes metastasis of pancreatic cancer through Wnt/Snail signaling and M2 polarization of macrophages
Jiao Wu1 , Yunpeng Wang2 , Yichun Yang1 , Fuqiang Liu1 , Jun Chen1 , Zhongxiang Jiang1 , Zheng Jiang1
doi : 10.18632/aging.203497
Volume 13, Issue 17 pp 21571—21586
Early metastasis of pancreatic cancer (PC) leads to high mortality, and the underlying mechanism of metastasis remains unclear. Tumor necrosis factor superfamily member 9 (TNFSF9) is associated with poor prognosis in PC. Here, we investigated the effect of TNFSF9 on PC proliferation and apoptosis, and focused on the effect of TNFSF9 on PC metastasis and its potential mechanism. We found that TNFSF9 promotes PC metastasis in vivo and in vitro, and may be partially dependent on the Wnt/Snail signaling pathway. In addition, TNFSF9 also regulates the release of cytokines IL-10 and transforming growth factor-? (TGF-?) in pancreatic cancer cells through Wnt signaling to induce the M2 polarization of macrophages and promote the migration of PC cells. Overall, our study found that TNFSF9 may directly promote PC metastasis or indirectly promote PC metastasis through macrophage M2 polarization. Our study provides a new costimulatory target for the treatment of PC.
FOXN3 inhibits cell proliferation and invasion via modulating the AKT/MDM2/p53 axis in human glioma
Chaojia Wang1 , Hanjun Tu2 , Ling Yang3 , Chunming Ma4 , Juntao Hu1 , Jie Luo1 , Hui Wang1
doi : 10.18632/aging.203499
Volume 13, Issue 17 pp 21587—21598
This study aimed to evaluate the biological role of forkhead box N3 (FOXN3) in human glioma and clarify the possible molecular mechanisms. FOXN3 expression patterns in clinical tissue specimens were characterized via qPCR and Western blotting. Kaplan-Meier survival curve was applied to assess the correlation between FOXN3 expression and overall survival. Effects of FOXN3 over-expression and depletion on glioma cell proliferation, apoptosis, migration and invasion were assessed by CCK8, colony formation assay, flow cytometry, scratch wound healing assay and Transwell invasion assay, respectively. Moreover, the involvement of AKT/murine double minute 2 (MDM2)/p53 pathway was evaluated. Additionally, tumor transplantation model assay was performed to determine the effects of FOXN3 over-expression on glioma cell growth in vivo. Results showed that FOXN3 was significantly down-regulated in glioma tissues compared with normal tissues. Patients with lower FOXN3 expression exhibited a shorter overall survival time. Gain- and loss-of-function analyses demonstrated that FOXN3 over-expression significantly suppressed proliferation, survival and motility of glioma cells, whereas FOXN3 knockdown remarkably promoted glioma cell proliferation, survival and motility. Furthermore, FOXN3 over-expression inhibited the activation of AKT/MDM2/p53 signaling pathway in glioma cells, while FOXN3 depletion facilitated its activation. Additionally, tumor xenograft assays revealed that FOXN3 over-expression retarded glioma cell growth in vivo. Collectively, these findings indicate that FOXN3 inhibits cell growth and invasion through inactivating the AKT/MDM2/p53 signaling pathway and that FOXN3-AKT/MDM2/p53 axis may represent a novel therapeutic target for glioma patients.
Association between tooth loss rate and risk of mild cognitive impairment in older adults: a population-based longitudinal study
Shuyu Xu1 , Xi Huang2 , Yin Gong2 , Jiangwei Sun3
doi : 10.18632/aging.203504
Volume 13, Issue 17 pp 21599—21609
Mild cognitive impairment (MCI) is a symptomatic predementia phase of the trajectory of cognitive decline, and its prevalence increases with age. Although the relationship between oral health and MCI have been explored previously, it is uncertain whether individuals with different tooth loss rates have altered MCI risks. We hereby conducted a longitudinal study by using data from the Chinese Longitudinal Healthy Longevity Survey to investigate the association. Tooth loss rate was defined as the difference of teeth between two interview waves divided by years of interval; participants were then grouped into four categories: stable, no tooth loss; mild, 0-1 tooth loss; middle, 1-2 tooth loss; and severe, more than 2 tooth loss per year. Cognitive function was assessed by the Chinese version of Mini-Mental State Examination. We used the generalized estimating equation model to estimate the odds ratio (OR) and the 95% confidence intervals (CIs) and applied the restricted cubic spline function to explore the dose-response association. Among 11,862 participants, 3,966 developed MCI in a median follow-up time of 5.93 years. Higher tooth loss rate was associated with an increased risk of MCI in elderly subjects. Compared with subjects with stable tooth, the corresponding ORs (95% CIs) were 0.94 (0.85-1.03), 1.16 (1.04-1.29) and 1.28 (1.17-1.40) for subjects with the mild, middle and severe rate of tooth loss. A nonlinear dose-response relationship was detected (Pnon-linearity = 0.0165). Similar results were observed in the subgroup analyses stratified by sex, age at baseline, and number of teeth at baseline. The positive association was only observed among denture nonwearers (OR middle vs stable: 1.19; 1.06-1.35; OR severe vs stable: 1.35; 1.22-1.50), but not among denture wearers. In conclusion, among elderly population in China, higher rate of tooth loss may be associated with an increased risk of MCI, while denture wearers may be less likely to develop MCI.
Genome-wide identification of altered RNA m6A profiles in vascular tissue of septic rats
Zhu-Jun Shen1 , Ye-Chen Han1 , Mu-Wen Nie1 , Yi-Ning Wang1 , Ruo-Lan Xiang2 , Hong-Zhi Xie1
doi : 10.18632/aging.203506
Volume 13, Issue 17 pp 21610—21627
Sepsis is the leading cause of death in hospital intensive care units. In light of recent studies showing that variations in N6-methyladenosine (m6A) levels in different RNA transcripts influence inflammatory responses, we evaluated the m6A profiles of rat aortic mRNAs and lncRNAs after lipopolysaccharide (LPS)-induced sepsis. LC-MS-based mRNA modification analysis showed that global m6A levels were significantly decreased in aortic tissue of rats injected intraperitoneally with LPS. This finding was consistent with downregulated expression of METTL3 and WTAP, two members of the m6A writer complex, in LPS-exposed aortas. Microarray analysis of m6A methylation indicated that 40 transcripts (31 mRNAs and 9 lncRNAs) were hypermethylated, while 223 transcripts (156 mRNAs and 67 lncRNAs) were hypomethylated, in aortic tissue from LPS-treated rats. On GO and KEGG analyses, ‘complement and coagulation cascades’, ‘transient receptor potential channels’, and ‘organic anion transmembrane transporter activity’ were the major biological processes modulated by the differentially m6A methylated mRNAs. In turn, competing endogenous RNA network analysis suggested that decreased m6A levels in lncRNA-XR_343955 may affect the inflammatory response through the cell adhesion molecule pathway. Our data suggest that therapeutic modulation of the cellular m6A machinery may be useful to preserve vascular integrity and function during sepsis.
Development and validation of a clinical model (DREAM-LDL) for post-stroke cognitive impairment at 6 months
Yi Dong1 , Mengyuan Ding1 , Mei Cui1 , Min Fang2 , Li Gong2 , Zhuojun Xu3 , Yue Zhang3 , Xiuzhe Wang4 , Xiaofeng Xu4 , Xueyuan Liu2 , Gang Li3 , Yuwu Zhao4 , Qiang Dong1
doi : 10.18632/aging.203507
Volume 13, Issue 17 pp 21628—21641
This multicenter, retrospective study assessed the prevalence of post-stroke cognitive impairment (PSCI) 6 months after acute ischemic stroke (AIS) and its risk factors to build a bedside early predictive model for PSCI using the Montreal Cognitive Assessment (MoCA).
Astrocyte-derived exosomes protect hippocampal neurons after traumatic brain injury by suppressing mitochondrial oxidative stress and apoptosis
Wenqian Zhang1,2 , Jun Hong1,2 , Hanwen Zhang1,3 , Wencheng Zheng4 , Ying Yang5
doi : 10.18632/aging.203508
Volume 13, Issue 17 pp 21642—21658
In this study, we investigated the mechanisms through which astrocyte-derived exosomes (AS-Exos) alleviate traumatic brain injury (TBI)-induced neuronal defects in TBI model rats and mice. Treatment with AS-Exos alleviated neurobehavioral deficits, cognitive impairment, and brain edema in TBI rats. AS-Exos also significantly reduced neuronal cell loss and atrophy in the TBI rats. AS-Exos significantly reduced oxidative stress and mitochondrial H2O2 levels by increasing the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) in the hippocampal neurons of TBI rats. TUNEL-staining assays showed that AS-Exos significantly reduced TBI-induced neuronal apoptosis. Mechanistically, AS-Exos ameliorated oxidative stress by activating Nrf2/HO-1 signaling in the hippocampus of TBI rats. In addition, the neuroprotective effects of AS-Exos were abrogated in brain-specific Nrf2-knockout mice subjected to TBI. These findings demonstrate that AS-Exos protects against TBI-induced oxidative stress and neuronal apoptosis by activating Nrf2 signaling in both rat and mouse models.
Alternation of brain intrinsic activity in patients with hypertensive retinopathy: a resting-state fMRI study
Jin-Yu Hu2, * , Hui-Ye Shu1, * , Qiu-Yu Li1, * , Shi-Nan Wu1 , Rong-Bin Liang1 , Qian-Min Ge1 , Li-Juan Zhang1 , Yi-Cong Pan1 , Yi Shao1
doi : 10.18632/aging.203510
Volume 13, Issue 17 pp 21659—21670
To investigate the changes of amplitude of low-frequency fluctuation (ALFF) in brain regions of patients with hypertensive retinopathy by using resting-state functional magnetic resonance imaging (rs-fMRI) and change in the relationship of ALFF value with potential emotional and psychological changes.
Integrated analysis identifies TfR1 as a prognostic biomarker which correlates with immune infiltration in breast cancer
Fei Chen1, * , Yumei Fan1, * , Jiajie Hou1 , Bing Liu1 , Bo Zhang1 , Yanan Shang1 , Yanzhong Chang1 , Pengxiu Cao1 , Ke Tan1
doi : 10.18632/aging.203512
Volume 13, Issue 17 pp 21671—21699
Breast cancer (BC) is the most common malignancy with high morbidity and mortality in females worldwide. Emerging evidence indicates that transferrin receptor 1 (TfR1) plays vital roles in regulating cellular iron import. However, the distinct role of TfR1 in BC remains elusive. TfR1 expression was investigated using the TCGA, GEO, TIMER, UALCAN and Oncomine databases. The prognostic potential of TfR1 was evaluated by Kaplan-Meier (KM) plotter and univariate and multivariate Cox regression analyses. Moreover, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) were used to explore the molecular mechanism of TfR1. The potential link between TfR1 expression and infiltrating abundances of immune cells was examined through the TIMER and CIBERSORT algorithm. The expression of TfR1 was dramatically upregulated in BC tissues. Increased TfR1 expression and decreased methylation levels of TfR1 were strongly correlated with multiple clinicopathological parameters. Elevated TfR1 expression was associated with a poor survival rate in BC patients. The nomogram model further confirmed that TfR1 could act as an independent prognostic biomarker in BC. The results of GO, KEGG and GSEA revealed that TfR1 was closely correlated with multiple signaling pathways and immune responses. Additionally, TfR1 was positively associated with the infiltration abundances of six major immune cells, including CD4+ T cells, CD8+ T cells, B cells, neutrophils, macrophages, and dendritic cells in BC. Interestingly, TfR1 influenced prognosis partially through immune infiltration. These comprehensive bioinformatics analyses suggest that TfR1 is a new independent prognostic biomarker and a potential target for immunotherapy in BC.
Effect of different exercise training intensities on age-related cardiac damage in male mice
Zuowei Pei1,2 , Chenguang Yang1 , Ying Guo1 , Min Dong1 , Fang Wang1
doi : 10.18632/aging.203513
Volume 13, Issue 17 pp 21700—21711
Aging is the most important risk factor for cardiovascular diseases. Although exercise is known to be beneficial for the health of aging heart, the optimal exercise training intensity to prevent natural aging-induced cardiac damage has not been defined. In this study, we used 32-week-old male mice and randomly divided them into three groups, namely, untrained (UNT) mice, moderate-intensity exercise training (MET) mice, and high-intensity interval training (HIIT) mice. Mice in the two exercise training groups were subjected to exercise 5 days per week for 24 consecutive weeks. Metabolic characteristics, cardiac function and morphology, myocardial remodeling, myocardial fibrosis (collagen III, ?-SMA, and TGF-?), oxidative stress (NRF2, HO-1, SOD, and NOX4), and apoptosis (BAX, Bak, Bcl-2, and Bcl-XL) were analyzed 24 weeks after the different treatments. MET improved cardiac function and reduced myocardial remodeling, myocardial fibrosis, and oxidative stress in the aging heart. MET treatment exerted an anti-apoptotic effect in the heart of the aging mice. Importantly, HIIT did not protect against cardiac damage during the natural aging process. These findings suggest that MET may be one of the main methods to prevent cardiac damage induced by natural aging.
The ceRNA PVT1 inhibits proliferation of ccRCC cells by sponging miR-328-3p to elevate FAM193B expression
Guohai Xie1,2,3, * , Xinyi Zheng4, * , Zhong Zheng5, * , Ruoyu Wu5 , Zhixian Yao5 , Wenjie Huang5 , Feng Sun5 , Xingyu Mu5 , Ke Wu5 , Junhua Zheng2,5, &
doi : 10.18632/aging.203514
Volume 13, Issue 17 pp 21712—21728
Clear cell renal cell carcinoma (ccRCC) is a common and fatal malignancy. Long noncoding RNAs (lncRNAs) have emerged as crucial biomarkers and regulators in many cancers, warranting the detailed investigation of their biological functions and molecular mechanisms. In this study, we explored the role and mechanism of plasmacytoma variant translocation 1 (PVT1), a competitive endogenous RNA (ceRNA) in ccRCC tissues in vitro and in vivo. We found that PVT1 is upregulated in ccRCC cells and promoted cell proliferation. Bioinformatic analysis, dual-luciferase reporter assays, argonaute 2-RNA immunoprecipitation (AGO2-RIP), quantitative PCR arrays, western blot assay, and rescue experiments were conducted to explore the underlying mechanisms of PVT1. Our analyses revealed that miR-328-3p was a direct target of PVT1 and that FAM193B was a direct target of miR-328-3p. FAM193B is upregulated in ccRCC tissues and promotes cell proliferation by activating the MAPK/ERK and PI3K/AKT pathways. Our results indicated that PVT1 promotes ccRCC cells proliferation by sponging miR-328-3p to upregulate FAM193B and activate the MAPK/ERK and PI3K/AKT pathways. Collectively, these results suggest that PVT1- miR-328-3p-FAM193B loop could serve as a potential biomarker and therapeutic target for ccRCC.
Cytokine antibody array-based analysis of IL-37 treatment effects in asthma
Shengnan Gao1,2 , Jingru Wang4 , Qing Zhang1,2 , Jun Shu3 , Chunxiao Li4 , Hongwen Li4 , Jiangtao Lin1,2, &
doi : 10.18632/aging.203515
Volume 13, Issue 17 pp 21729—21742
Asthma is driven by group 2 innate lymphoid cells, antigen-specific CD4+ T helper type 2 cells and their cytokines such as interleukin (IL)-4, IL-5, IL-13. IL-37 is decreased in asthma and negatively related to Th2 cytokines and other pro-inflammatory cytokines. Our study showed that IL-37 level in asthmatic peripheral blood mononuclear cells was lower than in healthy. Further, IL-37 was negatively correlated with exhaled nitric oxide, asthma control test score, atopy and rhinitis history in asthmatics. Then an OVA-induced asthma mice model treated with rhIL-37 was established. An antibody array was employed to uncover altered cytokines induced by IL-37 in mice lung tissue. 20 proteins differentially expressed after rhIL-37 treatment and five of them were validated in asthmatic peripheral blood mononuclear cells. Consistent with cytokine antibody array, CCL3, CCL4, CCL5 decreased after IL-37 administration. While CXCL9 and CXCL13 were no change. We concluded that IL-37 reduce asthmatic symptoms by inhibit pro-inflammatory cytokine such as CCL3, CCL4, CCL5.
lncRNA HCG11 suppresses human osteosarcoma growth through upregulating p27 Kip1
Jie Gu1 , Bo Dai1 , Xuchao Shi1 , Zhennian He1 , Yuanlin Xu1 , Xiangqian Meng2 , Junlan Zhu3
doi : 10.18632/aging.203517
Volume 13, Issue 17 pp 21743—21757
Osteosarcoma (OS) is a common malignant bone cancer threatening children and young adults. Emerging evidence indicates that long non-coding RNAs (lncRNAs) play crucial roles in the progression of OS. Herein, we want to clarify the roles of lncRNA human leukocyte antigen complex group 11 (HCG11) in OS. Our data revealed that HCG11 expression is decreased in OS, which is a result of transcriptional repression of YY1. Low HCG11 level is closely associated with larger tumor size and shorter overall survival of OS patients. HCG11 negatively regulates cell proliferation, cell cycle, DNA replication in vitro and tumor growth in vivo. HCG11 can raise p27 Kip1 expression via binding to miR-942-5p and IGF2BP2, and p27 Kip1 acts as a key effector for HCG11 exerting biological functions. In conclusion, HCG11 is downregulated in OS, and restrains OS growth both in vitro and in vivo by raising p27 Kip1 expression via binding to miR-942-5p and IGF2BP2.
The upregulated expression of RFC4 and GMPS mediated by DNA copy number alteration is associated with the early diagnosis and immune escape of ESCC based on a bioinformatic analysis
Jing Wang1, * , Fei-Fei Luo1, * , Tie-Jun Huang3 , Yan Mei1 , Li-Xia Peng1 , Chao-Nan Qian1,2 , Bi-Jun Huang1
doi : 10.18632/aging.203520
Volume 13, Issue 17 pp 21758—21777
Esophageal squamous cell carcinoma (ESCC) is a malignant tumor that commonly occurs worldwide. Usually, Asia, especially China, has a high incidence of esophageal cancer. ESCC often has a poor outcome because of a late diagnosis and lack of effective treatments.
Transfection of STAT3 overexpression plasmid mediated through recombinant lentivirus promotes differentiation of bone marrow mesenchymal stem cells into neural cells in fetal rats with spina bifida aperta
Mingyu Jiang1 , Jiale Feng1 , Rong Fu2 , Yanbo Pan3 , Xu Liu4 , Jicheng Dai1 , Chunming Jiang1 , Yunpeng Hao5 , Mingyong Ren1
doi : 10.18632/aging.203524
Volume 13, Issue 17 pp 21778—21790
We investigated the influence of signal transducer and activator of transcription-3 (STAT3) on the spinal cord tissue grafts of rat fetuses with spina bifida aperta. In particular, we hoped to identify whether transfection of the STAT3 overexpression plasmid increases the survival of spinal cord transplantation in order to improve therapeutic efficacy. The fetal rat model of spina bifida aperta was established using retinoic acid and treated with a microsurgical injection of bone marrow mesenchymal stem cells (BMSCs). The animals were divided into either the blank control group, negative control group or the experimental group. The optical density (OD) value of BMSCs viability was determined using the Cell Counting Kit-8 (CCK-8). The expression of STAT3, phosphorylated STAT3 (pSTAT3), neural markers and apoptosis-related factors were evaluated using real-time PCR and Western blot. The OD value in the experimental group was highest at eight hours after transplantation using CCK-8. The expression of pSTAT3, glial fibrillary acidic protein, neuron-specific enolase, neurofilament and nestin in the experimental group was significantly higher compared to the blank control group and negative control group (P<0.05). However, STAT3 expression in the experimental group was statistically significantly decreased (P<0.05). The relative expression of caspase-8 and bcl-2 in the experimental group were significantly lower compared to the blank control group and negative control group (P<0.05). Transfection of the recombinant lentivirus-mediated STAT3 overexpression plasmid with BMSCs can help improve the efficiency of transforming into neural cells and provide new seed cells for the treatment of congenital spina bifida aperta.
Involvement of cerebrovascular abnormalities in the pathogenesis and progression of Alzheimer’s disease: an adrenergic approach
Song Li1,2, * , Che Wang3, * , Zhen Wang4 , Jun Tan5
doi : 10.18632/aging.203482
Volume 13, Issue 17 pp 21791—21806
Alzheimer’s disease (AD), as the most common neurodegenerative disease in elder population, is pathologically characterized by ?-amyloid (A?) plaques, neurofibrillary tangles composed of highly-phosphorylated tau protein and consequently progressive neurodegeneration. However, both A? and tau fails to cover the whole pathological process of AD, and most of the A?- or tau-based therapeutic strategies are all failed. Increasing lines of evidence from both clinical and preclinical studies have indicated that age-related cerebrovascular dysfunctions, including the changes in cerebrovascular microstructure, blood-brain barrier integrity, cerebrovascular reactivity and cerebral blood flow, accompany or even precede the development of AD-like pathologies. These findings may raise the possibility that cerebrovascular changes are likely pathogenic contributors to the onset and progression of AD. In this review, we provide an appraisal of the cerebrovascular alterations in AD and the relationship to cognitive impairment and AD pathologies. Moreover, the adrenergic mechanisms leading to cerebrovascular and AD pathologies were further discussed. The contributions of early cerebrovascular factors, especially through adrenergic mechanisms, should be considered and treasured in the diagnostic, preventative, and therapeutic approaches to address AD.
Retraction: Downregulation of microRNA-218 is cardioprotective against cardiac fibrosis and cardiac function impairment in myocardial infarction by binding to MITF
Linfeng Qian1 , Shaobo Pan2 , Liping Shi1 , Yongyi Zhou1 , Lai Sun1 , Zhedong Wan1 , Yufang Ding2 , Jia Qian2
doi : 10.18632/aging.203548
Volume 13, Issue 17 pp 21807
