One-year access to more than 500 world journals available in the system
-
http://medilib.ir
- Duration of Time : 365 Day
Price : 300$- Special Price : 100$
Elevated metallothionein expression in long-lived species
Marco Malavolta, Kamil Pabis
doi : 10.18632/aging.203831
Volume 14, Issue 1 pp 1—3
AMP-activated protein kinase-dependent nuclear localization of glyceraldehyde 3-phosphate dehydrogenase in senescent human diploid fibroblasts
Jee Young Sohn1, * , Hyeok-Jin Kwak2, * , Ji Heon Rhim3 , Eui-Ju Yeo2,4
doi : 10.18632/aging.203825
Volume 14, Issue 1 pp 4—27
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme that participates in various cellular events, such as DNA repair and apoptosis. The functional diversity of GAPDH depends on its intracellular localization. Because AMP-activated protein kinase (AMPK) regulates the nuclear translocation of GAPDH in young cells and AMPK activity significantly increases during aging, we investigated whether altered AMPK activity is involved in the nuclear localization of GAPDH in senescent cells. Age-dependent nuclear translocation of GAPDH was confirmed by confocal laser scanning microscopy in human diploid fibroblasts (HDFs) and by immunohistochemical analysis in aged rat skin cells. Senescence-induced nuclear localization was reversed by lysophosphatidic acid but not by platelet-derived growth factor. The extracellular matrix from young cells also induced the nuclear export of GAPDH in senescent HDFs. An activator of AMPK, 5-Aminoimidazole-4-carboxamide-1-?-D-ribofuranoside (AICAR), increased the level of nuclear GAPDH, whereas an inhibitor of AMPK, Compound C, decreased the level of nuclear GAPDH in senescent HDFs. Transfection with AMPK? siRNA prevented nuclear translocation of GAPDH in senescent HDFs. The stimulatory effect of AICAR and serum depletion on GAPDH nuclear translocation was reduced in AMPK?1/?2-knockout mouse embryonic fibroblasts. Overall, increased AMPK activity may play a role in the senescence-associated nuclear translocation of GAPDH.
Reduced growth rate of aged muscle stem cells is associated with impaired mechanosensitivity
Mohammad Haroon1 , Heleen E. Boers1 , Astrid D. Bakker2 , Niek G.C. Bloks1 , Willem M.H. Hoogaars1 , Lorenzo Giordani3 , René J.P. Musters4 , Louise Deldicque5 , Katrien Koppo6 , Fabien Le Grand7 , Jenneke Klein-Nulend2 , Richard T. Jaspers1
doi : 10.18632/aging.203830
Volume 14, Issue 1 pp 28—53
Aging-associated muscle wasting and impaired regeneration are caused by deficiencies in muscle stem cell (MuSC) number and function. We postulated that aged MuSCs are intrinsically impaired in their responsiveness to omnipresent mechanical cues through alterations in MuSC morphology, mechanical properties, and number of integrins, culminating in impaired proliferative capacity. Here we show that aged MuSCs exhibited significantly lower growth rate and reduced integrin-?7 expression as well as lower number of phospho-paxillin clusters than young MuSCs. Moreover, aged MuSCs were less firmly attached to matrigel-coated glass substrates compared to young MuSCs, as 43% of the cells detached in response to pulsating fluid shear stress (1 Pa). YAP nuclear localization was 59% higher than in young MuSCs, yet YAP target genes Cyr61 and Ctgf were substantially downregulated. When subjected to pulsating fluid shear stress, aged MuSCs exhibited reduced upregulation of proliferation-related genes. Together these results indicate that aged MuSCs exhibit impaired mechanosensitivity and growth potential, accompanied by altered morphology and mechanical properties as well as reduced integrin-?7 expression. Aging-associated impaired muscle regenerative capacity and muscle wasting is likely due to aging-induced intrinsic MuSC alterations and dysfunctional mechanosensitivity.
PRCTC: a machine learning model for prediction of response to corticosteroid therapy in COVID-19 patients
Yue Gao1,2, * , Xiaoming Xiong1,2, * , Xiaofei Jiao1,2 , Yang Yu1,2 , Jianhua Chi1,2 , Wei Zhang1,2, & , Lingxi Chen3, & , Shuaicheng Li3 , Qinglei Gao1,2
doi : 10.18632/aging.203819
Volume 14, Issue 1 pp 54—72
Corticosteroid has been proved to be one of the few effective treatments for COVID-19 patients. However, not all the patients were suitable for corticosteroid therapy. In this study, we aimed to propose a machine learning model to forecast the response to corticosteroid therapy in COVID-19 patients. We retrospectively collected the clinical data about 666 COVID-19 patients receiving corticosteroid therapy between January 27, 2020, and March 30, 2020, from two hospitals in China. The response to corticosteroid therapy was evaluated by hospitalization time, oxygen supply duration, and the outcomes of patients. Least Absolute Shrinkage and Selection Operator (LASSO) was applied for feature selection. Five prediction models were applied in the training cohort and assessed in an internal and an external validation dataset, respectively. Finally, two (C reactive protein, lymphocyte percent) of 36 candidate immune/inflammatory features were finally used for model development. All five models displayed promising predictive performance. Notably, the ensemble model, PRCTC (prediction of response to corticosteroid therapy in COVID-19 patients), derived from three prediction models including Gradient Boosted Decision Tree (GBDT), Neural Network (NN), and logistic regression (LR), achieved the best performance with an area under the curve (AUC) of 0.810 (95% confidence interval [CI] 0.760–0.861) in internal validation cohort and 0.845 (95% CI 0.779–0.911) in external validation cohort to predict patients’ response to corticosteroid therapy. In conclusion, PRCTC proposed with universality and scalability is hopeful to provide tangible and prompt clinical decision support in management of COVID-19 patients and potentially extends to other medication predictions.
Decreased TMPRSS2 expression by SARS-CoV-2 predicts the poor prognosis of lung cancer patients through metabolic pathways and immune infiltration
Xiaopeng Liu1,2, * , Bing Liu1, * , Yanan Shang1, * , Pengxiu Cao1, * , Jiajie Hou1 , Fei Chen1 , Bo Zhang1 , Yumei Fan1 , Ke Tan1
doi : 10.18632/aging.203823
Volume 14, Issue 1 pp 73—108
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread around the world and became a global pandemic in 2020. One promising drug target for SARS-CoV-2 is the transmembrane protease serine 2 (TMPRSS2). This study was designed to explore the expression status, prognostic significance and molecular functions of TMPRSS2 in lung cancer. TMPRSS2 expression was investigated using the TIMER, Oncomine, UALCAN, GEO, HPA and TCGA databases. The prognostic value of TMPRSS2 was examined using Cox regression and a nomogram. KEGG, GO and GSEA were performed to investigate the cellular function of TMPRSS2 in lung cancer. The relationship between TMPRSS2 and immune infiltration was determined using the TIMER and CIBERSORT algorithms. TMPRSS2 mRNA and protein expression was significantly reduced in lung cancer. Decreased TMPRSS2 expression and increased DNA methylation of TMPRSS2 were associated with various clinicopathological parameters in patients with lung cancer. Low TMPRSS2 mRNA expression also correlated with poor outcome in lung cancer patients. Moreover, a nomogram was constructed and exhibited good predictive power for the overall survival of lung cancer patients. KEGG and GO analyses and GSEA implied that multiple immune- and metabolism-related pathways were significantly linked with TMPRSS2 expression. Intriguingly, TMPRSS2 expression associated with immune cell infiltration in lung cancer. More importantly, TMPRSS2 expression was markedly decreased in SARS-CoV-infected cells. These findings indicate that TMPRSS2 may be a promising prognostic biomarker and therapeutic target for lung cancer through metabolic pathways and immune cell infiltration.
Kampo formulas alleviate aging-related emotional disturbances and neuroinflammation in male senescence-accelerated mouse prone 8 mice
Naoki Ito1, * , Akiko Maruko2, * , Kenshiro Oshima2 , Masaaki Yoshida3 , Kengo Honma4 , Chika Sugiyama5 , Takayuki Nagai1,4,6 , Yoshinori Kobayashi1,5 , Hiroshi Odaguchi1,7 , Norihiro Okada2
doi : 10.18632/aging.203811
Volume 14, Issue 1 pp 109—142
Aging-induced neuroinflammation, also known as neuroinflammaging, plays a pivotal role in emotional disturbances, including depression and anxiety, in older individuals, thereby leading to cognitive dysfunction. Although numerous studies have focused on therapeutic strategies for cognitive impairment in older individuals, little research has been performed on treating its preceding emotional disturbances. Here, we examined whether Kampo formulas (kososan [KS], nobiletin-rich kososan [NKS], and hachimijiogan [HJG]) can ameliorate aging-induced emotional disturbances and neuroinflammation in mice. The depression-like behaviors observed in SAMP8 mice, relative to normally aging SAMR1 mice, were significantly prevented by treatment with Kampo formulas for 13 weeks. Western blot analysis revealed that hippocampal neuroinflammation was significantly abrogated by Kampo formulas. KS and NKS also significantly attenuated the hippocampal neuroinflammatory priming induced by lipopolysaccharide (LPS, 0.33 mg/kg, i.p.) challenge in SAMP8 mice. Hippocampal IL-1?, IL-6, and MCP-1 levels were significantly decreased in NKS-treated SAMP8 mice. KS and NKS showed significantly reduced tau accumulation in the brains of SAMP8 mice. RNA-sequencing revealed that each Kampo formula led to unique dynamics of hippocampal gene expression and appeared to abrogate hippocampal inflammatory responses. HJG significantly blocked the LPS-induced increase in serum IL-6 and MCP-1. These results suggest that Kampo formulas would be useful for treating aging-induced depression, in part by regulating neuroinflammatory pathways. This finding may pave the way for the development of therapeutic strategies for aging-related emotional disturbances, which may contribute to the prevention of cognitive dysfunction in older individuals.
Different phases of aging in mouse old skeletal muscle
Yong-Kook Kang1,2 , Byungkuk Min1 , Jaemin Eom1,2 , Jung Sun Park1
doi : 10.18632/aging.203812
Volume 14, Issue 1 pp 143—160
With a graying population and increasing longevity, it is essential to identify life transition in later years and discern heterogeneity among older people. Subclassifying the elderly population to inspect the subdivisions for pathophysiological differences is particularly important for the investigation of age-related illnesses. For this purpose, using 24- and 28-month-old mice to represent the “young-old” and “old-old”, respectively, we compared their skeletal muscle transcriptomes and found each in a distinct stage: early/gradual (E-aging) and late/accelerated aging phase (L-aging). Principal component analysis showed that the old-old transcriptomes were largely disengaged from the forward transcriptomic trajectory generated in the younger-aged group, indicating a substantial change in gene expression profiles during L-aging. By calculating the transcriptomic distance, it was found that the 28-month group was closer to the two-month group than to the 24-month group. The divergence rate per month for the transcriptomes was the highest in L-aging, twice as fast as the rate in E-aging. Indeed, many of the L-aging genes were significantly altered in transcription, although the changes did not seem random but rather coordinated in a variety of functional gene sets. Of 2,707 genes transcriptionally altered during E-aging, two-thirds were also significantly changed during L-aging, to either downturning or upturning way. The downturn genes were related to mitochondrial function and translational gene sets, while the upturn genes were linked to inflammation-associated gene sets. Our results provide a transcriptomic muscle signature that distinguishes old-old mice from young-old mice. This can help to methodically examine muscle disorders in the elderly.
Multivariate patterns of brain-behavior associations across the adult lifespan
Gaelle E. Doucet1,4 , Noah Hamlin1 , Anna West1 , Jordanna A. Kruse1 , Dominik A. Moser2,3 , Tony W. Wilson1,4
doi : 10.18632/aging.203815
Volume 14, Issue 1 pp 161—194
The nature of brain-behavior covariations with increasing age is poorly understood. In the current study, we used a multivariate approach to investigate the covariation between behavioral-health variables and brain features across adulthood. We recruited healthy adults aged 20–73 years-old (29 younger, mean age = 25.6 years; 30 older, mean age = 62.5 years), and collected structural and functional MRI (s/fMRI) during a resting-state and three tasks. From the sMRI, we extracted cortical thickness and subcortical volumes; from the fMRI, we extracted activation peaks and functional network connectivity (FNC) for each task. We conducted canonical correlation analyses between behavioral-health variables and the sMRI, or the fMRI variables, across all participants. We found significant covariations for both types of neuroimaging phenotypes (ps = 0.0004) across all individuals, with cognitive capacity and age being the largest opposite contributors. We further identified different variables contributing to the models across phenotypes and age groups. Particularly, we found behavior was associated with different neuroimaging patterns between the younger and older groups. Higher cognitive capacity was supported by activation and FNC within the executive networks in the younger adults, while it was supported by the visual networks’ FNC in the older adults. This study highlights how the brain-behavior covariations vary across adulthood and provides further support that cognitive performance relies on regional recruitment that differs between older and younger individuals.
Endothelial and systemic upregulation of miR-34a-5p fine-tunes senescence in progeria
Christina Manakanatas1 , Santhosh Kumar Ghadge1 , Azra Agic1 , Fatih Sarigol1 , Petra Fichtinger1 , Irmgard Fischer1 , Roland Foisner1 , Selma Osmanagic-Myers1,2
doi : 10.18632/aging.203820
Volume 14, Issue 1 pp 195—224
Endothelial defects significantly contribute to cardiovascular pathology in the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Using an endothelium-specific progeria mouse model, we identify a novel, endothelium-specific microRNA (miR) signature linked to the p53-senescence pathway and a senescence-associated secretory phenotype (SASP). Progerin-expressing endothelial cells exert profound cell-non-autonomous effects initiating senescence in non-endothelial cell populations and causing immune cell infiltrates around blood vessels. Comparative miR expression analyses revealed unique upregulation of senescence-associated miR34a-5p in endothelial cells with strong accumulation at atheroprone aortic arch regions but also, in whole cardiac- and lung tissues as well as in the circulation of progeria mice. Mechanistically, miR34a-5p knockdown reduced not only p53 levels but also late-stage senescence regulator p16 with no effect on p21 levels, while p53 knockdown reduced miR34a-5p and partially rescued p21-mediated cell cycle inhibition with a moderate effect on SASP. These data demonstrate that miR34a-5p reinforces two separate senescence regulating branches in progerin-expressing endothelial cells, the p53- and p16-associated pathways, which synergistically maintain a senescence phenotype that contributes to cardiovascular pathology. Thus, the key function of circulatory miR34a-5p in endothelial dysfunction-linked cardiovascular pathology offers novel routes for diagnosis, prognosis and treatment for cardiovascular aging in HGPS and potentially geriatric patients.
Dietary curcumin restores insulin homeostasis in diet-induced obese aged mice
Su-Jeong Lee1 , Prabha Chandrasekran2 , Caio Henrique Mazucanti2 , Jennifer F. O’Connell2 , Josephine M. Egan2 , Yoo Kim1
doi : 10.18632/aging.203821
Volume 14, Issue 1 pp 225—239
Although aging is a physiological process to which all organisms are subject, the presence of obesity and type 2 diabetes accelerates biological aging. Recent studies have demonstrated the causal relationships between dietary interventions suppressing obesity and type 2 diabetes and delaying the onset of age-related endocrine changes. Curcumin, a natural antioxidant, has putative therapeutic properties such as improving insulin sensitivity in obese mice. However, how curcumin contributes to maintaining insulin homeostasis in aged organisms largely remains unclear. Thus, the objective of this study is to examine the pleiotropic effect of dietary curcumin on insulin homeostasis in a diet-induced obese (DIO) aged mouse model. Aged (18-20 months old) male mice given a high-fat high-sugar diet supplemented with 0.4% (w/w) curcumin (equivalent to 2 g/day for a 60 kg adult) displayed a different metabolic phenotype compared to mice given a high-fat high-sugar diet alone. Furthermore, curcumin supplementation altered hepatic gene expression profiling, especially insulin signaling and senescence pathways. We then mechanistically investigated how curcumin functions to fine-tune insulin sensitivity. We found that curcumin supplementation increased hepatic insulin-degrading enzyme (IDE) expression levels and preserved islet integrity, both outcomes that are beneficial to preserving good health with age. Our findings suggest that the multifaceted therapeutic potential of curcumin can be used as a protective agent for age-induced metabolic diseases.
Kidney function, brain morphology and cognition in the elderly: sex differences in the Austrian Stroke Prevention Study
Michael Kolland1 , Edith Hofer2,3 , Lukas Pirpamer2 , Daniela Eibl2 , Christian Enzinger4,5 , Alexander R. Rosenkranz1 , Reinhold Schmidt2
doi : 10.18632/aging.203829
Volume 14, Issue 1 pp 240—252
Impaired kidney function is associated with structural brain changes and cognitive dysfunction. In the aging kidney, hemodynamic and structural alterations reduce the glomerular filtration rate (eGFR). Little is known about differences between men and women regarding decline of kidney function and brain damage.
Increased expression of osteopontin in subchondral bone promotes bone turnover and remodeling, and accelerates the progression of OA in a mouse model
Chuangxin Lin1,2, * , Zhong Chen1, * , Dong Guo3, * , Laixi Zhou2 , Sipeng Lin1 , Changchuan Li1 , Shixun Li1 , Xinjia Wang4, & , Bendan Lin2, & , Yue Ding1
doi : 10.18632/aging.203707
Volume 14, Issue 1 pp 253—271
Osteopontin (OPN) has been proved to be closely related to the pathogenesis of osteoarthritis (OA), but the role of OPN in the pathogenesis of OA has not been fully clarified. Current studies on OPN in OA mostly focus on articular cartilage, synovial membrane and articular fluid, while ignoring its role in OA subchondral bone turnover and remodeling. In this study, we used a destabilization OA mouse model to investigate the role of OPN in OA subchondral bone changes. Our results indicate that increased expression of OPN accelerates the turnover and remodeling of OA subchondral bone, promotes the formation of h-type vessels in subchondral bone, and mediates articular cartilage degeneration induced by subchondral bone metabolism. In addition, our results confirmed that inhibition of PI3K/AKT signaling pathway inhibits OPN-mediated OA subchondral bone remodeling and cartilage degeneration. This study revealed the role and mechanism of OPN in OA subchondral bone, which is of great significance for exploring specific biological indicators for early diagnosis of OA and monitoring disease progression, as well as for developing drugs to regulate the metabolism and turnover of subchondral bone and alleviate the subchondral bone sclerosis of OA.
The effects of metformin and alendronate in attenuating bone loss and improving glucose metabolism in diabetes mellitus mice
Qiyun Zhou1,2, * , Zhiqiang Guan3, * , Shengfu Liu1, * , Yanjiao Xuan4 , Gang Han2 , Hua Chen2 , Xiao Jin5 , Kun Tao1 , Zhiyuan Guan1
doi : 10.18632/aging.203729
Volume 14, Issue 1 pp 272—285
To explore the anti-osteoporosis and anti-diabetes effects and potential underlying mechanisms of treatment with metformin and alendronate in diabetes mellitus mice.
Yes-associated protein reacts differently in vascular smooth muscle cells under different intensities of mechanical stretch
Xinhao Wang1 , Xiangdang Liang2 , Lujun Zhou3 , Shen Liu2 , Zhuoqun Fang2 , Chuanzhong Hu2 , Yigong Hou2 , Zhanshe Guo4
doi : 10.18632/aging.203768
Volume 14, Issue 1 pp 286—296
Vascular smooth muscle cells (VSMCs) are stromal cells of the vascular wall and are continually exposed to mechanical signals. The loss of VSMCs is closely related to the occurrence of many vascular diseases, such as aortic aneurysms and aortic dissection. The proliferation and apoptosis of VSMCs are mechanically stimulated. Yes-associated protein (YAP), one of the core components of the Hippo pathway, plays a key role in the response of VSMCs to mechanical signals. In this study, we tested the impact of different intensities of mechanical stretch on the proliferation and apoptosis of VSMCs, as well as YAP. We tested VSMCs’ proliferation and apoptosis and YAP reaction via immunocytochemistry, western blotting, CCK-8 and flow cytometric analysis. We found that 10% elongation could increase the phosphorylation of YAP and prevent it from entering the nucleus, as well as inhibit cell proliferation and promote apoptosis. However, 15% elongation reduced YAP phosphorylation and promoted its nuclear entry, thereby promoting cell proliferation and inhibiting apoptosis. Accordingly, YAP knockdown suppressed the phenotype of VMSCs induced by 15% elongation. Taken together, YAP regulates proliferation and apoptosis of VSMCs differently under different intensity of mechanical stretch. Mechanical stretch with appropriate intensity can promote the proliferation and inhibit apoptosis of VSMCs by activating YAP.
TIMP-2 regulates 5-Fu resistance via the ERK/MAPK signaling pathway in colorectal cancer
Guolin Zhang1,2, * , Xin Luo1, * , Zian Wang1,3, * , Jianbin Xu4 , Wei Zhang1 , Engeng Chen1 , Qing Meng1 , Di Wang1 , Xuefeng Huang1 , Wei Zhou1 , Zhangfa Song1
doi : 10.18632/aging.203793
Volume 14, Issue 1 pp 297—315
5-Fluorouracil (5-Fu) is the first-line chemotherapeutic option for colorectal cancer. However, its efficacy is inhibited by drug resistance. Cytokines play an important role in tumor drug resistance, even though their mechanisms are largely unknown. Using a cytokine array, we established that tissue inhibitor metalloproteinase 2 (TIMP-2) is highly expressed in 5-Fu resistant colorectal cancer patients. Analysis of samples from 84 patients showed that elevated TIMP-2 expression levels in colorectal patients were correlated with poor prognostic outcomes. In a 5-Fu-resistant patient-derived xenograft (PDX) model, TIMP-2 was also found to be highly expressed. We established an autocrine mechanism through which elevated TIMP-2 protein levels sustained colorectal cancer cell resistance to 5-Fu by constitutively activating the ERK/MAPK signaling pathway. Inhibition of TIMP-2 using an anti-TIMP-2 antibody or ERK/MAPK inhibition by U0126 suppressed TIMP-2 mediated 5-Fu-resistance in CRC patients. In conclusion, a novel TIMP-2-ERK/MAPK mediated 5-Fu resistance mechanism is involved in colorectal cancer. Therefore, targeting TIMP-2 or ERK/MAPK may provide a new strategy to overcome 5-Fu resistance in colorectal cancer chemotherapy.
Deglycosylated EpCAM regulates proliferation by enhancing autophagy of breast cancer cells via PI3K/Akt/mTOR pathway
Liu Yang1 , Qijun Wang1 , Qian Zhao1 , Fan Yang1 , Tingjiao Liu2 , Xiaohua Huang3 , Qiu Yan1 , Xuesong Yang1
doi : 10.18632/aging.203795
Volume 14, Issue 1 pp 316—329
Autophagy is an important regulator of cellular homeostasis and its dysregulation often results in cancer. Aberrant glycosylation induced by oncogenic transformation contributes to tumor invasion and metastasis. In a previous study, we have demonstrated that EpCAM, a glycosylation protein, is associated with cell growth and metastasis in breast cancer. But the effect of EpCAM glycosylation on autophagy is not clear. the precise mechanism of regulation remains largely unknown. In this study, breast cancer cells were transfected with N-glycosylation mutation EpCAM plasmid to express deglycosylated EpCAM. The result showed that deglycosylated EpCAM promoted autophagy in breast cancer cells. We further confirmed this conclusion with the activator (Rapamycin, RAP) and inhibitor (Wortmannin) of autophagy. We also found that deglycosylated EpCAM promoted apoptosis and inhibited proliferation through activating autophagy by suppressing Akt/mTOR signaling pathway in breast cancer cells. These findings represent a novel mechanism by which deglycosylated EpCAM inhibits proliferation by enhancing autophagy of breast cancer cells via PI3K/Akt/mTOR pathway. In conclusion, the combination of autophagy modulation and EpCAM targeted therapy is a promising therapeutic strategy in the treatment of breast cancer.
m6A regulator-mediated methylation modification patterns and tumor immune microenvironment in sarcoma
Zhehong Li1, * , Junqiang Wei2,3,4, * , Honghong Zheng5 , Xintian Gan1 , Mingze Song1 , Yafang Zhang1 , Lingwei Kong1 , Chao Zhang2,3 , Jilong Yang2,3 , Yu Jin1
doi : 10.18632/aging.203807
Volume 14, Issue 1 pp 330—353
Studies have shown that the RNA N6-methyladenosine (m6A) modification patterns are extensively involved in the development of multiple tumors. However, the association between the m6A regulator expression patterns and the sarcoma tumor immune microenvironment (TIME) remains unclear.
Telomere length is maternally inherited and associated with lipid metabolism in Chinese population
Liyun Guo1,3, * , Yajuan Chen2, * , Huiqin Li1 , Fanqian Yin1,4 , Mingxia Ge1,4 , Li Hu1,5 , Meiting Zi1 , Zhenghong Qin3 , Yonghan He1
doi : 10.18632/aging.203810
Volume 14, Issue 1 pp 354—367
Telomere is a unique DNA-protein complex which covers the ends of chromosomes to avoid end fusion and maintain the stability and integrity of chromosomes. Telomere length (TL) shortening has been linked to aging and various age-related diseases in humans. Here we recruited a total of 1031 Chinese individuals aged between 12 and 111 years, including 108 families with parents and their offspring. DNA was extracted from peripheral white blood cells and TL was measured by quantitative PCR (qPCR). We explored the associations of TL with age, gender and clinical variables, and tested the parental effects on TL variation. First, we found that TL was shortened with age, however, TL was better maintained in females than males. Second, there was a robust association of TL between mother and offspring, but not between father and their offspring. In addition, TL was inversely associated with visceral fat index in females, and positively associated with apolipoprotein A levels. Knockdown of the key genes for lipid metabolism (PNPLA2 and CPT1) shortened the TL in HepG2 cells. These findings indicate that TL is maternally inherited, and impairment of lipid metabolism may contribute to the TL shortening in the Chinese population.
LINC02362 attenuates hepatocellular carcinoma progression through the miR-516b-5p/SOSC2 axis
Dezhi Li1, * , Tao Zhou1, * , Yaqin Li3 , Yanwei Xu1 , Xianyi Cheng1,2 , Junhui Chen1, & , Wei V. Zheng1
doi : 10.18632/aging.203813
Volume 14, Issue 1 pp 368—388
Hepatocellular carcinoma (HCC) is one of the most death-related cancers worldwide. Identifying cancer-associated genes and uncovering the vital molecular mechanisms of HCC progression contribute greatly to the prognosis and novel therapeutic strategies for HCC patients. Although lncRNAs have been proved to be critical modulators of various cellular processes, the functions of lncRNAs in HCC progression are just emerging. Here, we found that a long non-coding RNA (lncRNA) named LINC02362, whose biological effects have yet been unveiled in cancers, was associated with a better prognosis in patients with HCC. Gain-of-function analyses showed that LINC02362 inhibited the survival, migration, invasion and epithelial-to-mesenchymal transition (EMT) of HCC cells. Moreover, miR-516b-5p was enriched as a target of LINC02362, which functioned as a sponge to regulate the endogenous levels of miR-516b-5p. Furthermore, we confirmed that SOSC2 served as a downstream target gene which was negatively controlled by miR-516b-5p. Importantly, a series of rescue experiments indicated that the tumor-suppressive effects of LINC02362 were achieved through the modulation of the miR-516b-5p/SOSC2 axis. In summary, we identified LINC02362 as a candidate tumor-inhibitory lncRNA that might serve as a biomarker for the prognosis of HCC and a promising therapeutic agent for patients with HCC.
Chordin-like 1 is a novel prognostic biomarker and correlative with immune cell infiltration in lung adenocarcinoma
Bing Deng1 , Xiaorui Chen1 , Lingfang Xu1 , Li Zheng1 , Xiaoqian Zhu1 , Junwei Shi1 , Lei Yang1 , Dian Wang1 , Depeng Jiang1
doi : 10.18632/aging.203814
Volume 14, Issue 1 pp 389—409
Chordin-like 1 (CHRDL1), an inhibitor of bone morphogenetic proteins(BMPs), has been recently reported to participate in the progression of numerous tumors, however, its role in lung adenocarcinoma (LUAD) remains unclear. Our study aimed to demonstrate relationship between CHRDL1 and LUAD based on data from The Cancer Genome Atlas (TCGA). Among them, CHRDL1 expression revealed promising power for distinguishing LUAD tissues form normal sample. Low CHRDL1 was correlated with poor clinicopathologic features, including high T stage (OR=0.45, P<0.001), high N stage (OR=0.57, P<0.003), bad treatment effect (OR=0.64, P=0.047), positive tumor status (OR=0.63, P=0.018), and TP53 mutation (OR=0.49, P<0.001). The survival curve illustrated that low CHRDL1 was significantly correlative with a poor overall survival (HR=0.60, P<0.001). At multivariate Cox regression analysis, CHRDL1 remained independently correlative with overall survival. GSEA identified that the CHRDL1 expression was related to cell cycle and immunoregulation. Immune infiltration analysis suggested that CHRDL1 was significantly correlative with 7 kinds of immune cells. Immunohistochemical validation showed that CHRDL1 was abnormally elevated and negatively correlated with Th2 cells in LUAD tissues. In conclusion, CHRDL1 might become a novel prognostic biomarker and therapy target in LUAD. Moreover, CHRDL1 may improve the effectiveness of immunotherapy by regulating immune infiltration.
Extracorporeal shockwave relieves endothelial injury and dysfunction in steroid-induced osteonecrosis of the femoral head via miR-135b targeting FOXO1: in vitro and in vivo studies
Xinjie Wu1,2 , Yanlei Wang2,3 , Xiaoyu Fan1,2 , Xin Xu1,4 , Wei Sun1,2
doi : 10.18632/aging.203816
Volume 14, Issue 1 pp 410—429
Injury and dysfunction of endothelial cells (ECs) are closely related to the pathogenesis of steroid-induced osteonecrosis of the femoral head (ONFH), while MicroRNAs (miRNAs) play an essential role in the processes. Extracorporeal shockwave treatment (ESWT) has been used in the non-invasive treatment of various diseases including musculoskeletal and vascular disorders. In particular, ESWT with low energy levels showed a beneficial effect in ischemic tissues. However, there has been no comprehensive assessment of the effect of ESWT and miRNAs on steroid-induced ONFH. In the present study, we investigated the role and mechanism of ESWT and miRNAs both in vitro and in vivo. Using a steroid-induced ONFH rat model, we found that ESWT significantly enhances proliferation and angiogenesis as well as alleviates apoptosis. In two types of ECs, ESWT can promote cell proliferation and migration, enhance angiogenesis, and inhibit apoptosis. Notably, our study demonstrates that miR-135b is downregulated and modulated forkhead box protein O1 (FOXO1) in ECs treated with dexamethasone. Remarkably, both miR-135b knockdown and FOXO1 overexpression reversed the beneficial effect of ESWT on ECs. Additionally, our data suggest that ESWT activates the FOXO1-related pathway to impact proliferation, apoptosis, and angiogenesis. Taken together, this study indicates that ESWT relieves endothelial injury and dysfunction in steroid-induced ONFH via miR-135b targeting FOXO1.
Circular RNA circ_0000515 adsorbs miR-542-3p to accelerate bladder cancer progression via up-regulating ILK expression
Guohui Peng1, *,# , Jing Guan2, *,# , Pengfei Leng3 , Lijun Peng4 , Manchao Cao3 , Yuanfa Feng3
doi : 10.18632/aging.203818
Volume 14, Issue 1 pp 430—442
Bladder cancer (BC) is a common cause of cancer-relevant deaths globally. This study is designed to delve into expressions, biological functions and molecular mechanisms of circ_0000515 in BC.
PEGylation and antioxidant effects of a human glutathione peroxidase 1 mutant
Guang-Yuan Zhang1, * , Yan-Wei Wang1, * , Li-Ying Guo1 , Liang-Ru Lin1 , Shao-Peng Niu1 , Chang-Hao Xiong1 , Jing-Yan Wei1,2
doi : 10.18632/aging.203822
Volume 14, Issue 1 pp 443—461
Human glutathione peroxidase1 (hGPx1) is a good antioxidant and potential drug, but the limited availability and poor stability of hGPx1 have affected its development and application. To solve this problem, we prepared a hGPx1 mutant (GPx1M) with high activity in an Escherichia coli BL21(DE3)cys auxotrophic strain using a single protein production (SPP) system. In this study, the GPx1M was conjugated with methoxypolyethylene glycol-succinimidyl succinate (SS-mPEG, Mw = 5 kDa) chains to enhance its stability. SS-mPEG-GPx1M and GPx1M exhibited similar enzymatic activity and stability toward pH and temperature change, and in a few cases, SS-mPEG-GPx1M was discovered to widen the range of pH stability and increase the temperature stability. Lys 38 was confirmed as PEGylated site by liquid-mass spectrometry. H9c2 cardiomyoblast cells and Sprague-Dawley (SD) rats were used to evaluate the effects of GPx1M and SS-mPEG-GPx1M on preventing or alleviating adriamycin (ADR)-mediated cardiotoxicity, respectively. The results indicated that GPx1M and SS-mPEG-GPx1M had good antioxidant effects in vitro and in vivo, and the effect of SS-mPEG-GPx1M is more prominent than GPx1M in vivo. Thus, PEGylation might be a promising method for the application of GPx1M as an important antioxidant and potential drug.
Duo Chen1 , Lu Sui2 , Cao Chen1 , Sanchuan Liu1 , Xianfeng Sun1 , Junhong Guan1
Duo Chen1 , Lu Sui2 , Cao Chen1 , Sanchuan Liu1 , Xianfeng Sun1 , Junhong Guan1
doi : 10.18632/aging.203824
Volume 14, Issue 1 pp 462—476
Intracerebral hemorrhage (ICH) is a common neurological condition that causes severe disability and even death. Even though the mechanism is not clear, increasing evidence shows the efficacy of atorvastatin on treating ICH. In this study, we examined the impact of atorvastatin on the NOD-like receptor protein 3 (NLRP3) inflammasome and inflammatory pathways following ICH. Mouse models of ICH were established by collagenase injection in adult C57BL/6 mice. IHC mice received atorvastatin treatment 2 h after hematoma establishment. First, the changes of glial cells and neurons in the brains of ICH patients and mice were detected by immunohistochemistry and western blotting. Second, the molecular mechanisms underlying the microglial activation and neuronal loss were evaluated after the application of atorvastatin. Finally, the behavioral deficits of ICH mice without or with the treatment of atorvastatin were determined by neurological defect scores. The results demonstrated that atorvastatin significantly deactivated glial cells by reducing the expression of glial fibrillary acidic protein (GFAP), Ionized calcium binding adapter molecule 1 (Iba1), tumor necrosis factor (TNF)-?, and interleukin (IL)-6 in ICH model mice. For inflammasomes, atorvastatin also showed its efficacy by decreasing the expression of NLRP3, cleaved caspase-1, and IL-1? in ICH mice. Moreover, atorvastatin markedly inhibited the upregulation of toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88), which indicated deactivation of NLRP3 inflammasomes. By inhibiting the activities of inflammasomes in glial cells, neuronal loss was partially prevented by suppressing the apoptosis in the brains of ICH mice, protecting them from neurological defects.
Gut microbiota in patients with Alzheimer’s disease spectrum: a systematic review and meta-analysis
Chun-Che Hung1,2 , Chiung-Chih Chang3 , Chi-Wei Huang3 , Rui Nouchi4,5 , Chia-Hsiung Cheng1,2,6,7
doi : 10.18632/aging.203826
Volume 14, Issue 1 pp 477—496
Gut dysbiosis has been proposed as one of pathologies in patients with Alzheimer’s disease (AD) spectrum. Despite such enthusiasm, the relevant results remain substantially controversial.
Circular RNA CUL2 regulates the development of colorectal cancer by modulating apoptosis and autophagy via miR-208a-3p/PPP6C
Bin-Lin Yang1 , Guo-Qiang Liu1 , Ping Li2 , Xiao-Hui Li1
doi : 10.18632/aging.203827
Volume 14, Issue 1 pp 497—508
To explore the function of circular RNA CUL2 (circCUL2) in colorectal cancer progression.
PSMA3-AS1 induced by transcription factor PAX5 promotes cholangiocarcinoma proliferation, migration and invasion by sponging miR-376a-3p to up-regulate LAMC1
Dongsheng Sun1, * , Fujun Li2, * , Lang Liu1, * , Shaobo Yu1, * , Haicun Wang1 , Xin Gao1 , Guanglin Liu1 , Yuqiao Zhao1 , Gongcai Qiu1 , Xingming Jiang1
doi : 10.18632/aging.203828
Volume 14, Issue 1 pp 509—525
Long noncoding RNAs (lncRNAs) have been reported to exhibit a crucial regulatory role in tumor progression, including cholangiocarcinoma (CCA). As a promising lncRNA, proteasome 20S subunit alpha 3 antisense RNA 1 (PSMA3-AS1) is involved in development of various tumors. However, the role and function of PSMA3-AS1 in CCA remain unclear. The aim of this study is to examine the expression, function, mechanism, and clinical significance of PSMA3-AS1 in CCA development. By TCGA database analysis, we found that PSMA3-AS1 was overexpressed in CCA. Consistent with the TCGA analysis, PSMA3-AS1 was significantly overexpressed in CCA tissues and cells by RT-qPCR. Upregulated PSMA3-AS1 was related to lymph node invasion, advanced TNM stage and poor survival, and was an independent risk factor of prognosis for CCA patients. Functionally, CCK-8, EdU and colony formation assays confirmed that upregulated PSMA3-AS1 promoted CCA cell proliferation, whereas downregulated PSMA3-AS1 inhibited proliferation. This result was further confirmed by subcutaneous tumor formation in nude mice. Wound healing and transwell assays confirmed that increased PSMA3-AS1 promoted CCA cell migration and invasion, whereas decreased PSMA3-AS1 inhibited these biological phenotypes. In addition, PSMA3-AS1 promoted the EMT process of CCA by downregulating E-cadherin and upregulating N-cadherin and vimentin. Mechanistically, transcription factor PAX5 bound to the promoter region of PSMA3-AS1 and promoted its transcription. Simultaneously, PSMA3-AS1 primarily localized in the cytoplasm could competitively bind miR-376a-3p to upregulate LAMC1, thereby accelerating CCA progression. This study uncovers that PSMA3-AS1 functions as a cancer-promoting gene in CCA, and PAX5/PSMA3-AS1/miR-376a-3p/LAMC1 axis plays a vital role in CCA development.
Correction for: Integrative analysis of exosomal microRNA-149-5p in lung adenocarcinoma
Wen Tian1 , He Yang1 , Baosen Zhou1,2
doi : 10.18632/aging.203836
Volume 14, Issue 1 pp 526—527
Correction for: Silencing DSCAM-AS1 suppresses the growth and invasion of ER-positive breast cancer cells by downregulating both DCTPP1 and QPRT
Zhang Yue1, * , Jia Shusheng2, * , Song Hongtao3 , Zhao Shu1 , Huang Lan1 , Zhang Qingyuan1 , Cheng Shaoqiang2 , Huang Yuanxi2
doi : 10.18632/aging.203837
Volume 14, Issue 1 pp 528—529
